MXPA00004226A - 2-halo-6-o-substituted ketolide derivatives - Google Patents

Abstract

Novel 2-halo-6-O-substituted ketolide derivatives and pharmaceutically acceptable salts and esters thereof having antibacterial activity having formula (I) or (II), compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, a method for treating bacterial infections by administering to a mammal a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention, and processes for their preparation.

Description

DERIVATIVES OF QUETOLITO 2-HALO-6-O-SUBSTITUIDOS Technical Field This invention relates to novel semi-synthetic macrolites having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a method of medical treatment. More particularly, the invention relates to novel substituted 2-halo-6-O quetolite derivatives, methods for preparing them, compositions containing these compounds, and a method of treating bacterial infections with such compositions.

BACKGROUND OF THE INVENTION Erythromycins A to D, represented by the formula (AND), (E) are powerful and well-known antibacterial agents, widely used to treat and prevent bacterial infections. However, as with other antibacterial agents, bacterial strains that have resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram negative bacteria. Therefore, there is a continuing need to identify new compounds derived from erythromycin which possesses an improved antibacterial activity, which has less potential to develop resistance, which possesses the desired negative Gram activity, or which possesses an unexpected selectivity against the target microorganisms. Consequently, numerous investigators have prepared erythromycin chemical derivatives in an attempt to obtain analogs having modified or improved profiles of antibiotic activity. Morimoto et al. describe the preparation of 6-O-methyl erythromycin A in J. Antibiotics, 37: 1 87 (1984). Morimoto et al. further describe the 6-O-alkyl erythromycin A derivatives in J. Antibiotics, 43: 286 (1990) and in the U.S. Patent. No. 4, 990,602. U.S. Patent No. 5,444,051 discloses some 6-O-substituted-3-oxoerythromycin A derivatives. PCT application WO 97/1 0251, published March 20, 1997, discloses useful intermediates for the preparation of derivatives of 6-O-methyl-3-descladose erythromycin. U.S. Patent No. 5,403,923 discloses some tricyclic 6-O-methyl erythromycin A derivatives (Asaka, TAISHO) corresponding to PCT application WO 92/09614 published June 1, 1992, and US Pat. United 5, 631, 355 discloses some erythromycin derivatives of 6-O-methyl-3-oxo tricyclic. The Patent of E. U. No. 5, 527, 780 discloses some 6-O-methyl-3-oxo bicyclic erythromycin A derivatives (Agouridas, ROUSSEL) corresponding to the application EP 596802, published May 1, 1994. The PCT application WO 97/1 7356, published May 5, 1997, describes the tricyclic 6-O-methyl erythromycin A derivatives. Some intermediates to the present invention are described in U.S. Patent Application Serial No. 08/888, 350. Some 6-O-methyl-2-halogenated quetolites are disclosed in FR 2,742, 757 published June 27, 1 997.

Brief Description of the Figure. Figure 1 is a representation of the 3-dimensional structure of Example 4 showing the stereochemistry of the 2-fluoro-substituted carbon atom.

Summary of the invention. The present invention provides a novel class of 2-halo-6-O-substituted quetolite derivatives which possesses antibacterial activity. In one aspect of the present invention, are pharmaceutically acceptable compounds or salts and esters thereof, having a formula selected from the group consisting of wherein R p is hydrogen or a hydroxy protecting group; X is F, Cl, Br or I; and R1 is selected from the group consisting of (1) d-Ce-alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) -NR3R4 wherein R3 and R4 are independently selected from hydrogen and d-alkyl, or R3 and R4 are taken together with the atom to which they are attached to form a ring composed of 3-7 members containing a residue selected from the group consisting of -O-, -N H-, -N (d- Cß-alkyl-) -, -N (aryl-C1-C6-alkyl-) - , -N (substituted aryl-Ci -Ce-alkyl-) -, -N (heteroari ld -Ce- alkyl-) -, and -N (heteroaryl substituted -d -C6-alky1-) -; (2) -CH2-CH = CH-Y, wherein Y is independently selected from the group consisting of (a) H, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) heteroaryl substituted, (f) -CH = H2 l (g) -CH = CH-aryl, (h) -CH = CH-substituted aryl, (i) -CH = CH-heteroaryl, and (j) -CH = CH- substituted heteroaryl, (k) (aryl) oil, (I) (substituted aryl) oil, (m) (heteroaryl) oil, and (n) (substituted heteroaryl) oil; and (3) -CH2-C? CY, wherein Y is as previously defined, with the proviso that in the compounds of Formula (II) wherein R1 is selected from option (1) the group C? -C6-alq u1lo. The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier. The invention further relates to a method of treating bacterial infections in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined above. In a further aspect of the present invention, the processes for the preparation of 2-halo-6-O-substituted quetolite derivatives of the above-mentioned Formulas (1) - (1) are provided.

