MXPA06003186A - 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones - Google Patents

Abstract

The present invention relates to compounds having a structure according to Formula I wherein n, m, z, R, R2, R3, R4, R5, R6, A, E, X, Y a and b are as defined above;or an optical isomer, diastereomer or enantiomer thereof;a pharmaceutically acceptable salt, hydrate, or prodrug thereof.

Description

QU1NOLONAS AND NAFT1RIDONAS 7-AMINO ALQUÍLÍDENIL HETEROC.CL1CAS CROSS REFERENCE TO THE RELATED APPLICATION This application claims the benefit under 35 U.S.C. §119 (e) of provisional application Serial No. 60 / 504,924, filed on September 22, 2003, which is hereby incorporated in its entirety.

FIELD OF THE INVENTION The subject invention relates to novel antimicrobial compounds, their compositions and their uses.

BACKGROUND OF THE INVENTION The chemical and medical literature describes compounds that may be antimicrobial, that is, capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. For example, such antibacterial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Greyson, ed., 1982), E. Gale et al., The Molecular Basis of Antibiotic Action 2nd edition (1981), Recent Research Developments in Antimicrobial Agents & Chemotherapy (SG Pandalai, Editor, 2001), Quinolone Antimicrobial Agents (John S Wolfson., David C Hooper, Editors, 1989), and F. O'Grady, HP Lambert, RG Finch, D. Greenwood, Martin Dedicoat, "Antibiotic and Chemotherapy, 7th edition "(1997). The mechanisms of action of these antibacterial agents vary. However, it is believed that they generally work in one or more ways: inhibiting the synthesis or repair of the cell wall; altering the permeability of the cell wall; inhibiting the synthesis of proteins; or inhibiting the synthesis of nucleic acids. For example, beta-lactam antibacterial agents act through the inhibition of essential penicillin binding proteins (PBP) in bacteria, which are responsible for the synthesis of the cell wall. As another example, the quinolones act, at least in part, by inhibiting DNA synthesis, thus preventing the replication of the cells. The pharmacological characteristics of the antimicrobial agents, and their suitability for any given clinical use varies. For example, classes of antimicrobial agents (and members within a class) can vary in 1) their relative efficacy against different types of microorganisms, 2) their susceptibility to the development of microbial resistance and 3) their pharmacological characteristics such as their bioavailability and biodistribution. Accordingly, the selection of an appropriate antimicrobial agent in a given clinical situation requires the analysis of many factors, including the type of organism involved, the method of administration desired, the location of the infection to be treated, and other considerations. However, many such attempts to produce improved antimicrobial agents gave the wrong results. In reality, few antimicrobial agents are produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, prevention of microbial resistance, and pharmacology. Thus, there is a continuing need for broad spectrum antimicrobial agents, which are effective against resistant microbes. Some 1,4-dihydroquinolones, naphthyridines or related heterocyclic moieties are known in the art, which have antimicrobial activity and are described in the following references: R. Albrecht Prog. Drug Research, Vol. 21, p. 9 (1977); J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", Antimicrob. Agents and Chemother., Vol. 28, p. 581 (1985); G. KIopman et al. Antimicrob. Agents and Chemother., Vol. 31, p. 1831 (1987); M. P. Wentland et al., Ann. Rep. Med. Chem., Vol. 20, p. 145 (1986); J. B. Cometí et al., Ann. Rep. Med. Chem., Vol. 21, p. 139 (1986); P. B. Femandes et al. Ann. Rep. Med. Chem., Vol. 22, p. 117 (1987); A. Koga, et al. "Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-alkyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic Acids" J. Med. Chem. Vol. 23, p. 1358-1363 (1980); J. M. Domagala et al., J. Med. Chem. Vol. 31, p. 991 (1988); T. Rosen et al., J. Med. Chem. Vol. 31, p. 1598 (1988); B. Ledoussal et al., "Non-Fluoro Substituted Quinolone Antibacterials: Structure and Activity", J. Med. Chem. Vol. 35, p. 198-200 (1992); Patent of E.U.A. 6329391; A. M Emmerson et al., "The quinolones: Decades of development and use", J. Antimicrob. Chemother., Vol 51, pp. 13-20 (2003); J. Ruiz, "Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection" J. Antimicrob. Chemother. Vol. 51, pp 1109-1117 (2003); Y. Kuramoto et al., "A Novel Antibacterial 8-Chloroquinolone with a Distorted Orientation of the N1- (5-Amino-2,4-difluoropheniI) Group" J. Med. Chem. Vol. 46, pp 1905-1917 ( 2003); Japanese Patent Publication 06263754; European Patent Publication 487030; International Patent Publication WO0248138; International Patent Publication W09914214; Patent Publication of E.U.A. 2002/0049192; International Patent Publication WO02085886; European Patent Publication 572259; Publication of International Patent WO0136408; Patent of E.U.A. 5677456; European Patent Publication 362759; Patent of E.U.A. 5688791; Patent of E.U.A. 4894458; European Patent Publication 677522; Patent of E.U.A. , 4822801; Patent of E.U.A. 5256662; Patent of E.U.A. 5017581; European Patent Publication 304087; International Patent Publication WO0136408; International Patent Publication WO02085886; Japanese Patent Publication 01090184; International Patent Publication WO9209579; International Patent Publication WO0185728; European Patent Publication 343524; Japanese Patent Publication 10130241; European Patent Publication 413455; International Patent Publication WO0209758; International Patent Publication WO0350107; International Patent Publication W09415933; International Patent Publication WO9222550; Japanese Patent Publication 07300472; International Patent Publication WO0314108; International Patent Publication WO0071541; International Patent Publication WO0031062; and Patent of E.U.A. 5869670. WO03050107 describes a series of dihydroquinolones, naphthyridines and related antibacterial heterocyclic agents. Of particular interest, is the description of the compounds of formula, wherein Rs and Rs' are hydrogen, alkyl, substituted alkyl, alkylamino or aralkyl, Rg is hydrogen, alkyl, alkylamino, dialkylamino, aryl, aralkyl or trihaloalkyl, and X is hydroxy, alkoxy, acyloxy, amino or substituted amino. European Patent Publication 362759 discloses 1,4-dihydroquinolone and naphthyridine antibacterial agents of formula, wherein W is C1-3 alkylidene and R5 and Re are hydrogen or alkyl. The International Patent Publication WO 99/14214 and the Patent of E.U.A. 6329391, describe quinolone antibacterial agents with C7 piperdinyl substituents, C7 azetidinyl or C7 pyrrolidinyl substituents of formula, Of particular interest are those compounds wherein R7 is amino, aminoalkyl or substituted aminoalkyl and R9 is selected from hydrogen, CrC4 alkanyl, C2-C2 alkenyl, C2-C6 alkynyl or a C3-C6 alkyl ring fused or spirocyclic . For compounds with a piperidine substituted at the 7-position of the quinolonecarboxylic acid, preferred substituents include 3-amino-4-methyl, 3-amino-4,4-dimethyl, 3-amino-4-spirocyclopropy, 3-amino -6-cyclopropyl, 3-aminomethyl, 4-aminomethyl and 3-methylamino. For compounds with a substituted pyrrolidine in the 7-position of the quinolonecarboxylic acid core, preferred substituents include 3- (1-aminoethyl), 3-aminomethyl, 4- (1-aminoethyl) -2,2-dimethyl and 2- aminomethyl. For compounds with an azetidine substituent at the 7-position of the quinolonecarboxylic acid, compounds having the 3-amino, 3-aminomethyl and 3- (1-amino-1-methyl) ethyl substituents are included among the preferred examples. European Patent Publication 241206A2 describes the compounds of formula, wherein B is -CH2-, - (CH2) 2- or ~ (CH2) 3-, R is hydrogen, C1-C3 alkyl, hydroxy or C1-C3 alkoxy, W is hydroxy, C1-C3 alkoxy, or a group of formula R5R6N- (CH2) n-, in which n is 0 or 1 and R5 and Re are the same or different, and each represents a hydrogen atom, a C1-C3 alkyl group or a group aralkyl, and m is 1 or 2, each symbol is as defined in the specification of the publication mentioned above. For the piperidine substituent in the 7-position of the quinolonecarboxylic acid, the compounds having the substituents of 4-amino-3-methyl, 4-methylamino-3-methyl, 4-hydroxy-3-methyl are included in the preferred examples herein .

European Patent Publication 0394553B1 describes antiviral compounds of formula, wherein R2 ?, R22 and R23 are each independently a hydrogen atom, a halogen atom, amino, C? -C6 alkyl, Cs alkoxy or aminoalkyl of C-pCs and two of them can be combined with the other to form a spiro ring, and n is 1 or 2. European Patent Publication 0572259A1 describes antiviral compounds of formula, wherein R6 and R7 may be the same or different and each represents a hydrogen atom or a lower alkyl group, m is 0 or 1, n 'is 1 or 2, n "is 1, 2, 3 or 4, and R8 is a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group. International Patent Publication W09324479 describes the compounds of formula, wherein Z is an amino radical, Ri is hydrogen, a radical (optionally hydroxylated lower alkyl), an acyl radical derived from a carboxylic acid, an alkyl carbonic acid or an arylsulfonic acid or an arylamino carbonyl radical, R2 is an atom of oxygen, and n is 0 or 1. Examples of bacterial infections resistant to antibiotic therapy have been reported in the past; they are now a significant threat to public health in the developed world. The development of microbial resistance (perhaps as a result of the intensive use of antibacterial agents for extended periods of time) is of increasing interest in medical science. "Resistance" can be defined as the existence of organisms, within a population of a given species of microbes, that is less susceptible to the action of a given antimicrobial agent. This resistance is of particular importance in environments such as hospitals and nursing homes, where the relatively high proportions of infection and intense use of antibacterial agents are common. See, for example, W. Sanders, Jr. et al., "Inducible Beta-lactamases: Clinical and Epidemiologic Implications for the Use of Newer Cephalosporins", Review of Infectious Diseases. p. 830 (1988). It is known that pathogenic bacteria acquire resistance via several different mechanisms, including the inactivation of the antibiotic by bacterial enzymes (for example, ß-lactamases that hydrogenate penicillin and cephalosporins); the elimination of the antibiotic using discharge pumps; modification of the target of the antibiotic via mutation and genetic recombination (for example, resistance to penicillin in Neisseria gonorrhoeae); and the acquisition of a gene easily transferable from an external source to create a resistant target (eg, resistance to methicillin in Staphylococcus aureus). There are certain Gram-positive pathogens, such as vancomycin-resistant Enterococcus faecium, that are resistant to virtually all commercially available antibiotics. Therefore, existing antibacterial agents have a limited capacity to overcome the threat of resistance. This would be advantageous to provide new antibacterial agents that can be used against resistant microbes.

BRIEF DESCRIPTION OF THE INVENTION Applicants have found a novel series of quinolones and related compounds, which are effective against resistant microbes, and provide significant activity advantages in the art.