Detailed Description of the invention Definitions As used throughout this specification and the appended claims, the following terms have the specified meanings. The terms "d-C3-alkyl", "d-C6-alkyl", and "d-C12-alkyl" as used herein refer to straight or branched chain hydrocarbon radicals, saturated, derived from a hydrocarbon residue containing between one and three, one and six, and one and twelve carbon atoms, respectively, by the removal of a single hydrogen atom. Examples of d-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of d-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl. , rerr-butyl, neopentyl and n-hexyl. Examples of C radicals? -C12-alkyl include, but are not limited to, all of the following examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3 -propylene, 2, 2-dimethylpropylene, and the like. The term "C2-C? 2-alkenyl" denotes a monovalent group derived from a hydrocarbon residue containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by removal of one carbon atom. only hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. The term "C2-C1 2-alkenylene" denotes a monovalent group derived from a hydrocarbon residue containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by removal of two carbon atoms. hydrogen. Alkenyl groups include, for example, 1,1-ethenyl, 1,2-propenyl, 1,4-butenyl, 1-methyl-but-1-en-1,4-yl, and the like. The term "d -C6-alkoxy" as used herein refers to a d -C6-alkyl group, as previously defined, attached to the origin molecular residue through an oxygen atom. Examples of d-C6-alkoxy include but are not limited to, methoxy, ethoxy, propoxy, / 'so-propoxy, / -butoxy, ferf-butoxy, neo-pentoxy and n-hexoxy. The term "d-Cs-alkylamino" as used herein refers to one or two d -C3-alkyla groups, as previously defined, attached to the parent molecular residue through a nitrogen atom. Examples of d -C3-alkylamine include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino and propylamino. The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to the activity of the proton, that is, it does not act as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heteroaryl compounds, such as , for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Additional discussions of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed. , edited by John A. Riddick et al. , Vol. I I, in the Techniques of Chem istry Series, John Wiley & amp;; Sons, NY, 1986. The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system radical derived from a hydrocarbon residue containing one or more aromatic rings, respectively, by withdrawing a single atom of hydrogen. Such aryl radicals include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The term "(aryl) oil" as used herein refers to an aryl group, as defined herein, connected to the origin molecular group through a carbonyl group. The term "C3-C7-cycloalkyl" denotes a monovalent group derived from a saturated monocyclic or bicyclic carbocyclic ring composed of the removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo [2.2, 1] heptyl.

The terms "halo" and "halogen" as used herein refers to an atom selected from fluorine, chlorine, bromine and iodine. The term "alkylamino" refers to a group having the structure -N H R 'wherein R' is alkyl, as previously defined. Examples of alkylamino include methylamino, ethylamino, iso-propylamino and the like. The term "dialkylamino" refers to a group having the structure -N R'R "wherein R 'and R" are independently selected from alkyl, as previously defined. Additionally, R 'and R "taken together can optionally be - (CH2) K- where k is an integer from 2 to 6. Examples of dialkylamino include, diethylamino, diethylaminocarbonyl, methylethylamine, piperidino and the like. The term "haloalkyl" denotes an alkyl group, as defined above, which has one, two or three halogen atoms attached to it and is exemplified by groups such as chloromethyl, bromoethyl, trifluoromethyl and the like. The term "alkoxycarbonyl" represents an ester group, that is, an alkoxy group, attached to the parent molecular residue through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like The term "thioalkoxy" refers to a alkyl group as previously defined attached to the origin molecular residue through a sulfur atom.

The term "carboxaldehyde" as used herein refers to a group of the formula -CHO. The term "carboxy" as used herein refers to a group of the formula -CO2H. The term "carboxamide" as used herein refers to a group of the formula -CONHR'R "wherein R 'and R" are independently selected from hydrogen or alkyl, or R' and R "taken together they may be optionally - (CH2) K- wherein k is an integer from 2 to 6. The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten atoms of ring of which one ring atom is selected from S, O and N, zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N, and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule by means of any of its ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl or, quinoxalinyl, naphthyridinyl, and the like. The heteroaryl groups of this invention can also be fused to an adjacent aryl heteroaryl ring. Examples of these types of ring systems include thieno [2, 3-bipyridyl, 1 / - / - pyrrolo [2, 3-b] pyridinyl, 3 / - / - methylimidazo [4, 5, -b] pyridinyl, and the sim ilar. The term "(heterocycle) oil" as used herein refers to a heterocyclic group, as defined herein, connected to the origin molecular group through a carbonyl group. The term "heterocycloalkyl" as used herein, refers to a ring system composed of 3 to 10 μm members partially unsaturated or fully saturated non-aromatic, which includes individual rings of 3 to 8 atoms in size and systems of bi- or tri-cyclic ring which may include aryl or heteroaryl rings composed of six aromatic members fused to a non-aromatic ring. These heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as defined above attached to the parent molecular residue through an alkylene group wherein the alkylene group is from one to four carbon atoms. The "hydroxy protecting group", as used herein, refers to an easily extractable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively extractable. The use of hydroxy protecting groups is well known in the field of protecting groups against undesirable reactions during a synthetic process and many protective groups are well known, cf. , for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Svnthesis, 2nd edition, John Wiley & amp; amp;; Sons, New York (1 991). Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, ferf-dimethylsilyl, ferf-butyldiphenylsilyl, ethers such as methoxymethyl and esters including acetyl benzoyl, and the like. The term "acetone protecting group", as used herein, refers to an easily removable group which is known in the art to protect an acetone group against undesirable reactions during synthetic procedures and to be selectively extractable. The use of acetone protecting groups is well known in the field of protecting groups against undesirable reactions during a synthetic process and many such protective groups are known, cf. , for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Svnthesis, 2nd edition, John Wiley & Sons, New York (1 991). Examples of acetone protecting groups include, but are not limited to, quetals, oximes, O-substituted oximes such as O-benzine oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.