In particular, the invention relates to compounds having a structure according to Formula (I) Formula I wherein: n is an integer from 1 to 3; m is an integer from 1 to 3; z is an integer from 0 to 3; R is selected from hydrogen, hydroxy and alkoxy; R2 is hydrogen; R3 and R4 are independently selected from hydrogen, halogen, amino, hydroxy, alkoxy, alkylthio, alkyl, alkenyl and alkynyl; Rs is selected from hydrogen, halogen, alkyl, aryl, alkoxy, and alkylthio; R6 is independently selected from alkyl, hydroxy, alkoxy, alkylthio, alkenyl, alkynyl, aryl, alkoxyimino and halogen; or R5 and Re join to form a 4- to 7-membered carbocyclic ring, wherein each ring carbon atom may be optionally substituted with R-? 2, wherein R-? 2 is selected from the group consisting of halogen, amino, hydroxy, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, oxo, alkoxyimino and hydroxyimino; E is selected from the group consisting of: 1) where ' q is an integer from 1 to 3; R7 and R8 are each independently selected from hydrogen and alkyl, or R7 and Rs are joined to form a carbocyclic ring of 3 to 6 members, or any of R7 or R8 can independently bind to either Rg or R10 to form a heterocyclic ring containing the nitrogen atom to which Rg or R10 are attached, wherein R9 and R10 are each selected independently of hydrogen, alkyl, acyl, alkoxycarbonyl or sulfonyl, or alternatively R9 and R10 are joined to form a heterocyclic ring containing the nitrogen atom to which they are attached; 2) where, q is as defined above; R7 and R8 are each independently selected from hydrogen and alkyl, or R7 and R8 are joined to form a 3-6 membered carbocyclic ring, and Rg is selected from hydrogen, alkyl, acyl, alkoxycarbonyl or sulfonyl; and 3) alkenyl; A is selected from N and C (R-n), wherein Rn is selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, alkylthio and cyano; X is selected from C and N, where if X is C, a is a double bond and b is a single bond, and if X is N, a is a single bond and b is a double bond; and Y is selected from N (R-?) and C (R-?), with the proviso that when Y is N (R-?), X is C and when Y is C (R?), X is N , wherein Ri is selected from C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl, alkyl, alkene, a 6-membered aryl and a 6-membered heteroaryl; with the proviso that if A is C (Rp), X is C and Y is N (R?), then Rn and Ri can join to form a 6-membered heterocyclic ring, or if A is C (Rp), X is C and Y is N (R?), then R2 and Ri can join to form a monocyclic or bicyclic ring, or if A is C (Rn), X is C and Y is N (R?), then R2 and R they can join to form a 5-membered heterocyclic ring; or an optical isomer, diastereomer or enantiomer thereof; a pharmaceutically acceptable salt, hydrate or prodrug thereof. In addition, methods of using the compounds of the invention as raw materials are also contemplated in this invention. It has been found that the compounds of this invention, and the compositions containing these compounds, are effective antimicrobial agents against a wide range of pathogenic microorganisms with activity advantages against resistant microbes. Accordingly, the present invention is also directed to a method for treating a subject having a condition caused by, or contributing to a bacterial infection, which comprises administering to a mammal a therapeutically effective amount of the compound of Formula 1. - The present invention is further directed to a method for preventing a subject from suffering from a condition caused by or contributing to a bacterial infection, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula 1.

DETAILED DESCRIPTION OF THE INVENTION The subject invention provides compounds of Formula (I) Formula wherein: a, b, n, m, z, R, R2, R3, R4, R5, Re, A, E, X and Y are as defined in the section of the Brief Description of the previous Invention. With regard to the above description, certain definitions are applied as follows. Unless otherwise indicated, under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is described first, followed by functionality adjacent to the point of attachment. Unless otherwise specified, the terms "alkyl", "alkenyl" and "alkynyl", when used alone or as part of a substituent group, include straight and branched chains having from 1 to 8 carbon atoms, or any number within this range. The term "alkyl" refers to a straight or branched hydrocarbon chain. "Alkenyl" refers to a straight or branched hydrocarbon chain with at least one carbon-carbon double bond. "Alkynyl" refers to a straight or branched hydrocarbon chain with at least one triple carbon-carbon bond. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2- pentyl, 2-methylbutyl , neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. The "alkoxy" radicals are oxygen ethers formed from the straight or branched chain alkyl groups described previously. The "cycloalkyl" groups contain from 3 to 8 carbons in the ring, and preferably from 5 to 7 carbons in the ring. The alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy groups can be substituted, independently with one or more members of the group including, but not limited to, hydroxyimino, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, alkoxyimino aryl, heteroaryl, heterocycle, CN, nitro, -OCOR13, -OR? 3 >; -SR13, -SOR13, -SO2R13, -COOR13, -NR13R14, -CONR13Ri4, -OCONR? 3R-i4, -NHCOR13, -NHCOOR13 and -NHCONR13R, wherein R13 and R14 are independently selected from hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, aralkyl, heteroaralkyl and heterocycloalkyl, or alternatively, R14 and R15 can be joined to form a heterocyclic ring containing the nitrogen atom to which they are attached. The term "acyl" as used herein, when used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain), derived from an organic acid by the elimination of the hydroxyl group. The term "Ac" as used herein, when used alone or as part of a substituent group, means acetyl. The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine. (Mono, di, tri and per) haloalkyl is an alkyl radical substituted by the independent replacement of the hydrogen atoms thereof with the halogen. "Aryl" or "Ar", when used alone or as part of a substituent group, is an aromatic carbocyclic radical that includes, but is not limited to, phenyl, 1 or 2-naphthyl and the like. The aromatic carbocyclic radical can be substituted by the independent replacement of 1 to 3 of the hydrogen atoms thereof with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, CrC8 alkyl) C2-C8 alkenyl, alkoxy of CrC8, CrC8 alkylthio, C?-C8-amino alkyl, di (C?-C8 alkyl) amino, (mono, di, tri and per) haloalkyl, formyl, carboxy, alkoxycarbonyl, Ci-Cs alkyl CO-O-, C? -C8-CO-NH- or carboxamide alkyl. Exemplary aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. "Ph" or "PH" denotes phenyl. "Bz" denotes benzoyl. When used alone or as part of a substituent group, "heteroaryl" refers to a cyclic radical, completely unsaturated having five to ten ring atoms, of which one ring atom is selected from S, O and N; 0-2 atoms in the ring are additional heteroatoms selected independently of S, O and N; and the remaining ring atoms are carbon. The radical can be linked to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N -oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolicinyl, benzofuryl, cinolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinium or furo [2,3-b] pyridinyl), imidazopyridinyl (such as midazo [4,5-b] pyridinyl or imidazo [4,5-c] pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl and thienothienyl. The heteroaryl group can be substituted by the independent replacement of 1 to 3 of the hydrogen atoms thereof with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, Ct-Cs alkyl, C? -C8 alkoxy , CrC8 alkylthio, CrC8-amino alkyl, di (CrC8 alkyl) amino, (mono, di, tri and per) haloalkyl, formyl, carboxy, alkoxycarbonyl, C8-alkyl-CO-0-, C8-alkyl -CO-NH- or carboxamide. The heteroaryl may be substituted with a mono-oxo to provide, for example, a 4-oxo-1 H-quinoline.

The terms "heterocycle", "heterocyclic" and "heterocycle", refer to an optionally substituted, fully saturated, partially saturated or non-aromatic cyclic group which is, for example, a monocyclic 4- to 7-membered ring system, of 7 to 11 member bicyclic or 10 to 15 member tricyclic, having at least one heteroatom on at least one carbon atom containing the ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also be optionally oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group can be attached to any hetero atom or carbon atom. The heterocyclic group may be substituted by independently replacing 1 to 3 of the hydrogen atoms thereof with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, CrC8 alkyl, CrC8 alkoxy, CrC8 alkylthio, C8-amino alkyl, di (C? -C8 alkyl) amino, (mono, di, tri and per) haloalkyl, formyl, carboxy, alkoxycarbonyl, C? -C8 alkyl-CO-0-, alkyl of C? -C8-CO-NH- or carboxamide. Exemplary heterocyclic monocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanil; thietanyl; tiiranil; 2-oxazepinyl; azepinyl; and the similar. Exemplary heterocyclic bicyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the similar. The term "carbocyclic" refers to a saturated or unsaturated, non-aromatic, monocyclic ring of 3 to 7 carbon atoms. The substituted aryl, substituted heteroaryl and substituted heterocycle may also be substituted with a second substituted aryl, a second substituted heteroaryl or a second substituted heterocycle to provide, for example, a 4-pyrazol-1-yl-phenyl or a 4-pyridin- 2-yl-phenyl. The designated numbers of carbon atoms (eg, CrC8 or C? -8), will be referred independently to the number of carbon atoms in an alkyl or cycloalkyl portion or to the alkyl portion of a larger substituent in which the alkyl appears as its prefix root. Unless otherwise specified, it is intended that the definition of any substituent or variable in a particular location in a molecule be independent of the definitions elsewhere in that molecule. It will be understood that substituents and substitution patterns of the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the art, as well as those methods exposed in the present. The term "hydroxy protecting group" refers to groups known in the art for such a purpose. The hydroxy protecting groups commonly used are described, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), which are incorporated herein by reference. Illustrative hydroxyl protecting groups include, but are not limited to, tetrahydropyranyl; benzyl; methylthiomethyl; ethylthiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethylsilyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl; acyl and aroyl such as acetyl, benzoyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and arylacil. Where the compounds according to this invention have at least one stereogenic center, they can therefore exist as enantiomers. Where the compounds possess two or more stereogenic centers, these may additionally exist as diastereomers. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such, are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and it is intended that such solvates are also encompassed within the scope of this invention. Some of the compounds of the present invention may be the trans and cis isomers. Furthermore, where the processes for the preparation of the compounds according to the invention give rise to the mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared as a single stereoisomer or in a racemic form as a mixture of some possible stereoisomers. The non-racemic forms can be obtained either by synthesis or resolution. The compounds can, for example, be resolved into their enantiomeric components by standard techniques, such as the formation of diastereomeric pairs by the formation of salts. The compounds can also be resolved by covalent attachment to a chiral auxiliary, followed by chromatographic separation and / or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using chiral chromatography. The phrase "a pharmaceutically acceptable salt" denotes one or more salts of the free base or the free acid, which possess the desired pharmacological activity of the free base or the free acid in an appropriate manner, and which are neither biologically nor otherwise Undesirable These salts can be derived from inorganic or organic acids. Examples of the inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, masonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, acid mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, salicylic acid and the like. Suitable salts are also those of inorganic or organic bases, such as KOH, NaOH, Ca (OH) 2, AI (OH) 3, piperidine, morpholine, ethylamine, triethylamine and the like. Included within the scope of the invention are the hydrated forms of the compounds containing various amounts of water, for example, the hydrate, hemihydrate and sesquihydrate forms. The present invention also includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs can be functional derivatives of the compounds that are readily convertible in vivo to the required compound. Thus, in the methods of treatment of the present invention, the term "administer" will encompass the treatment of the various disorders described with the specifically described compound or with a compound that may not be specifically described, but which is converted to the compound specified in I live after the administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The term "subject" includes, in a non-exclusive manner, any artificially modified animal or animal. As a particular modality, the subject is a human. The term "drug resistant" or "drug resistance" refers to the characteristics of a microbe to survive in the presence of a currently available antimicrobial agent, such as an antibiotic in its effective routine concentration. Table 1 contains a non-limiting list of the preferred compounds of Formula I.

TABLE 1 General Reaction Scheme for the Preparation of the Compound In the manufacture of the compounds of the invention, the order of the synthetic steps may be varied to increase the yield of the desired product. In addition, the person skilled in the art will also recognize that the judicious choice of reactions, solvents and temperatures are an important component in the success of the synthesis. Although the determination of optical conditions, etc., is routine, it should be understood that a variety of compounds can be generated in a similar way, using the guidelines of the following reaction schemes. The raw materials used in the preparation of the compounds of the invention are known, manufactured by synthetic methods published or available from commercial suppliers. It will be recognized that someone skilled in the art of organic chemistry can easily carry out standard manipulations of the organic compounds without additional guidance, that is, it is within the scope and practice of one skilled in the art to carry out such manipulations. . These include, but are not limited to, reductions of the carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Orqanic Chemistrv (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2), Feiser & Feiser, Reagents for Organic Svnthesis (16 volumes), L. Paquette, Encvclopedia of Reagents for Organic Synthesis (8 volumes), Frost & Fleming, Comprehensive Organic Svnthesis (9 volumes) and the like. The person skilled in the art will readily appreciate that certain reactions can be best carried out when another functionality is masked or protected in the molecule, thus avoiding any unwanted side reactions and / or increasing the reaction yield. Frequently, the expert uses protective groups to achieve such increased yields or to avoid unwanted reactions. Examples of these manipulations can be found, for example, in T. Greene, Protecting Groups in Organic Svnthesis. The general procedures for the preparation of heterocyclic nuclei in the manufacture of the compounds of the invention are described in the following references, all incorporated by reference herein (including the articles listed within the references): U.S. Pat. 6329391, European Patent Publication 342849, International Patent Publication WO9711068, European Patent Publication 195316, European Patent Publication 1031569, US Patent. 6025370, the European Patent Publication 153828, the European Patent Publication 191451, the European Patent Publication 153163, the European Patent Publication 230053, the European Patent Publication 976749, the International Patent Publication WO0118005, the International Patent Publication WO9407873 , the US Patent 4777253, European Patent Publication 421668, International Patent Publication WO0248138, European Patent Publication 230295, International Patent Publication W09914214, Patent Publication of E.U.A. 20020049223, International Patent Publication W09921849, International Patent Publication WO9729102, International Patent Publication WO0334980, International Patent Publication WO0209758, International Patent Publication W09619472, German Patent Publication DE 3142854, International Patent Publication WO0334980, International Patent Publication WO0328665 , European Patent Publication 47005, International Patent Publication WO0311450 and European Patent Publication 688772. The subject compounds of the invention may be prepared in various manners. Versatile methodologies for the preparation of the compounds of the invention are shown in Reaction Scheme I below, wherein L is a leaving group such as fluorine or chlorine: REACTION SCHEME I Sintests usual of the quinolone or naftiridone L A L Coupling of the Side Chain Ifi IV In the case where E is and at least one of Rg and R-io is hydrogen, it may be necessary to protect the terminal nitrogen to effect selective conversion to the desired product (Reaction Scheme II). In such a case, the amine protecting groups standard known to those skilled in the art, such as t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), 9-fluorenylmethoxycarbonyl (Fmoc), alioxycarbonyl (Alloc), 2- trimethylsilylethoxycarbonyl (Teoc), N- formyl, N-acetyl, N-benzoyl or phthalimide, can be used to mask the terminal amine, as in compound V. After coupling the side chain, the protecting group can be removed under standard conditions known to those skilled in the art. to obtain the desired product VII. Vil can be further elaborated, for example, by alkylation to other compounds of the invention VIII.