The term "oxo" denotes a group in which two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (ie, a carbonyl group). The term "protecting group N" or "N-protected" as used herein refers to those groups which are intended to protect an amino group against undesirable reactions during synthetic procedures. Protecting groups N comprise carbamates, amides including those containing heteroaryl groups, N-alkyl derivatives, amino acid derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), nicotinoyl and the like. The commonly used protective gages are described in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Svnthesis, 2nd edition, John Wiley & Sons, New York (1 991), which is incorporated herein by reference. The term "amino-protected" refers to an amino group protected with a protecting group N, as defined above, which includes benzoyl, acetyl, tri-methyl isyl, triethylsilyl, methoxymethyl groups, for example. The term "hydroxy-protected" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, which includes formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl groups. (Boc), and benzyloxycarbonyl (Cbz), for example. The term "protogenic organic solvent" as used herein refers to a solvent that attempts to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility of the reactants. , the reactivity of the reagents and the preferred temperature ranges, for example. Additional explanations of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed. , edited by John A. Riddick et al. , Vol. I I, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term "substituted aryl" as used herein refers to an aryl group as defined herein by the independent replacement of one, two or three of the hydrogen atoms in the same with halo, hydroxy, cyano, d -C -alkyl, d -C6-alkoxy, d -C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl and carboxamide. In addition, any substituent can be an aryl, heteroaryl or heterocycloalkyl group. The substituted aryl groups also include tetrafluorophenyl and pentafluorophenyl. The term "substituted heteroaryl" as used herein refers to a heteroaryl group as defined herein substituted by the independent replacement of one, two or three of the hydrogen atoms therein with -Cl, -Br, -F, -I, -OH, -CN, -C3-alkyl, -C6-alkoxy, C3-C3-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, carboxamide, N-protected amino, -CH (= N-OH), -CH (= N-NH2), and -CH (= NN = C (CH3) 2). In addition, any substituent can be an aryl, heteroaryl, or heterocycloalkyl group. The term "substituted (aryl) oil" as used herein refers to a group (aryl) oil as defined herein substituted by the independent replacement of one, two or three of the hydrogen atoms in the same with -Cl, -Br, -F, -I, -OH, -CN, d -C3 -alkyl, d -C6-alkoxy, d -C6- alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, carboxamide, N-protected amino, -CH (= N-OH), -CH (= N-NH2), and -CH (= NN = C (CH3) 2). In addition, any substituent may be an aryl, heteroaryl, or heterocycloalkyl group. The term "substituted (heteroaryl) oil" as used herein refers to a group (heteroaryl) oil as defined herein substituted by the independent replacement of one, two or three of the hydrogen atoms therein with -Cl, -Br, -F, -I, -OH, -CN, -C3-alkyl, d-C6-alkoxy, -C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkyl , mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, carboxamide, N-protected amino, -CH (= N-OH), -CH (= N-NH2), and -CH (= NN = C (CH3) 2). In addition, any substituent may be an aryl, heteroaryl, or heterocycloalkyl group. There may be numerous asymmetric centers in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures of the same. According to the above, at any time a link is represented by means of a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be presented. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and crawling animals without undue toxicity. , irritation, allergic response and the like, and are in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.

The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the independent base function with a suitable organic acid. Examples of non-toxic, pharmaceutically acceptable acid addition salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, acid maleic, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the matter such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butrirate, camforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate. , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, salts of valerate and the like. Representative alkaline earth or alkali metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed by using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, low alkyl sulfonate and aryl sulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters which are hydrolyzed in vivo and include those which are readily decomposed in the human body to leave the original source or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each residue of alkylene or alkenyl has advantageously no more than 6 carbon atoms. . Examples of particular esters include formats, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein refers to those medicaments of the compounds of the present invention which are within the scope of sound medical judgment, suitable for use in contact with human tissues. and creeping animals with undue toxicity, irritation, allergic response and the like, in proportion to a reasonable rate of benefit / risk, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention . The term "prodrug" refers to compounds that rapidly transform in vivo to produce the compound origin of the above formula, for example by hydrolysis in the blood. A full explanation is given in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, de. , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1 987, both of which are incorporated herein by reference.

Preferred Modes In a first embodiment of the invention is a compound having the Formula (I). In a preferred embodiment of the formula (I), X is F. In a second embodiment of the invention there is found a compound having the Formula (I I). In a preferred embodiment of the formula (I I), X is F. In a third embodiment of the invention is found a com position having Formula (1) b wherein Y and R p are defined herein. (ll) b Representative compounds of the invention are those selected from the group consisting of: Compound of Formula (I), Rp is H, R1 is methyl, X is F; Compound of Formula (I), Rp is H, R1 is methyl, X is Cl; Compound of Formula (I), Rp is H, R1 is methyl, X is Br Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is hydrogen, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is (3-quinolyl), X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-nitro-3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is phenyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-tert-butoxycarbonylamino-3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is 6- amino-3-quinolinyl-, X is F; Compound of Formula (ll) b, R p is H, R 1 is -CH 2 -CH = CH Y, Y is 6- quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 3- (1,8-naphthyridinyl), X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH -Y, Y is 6-quinoxalinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH -Y, Y is 6- (dimethylamino) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 6- (aminosulfonylmethyl) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 6- (aminocarbonyl) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH -Y, Y is 6- (N-methylamino) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 6- (formyl) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 6- [(hydroxyimino) methyl] -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH -Y, Y is 6- [aminoimino (methyl)] - 3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH -Y, Y is 6- [[(1-methylethylidene) aminoimino] methyl] -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH Y, Y is 3- (5-cyano) pyridinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, Y is hydrogen, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is phenylcarbonyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, Y is 2-thienylcarbonyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, and is (6-chloro-3-pyridinyl) carbonyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, Y is 3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, Y is 8-sulfonylamino-3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH? CH-Y, and is (2,2'-bistiene) -5-yl-, X is F; and Compound of Formula (ll) b, R is H, R1 is -CH2-CH? CH-Y, and is [5- (2-pyridyl) -2-thienyl] -, X is F; Antibacterial Activity In Vitro Analysis The representative compounds of the present invention were analyzed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous solutions of the test compound mixed with 10 mL of agar were prepared (Difco 0418-01-5 ) Sterilized Brain Heart Infusion (BHI) Each plate was inoculated with 1: 100 solutions (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37 ° C for 20 to 24 hours. In addition, a control plate was prepared and incubated, using a BH I agar that did not contain a test com pont, at the beginning and end of each test. An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same class of antibiotics as the test compound was prepared and incubated also as an additional control, as well as to provide be comparable test-to-test. Erythromycin A was used for this purpose. After the incubation, each plate was visually inspected. The minimum inhibitory concentration (M IC) was defined as the lowest concentration of drug that did not produce growth, a tenuous vapor, or sparsely isolated colonies, at the site of inoculation as controlled by growth control. The results of this analysis, shown below in Table 1 B, demonstrate the antibacterial activity of the compounds of this invention.

Table 1 A Abbreviations of organisms placed in Table 1 B Microorganism Organism code Staphylococcus aureus ATCC 6538P AA Staphylococcus aureus A5177 BB Staphylococcus aureus A-5278 CC Staphylococcus aureus CMX 642A DD Staphylococcus aureus NCTC 1 0649M EE Staphylococcus aureus CMX 553 FF Staphylococcus aureus 1 775 GG Staphylococcus epidermis 351 9 HH Enterococcus faecium ATCC 8043 II Streptococcus bovis A- 51 69 JJ Streptococcus agalactiae CMX 508 KK Streptococcus pyogenes EES61 LL Streptococcus pyogenes 930 MM Streptococcus pyogenes PI U 2548 NN Micrococcus luteus ATCC 9341 OO Micrococcus luteus ATCC 4698 PP Escherichia coli JUHL QQ Escherichia coli SS RR Escherichia coli DC-2 SS Candida albicans CCH 442 TT Mycrobacterium smegmatis ATCC 1 14 UU Nocardia asteroides ATCC 9970 VV Haemophilis influenzae DILL AMP R WW Streptococcus pneumoniae ATCC 6303 XX Streptococcus pneumoniae GYR 1 1 71 YY Streptococcus pneumoniae 5979 ZZ Streptococcus pneumoniae 5649 ZZA Table 1B Amylobacterial Activity (MIC's) d < 3 Composites Reached Example Code Example Example Example Eri. TO Organization 1 2 3 4 standard AA 0.1 25 0.39 0.78 0.2 BB 0.1 25 0.39 0.78 3.1 CC > 100 > 100 > 100 > 100 > 100 DD 0.1 50 0.39 0.78 0.39 EE 0.2 25 0.39 0.78 0.39 FF 0.1 25 0.39 0.78 0.39 GG > 100 > 100 > 100 > 100 > 100 HH 0.2 25 0.39 0.78 0.39 II 0.05 12.5 0.1 0.2 0.05 JJ 0.01 1.56 0.2 0.2 0.02 KK 0.02 3.1 0.2 0.2 0.05 LL 0.01 3.1 0.05 0.2 0.05 MM > 100 > 100 > 100 > 100 > 100 NN 0.2 6.2 0.39 0.39 6.2 OO 0.02 3.1 0.05 0.39 0.05 PP 0.2 6.2 0.39 0.78 0.2 QQ > 50 > 100 > 100 > 100 > 100 RR 0.2 0.78 0.39 0.78 0.78 SS 25 > 100 > 100 > 100 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 0.2 > 100 1.56 6.2 3.1 VV 0.05 50 0.39 0.39 0.1 WW 2 32 8 8 4 XX 0.03 4 0.125 0.06 0.06 YY 0.03 4 0.125 0.03 0.06 zz > 128 > 128 128 > 128 > 128 ZZA 0.5 4 2 0.25 16 Table 1B (continued) Organism Example Example Example Example Eri. A 5 6 7 8 standard AA 0.05 0.05 0.05 0.39 0.2 BB 0.05 0.05 0.05 0.39 6.2 CC > 100 100 100 > 100 > 100 DD 0.05 0.05 0.05 0.39 0.39 EE 0.05 0.1 0.05 0.39 0.39 FF 0.05 0.05 0.05 0.39 0.39 GG > 100 100 100 > 100 > 100 HH 0.05 0.05 0.05 0.39 0.2 II 0.02 0.05 0.02 0.2 0.05 JJ 0.005 0.01 < 0.005 0.05 0.05 KK 0.01 0.02 < 0.005 0.05 0.05 LL 0.01 < 0.005 < 0.005 0.05 0.02 MM 0.2 0.39 25 12.5 > 100 NN 0.05 0.05 0.05 0.39 12.5 OO 0.01 0.01 < 0.005 0.05 0.02 PP 0.1 0.05 0.02 0.39 0.39 QQ 25 25 50 > 100 50 RR 0.2 0.05 0.1 6.2 0.39 SS 25 25 25 > 100 > 100 TT 12.5 100 > 100 > 100 > 100 uu 0.2 0.1 0.05 0.78 6.2 vv 0.005 0.02 < 0.005 0.78 0.05 ww 1 2 2 16 4 XX 0.03 < 0.004 < 0.004 0.06 0.125 YY 0.03 < 0.004 < 0.004 0.06 0.06 ZZ 1 1 64 16 > 128 ZZA 0.25 0.125 0.25 1 16 Table 1B (continued) Organism Example Example Example Example Eri. A 9 10 11 12 standard AA 0.02 0.1 0.05 0.05 0.2 BB 0.02 0.1 0.05 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 0.02 0.1 0.05 0.05 0.39 EE 0.05 0.1 0.05 0.05 0.39 FF 0.02 0.1 0.05 0.05 0.39 GG > 100 > 100 100 > 100 > 10Ó HH 0.02 0.2 0.05 0.05 0.2 II 0.01 0.05 0.05 0.01 0.05 JJ < 0.005 0.01 0.01 < 0.005 0.05 KK < 0.005 0.05 0.01 0.01 0.05 LL < 0.005 0.02 0.39 0.01 0.02 MM 0.2 0.39 0.1 0.2 > 100 NN 0.1 0.1 0.01 0.05 12.5 OO < 0.005 0.02 0.01 < 0.005 0.02 PP 0.02 0.1 0.05 0.05 0.39 QQ 25 100 25 12.5 50 RR 0.2 0.1 0.2 0.1 0.39 SS 25 100 12.5 12.5 > 100 TT > 100 > 100 > 100 > 100 > 100 uu 0.78 0.1 0.78 