REACTION SCHEME II Simesls usisa! vill Vill P "= protecting group The methodologies for providing the compounds of the invention, wherein X is N and Y is C (R-?), are shown in Reaction Scheme III below: REACTION SCHEME lll useful As above, where E is and at least one of Rg and R-io is hydrogen, it may be necessary to protect the terminal nitrogen to effect selective conversion to the desired product (Reaction Scheme IV). In such case, the standard amine protecting groups known to those skilled in the art, such as t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc) , 2-trimethylsilylethoxycarbonyl (Teoc), N-formyl, N-acetyl, N-benzoyl or phthalimide, can be used to mask the terminal amine, as in compound V. After coupling the side chain, the protecting group can be removed under standard conditions known to those skilled in the art to obtain the desired product XIII. XIII can be further elaborated, for example, by alkylation to other compounds of the invention XIV.

REACTION SCHEME IV Sirtícsís usual íic ta £) Li ?? slerta a nafl pdonq D & sprotection P "= protecting group Occasionally, the side chain amines are insufficiently reactive to efficiently aggregate to the heterocyclic core (II or X) under the conditions illustrated in Reaction Schemes I-1V, particularly when A is C (RH), wherein Rp is alkoxy The nucleus can be activated towards nucleophilic attack by the addition of a Lewis acid such as, but not limited to, boron trifluoride, triacetoxyborate and lithium chloride The preferred method of activation is described in US Pat. 5,157,117 The quinolone core is treated with triacetoxybrate, prepared in situ, in a solvent such as, but not exclusively, acetic acid or propionic acid and heated for 1 to 24 hours at a temperature between 60 ° C and 120 ° C. The diacyl quinolinylborate (XV) was isolated by filtration after solvent removal, Reaction Scheme V illustrates this preferred method of activation.

REACTION SCHEME V 4) HgO Preparation of the precursor - Side chain of amine III Reaction Scheme VI illustrates the synthesis of the side chain of amine III, where E is R7 j ^ h- Rio R7 and R8 are hydrogen, and q is 1. The alkylidenes trisubstituted or tetrasubstituted XX can be prepared by an olefination of Peterson, Wittig or Wadsworth-Horner-Emmons of an appropriate substituted ketone (XVI) in a solvent such as, but not limited to, tetrahydrofuran, dimethyl sulfoxide, or methylene chloride for 1 to 10 minutes. at 24 hours at a temperature between -78 ° C to 120 ° C in the presence of a base such as, in a non-exclusive manner, n-butyllithium, sodium hydride or potassium carbonate. The resulting ester (XVII) can be reduced with a reducing agent such as, but not limited to, diisobutylaluminum hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride, or tetrahydrofuran. for 1 to 24 hours at a temperature between 0 ° C and 120 ° C to provide the corresponding alcohol XVIII, where q = 1. Converting the alcohol XVIII to the leaving group XIX, such as, in a non-exclusive manner, chloride, bromide, mesylate or tosylate under standard conditions and displacing the leaving group with an appropriate substituted amine in a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C converts alcohol XVIII to an amine XX. Removal of the protecting group, P, under standard conditions known to those skilled in the art provides the amine III, wherein E is R and Rs are hydrogen, and q is 1. Alternatively, the direct replacement of alcohol XVIII can be performed via a Mitsunobu reaction with phthalimide and dialkyo azodicarboxylate to provide XXI. Deprotection of phthalimide (XXI) with hydrazine in a solvent such as methanol or ethanol provides the amine (XX), wherein Rg and R-io are hydrogen. The protecting group, P, can be removed from XXI under standard conditions known to those skilled in the art to provide the amine V, wherein R7 and R8 are hydrogen and Rg and P "together with the nitrogen to which they are attached form a group phthalimide.

REACTION SCHEME VI XXI L is a leaving group P is a protecting group. Reaction Scheme XXII illustrates the conversion of alcohols of formula XVIII to compounds of formula III, wherein E is alkenyl (LVIII). In addition, the Reaction Scheme defines the synthesis of the compounds of formula III, wherein E is R7 and R8 are hydrogen and Rg is acyl, alkoxycarbonyl or sulfonyl (LX). Oxidation of the alcohol XVIII with any number of suitable oxidizing agents, such as Dess-Martin periodinane, the Corey-Kim reagent or the Swern reagent, provides the corresponding aldehyde (LVI). The aldehyde can be subjected to an olefination reaction promoted by a base, such as, but not exclusively, the Wittig reaction to provide LVII, wherein Rc is hydrogen or alkyl. Removal of the protecting group, P, from LVII under standard conditions known to those skilled in the art provides the amine III, wherein E is alkenyl (LVIII). Reaction Scheme XX also illustrates the conversion of alcohols of formula XVIII to compounds of formula III, wherein E is R7 and Rs are hydrogen, and Rg is acyl, alkoxycarbonyl or sulfonyl (LX). The reaction of alcohol XVIII with an acylating agent in the presence of an amine base, such as pyridine, in an inert solvent such as dichloromethane, tetrahydrofuran or toluene at temperatures ranging from -20 ° C to 60 ° C for 1-48 hours, provides the compounds of formula III, wherein, E is R7 and R8 are hydrogen and R9 is acyl (LIX). The acylating agents include acid halides, acid anhydrides and acids in the presence of an activating agent such as dicyclohexylcarbodiimide, EDCl, BOP-CI, BOP, PyBOP and the like. The alcohols of formula XVIII can be converted to the compounds of formula III, wherein E is R7 and R8 are hydrogen and Rg is alkoxycarbonyl (LIX), by reaction with a carbonylating agent in the presence of an amine base, such as pyridine, in an inert solvent such as dichloromethane, tetrahydrofuran or toluene at temperatures varying from - 20 ° C to 60 ° C for 1-48 hours. Carbonylating agents include chloroformates, fluoroformates, pyrocarbonate azidoformates. The alcohols of formula XVIII can be converted to the compounds of formula III, wherein E is R and Rs are hydrogen and Rg is sulfonyl (LIX), by reaction with sulfonyl chloride or sulfonic anhydride in the presence of an amine base, such as pyridine, in an inert solvent such as dichloromethane, tetrahydrofuran or toluene at temperatures that They vary from -20 ° C to 60 ° C for 1-48 hours. Removal of the protecting group, P, from LIX under standard conditions known to those skilled in the art, provides the amine III, wherein E is R7 and R8 are hydrogen, and Rg is acyl, alkoxycarbonyl or sulfonyl (LX).

REACTION SCHEME XXII P is a Prototyping Group,, «LX The Reaction Scheme VII illustrates a direct conversion of the ketone XVI to the olefin XX using an olefination reaction promoted by a base such as, in a non-exclusive way, the olefination procedures of Wittig , Wadsworth-Horner-Emmons or Peterson. Alternately, the. Amine XX can be prepared by a metathesis process of an olefin from the terminal olefin XXII, using an appropriately substituted amine XXIII. Removal of the protecting group, P, from XX under standard conditions known to those skilled in the art provides the amine III, wherein E is and R and R8 are hydrogen.

REACTION SCHEME Vil It is a ropo ropo XXII Reaction Scheme VIII illustrates hydroxylation of XXIV with selenium dioxide to provide allyl alcohol XXV. The transformation is carried out in a solvent such as, but not limited to, methylene chloride, toluene or tetrahydrofuran at a temperature between 25 ° C and 150 ° C, optionally in the presence of a co-oxidant such as tert-butyl hydroperoxide. Removal of the protecting group, P, from XXV under standard conditions known to those skilled in the art provides the amine III, wherein E is and one of R6 is hydroxy.

REACTION SCHEME VIII P is a Protecting Group Reaction Scheme IX illustrates the preparation of a α, β-unsaturated carbonyl compound XXVI, wherein R7 is as previously defined, using an olefinization procedure of Peterson, Wittig or Wadsworth-Horner-Emmons of a ketone (XVI) suitably substituted in a solvent such as, but not limited to, tetrahydrofuran, dimethyl sulfoxide or methylene chloride for 1 to 24 hours at a temperature between -78 ° C to 120 ° C in the presence of a base such as, but not limited to, n-butyllithium, sodium hydride or potassium carbonate. The resulting carbonyl compound (XXVI) can be reduced with a reducing agent such as, but not limited to, diisobutylaluminium hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide the corresponding alcohol XXVII. Alternatively, the carbonyl compound can be subjected to nucleophilic addition with an appropriately substituted organometallic agent (RsM, where M is a metal), such as organolithium species or a Grignard reagent, to provide the corresponding alcohol XXVII, wherein Rs is alkyl. Suitable solvents for subsequent processing include diethyl ether, tetrahydrofuran or toluene, at temperatures ranging from -78 ° C to 20 ° C for 30 minutes to 48 hours. Wherein one of R7 or R8 are hydrogen, converting the alcohol functionality in XXVII to a leaving group such as, in a non-exclusive manner, bromine, mesylate or tosylate as in XXVIII under standard conditions and displacing the leaving group with a substituted amine so In a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, converts alcohol XXVII to an amine XXX. Removal of the protecting group, P, from XXX under standard conditions known to those skilled in the art, provides amine III, wherein E is and one of R7 and R8 is hydrogen. Alternatively, where one of R7 or R8 is hydrogen, the direct replacement of the alcohol XXVII can be performed via a Mitsunobu reaction with phthalimide and a dialkyl azodicarboxylate followed by deprotection of the phthalimide with hydrazine in a solvent such as methanol or ethanol, to provide XXX amine. The protecting group, P, can be removed from XXIX under standard conditions known to those skilled in the art, by providing the amine V, wherein R8 is hydrogen and Rg and P "together with the nitrogen to which they are attached form a group phthallmide.

REACTION SCHEME IX 2) HCl, THF, H20 L is a Protrg Group P is a Protective Group Reaction Scheme X describes the preparation of XXXVI, wherein R5 is halogen. The alkylidenes XXXI, wherein R5 is hydrogen, can be halogenated with an appropriate halogenating agent such as, but not limited to, 1-bromo-2,5-pyrrolidinedione, 1,1,1-tris (acetyloxy) -1, 1 -dihydro-2-benziodoxol-3 (1 H) -one and a tetraalkylammonium bromide or thionyl chloride to provide XXXII. The alkylidene XXXII can be reduced with a reducing agent such as, non-exclusively, diisobutylaluminum hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide the corresponding XXXIII alcohol. Alternatively, the carbonyl compound can be subjected to nucleophilic addition with an appropriately substituted organometallic agent, such as an organolithium species or a Grignard reagent, to provide the corresponding alcohol XXXIII, wherein R8 is alkyl. Suitable solvents for further processing include diethyl ether, tetrahydrofuran or toluene, at temperatures ranging from -78 ° C to 20 ° C for 30 minutes to 48 hours. Wherein one of R7 or R8 is hydrogen, converting the alcohol functionality to XXXIII to a leaving group such as, in a non-exclusive manner, bromine, methylate or tosylate as in XXXIV under standard conditions and displacing the leaving group with a substituted amine so Suitable in a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, converting XXXIV to an amine XXXVI. Removal of the protecting group, P, from XXXVI under standard conditions known to those skilled in the art provides the amine III, wherein E is and one of R and R8 is hydrogen. Alternatively, wherein one of R7 or R8 is hydrogen, the direct replacement of the alcohol XXXIII can be performed via a Mitsunobu reaction with phthalimide and a dialkyl azodicarboxylate followed by deprotection of the phthalimide with hydrazine in a solvent such as methanol or ethanol, to provide amine XXXVI. The protecting group, P, can be removed from XXXV under standard conditions known to those skilled in the art, to provide the amine V, wherein R8 is hydrogen and Rg and P "together with the nitrogen to which they are attached form a phthalimide group.