0.2 6.2 VV < 0.005 0.01 0.01 < 0.005 0.05 WW 2 2 2 2 4 XX 0.015 0.015 < 0.004 < 0.004 0.125 YY 0.015 0.015 < 0.004 < 0.004 0.06 zz 0.25 0.25 0.125 1 > 128 ZZA 1 0.25 0.25 0.25 16 Table 1B (continued) Organism Example Example Example Example Eri. A 13 14 15 16 standard AA 0.2 0.05 0.05 0.05 0.2 BB 0.2 0.1 0.05 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 0.2 0.1 0.05 0.05 0.39 EE 0.2 0.1 0.05 0.05 0.39 FF 0.2 0.1 0.05 0.05 0.39 GG > 100 > 100 > 100 > 100 > 100 HH 0.2 0.1 0.05 0.05 0.2 II 0.1 0.1 0.05 0.02 0.05 JJ 0.02 < 0.005 0.01 < 0.005 0.05 KK 0.02 0.01 0.01 0.01 0.05 LL 0.05 0.01 0.01 0.01 0.02 MM 0.78 - 0.1 0.39 > 100 NN 0.2 0.2 0.1 0.05 12.5 OO 0.02 0.01 0.01 0.01 0.02 PP 0.2 0.2 0.05 0.05 0.39 QQ 50 50 25 50 50 RR 0.78 0.1 0.2 0.2 0.39 SS 100 100 12.5 50 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 0.78 3.1 0.39 0.39 6.2 VV 0.05 0.1 0.05 0.01 0.05 WW 8 2 4 2 4 XX 0.06 < 0.004 < 0.004 0.03 0.125 YY 0.06 < 0.004 < 0.004 0.03 0.06 zz 1 2 0.5 1 > 128 ZZA 0.5 0.25 0.25 0.25 16 Table 1B (continued) Organism Example Example Example Example Eri. A 17 18 19 20 standard AA 0.05 0.02 0.1 0.1 0.2 BB 0.1 0.05 0.2 0.1 6.2 CC > 100 50 > 100 > 100 > 100 DD 0.1 0.05 0.2 0.1 0.39 EE 0.2 0.05 0.2 0.2 0.39 FF 0.1 0.05 0.2 0.1 0.39 GG > 100 50 > 100 > 100 > 100 HH 0.1 0.05 0.2 0.2 0.2 II 0.05 0.02 0.05 0.1 0.05 JJ 0.01 < 0.005 < 0.005 0.01 0.05 KK 0.02 0.01 0.02 0.02 0.05 LL 0.02 < 0.005 0.02 0.02 0.02 MM 0.78 0.2 1.56 1.56 > 100 NN 0.2 0.2 0.2 0.2 12.5 OO 0.02 0.01 0.02 0.02 0.02 PP 0.05 0.02 0.1 0.1 0.39 QQ 100 25 100 > 100 50 RR 0.78 0.2 0.78 0.78 0.39 SS 100 50 100 > 100 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 0.39 0.78 0.78 0.78 6.2 VV 0.02 0.01 0.02 0.02 0.05 WW 2 2 2 4 4 XX 0.03 0.015 0.06 0.125 0.125 YY 0.015 0.015 0.06 0.06 0.06 ZZ 1 0.25 1 2 > 128 ZZA 0.5 0.25 0.5 1 16 Table 1B (continued) Organism Example Example Example Example Eri. A 23 24 25 26 standard AA 1.56 1.56 0.39 0.05 0.2 BB 0.78 1.56 0.39 0.05 6.2 CC > 100 > 100 > 100 > 100 > 100 DD 1.56 1.56 0.39 0.05 0.39 EE 1.56 1.56 0.78 0.1 0.39 FF 0.78 1.56 0.39 0.05 0.39 GG > 100 > 100 > 100 > 100 > 100 HH 1.56 1.56 0.39 0.05 0.2 II 0.78 0.39 0.2 0.02 0.05 JJ 0.1 0.2 0.1 0.01 0.05 KK 0.39 0.39 0.1 0.02 0.05 LL 0.39 0.39 0.1 0.02 0.02 MM > 100 100 6.2 0.1 > 100 NN 1.56 3.1 0.39 0.05 12.5 OO 0.2 0.2 0.2 0.02 0.02 PP 1.56 0.78 0.39 0.05 0.39 QQ > 100 100 > 100 25 50 RR 3.1 3.1 0.78 0.2 6.2 SS > 100 > 100 > 100 25 > 100 TT > 100 > 100 > 100 > 100 > 100 UU 3.1 3.1 0.78 0.2 6.2 VV 0.78 0.78 0.2 0.01 0.05 WW 8 16 2 2 4 XX 0.03 0.06 < 0.004 < 0.004 0.125 YY 0.03 0.03 < 0.004 < 0.004 0.06 zz > 128 > 64 0.06 16 > 128 ZZA 2 1 0.06 0.25 16 Table 1B (continued) Organism Example Example Eri. A 27 28 standard AA 0.1 0.05 0.2 BB 0.1 0.1 6.2 CC 50 > 100 > 100 DD 0.1 0.1 0.39 EE 0.1 0.2 0.39 FF 0.1 0.1 0.39 GG 25 > 100 > 100 HH 0.1 0.1 0.2 II 0.02 0.05 0.05 JJ < 0.005 0.01 0.05 KK 0.01 0.02 0.05 LL 0.01 0.02 0.02 MM 0.78 0.78 > 100 NN 0.1 0.2 12.5 OO < 0.005 0.02 0.02 PP 0.1 0.05 0.39 QQ 100 100 50 RR 0.2 0.78 0.39 SS > 100 100 > 100 TT, > 100 > 100 > 100 UU 0.2 0.39 6.2 VV 0.02 0.02 0.05 WW 4 2 4 XX 0.015 < 0.004 0.125 YY 0.015 < 0.004 0.06 ZZ 0.5 16 > 128 ZZA 0.125 0.25 16 Table 1C Effect of an ib-II-lysing SL in the In vitro antibacterial activity (MIC s) of the compounds Reacted from Formula (I), Rp is H, R is methyl.

Standard Organism Example Example Example 1 2 3 (X is H) (X is F) (X is Cl) (X is Br) AA 0.2 0.1 25 0.78 BB 0.2 0.1 25 0.78 CC > 100 > 100 > 100 > 100 LL 0.02 0.03 4 < 0.125 MM > 100 > 128 128 128 NN 0.39 0.5 16 4/32 WW 4 2 32 8 XX 0.06 0.03 4 0.25 ZZ > 128 > 128 > 128 > 128 ZZA 0.5 0.5 4 1 As seen in Table 1C, the introduction of fluorine into the 2 position of quetolites to produce compounds of Formula I provides surprisingly improved inhibitory activity when compared to the compounds wherein X is hydrogen, Br or Cl.

Table 1 D Effect of 2-H versus 2-F Substitution in In Vitro Antibacterial Activity (MIC's) of the Selected Compounds of the Formula (1) b.

Organis Standard Example Standard Example Standard Example mo A 5 B 7 C 1 2 (X is H) (X is F) (X is H) (X is F) (X is H) (X is F) LL 0.03 0.03 0.03 < 0.04 0.03 < 0.04 MM 1 0.25 64 16 1 0.5 N N 0.25 0.25 0.25 0.25 0.25 0. 1 25 WW 2 1 4 2 2 2 XX 0.03 0.03 0.03 < 0.04 0.01 5 < 0.004 zz 1 6 1 1 28 64 64 1 ZZA 0.25 0.25 0.25 0.25 0.5 0. 1 25 As seen in Table 1 D, the introduction of fluorine into the position 2 of uetolites produces a surprisingly improved inhibitory activity when compared to the corresponding compounds wherein X is hydrogen (Standards A, B and C) In Vivo Assays Representative posts of the present invention were tested in vivo with respect to antibacterial activity as follows: Mouse Protection Test The efficacy of tricyclic quetolites was evaluated in mouse models of acute bacterial infections. Female CF-1 mice weighing 20-28 g were inoculated intraperitoneally with 24-hour cultures of S. aureus NCTC 1 0649 or S. pneumoniae AC6303 adjusted to produce approximately 1 00 times the 50% lethal dose (LD50 ). Concurrently with each experiment, the LD50 test was validated by inoculating untreated mice with logarithmic dilutions of the bacterial inoculations. A logarithmic dilution range of 5 of the bacterial tests was inoculated into five groups of 10 mice each (10 mice by logarithmic dilution). There was a mortality rate of 1 00% in all groups of untreated mice with 1 00 x LD50. The test compounds were formulated in 2% ethanol in PBS and orally administered by priming or subcutaneously at 1 hour and 5 hours after infection. Mortality was determined for 7 days and the effective average doses needed to protect 50% of the mice (ED50) was calculated from the cumulative mortality by ordered logic analysis.

Lung infection of H. influenzae The efficacy of tricyclic quetolites was evaluated in a mouse model of lung infection of H. influenzae. H. influenzae 1435 was developed overnight in BH I. Female CF-1 non-immunosuppressed, normal mice, weighing 20-26 g, were inoculated intranasally with 1 00 m icrolitres of broth containing approximately 4.0 x 1 06 cfu of H. influenzae. The compounds were administered 1, 2, 24 and 36 hours after infection by oral dose (priming) or subcutaneous injection. The bacterial load was determined 48 hours after the infection by plating by dilution of the lung tissue on chocolate agar gum. The therapeutic doses were established by determining the dose that produced a logarithmic reduction > 2 in bacterial load (compared to untreated controls) in 70% of mice. The results of these tests are shown in Table 1 E.

Table 1 E The Effect of Substitution 2-F on In Vivo Antibacterial Activity (M IC's) of Formula (I), Rp is hydrogen, R 1 is methyl Organism X is H X is F Staphvlococcus aureus 1 3 9.4 Haemophilis influenzae 10 7.2 Streptococcus pneumoniae > 60 35.9 Table 1 F The Effect of Substitution 2-F on the In Vivo Antibacterial Activity (MIC's) of the Formula (l l) b, R p is hydrogen, R 1 is 6-guinolinyl Organism X is H X is F Staphylococcus aureus - < 6.5 Streptococcus pneumoniae 25.9 5.5 As shown in Tables 1 E and 1 F, the introduction of fluoride to position 2 of the quetolites produces a surprisingly improved in vivo inhibitory activity when compared to the corresponding compounds wherein X is hydrogen.