X REACTION SCHEME Reaction Scheme XI illustrates the synthesis of the side chain amine III, where E is R7 and R8 are hydrogen and R5 is substituted with a branched chain alkyl. In Reaction Scheme XI, the halogenated carbonyl compound XXXVII, wherein Ra is hydrogen or alkyl, can be prepared in a manner similar to the halogenated carbonyl compound XXXII. The carbonyl compound XXXVII, wherein Ra is hydrogen or alkyl, can be reduced with a reducing agent such as, but not limited to, diisobutylaluminum hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not exclusively, toluene, methylene chloride or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide the corresponding alcohol XXXVIII, wherein Ra is hydrogen or alkyl, one of Rb is hydrogen, and the other of Rb It is hydroxyl. Alternatively, the carbonyl compound XXXVII, wherein Ra is alkyl, can be subjected to nucleophilic addition with an appropriately substituted organometallic agent, such as an organolithium species or a Grignard reagent, to provide the corresponding alcohol XXXVIII, where Ra is alkyl, one of Rb is alkyl, and the other of Rb is hydroxyl. Finally, the carbonyl compound XXXVII, wherein Ra is hydrogen or alkyl or alcohol XXXVIII, wherein Ra is hydrogen or alkyl, one of Rb is hydrogen, and the other Rb is hydroxyl, can be fluorinated using a nucleophilic fluorinating reagent, such as, non-exclusively, (N-ethylethanamine) trifluoroazufre (DAST) or bis (2-methoxyethyl) aminoazufre trifluoride (Deoxofluor), in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature between 0 ° C and 60 ° C, to provide XXXVIII, where, in the case of the carbonyl compound XXXVII as a substrate, Ra is hydrogen or alkyl and Rb is fluorine, and wherein in the case of alcohol XXXVIII as a substrate, Ra is hydrogen or alkyl, one of Rb is hydrogen, and the other of R is fluorine. The halogenated alkylidene XXXVIII may be carbonylated in the presence of a transition metal catalyst, such as, but not limited to, palladium acetate, dicarbonylbis (triphenylphosphine) nickel or tetracis (triphenylphosphine) palladium, under a monoxide atmosphere. carbon in the presence of a second additive such as methanol, optionally as a solvent, or in a solvent such as, but not limited to, dimethyl sulfoxide or tetrahydrofuran, for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide ester XXXIX. XXXIX can be reduced with a reducing agent such as, but not limited to, diisobutylaluminum hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide the corresponding alcohol XL, where q = 1. Converting the alcohol XL to the leaving group XLI, such as, in a non-exclusive manner, bromide, mesylate or tosylate, under standard conditions and displacing the leaving group with an appropriately substituted amine in a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, converts the alcohol XL to an amine XLIII. Removal of the protecting group, P, from XLI1I under standard conditions known to those skilled in the art, provides the amine III, wherein E is R7 and R8 are hydrogen and R5 is CRaRaRb. Alternatively, the direct replacement of the alcohol XL can be performed via a Mitsunobu reaction with phthalimide and dialkyl azodicarboxylate to provide XLII. Deprotection of phthalimide XLII with hydrazine in a solvent such as methanol or ethanol provides the amine XLIII. The protecting group, P, can be removed from XLII under standard conditions known to those skilled in the art, to provide the amine V, wherein R7 and R8 are hydrogen, Rg and P "together with the nitrogen to which they are attached form a phthalimide group and R5 is CRaRaRb- XI REACTION SCHEME XXXVII JÍXXVIH X III Reaction Scheme XII illustrates the synthesis of the side chain amine III, where E is one of R7 or R8 is hydrogen and the other is alkyl, R5 is a substituted or branched alkyl, and q is 1. Compound XXXVIII, prepared as described above, can be carbonized in the presence of a transition metal catalyst, such as, but not limited to, palladium acetate, dicarbonylbis (triphenylphosphine) nickel or tetracis (triphenylphosphine) palladium, under an atmosphere of carbon monoxide in the presence of an organometallic reagent RM, wherein R7 is as previously defined and includes reagents such as tributyltin hydride or alkyl indium agents (Organic Letters 2003, 5 (7), 1103-1106), in a solvent such as, but not limited to, methanol, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours a a temperature between 0 ° C and 120 ° C, to provide XLIV, where R7 is as previously defined. The carbonyl compound XLIV can be reduced with a reducing agent such as, but not limited to, diisobutylaluminium hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride or tetrahydrofuran for 1 hour. at 24 hours at a temperature between 0 ° C and 120 ° C, to provide the corresponding XLV alcohol. Alternatively, the carbonyl compound can be subjected to nucleophilic addition with an appropriately substituted organometallic reagent, such as an organolithium species or a Grignard reagent, to provide the corresponding XLV alcohol, wherein R8 is alkyl. Suitable solvents for further processing include diethyl ether, tetrahydrofuran or toluene, at temperatures ranging from -78 ° C to 20 ° C for 30 minutes to 48 hours. Wherein one of R7 or R8 are hydrogen, converting the functionality alcohol to XLV to a leaving group, such as, in a non-exclusive manner, bromide, mesylate or tosylate as in XLVI under standard conditions and displacing the leaving group with a substituted amine of Properly in a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, converting the alcohol XLV to an amine XLVIII. Removal of the protecting group, P, from XLVIII under standard conditions known to those skilled in the art provides the amine III, wherein E is one of R and R8 is hydrogen and the other is alkyl, R5 is a substituted or branched chain alkyl, and q is 1. Alternatively, where one of R7 or R8 is hydrogen, the direct replacement of the XLV alcohol can be done via a reaction of Mitsunobu with phthalimide and a dialkyl azodicarboxylate followed by deprotection of the phthalimide with hydrazine in a solvent such as methanol or ethanol, to provide the amine XLVIII. The protecting group, P, can be removed from XLVIII under standard conditions known to those skilled in the art, to provide the amine V, wherein one of R7 and R8 is hydrogen and the other is alkyl, Rg and P "together with the nitrogen to which they are attached they form a phthalimide group, Rs is a substituted or branched alkyl, and q is 1.

REACTION SCHEME XII Reduction of organometallic addition XXXVHt xuv L cs a Salient Group P is a Protective Group XLVIJÍ Reaction Scheme XIII illustrates the conversion of the ketone XVIa to the olefin Lili using a Robinson nullification protocol with Stork-Jung vinylsilane promoted with a base (Tetrahedron Letters, 2001, 42, 9123). The condensation of ketone XVIa with allyl iodide XLIX, wherein Rc is an alkyl group and P 'is a hydroxy protecting group (Tetrahedron Letters, 2001, 42, 9123), provides the alkylated ketone L. The epoxidation of the Ketone L with epoxidizing agents such as, in a non-exclusive manner, dimethyl dioxirane or m-chloroperbenzoic acid, provided the oxirane Ll. The protodesilylation of Ll with agents such as, but not limited to, tetra-n-butylammonium fluoride or poly (acid fluoride) pyridinium and aqueous acid, with the concomitant opening of the epoxide ring provides the ketone Lll. The annulment of the Lll ring can be accomplished by treating Lll with a base such as, but not exclusively, sodium methoxide to provide Llll. The α, β-unsaturated ketone Llll can be reduced with a reducing agent such as, but not limited to, diisobutylaluminum hydride, lithium triethylborohydride or sodium borohydride in a solvent such as, but not limited to, toluene, methylene chloride or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, to provide, after removal of the hydroxy protecting group, the corresponding alcohol LIV, wherein one of R-? 2 is hydrogen and the other R12 is hydroxy. Alternatively, Llll can be subjected to nucleophilic addition with an appropriately substituted organometallic reagent, such as an organolithium species or a Grignard reagent, to provide, after removal of the hydroxy protecting group, the corresponding LIV alcohol, in where one of R-? 2 is alkyl and the other R12 is hydroxy. Suitable solvents for further prsing include diethyl ether, tetrahydrofuran or toluene, at temperatures ranging from -78 ° C to 20 ° C for 30 minutes to 48 hours. Finally, the carbonyl compound Llll can be fluorinated using a nucleophilic fluorination reagent such as, but not limited to, (N-ethylethanamine) trifluoroazufre (DAST) or bis (2-methoxyethyl) aminoazufre trifluoride (Deoxofluor), in a solvent suitable, such as methylene chloride, for 1 to 24 hours at a temperature between 0 ° C and 60 ° C to provide, after removal of the hydroxy protecting group, the alcohol LIV, wherein R-12 is fluorine.

REACTION SCHEME XIII Lll Ull UV LV P is a GGUSÍQ Protector The LIV alcohol can be converted to a leaving group such as, in a non-exclusive way, bromide, mesylate or tosylate under standard conditions. The displacement of the leaving group with an appropriately substituted amine in a solvent such as, but not limited to, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for 1 to 24 hours at a temperature between 0 ° C and 120 ° C, converts LIV to the amine LV. Removal of the protecting group, P, from LV under standard conditions known to those skilled in the art, provides the corresponding secondary amine III, wherein E is R7 and R8 are hydrogen, and R5 and Re join to form a 6-membered carbocyclic ring, and q is 1. Alternatively, the direct displacement of the hydroxyl group of the LIV alcohol, can be carried out via a Mitsunobu reaction with phthalimide and a dialkyl azodicarboxylate, followed by deprotection of the phthalimide with hydrazine in a solvent such as methanol or ethanol, to provide the amine LV, wherein R9 and R10 are hydrogen.

Experimental section Preparation of the precursor - Heterocyclic nuclei All heterocyclic nuclei such as 1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid, 7-cyclo-1-cyclopropylo-6-fluoro-4-oxo-1,4-dihydro-naphthipyridin-3-carboxylic acid, 9,10-difluoro-2,3-dihydro-3 acid -methyl-7-oxo-7H-pyrido [1, 2,3-de] -1,4-benzoxacin-6-carboxylic acid, 1-cyclopropyl-1,4-dihydro-6,7-difluoro-4-acid oxo-quinoline-3-carboxylic acid, 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid and 1-cyclopropyl- 1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid was prepared according to the methods of the literature (see the discussion above about the general procedures for the preparation of the heterocyclic nuclei), or were purchased from commercial sources.

Preparation of precursor A - Preparation of diacyl quinolinyl borates 19 Compound 19 (Formula XV: L = F. A = C-OMe, R-, = Cyclopropyl, R? = H, R3 = F, R4 = H) Diacyl quinolinyl borates were prepared by the procedure reported in the patent from the USA 5,157,117. A mixture of boric acid (2.4 g, 38.7 mmol), acetic anhydride (13.8 mL, 146 mmol) and zinc chloride (52 mg, 0.38 mmol) was heated at 110 ° C for 1.5 hours, treated with acetic acid ( 51 mL) and an additional hour was allowed to stir at 110 ° C.

The resulting mixture was allowed to cool to 60 ° C, treated with 1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (18) (7.3 g, 25.9 mmol) and acetic acid (26 mL). The resulting solution was heated at 60 ° C for 5 hours, cooled to room temperature, and concentrated in vacuo.

The residue was treated with water (50 mL), and the solid was collected by filtration. The resulting solid was washed with water (3 x 50 mL), and dried to provide the title compound as a white solid, which was used as such in the next reaction. The same procedure as above, was used to convert each of the respective heterocyclic carboxylic acids listed in Table 2 to the corresponding diacyl borate derivative (17, 21, 23 and 83).

TABLE 2 Preparation of precursor B - Side chain lll XIV REACTION SCHEME O j 26 27 Compound 27 of Reaction Scheme XIV: 4- (2-Ethoxy-2-oxoethylidene) piperidinyl-1-t-butylcarboxylate (24), was prepared according to the procedure described in Sato et al. Heterocycles, 2001, 54, 747. 4- (2-Hydroxyethylidene) piperidinyl-1-t-butylcarboxylate (25). was prepared according to the procedure described in Sato et. to Heterocycles, 2001, 54, 747.