Pharmaceutical Compounds The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention together with one or more pharmaceutically acceptable carriers. As used in this, the term "pharmaceutically acceptable carrier" means an encapsulating, diluting, filling, liquid, semi-solid, inert solid, non-toxic material, or an auxiliary formulation of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, lucid g and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; regulating agents such as magnesium hydroxide and aluminum hydroxide; algic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and flavoring agents , preservatives and antioxidants may also be present in the composition, according to the formulator's judgment. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), orally, or as an oral or nasal spray . Liquid forms of oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, beaver and sesame oils) i), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. Apart from the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. Injectable preparations, for example, injectable, sterile aqueous or oleaginous suspensions, can be formulated according to the known art by the use of suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil may be used, including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter or by the incorporation of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile, injectable medium, before to be used. In order to prolong the effect of a drug, it is often desirable to decrease the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its rate of dissolution, which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a medicament administered parenterally is carried out by dissolving or suspending the medicament in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the polymer used in particular, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by capturing the drug in liposomes or micro ions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the com positions of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol or a suppository wax which is solid at temperature environment but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and glands. In such solid dose forms, the active compound is mixed with at least one pharmaceutically acceptable excipient or carrier, inert, such as sodium citrate or dicalcium phosphate and / or a) fillers or expanders such as starches, lactose, sucrose , g lucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar gum, carbonate calcium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example , cetyl alcohol and glycerol monostearate, h) absorbents such as caolin and bentonite clay, and i) lubricants such as talc, calcium stearate, mag stearate nesium, polyethylene solid glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise regulatory agents.

Solid compositions of a similar type can also be used as filling materials in soft and hard filled gelatin capsules by the use of excipients such as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of a composition that they release only the active network (s) active, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner . Examples of incorporation of com positions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as filling materials in soft and hard filled gelatin capsules by the use of excipients such as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and the like. The active compounds can also be present in micro-encapsulated form with one or more excipients such as those mentioned above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dose forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise regulatory agents. Optionally, they may comprise opacifying agents and may also be of a composition that they release only the active network (s) active, or preferentially, in a certain part of the intestinal tract, optionally in a delayed way. Examples of incorporated compositions that may be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, aerosols, inhalants or patches. The active components are mixed under sterile conditions with a pharmaceutically acceptable carrier and any condom or regulator necessary that may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. The powders and aerosols may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, alumium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The aerosols may additionally contain customary impellents such as chlorofluorohydrocarbons. Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or distributing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled either by the ratio of a velocity controlling membrane or by dispersion of the compound in a polymer or gel matrix. According to the treatment methods of the present invention, bacterial infections are treated or prevented in a patient, such as a human or crawling mammal, by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for the time necessary to achieve the result. wanted. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the com pound to treat bacterial infections, at a reasonable rate of benefit / risk applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the responsible physicians within the scope of the correct medical judgment. The therapeutically effective, specific dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific position employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the specific commis- sion used; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical field. The total daily dose of the compounds of this invention administered to a human or other mammal in a single dose or divided doses may be in amounts from, for example, 0.01 to 50 mg / kg of body weight or more usually from 0. 1 up to 25 mg / kg of body weight. The single dose compositions may contain such amounts or submultiples thereof to form the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment, from about 10 mg to about 2000 mg of the compound (s) of this invention per day. in a single dose or multiple doses. The process for preparing a compound that has the formula wherein R p is hydrogen or a hydroxy protecting group; X is F, Cl, Br, or I; and R1 is selected from the group consisting of (1) d-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c) ) heteroaryl, (d) substituted heteroaryl (e) -NR3R4 wherein R and R are independently selected from hydrogen and d-C3-alkyl, or R3 and R4 are taken together with the atom to which they are attached to form a ring integrated by 3-7 members containing an element selected from the group consisting of -O-, -N H-, -N (d- Ce-alkyl-) -, -N (arid C6- alkyl-) -, N (substituted aryl-d -C6-alkyl-) -, N (heteroaryl-d-C6-alkyl-) -, and - N (heteroaryl substi tute -d -C6-alkyl- ) -; (2) -CH2-CH = CH-Y, wherein Y is selected from the group consisting of (a) H, (b) aryl, (c) substituted aryl (d) heteroaryl (e) substituted heteroaryl (f) ) -CH = H2, (9) -CH = CH-aryl, (h) -CH = substituted CH-aryl, (i) -CH = CH-heteroaryl, and (j) -CH = CH- substituted heteroaryl, (k) (aryl) oil, (I) (aryl) substituted oil, (m) (heteroaryl) oil, (n) (heteroaryl) substituted oil; and (3) -CH2-C = CY, wherein Y is as previously defined, with the proviso that in the compounds of Formula (II) wherein R is selected from option (1), it must be substituting the group -C6-alkyl, comprises (a) the treatment of a compound selected from the group consisting of respectively, with a halogenising reagent and optionally deprotective. In a preferred method of the above-described process, the halogenising reagent is selected from the group consisting of? / -fluorobenzenesulfonimide in the presence of the base, 1.0% F2 in formic acid, 3,5-dichloro-1-tetrafluoroborate. fluoropyridinium, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2) 2N F, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of the base, N-fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presence of the base, hexachloroethane in the presence of the base, CF3CF2CH2ICI2, SO2CI2, SOCI2, CF3SO2CI in the presence of the base, Cl2, NaOCI in the presence of acetic acid, Br2 »pyridine« HBr, Br2 / acetic acid, N-bromosuccinimide in the presence of the base, LDA / BrCH2CH2Br, LDA / CBr4,? / - Yodosuccinimide in the presence of the base and l2. In a preferred method of the process described above, the product is of the formula (I), X is F and the halogenating reagent is N-fluorobenzenesulfonimide in the presence of sodium hydride. In another preferred method of the process described above, the product is of the formula (I I), X is F and the halogenating reagent is N-fluorobenzenesulfonimide in the presence of sodium hydride. In a more preferred method, the product is of the formula (II), X is F, R is -CH2-CH = CH-Y and Y is (3-quinolyl) and the halogenating reagent is N-fluorobenzenesulfonimide in the presence of sodium hydride.

Abbreviations The abbreviations that have been used in the descriptions of the scheme and the examples that follow are: DMF for dimethylformamide; LDA for lithium diisopropylamide; MeOH for methanol; THF for tetrahydrofuran and triflate for trifluo rom eta nos ulf onato.