The 4-r2- (1,3-dihydro-1,3-dioxo-2H-yndolendol-2-yl) ethylidene-1-piperidinyl-1-t-butylcarboxylate (26). was prepared by a procedure adapted from Synthesis 1995, 756. A solution of 25 (250 mg, 1.10 mmol), phthalimide (208 mg, 1.40 mmol) and triphenylphosphine (366 mg, 1.40 mmol) in dry THF (10 mL) , it was treated with diethyl azodicarboxylate (0.25 mL, 1.40 mmol), adding it via a syringe in the dark under nitrogen. After 5 hours, the reaction mixture was treated with water (10 mL), diluted with ethyl acetate (50 mL), washed with 10% aqueous sodium bicarbonate (2 x 25 mL), and dried ( MgSO4). Purification by flash chromatography (0-30% ethyl acetate / hexanes) gave the title compound (389 mg, 78%) as a white foam. MS 357 (M + H).

Trifluoroacetate of 4-f2- (1,3-dihydro-1,3-dioxo-2H-iso-undol-2-yl) ethylidene-1-piperidine (27). A solution of 26 (380 mg, 1.03 mmol) was dissolved in CH2Cl2 (50 mL) and treated with trifluoroacetic acid (1 mL) at room temperature. After 1 hour, the reaction mixture was concentrated in vacuo to give the title compound 27 (363 mg, 100%) as an oil. MS 257 (M + H).

The 1 - (tert-butoxycarbonyl) -4-piperidinone was reacted with each of the respective phosphoacetates listed in Table 3, and the products were subjected to analogous procedures as in the synthesis of 27, to prepare the corresponding alcohols (28-30, 84) and the derived amines (31-33, 85). TABLE 3 REACTION SCHEME XXIII The diethyl ester of (2-oxo-tetrahydro-furan-3-yl) -phosphonic acid (86: Reaction Scheme XXIII), was prepared according to the procedure described in Murphy et al. Chemical Communications 1996, 6, 737-8.

The 4- (2-oxo-dihydrofuran-3-ylidene) p -peridin-1-carboxylic acid tert-butyl ester (87: Reaction Scheme XXIII) was prepared by a procedure analogous to that described in Sato et al. Heterocycles, 2001, 54, 747; MS = 267 (M + H).

REACTION SCHEME XXIV 89 The tert-butyl ester of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid (88; Reaction Scheme XXIV) was prepared according to the procedure described in Vice et al., J. Org. Chem. 2001, 66, 2487-2492.

The 4- (2-ethoxy-1-fluoro-2-oxoethylidene) -3,3-dimethylpiperidin-1-carboxylic acid tert-butyl ester (89; Reaction Scheme XXIV) was prepared by a procedure analogous to that described in Sato et al. Heterocycles, 2001, 54, 747.

REACTION SCHEME XXV 1) NaH, THF 4- (1-Ethoxycarbonyl-but-3-enyl) -peridyl-1-carboxylic acid tert-butyl ester (90; Reaction Scheme XXV). A suspension of sodium hydride (1.50 g, 37.6 mmol) in THF (100 mL) at 0 ° C under nitrogen was carefully treated with triethyl phosphonoacetate (8.12 mL, 37.6 mmol), via syringe. After 30 minutes, the reaction mixture was treated with allyl bromide (3.3 mL, 37.6 mmol), and the resulting mixture was allowed to warm to 25 ° C for 12 hours. The resulting mixture was again cooled to 0 ° C, treated with sodium hydride (1.50 g, 37.6 mmol), and the resulting suspension allowed to stir for 30 minutes at 0 ° C. A solution of 1- (tert-butoxycarbonyl) -4-piperidinone (5.0 g, 25 mmol) in THF (50 mL) was added via a cannula for 10 minutes, and the resulting solution was allowed to warm to 25 ° C. 12 hours. The reaction was quenched by the addition of 15% aqueous sodium bicarbonate (50 mL), and the resulting mixture was diluted with ethyl acetate (100 mL), washed with 15% aqueous sodium bicarbonate (2 x 100 mL) and concentrated in vacuo. Purification by chromatography (0-50% EtOAc / hexanes), gave the title compound (1.93 g, 25%), as a yellow oil: MS (M + H) = 310.

The 4- (1-ethoxycarbonyl-3-methyl-but-3-enylidene) piperidin-1-carboxylic acid tert-butyl ester (91; Reaction Scheme XXV). it was prepared according to the procedure described for 90, except that methylallyl chloride was used instead of allyl bromide.

REACTION SCHEME XXVI Ethyl ester (1-benzyl-p-peridin-4-ylidene) bromoacetic acid (92; Reaction Scheme XXV). A suspension of sodium hydride (1.50 g, 37.6 mmol) in THF (100 mL) at 0 ° C under nitrogen was carefully treated with triethyl phospho-noacetate (8.12 mL, 37.6 mmol) via a syringe. After 30 minutes, the reaction mixture was treated with bromine (1.95 mL, 37.6 mmol) via a dropping funnel for 10 minutes, and the resulting mixture was allowed to stir for 3 hours. The reaction mixture was treated with sodium hydride (1.50 g, 37.6 mmol), and the resulting suspension was allowed to stir for 30 minutes at 0 ° C. A solution of 1-benzylpiperidin-4-one (5.0 g, 25 mmol) in THF (50 mL) was added via a cannula for 10 minutes, and the resulting solution was allowed to warm to 25 ° C for 12 hours. The reaction was quenched by the addition of 15% aqueous sodium bicarbonate (50 mL), and the resulting mixture was diluted with ethyl acetate (100 mL), washed with 15% aqueous sodium bicarbonate (2 x 100 mL). ), and concentrated in vacuo. Purification by chromatography (0-50% EtOAc / hexanes), gave the title compound (6.35 g, 74%) as a red-orange oil: MS (M + = H) = 339. The alcohols listed in Table 6 were prepared in a similar manner as described for 4- (2-hydroxyethylidene) piperidinyl-1-carboxylic acid t-butyl ester (25), except that the corresponding ethylidene carboxylate was used in place of 4- (2- ethoxy-2-oxoethylidene) piperidinyl-1-t-butylcarboxylate (24).

TABLE 6 REACTION SCHEME XXVII 2S: R5 ^ H 103: R5: = H 2S, R5 = F 104: R5 = = F 29: Rgl = CH3 105; R5: = CH3 2-Piperidin-4-ylidene-ethanol trifluoroacetate (103; Reaction Scheme XXVII). A solution of 25 (191 mg, 0.5 mmol) was dissolved in CH2Cl2 (10 mL) and treated with trifluoroacetic acid (0.5 mL) at room temperature. ambient. After 1 hour, the reaction mixture was concentrated in vacuo to give the title compound (64 mg, 100%) as an oil. MS 129 (M + H).

The trifluoroacetate of 2-piperidin-4-ylidene-propan-1-ol (105; Reaction Scheme XXVII). was prepared according to the procedure described for 103, except that 29. MS 142 (M + H) was used.

The trifluoroacetate of 2-fluoro-2-piperidin-4-ylidene-ethanol (104; Reaction Scheme XXVII), was prepared according to the procedure described for 103, except that 28. MS 146 (M + H) was used.

REACTION SCHEME XXVIII 105 10? 4- (2-Ethoxycarbonyloxy-1-fluoroethylidene) piperidin-1-t-butylcarboxylate (106; Reaction Scheme XXVIII). To alcohol 28 (0.5064 g, 2.064 mmol) in CH CI2 (10 mL) at room temperature, pyridine (0.23 mL, 2.8 mmol) and then ethyl chloroformate (0.22 mL, 2.2 mmol) were added. After stirring overnight, saturated aqueous NH CI (10 mL) was added, and the mixture was extracted with CH2Cl2 (5 X 10 mL), dried over Na2SO4, concentrated and chromatographed on silica (20%). of EtOAc / hexane as eluent), to provide the title compound 106 (0.4546 g, 69%) as a clear oil. MS 318 (M + H). 4- (2-Ethoxycarbonylloxy-1-fluoro-ethylidene) -piperidine (107; Reaction Scheme XXVIII). To compound 106 (0.1787 g, 0.5631 mmol) in CH2Cl2 (3 mL) was added TFA (0.56 mL, 7.3 mmol), and the mixture was stirred for 3 hours, whereupon all volatile materials were removed in vacuo to provide the crude title compound, which was used without further purification. MS 218 (M + H).

REACTION SCHEME XXIX 110 4- (1-Chloro-2-oxoethylidene) -piperidine-1-t-butylcarboxylate (108; Reaction Scheme XXIX). To alcohol 30 (6.01 g, 23.0 mmol) in CH2Cl2 at room temperature and open to air, Dess-Martin reagent (21.17 g, 49.9 mmol) was added, and the reaction mixture was stirred overnight, after The mixture was washed with saturated aqueous Na 2 S 2 3 3 (60 mL) and saturated aqueous NaHCO 3 (3 X 30 mL). The organic layer was dried over Na 2 SO 4, concentrated and chromatographed on silica (25% EtOAc / Hexane as eluent) to give the title compound 108 (5.22 g, 88%) as a white crystalline solid. MS 260 (M + H). 4- (1-Chloro-2-propenylidene) piperidin-1-t-butylcarboxylate (109; Reaction Scheme XXIX). Methyltriphenylphosphonium bromide (5.51 g, 15.4 mmol) in THF (40 mL) at 0 ° C was treated with sodium bis (tritymethylsilyl) amide (15.4 mL, 1.0 M in THF), and stirred for 20 minutes , after which compound 108 (2.05 g, 7.89 mmol) in THF (15 mL) was added via a cannula, and the mixture was stirred for 3 hours, warming to room temperature. The mixture was quenched by the addition of saturated aqueous NH 4 Cl (20 mL), and the aqueous layer was extracted with EtOAc (6 X 20 mL). The combined organic layers were dried over Na2SO, concentrated and subjected to chromatography on silica (elution gradient with 0-10% MeOH / CH2CI2), to give the title compound 109 (1.94 g, 96%) as a solid. white crystalline MS 258 (M + H). TFA salt of 4- (1-Chloro-2-propenylidene) piperidine (110; Reaction Scheme XXIX). To compound 109 (0.1415 g, 0.5489 mmol) in CH2Cl2 (5 mL), TFA (0.55 mL, 7.1 mmol) was added and the mixture was stirred for 3 hours, after which all volatile materials were removed in vacuo. The crude title compound thus obtained was used without further purification. MS 158 (M + H). The protected amines listed in Table 7 were prepared in a manner similar to that described for 4-f2- (1,3-dihydro-l, 3-d -oxo-2H-isoindol-2-yl) et Lide] -peridyl-1-t-butylcarboxylate (26). except that the corresponding alcohol was used in place of 4- (2-hydroxyethylidene) piperidinyl-1-t-butylcarboxylate (25).

TABLE 7 The amines listed in Table 8 were prepared in a manner similar to that described for the trifluoroacetate of 4-l "2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethylidene. -1-piperidine (27), except that the corresponding protected amine was used instead of 4-β2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl-inden-1 - piperidinyl-1-t-butyl carboxylate (26).

TABLE 8 REACTION SCHEME XXX 102 120 2- (2-bromo-2-piperidin-4-ylidenethyl) isoindol-1 hydrochloride, 3-dione (120: Reaction Scheme XXX). A mixture of 102 (0.50 g, 1.17 mmol) and 1-chloroethyl chloroformate (0.7 mL, 6.2 mmol) in dichloroethane (10 mL) was heated at reflux temperature for 2 hours. The resulting solution was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in methanol (50 mL) and heated at reflux temperature for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo to give a white solid. The residue was washed with diethyl ether (2x) and dried to provide the title compound (432 mg, 100%), as an orange oil. MS 336 (M + H).

Compounds Z-37 and E-37 of Reaction Scheme XV: (E / Z) -Cloro (1-benzyl-3-pyrrolidinylidene) ethyl acetate (34).

Prepared by the same procedure as in the synthesis of 24, except that 1-benzyl-pyrrolidin-3-one was used in place of 1- (tert-butoxycarbonyl) -4-piperidinone and triethyl 2-chlorophosphonoacetate, triethyl phosphonoacetate. MS 280 (M + H).

(E / Z) -2- (1-Benzyl-3-pyrrolidinylidene) -2-chloroethanol (35). Prepared by the same procedure as in the synthesis of 25, except that 34 was used instead of 24. MS 283 (M + H).

XV REACTION SCHEME &37 (E / Z) -2-r2- (1-Benzyl-3-pyrrolidinylidene) -2-chloroetip-1H-isoindol-1.3 (2H) -dione (E-36 v Z-36). Prepared by the same procedure as in the synthesis of 26, except that 35 (1.58 g) was used instead of 25. The E / Z isomers were separated by MPLC (0-45% ethyl acetate / hexanes), to provide Z-36 (430 mg, MS 367 (M + H)), as a reddish oil and E-36 (420 mg, MS 367 (M + H)) as a reddish oil.

Hydrochloride of the (E) -2-r2-chloro-2- (3-pyrrolidinylidene) etn-1 H-isoindol-1.3 (2H) -dione (E-37). A mixture of E-36 (0.430 g, 1.45 mmol) and 1-chloroethyl chloroformate (0.7 mL, 6.2 mmol) in dichloroethane (10 mL) was heated at reflux temperature for 2 hours. The resulting solution was allowed to cool to room temperature, and concentrated in vacuo. The residue was dissolved in methanol (50 mL) and heated at reflux temperature for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo to give a white solid. The residue was washed with diethyl ether (2x) and dried to give E-37 (200 mg, 50%) as a brown oil. MS 277 (M + H).

Hydrochloride of the (Z) -2-r2-chloro-2- (3-pyrrolidinylidene) ethip-1 H-isoindol-1,3 (2H) -dione (Z-37). Prepared by the same procedure as in the synthesis of E-37, except that Z-36 was used instead of E-36. MS 277 (M + H).

REACTION SCHEME XVI 2S 33 40 t TFA 33 « Compounds 39 and 41 of Reaction Scheme XVI: (E) -4-r2- (1,3-dioxo-1,3-dhydro-2H-isoindol-2-yl) ethylidene-3-hydroxy-piperidinyl-1-t-butylcarboxylate (38). A suspension of SeSO2 (0.5 g, 6.06 mmol) in CH2Cl2 (5 mL) at 0 ° C was treated with tert-butyl hydroperoxide (2.5 mL, 9.09 mmol, 5-6 M, 10% in undecane) via a syringe . After 20 minutes, the reaction mixture was treated with a solution of ethylidene 26 (1.44 g, 4.04 mmol) in CH 2 Cl 2 (15 mL), and the resulting mixture was allowed to stir for 12 hours at room temperature. The reaction was carefully quenched by the addition of 15% aqueous sodium thiosulfate (15 mL), and the reaction mixture was diluted with CH2Cl2 (25 mL). The layers were separated, and the organic layer was washed with 15% aqueous sodium thiosulfate (15 mL), dried (MgSO 4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-75% ethyl acetate / hexanes), gave the title compound 38 (0.51 g, 33%) as a white solid. MS 373 (M + H).

(E) -4-y2- (1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethylidene-3-hydroxypiperidine (39). Prepared by the same procedure as in the synthesis of 27, except that 38 was used instead of 26. MS 273 (M + H).

(E) 4-β2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethylidene-3-methoxyimino-piperidinyl-1-t-butylcarboxylate (40). A solution of 38 (0.51 g, 1.37 mmol) in CH2Cl2 (15 mL) at 25 ° C was treated with Dess-Martin periodinane (0.254 g, 0.60 mmol). After 1 hour, the reaction mixture was diluted with CH2Cl2 (25 mL), washed with 10% aqueous NaHCO3 (3 x 25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was used in the next step without further purification. A solution of the residue in pyridine (6 mL) in methanol (36 mL) at 25 ° C was treated with methoxyamine hydrochloride (0.835 g, 6.0 mmol). After 2 minutes, the reaction mixture was heated to reflux for 5 hours, diluted with ethyl acetate (25 mL), washed with 10% aqueous NaHCO 3 (3 x 25 mL), dried (MgSO 4), filtered and concentrated in vacuo to give 40 (230 mg, 42%) as an orange residue. The residue was used in the next step without further purification. MS 400 (M + H).

(E) -4-22- (1,3-dioxo-1,3-dihydro-2H-α-butol-2-yl) ethylidene-3-methoxyimino-piperidine (41). Prepared by the same procedure as in the synthesis of 27, except that 40 was used instead of 26. MS 300 (M + H).

REACTION SCHEME XVII 23 AZ 43 Compound 43 of Reaction Scheme XVII: (Z) -4-f2-1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-methylethylidene-3-hydroxy-piperidinyl-1-t-butylcarboxylate (42). A suspension of Se02 (1.3 g, 11.4 mmol) in CH2Cl2 (15 mL) at 0 ° C was treated with tert-butyl hydroperoxide (4 mL, 22 mmol, 5-6 M, 10% in undecane) via syringe . After 20 minutes, the reaction mixture was treated with a solution of ethylidene 29 (3.4 g, 9.1 mmol) in CH 2 Cl 2 (15 mL), and the resulting mixture was allowed to stir for 12 hours at room temperature. The reaction died 6 carefully by the addition of 15% aqueous sodium thiosulfate (15 mL), and the reaction mixture was diluted with CH2Cl2 (25 mL). The layers were separated, and the organic layer was washed with 15% aqueous sodium thiosulfate (15 mL), dried (MgSO 4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-75% ethyl acetate / hexanes), gave the title compound 42 (1.2 g, 34%) as a white solid. MS 387 (M + H).

(Z) -4-f2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1-methyl-ethyl-3-hydroxy-piperidine (43). Prepared by the same procedure as in the synthesis of 27, except that 42 was used instead of 26. MS 287 (M + H).

REACTION SCHEME XVIII A7? 3 Compound 48 of Reaction Scheme XVIII: The t-butyl-3-fluoro-4-oxopiperidinyl-1-carboxylate (44) was prepared according to the patent of E.U.A. 5837715.

(E / Z) -4- (2-Ethoxy-2-oxoethyl-diene) -3-fluoropiperidinyl-1-carboxylic acid t-butyl ester (45). Prepared by the same procedure as in the synthesis of 24, except that 44 was used instead of 1- (tert-butoxycarbonyl) -4-piperidinone. MS 288 (M + H).

(E / Z) -4- (2-Hydroxyethylidene) -3-fluoropiperidinyl-1-t-butylcarboxylate (46). Prepared by the same procedure as in the synthesis of 25, except that 45 was used instead of 24. MS 246 (M + H).

(E / Z) -4-r2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethylidene-3-fluoro-piperidinyl-1-t-butylcarboxylate (47). Prepared by the same procedure as in the synthesis of 26, except that 46 was used instead of . MS 375 (M + H).

(E / Z) -4-y2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethylidene-3-fluoropiperidine trifluoroacetate (48). Prepared by the same procedure as in the synthesis of 27, except that 47 was used instead of 26. MS 275 (M + H).

REACTION SCHEME XIX Compounds Z-53 and E-53 of Reaction Scheme XIX: 1 - . 1 -1"ethyl 3-methyl-1 - (phenylmethyl) -4-piperidinylidene-1-fluoroacetate (50), prepared by the same procedure as in the synthesis of 24, except that 49 was used instead of 1- (tert-butoxycarbonyl) -4-piperidinone and triethyl 2-fluorophosphonoacetate was used in place of triethyl phosphonoacetate MS 292 (M + H). 2-l3-Methyl-1- (phenylmethyl) -4-piperidinyl-adenine-2-fluoroethanol (E-51 and Z-51). A solution of 50 (2.68 g, 9.19 mmol) in tetrahydrofuran (50 mL) at 0 ° C was treated with a Super-Hydride ™ solution (23 mL, 23 mmol, 1.0 M in tetrahydrofuran, Aldrich) under nitrogen. After 1 hour, the reaction mixture was carefully treated with methanol (10 mL), diluted with ethyl acetate (50 mL), washed with 10% aqueous NaHCO3 (3 x 50 mL), dried (MgSO4) and concentrated in vacuo. Purification by MPLC (silica gel, 0-50% ethyl acetate / hexanes), provided the Z 51 isomer (0.84 g, 37%) (MS 250 (M + H)), as a colorless oil and the isomer E 51 (0.97 g, 42%) (MS 250 (M + H)) as a colorless oil.

(Z) -2-22- (3-methyl-1- (phenylmethyl) -4-piperidinylidenyl) -2-fluoroethanol-1 H-isoindole-1,3 (2H) -dione (Z-52). Prepared by the same procedure as in the synthesis of 26, except that Z-51 was used instead of 25. MS 379 (M + H) ..}.

(E) -2-f2- (3-methyl-1- (phenylmethyl) -4-piperidinylidene) -2-fluoroethyl-1 H-isoindole-1,3 (2H) -dione (E-52) . Prepared by the same procedure as in the synthesis of 26, except that E-51 was used instead of 25. MS 379 (M + H).

Hydrochloride of (Z) -2-f2-fluoro-2- (3-methyl-4-piperidinylidenyl) -etin-1 H-isoindol-1,3 (2H) -dione (Z-53). A mixture of Z-52 (0.550 g, 1.45 mmol) and 1-chloroethyl chloroformate (0.63 mL, 5.8 mmol) in dichloroethane (15 mL) was heated at reflux temperature for 2 hours. The resulting solution was allowed to cool to room temperature, and concentrated in vacuo. The residue was dissolved in methanol (50 mL) and allowed to warm to reflux temperature for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo to give a white solid. The residue was washed with diethyl ether (2x) and dried to give Z-53 (260 mg, 55%) as a white solid. MS 289 (M + H).

Hydrochloride of (E) -2-f2-fluoro-2- (3-methyl-4-piperidinyl) adenyl-1 H-isoindol-1,3 (2H) -dione (E) -53). Prepared by the same procedure as in the synthesis of Z-52, except that E-52 was used instead of Z-52. MS 289 (M + H).

REACTION SCHEME XX 58 4- (2-Oxo-propylidene) piperidine-1-carboxylic acid tert-butyl ester (54). Prepared by the same procedure as described in International Patent Publication WO0285901. 4- (1-Chloro-2-oxo-propylidene) piperidine-1-carboxylic acid tert-butyl ester (55). A suspension of tetrabutylammonium chloride (11.1 g, 40.1 mmol) in CH2Cl2 (50 mL) at 25 ° C was treated with 1,1,1-tris (acetyloxy) -1, 1-dihydro-1,2-benzophoxy. 3 (1 H) -one (17.0 g, 40.1 mmol), and the resulting light yellow solution was allowed to stir for 10 minutes. The reaction mixture was treated with a solution of 54 in CH2Cl2 (50 mL), and the resulting solution was allowed to stir for 3 hours. The light yellow solution was carefully poured into a 10% aqueous solution of sodium bicarbonate (100 mL), diluted with CH2Cl2 (50 mL), to induce precipitation, filtered and the precipitate was discarded. The resulting clear solution was washed with a 10% aqueous solution of sodium bicarbonate (1 x 100 mL), brine (1 x 100 mL), dried (MgSO 4), and concentrated in vacuo. Purification by MPLC (0-40% ethyl acetate / hexanes) gave 55 (1.24 g, 34%) as a colorless oil. MS 274 (M + H). 1-Chloro-2-hydroxypropylidene) piperidine-1-carboxylic acid tert-butyl ester (56). A solution of 55 (1.24 g, 4.53 mmol) in ethanol (25 mL) was treated with sodium borohydride (102 mg, 2.72 mmol) at 25 ° C. After 1 hour, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (40 mL), treated carefully with 5% aqueous hydrochloric acid (1 x 25 mL), the layers separated and dried ( MgS0). The resulting solution was concentrated in vacuo to give 56 (902.1 mg, 72%) as a colorless residue, which was used without further purification. MS 298 (M + Na). 4-F1-chloro-2- (1,3-dioxo-1,3-dihydro-isondol-2-yl) propylidene-piperidin-1-carboxylic acid tert-butyl ester (57). Prepared by the same procedure as in the synthesis of 26, except that 56 was used instead of 25. MS 427 (M + Na). 2-r (2-chloro-1-methyl-4-piperidinylidene) etn-1 H-isoindol-1,3 (2H) -dione (58). Prepared by the same procedure as in the synthesis of 27, except that 56 was used instead of 26. MS 305 (M + H).

REACTION SCHEME XXXI 1-H-Ethyl diphenylmetilazetdin-3-ylidene-1-fluoroacetate (122: R.g = F). Triethyl 2-fluoro-2-phosphonoacetatic acid (0.63 mL, 3.10 mmol) was added to NaH (60% in oil, 115 mg, 2.87 mmol) in anhydrous THF (6 mL) at 0 ° C. After stirring for 15 minutes, a solution of ketone 121 (562 mg, 2.37 mmol) in anhydrous THF (6 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO 3 (2 x 100 mL), dried (MgSO 4), filtered and concentrated in vacuo. The crude material was subjected to chromatography (100% CH2Cl2) to provide ester 122 (R5 = F) as a yellow oil (392 mg, 66%). MS 326 (M + H). 1- [1-Diphenylmetilazetidin-3-ylidene-ethyl chloroacetate (123; = Cl). This was prepared in a manner similar to the procedure described above, except that triethyl 2-chloro-2-phosphonoacetate was used in place of triethyl 2-fluoro-2-phosphonoacetate in the reaction. Ester 123 (R5 = Cl) was isolated as a white solid (77%). MS 342.344 (M + H). 2- (1-Diphenylmethylazetidin-3-ylidene) -2-fluoroethanol (124; Rg = F). DIBAL (1M in toluene, 4.2 mL, 4.2 mmol) was added to a solution of ester 122 (R5 = F) (510 mg, 1.56 mmol) in toluene (8 mL) at -78 ° C for several minutes. The reaction was stirred for 5 hours and then quenched by the slow addition of a solution of methanol in toluene. The reaction was diluted with ethyl acetate (100 mL), washed with NaOH (1 N, 2 x 50 mL), water (50 mL), dried (MgSO) and concentrated in vacuo to provide alcohol 124 (R s). = F, 289 mg, 65%) as a pale yellow solid after trituration with ether / hexanes. MS 284 (M + H). 2- (1-Diphenylmethiazetidin-3-ylidene) -2-chloroethanol (125; Rg = Cl). This was prepared in a manner similar to the procedure described above, except that ester 123 (R5 = Cl) was used in place of ester 122 (R5 = F). Alcohol 125 (R5 = Cl) was isolated by chromatography (20% ethyl acetate / hexanes) as a white solid (53%). MS 300, 302 (M + H). 2-r2- (1-Diphenylmetilazetidin-3-ylidene) -2-fluoroetipisoindole-1,3-dione (126; Rg = F). DIAD (0.89 mL, 4.489 mmol) was added to a solution of alcohol 124 (R5 = F) (1.00 g, 3.533 mmol), triphenyl phosphine (1.14 g, 4.34 mmol) and phthalimide (0.648 g, 4.527 mmol) in anhydrous THF (30 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 36 hours. The volatiles were evaporated and the residue was chromatographed on silica gel (5% ethyl acetate / hexanes) to give phthalimide 126 (R5 = F) (952 mg, 65%) as a white solid. MS 413 (M + H). 2-í2- (1-Diphenylmetilazetin-3-ylidene) -2-chloroetinisoindole-1,3-dione (127; Rp = Cl). This was prepared in a manner similar to the procedure described above, except that alcohol 125 (Rs = Cl) was used instead of alcohol 124 (R5 = F) in the Mitsunobu reaction. Phthalimide 127 (R5 = Cl) was isolated by chromatography (15% ethyl acetate / hexanes) as a white solid (68%). MS 429, 431 (M + H). 2- (2-Azetidin-3-ylidene-2-fluoroethyl) isoindol-1,3-dione hydrochloride (128: Rg = F). Phthalimide 126 (R5 = F) (350 mg, 0.8491 mmol) and ACE-CI (0.50 mL, 4.65 mmol) in 1,2-dichloroethane (20 mL) were heated at reflux temperature under a nitrogen atmosphere for 24 hours. hours. After cooling, the volatiles were evaporated and methanol (25 mL) was added to the resulting residue. This was heated at reflux temperature for 3 hours, after which the methanol was evaporated to provide 128 (Rs = F) as a beige powder (230 mg, 96%). MS 247 (M + H). 2- (2-Azetidin-3-ylidene-2-chloroethyl) isoindol-, 3-dione (129; Rg = Cl) hydrochloride. This was prepared in a manner similar to the procedure described above, except that phthalimide 127 (R5 = Cl) was used in place of phthalimide 126 (R5 = F) in the reaction. The compound was isolated as a white powder (86%). MS 263, 265 (M + H).

REACTION SCHEME XXXII fc Rd * F 130: R5 = F 132; 144-147: R5 = f: R3 = Cl 131: Rβ = Cf 133; 136-143: R5 = Ci 4- (1,2-Dichloroethylidene) piperidinyl-1-t-butylcarboxylate (131: Rg = Cl). A solution of 30 (R5 = Cl) (4.24 g, 16.20 mmol)) and triethylamine (6.8 mL, 48.60 mmol) in CH2Cl2 (120 mL) was treated with methanesulfonyl chloride (1.9 mL, 24.30 mmol) at 0 ° C. , then it was warmed to room temperature and stirred overnight. The resulting mixture was quenched by the addition of saturated aqueous NaHCO3 (100 mL), and the product was extracted into CH2Cl2. Purification by flash chromatography (0-20% ethyl acetate / hexanes) gave the title compound (3.1 g, 68%) as a white solid. , 4- (2-Chloro-1-fluoroethylidene) piperidinyl-1-t-butylcarboxylate (130; R.g = F). This was prepared in a manner similar to the procedure described above, except that alcohol 28 (R5 = F) was used in place of alcohol 30 (R5 = Cl). 4- | "2- (N-benzyl-N-methylamino) -1-chloroethylidene piperidinyl-1-t-butylcarboxylate (133; Rg = Cl; Rg = methyl; Rio = benzyl) A solution of 131 (R5 = Cl ) (600 mg, 2.14 mmol)) and triethylamine (1.5 mL, 10.71 mmol) in acetonitrile (18 L) was treated with N-benzylmethylamine (0.45 mL, 3.43 mmol) at room temperature and stirred overnight. It was concentrated in vacuo, and the residue was diluted with ethyl acetate (20 mL), washed with water (2 x 10 mL), and dried (MgSO 4). Purification by flash chromatography (0-15% acetate). ethyl / hexanes), gave the title compound (690 mg, 88%) as a white solid MS 365 (M + H). 4-r2- (N-benzyl-N-methylamino) -1-fluoroethylidenepiperidinyl-1-t-butylcarboxylate (132; Rg = F; Ra = methyl; R n = benzyl) This was prepared in a manner similar to the procedure described above, except that chloride 130 (R5 = F) was used instead of chloride 131 (R5 = Cl). MS 349 (M + H).

N-Benzyl-N-methy1- (2-chloro-2-pperidin-4-ylden) ethylamine (135, Rg = Cl). A solution of 133 (R5 = Cl) (690 mg, 1.89 mmol) was dissolved in CH2Cl2 (15 mL) and treated with trifluoroacetic acid (1.5 mL) at room temperature. After 5 hours, the reaction mixture was concentrated in vacuo to give the title compound (quantitative) as an oil, which was used in the next step without further purification. MS 265 (M + H).

N-Benzyl-N-methy1- (2-fluoro-2-pyridin-4-ylidene) ethylamine (134, Rg = F). This was prepared in a manner similar to the procedure described above, except that the amine 132 (R5 = F) was used in place of the amine 133 (R5 = Cl). MS 249 (M + H). Table 9 lists the protected Boc amines (136-147) and the derived amines (148-159), prepared by procedures analogous to those detailed above.

PICTURE XX Preparation of the final product 7- [4- (2-Amino-1-fluoro-ethylidene) piperidin-1-yl-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydronaphthyridine-3-carboxylic acid (1). A solution of amine 31 (612 mg, 1.57 mmol) and triethylamine (0.7 mL, 5.0 mmol) in acetonitrile (4 mL) was treated with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1 acid. , 4-dihydro-naphthypyridine-3-carboxylic acid (222 mg, 0.787 mmol) under nitrogen and the reaction mixture was allowed to stir for 12 hours. The resulting mixture was concentrated in vacuo, and the residue was washed with water (3 x 10 mL). The residue was allowed to dry for 15 minutes. The solid was collected, resuspended in methanol (5 mL) and the reaction mixture was treated with hydrazine (1 mL). After 5 minutes, the reaction mixture was heated to reflux and the resulting mixture was allowed to stir for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water and the solids were collected by filtration. The mat white product was washed with water (3 x 20 mL), allowed to dry overnight to provide compound 1 of title 1 (40.4 mg, 13%). MS 391 (M + H).

Salt of trifluoroacetic acid acid 7-- (2-amino-1-fluoro-ethylidene) piperidin-1 -yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 5). A solution of amine 31 (311 mg, 0.80 mmol) and triethylamine (0.55 mL, 4.0 mmol) in acetonitrile (4 mL) was treated with diacetyl quinolinyl borate 17 (300 mg, 0.60 mmol) under nitrogen. After 5 minutes, the reaction mixture was heated to reflux and the reaction mixture was allowed to stir for 12 hours. The resulting mixture was allowed to cool to room temperature, concentrated in vacuo, and the residue was washed with water (3 x 10 mL). The residue was dissolved in tetrahydrofuran (3 mL) and treated with 10% aqueous hydrochloric acid (5 mL) at room temperature. After 30 minutes, the reaction mixture was concentrated in vacuo, it was diluted with water (10 minutes) and the solid was collected by filtration. The solid residue was washed with water (3 x 5 mL) and allowed to dry for 15 minutes. The solid was collected and resuspended in methanol (5 mL) and the reaction mixture was treated with hydrazine (1 mL). After 5 minutes, the reaction mixture was heated to reflux temperature and the resulting mixture was allowed to stir for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (reverse phase C-18 column, 0-55% acetonitrile / water containing 0.1% trifluoroacetic acid), to provide the trifluoroacetic acid sai of 5%. (61.3 mg, 20%) as a light yellow solid. MS 390 (M + H). 7-R3- (2-amino-1-fluoro-ethylidene) azetidin-1-yl-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-M, 81-naphthyridine-3-carboxylic acid (80) . 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydronaphthyridine-3-carboxylic acid (57 mg, 0.2016 mmol), amine 128 (R = F) (67 mg, 0.2389) mmoles) and triethylamine (0.5 mL) in acetonitrile (10 mL) were heated at reflux temperature overnight. After cooling, the volatiles were evaporated and the residue was suspended in water (25 mL). The resulting solid was collected by filtration and dried. Ethanol (5 mL) was added to the solid followed by hydrazine (0.01 mL, 0.3138 mmol). The reaction mixture was heated to reflux temperature for 1 hour, after which the volatiles were evaporated. Water (15 mL) was added to the residue and the resulting solid was collected by filtration, washed with additional water and dried to give 87 (49.1 mg, 69%) as a white matte powder. MS 363 (M + H). 7-R3- (2-amino-1-fluoro-ethylidene) azetidin-1-yn-1-cyclopropyl-8-di-fluoro-methoxy-6-fluoro-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (160). A solution of amine 128 (R5 = F) (83 mg, 0.2923 mmole), diacetyl quinolinyl borate 83 (111 mg, 0.2413 mmole) and triethylamine (0.5 mL) in acetonitrile (10 mL), was heated to reflux temperature overnight. The volatiles were evaporated and then THF (5 mL) and 10% aqueous HCl (4 mL) were added to the residue. This mixture was stirred for about 1 hour. The resulting solid was collected by filtration, washed with water and dried. Ethanol (4 mL) and hydrazine (0.01 mL) were added to the solid and the reaction was heated at reflux temperature for 1.5 hours. The ethanol was evaporated in vacuo and (20 mL) was added to the remaining material. The solid was collected and dried to provide 160 as a yellow solid (20%). MS 428 (M + H).

Salt of trifluoroacetic acid acid 7- (4-r2- (N-benzyl-N-methylamino) -1-chloroethylidejpiperidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1,4-dihydro-quinoline-3-carboxylic acid (161) A solution of amine 135 (1.89 mmol) and triethylamine (1.2 mL, 8.59 mmol) in acetonitrile (15 mL) was treated with diacetyl quinolinyl borate 19 (727 mg, 1.72 mmol) under nitrogen. After 5 minutes, the reaction mixture was heated to reflux temperature and the reaction mixture was allowed to stir for 24 hours. The resulting mixture was allowed to cool to room temperature, and then concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), treated with 10% aqueous hydrochloric acid (5 mL) at room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was purified by HPLC (reverse phase C-18 column, 30-90% acetonitrile / water containing 0.1% trifluoroacetic acid), to provide the trifluoroacetic acid salt of 161 ( 632 mg, 56%) as a yellow solid. MS 540 (M + H).

Acid 7-. { 4-r2- (N-benzyl-N-methylamino) -1-chloroethylidene | piperidin-1-yl} -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-f1,8] naphthyridine-3-carboxylic acid (162) A solution of amine 135 (0.48 mmole) and triethylamine (0.28 mL, 2.0 mmole) in acetonitrile (7 mL), treated with 7-cyoro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid (113 mg, 0.40 mmol) under nitrogen. After 5 minutes, the reaction mixture was heated to reflux temperature and the reaction mixture was allowed to stir for 24 hours. The resulting mixture was allowed to cool to room temperature, concentrated in vacuo and the residue was diluted with water. The product was collected by filtration, and then washed with water and a small amount of methanol, to give the title compound (178 mg, 87%) as a white solid. MS 511 (M + H). 7-f4- (2-Hydroxyethylidene) pyrimidn-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydronaphthyridine-3-carboxylic acid (163). A solution of amine 103 (256 mg, 1.06 mmol) and triethylamine (0.5 mL, 3.55 mmol) in acetonitrile (4 mL) was treated with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo- 1,4-dihydro-naphthyridine-3-carboxylic acid (200 mg, 0.71 mmol) under nitrogen and the reaction mixture was allowed to stir for 16 hours. The resulting mixture was concentrated in vacuo, and the residue was washed with water (3 x 10 mL), and allowed to dry overnight to give the title compound 163 (105 mg, 40%). MS 374 (M + H). 7- [- (Hydroxyethylidene) piperidn-1-yl-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (164). A solution of amine 103 (146 mg, 0.61 mmol) and triethylamine (0.55 mL, 4.0 mmol) in acetonitrile (4 mL) was treated with diacetyl quinolinyl borate 17 (125 mg, 0.60 mmol) under nitrogen. After 5 minutes, the reaction mixture was heated to reflux temperature and the reaction mixture was allowed to stir for 12 hours. The resulting mixture was allowed to cool to room temperature, concentrated in vacuo, and the residue was washed with water (3 x 10 mL). The residue was dissolved in tetrahydrofuran (3 mL) and treated with 10% aqueous hydrochloric acid (5 mL) at room temperature. After 30 minutes, the reaction mixture was concentrated in vacuo, diluted with water (10 minutes) and the solid was collected by filtration. The solid residue was washed with water (3 x 5 mL) and allowed to dry for 15 minutes. The solid was collected to give 157 (5.1 mg, 2.2%) as a light yellow solid. MS 373 (M + H). Table 4 illustrates the additional compounds of the present invention by the experimental procedures detailed above. In the case of naphthyridines 2-4, 59-63, 69 and 173-176, an experimental procedure analogous to that of compound 1 in its preparation was used. For the naphthyridines 171, 172 and 185, a procedure analogous to that of 163. was used. For the naphthyridines 81, 183 and 184, an experimental procedure similar to that of 80 was used. For naphthyridines 165-170, 177-182 and 186, a procedure similar to that of 162 was used in its preparation. For the quinolones 6-15, 64-66, 70, 71, 73, 78, 187, 188, 201-204, 206-208 and 210, an experimental procedure analogous to that of compound 5 was used in its preparation. For quinolones 76, 77, 189, 205 and 209, a procedure analogous to that of 160 was used in their preparation. For quinolones 190-200, a procedure analogous to that of 161. was used. For quinolone 211, a procedure similar to that of 163 was used in its preparation.

TABLE 4 TABLE 4 continued REACTION SCHEME XXXIII ambient Salt of trifluoroacetic acid of 7-r4- (1-chloro-2-methylamidenoxyden) piperidin-1-in-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (72) A solution of 154 (160 mg, 0.24 mmol), was dissolved in 1,2-dichloroethane (4 mL) and treated with 1-chloroethyl chloroformate (0.8 mL, 7.3 mmol ) under nitrogen. After 5 minutes, the reaction mixture was heated to reflux temperature and the reaction mixture was allowed to stir for 3 hours. The resulting mixture was allowed to cool to room temperature, and then concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), adjusted to pH > 7 by the addition of NaHCO3 and water at room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was purified by HPLC (reverse phase C-18 column, 35-90% acetonitrile / water containing 0.1% trifluoroacetic acid), to provide the trifluoroacetic acid salt of 72 ( 37 mg, 27%) as a yellow solid. MS 450 (M + H). Table 10 lists the final products (74, 75, 79, 213-220) prepared by a procedure analogous to the previous one.

TABLE 10 REACTION SCHEME XXXIV Salt of trifluoroacetic acid of 1-cyclopropyl-6-fluoro-8-methoxy-7-y4- (2-methylaminoethylidene) piperidin-1-n-4-oxo-1,4-dihydroquinoline-3 -carboxylic (221). A solution of 161 (70 mg, 0.11 mmol) in methanol / formic acid (volume / volume = 20/1) (14 mL) was treated with 10% Pd / C (35 mg, 7.3 mmol) under nitrogen at room temperature. environment for 3 hours. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by HPLC (reverse phase C-18 column, 35-90% acetonitrile / water containing 0.1% trifluoroacetic acid), to provide the trifluoroacetic acid salt of 221 (8.3 mg, 15%) as a solid yellow. MS 416 (M + H).

REACTION SCHEME XXI 3 6B A solution of amine 31 (534 mg, 1.94 mmol), quinolone 67 (587 mg, 1.46 mmol) (prepared as described in EP1031569), cesium carbonate (717 mg, 2.2 mmol), (1S) was treated. ) - [1,1'-binaphthalene] -2,2'-diilbys [d-phenylphosphine] (137 mg, 0.22 mmole) in toluene (75 mL) with Pd2 (dba) 3 (66 mg, 0.072 mmol) and the reaction mixture was heated to reflux. After 12 hours, the resulting mixture was allowed to cool to room temperature, concentrated in vacuo, and the residue was washed with water (3 x 10 mL). Purification by MPLC (0-100% ethyl acetate / hexanes) gave a yellow residue. The residue was dissolved in concentrated hydrochloric acid (5 mL) and heated to reflux. After 3 hours, the reaction mixture was concentrated in vacuo, diluted with water (10 minutes) and the solid was collected by filtration. The solid residue was washed with water (3 x 5 mL) and allowed to dry for 15 minutes. The solid was collected and resuspended in methanol (5 mL) and the reaction mixture was treated with hydrazine (1 mL). After 5 minutes, the reaction mixture was heated to reflux and the resulting mixture was allowed to stir for 1 hour. The reaction mixture was concentrated in vacuo and purified by HPLC (reverse phase C-18 column, 0-55% acetonitrile / water containing 0.1% trifluoroacetic acid), to provide the trifluoroacetic acid salt of the title compound 68 (75 mg, 12%) as a light yellow solid. MS 438 (M + H).

REACTION SCHEME XXXV 7- [4- (2-Acetylamino-ethylidene) -piperidn-1-yl-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1, 81-naphthyridine-3-carboxylic acid (222). A mixture of 59 (25 mg, 0.067 mmol) and acetic anhydride (94 μL, 0.100 mmol) in pyridine (1 mL) was allowed to stir for 12 hours at 25 ° C. The resulting mixture was concentrated in vacuo, and the residue was washed with water (3 x 10 mL) and allowed to dry overnight to give the title compound 222 (15 mg, 54%). MS 415 (M + H).

Biological activity The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals. The minimum inhibitory concentration (MIC) has been an indicator of the in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method, followed by the test method of the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in NCCLS Document M7-A4, Vol. 17, No. 2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically - Fourth Edition", which is incorporated herein by reference. In this method, twice-serial dilutions of the drug in Mueller-Hinton broth adjusted by the cation were added to the wells in microdilution plates. The test organisms were prepared by adjusting the turbidity of the actively growing broth cultures, so that the final concentration of the test organism after being added to the wells is approximately 5 x 104 CFU / well. After inoculation of the microdilution plates, the plates were incubated at 35 ° C for 16-20 hours and then read. MIC is the lowest test compound concentration that completely inhibits the growth of the test organism. The amount of growth in the wells containing the test compound was compared to the amount of growth in the growth control wells (non-test compound) used in each plate. As shown in Table 5, the compounds of the present invention were tested against a variety of pathogenic bacteria, which resulted in a range of activities depending on the organism tested. 7 TABLE 5 MIC values (μg / mL) of some compounds of the present invention (A: Staphylococcus aureus OC4172; strains B, C and D are clinical isolates resistant to the fluoroquinolone of Streptococcus pneumoniae, which contain different constellations of amino acid substitutions. in the QRDR region: E: Streptococcus pneumoniae ATCC 49619) "ND = not determined

Claims (15)

1 9 NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has a structure according to the Formula Formula I wherein: n is an integer from 1 to 3; m is an integer from 1 to 3; z is an integer from 0 to 3; R is selected from hydrogen, hydroxy and alkoxy; R2 is hydrogen; R3 and R4 are independently selected from hydrogen, halogen, amino, hydroxy, alkoxy, alkylthio, alkyl, alkenyl and alkynyl; R5 is selected from hydrogen, hydroxy, halogen, alkyl, aryl, alkoxy and alkylthio; Re is independently selected from alkyl, hydroxy, alkoxy, alkylthio, alkenyl, alkynyl, aryl, alkoxyimino and halogen; or R5 and R6 join to form a 4- to 7-membered carbocyclic ring, wherein each ring carbon atom may be optionally substituted with R12, wherein R12 is selected from the group consisting of halogen, amino, hydroxy, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, oxo, alkoxyimino and hydroxyimino; E is selected from the group consisting of: 1) where, q is an integer from 1 to 3; R7 and R8 are each independently selected from hydrogen and alkyl, or R7 and R8 join to form a 3 to 6 membered carbocyclic ring, or either R or Rs can independently bind to either Rg or Rio to form a heterocyclic ring containing a nitrogen atom to which Rg or Rio are attached, wherein Rg and Rio are each independently selected from hydrogen, alkyl, acyl, alkoxycarbonyl or sulfonyl, or alternatively Rg and R-io are joined to form a heterocyclic ring containing the nitrogen atom to which they are attached; 2) where, q is as defined above; R and Rs are each independently selected from hydrogen and alkyl, or R and R8 are joined to form a 3-6 membered carbocyclic ring, and Rg is selected from hydrogen, alkyl, acyl, alkoxycarbonyl or sulfonyl; and 3) alkenyl; A is selected from N and C (R- ??), wherein R-p is selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, alkylthio and cyano; X is selected from C and N, where if X is C, a is a double bond and b is a single bond, and if X is N, a is a single bond and b is a double bond; and Y is selected from N (R-?) and C (R-?), with the proviso that when Y is N (R?), X is C and when Y is C (R-?), X is N , wherein R1 is selected from C3 to C6 cycloalkyl, C4 to C6 heterocycloalkyl, alkyl, alkene, a 6-membered aryl and a 6-membered heteroaryl; with the proviso that if A is C (Rn), X is C and Y is N (R-?), then Rn and Ri can join to form a 6-membered heterocyclic ring, or if A is C (Rn), X is C and Y is N (R-?), Then R2 and Rt can join to form a monocyclic or bicyclic heterocyclic ring, or if A is C (Rn), X is C and Y is N (R-?), then R2 and R can be joined to form a 5-membered heterocyclic ring; or an isomer, diastereomer or optical enantiomer thereof; a pharmaceutically acceptable salt, hydrate or prodrug thereof.

2. The compound according to claim 1, further characterized in that A is C (OCH3), C (OCHF2) or N.

3. The compound according to claim 1, further characterized in that Y is N (R? ) and Ri is selected from C3 to C6 cycloalkyl.

4. The compound according to claim 1, further characterized in that E is

5. The compound according to claim 1, further characterized in that m is 1 and n is 1 or m is 2 and n is 2.

6. The compound according to claim 1, further characterized in that z is 0 or Re is methyl and z is 1.

7. The compound according to claim 4, further characterized in that R7 and R8 are hydrogen.

8. The compound according to claim 7, further characterized in that q is 1.

9. The compound according to claim 8, further characterized in that Rg is hydrogen, methyl or ethyl and R-io is hydrogen.

10. The compound according to claim 1, further characterized in that it is selected from the group consisting of:

11. - The compound according to claim 1, further characterized in that it has the formula:

12. - The compound according to claim 1, further characterized in that it has the formula:

13. - The compound according to claim 1, further characterized in that it has the formula:

14. - The use of the compound defined in claim 1, for preparing a medicament for treating a subject having a condition caused or contributing to a bacterial infection.

15. - The use of a compound as defined in claim 1, for preparing a medicament for preventing a subject from suffering from a condition caused by or contributing to a bacterial infection.