Synthetic Methods The compounds and processes of the present invention will be better understood in connection with Schemes 1-4 which illustrate the methods by which the compounds of the invention can be prepared. The compounds of the present invention are prepared by the representative methods described below. The groups X, Rp and R are as previously defined. Schemes 1-4 are shown after the text section below. The preparation of the compounds of the invention of the formula (I) and (I I) of erythromycin A is outlined in Schemes 1-5. The preparation of protected erythromycin A is described in the following E patents. U., U.S. 4,990,602; EU 4, 331, 803; US 4,680,368 and US 4,670, 549, which are incorporated for reference. Also incorporated for reference is European Patent Application EP 260, 938. As shown in Scheme 1, the C-9-carbonyl group of Compound 1 is protected with an oxime to give compound 2, wherein V is = NO-Ra or = NOC (Rb) (Rc) -O-Ra, where Ra is selected from the group consisting of d -C1 2-unsubstituted alkyl, d-C12-alkyl substituted with aryl, C? -C12-alkyl substituted with substituted aryl, C? -C1 2-alkyl substituted with heteroaryl, d-C12-substituted alkyl with substituted heteroaryl, C3-C12-cycloalkyl, -Si- (R *) (R **) (R ***) wherein R *, R * * and R *** are each independently selected from d -C1 2 -alkyl, and -Si- (aryl) 3 and R and Rc are each independently selected from the group consisting of ( a) hydrogen, (b) Ci -C1 2-unsubstituted alkyl, (c) C? -C? 2-alkyl substituted with aryl, and (d) d -Ci 2 -alkyl substituted with substituted aryl, or Rb and Rc they are taken in conjunction with the carbon to which they are attached to form a C3-C1-C2-cycloalkyl ring. An especially preferred carbonyl protecting group V is O- (l-isopropoxycyclohexyl) oxime. The 2'- and 4"-hydroxy groups of 2 are protected by reaction with a suitable hydroxy-protecting reagent, such as those described by TW Greene and P.G.M.Wuts in Protective Groups in Organic Svnthesis, 2nd of ., John Wiley &Son, I nc., 1 991, which is incorporated by reference .. Reagents of the hydroxy protecting group include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride. in an aprotic solvent Examples of aprotic solvents are dichloromethane, chloroform, tetrahydrofuran (TH F), N-methyl pyrrolidinone, dimethisulfoxide, diethylsulfoxide, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, triam ida hexamethylphosphoric, mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like.The aprotic solvents do not adversely affect the reaction and are pr preferably dichloromethane, chloroform, DMF, tetrahydrofuran (TH F), N-methyl pyrrolidinone or a mixture thereof. Protection of 2 'and 4"-hydroxy groups from 2 can be carried out sequentially or simultaneously to provide compound 3 where Rp is a hydroxy protecting group The preferred Rp protecting groups include acetyl, benzoyl and tri-methylsilyl The 6-hydroxy group of compound 3 is then alkyl by reaction with an alkylating agent in the presence of the base to give com 4. The alkylating agents include alkyl chlorides, alkyl bromides, iodides or sulfonates. Specific examples of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromine. -p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propine, 3 -bromo-2-octine, 1-bromo-2-butine, 2-picolylchloru ro, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl qinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene and the like. Examples of alkyl sulphonates are: allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl-O-methanesulfonate and the like. Examples of the solvents used are aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide., a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Examples of the base that can be used include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium ferf-butoxide, potassium isobutoxide and the like. The deprotection of the 2'- and 4"-hydroxy groups is then carried out according to the methods described in the literature, for example, by TW Greene and P. G. M. Wuts in Protective Groups in Organic Svnthesis, 2pd ed., John Wiley & amp;; They are, I nc. , 1 991, which is incorporated herein by reference. The conditions used for the deprotection of the 2'- and 4"-hydroxy groups usually results in the conversion of X a = N-OH. (For example, the use of acetic acid in acetonitrile and water results in the deprotection of the 2'- and 4"-hydroxy groups and the conversion of X of = NO-Ra or = NOC (Rb) (Rc) -O-Ra where Ra, Rb and Rc are as defined above for = N-OH) . If this is not the case, the conversion takes place in a separate stage. The deximation reaction can be carried out according to the methods described in the literature, for example by Greene (op.cit.) And others. Examples of the deoximation agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, thiosulfate of potassium, potassium metabisulfite and the like. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the mentioned solvents and the like. The deoximation reaction is most conveniently carried out in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 5 used. In a preferred embodiment, deoximation is carried out by the use of an organic acid such as formic acid in ethanol and water to give 6-O-substituted erythromycin compound 6, wherein R 1 is as previously defined. In the preferred processes of this invention, R1 is methyl or allyl in compound 6. Scheme 2 illustrates the methods used to prepare intermediates of the invention. The 6-O-substituted compound 6 can be converted to a hydroxy-protected compound by methods previously mentioned. Compound 7 is treated by hydrolysis of mild aqueous acid or by enzymatic hydrolysis to remove the cladinose residue and give compound 8. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol, acetone and the like. Reaction times are typically 0.5 to 24 hours. The reaction temperature is preferably from -1 0 to 60 ° C. Compound 8 can be converted to compound 9 by oxidation of the 3-hydroxy group to an oxo group by using a Corey-Kim reaction with N-chlorosuccinimide-dimethyl sulfide or with a Swern oxidation process modified by the use of carbodiimide- dimethylsulfoxide. In a preferred reaction, 8 is added in a pre-formed complex of N-chlorosuccinimide and dimethyl sulfide in a chlorinated solvent such as methylene chloride at -1 0 to 25 ° C. After stirring for about 0.5 to about 4 hours, a tertiary amine such as triethylamine or Hunig's base is added to produce acetone 9. The compounds 9 can then be treated with an excess of sodium hexamethyldisilazide or a hydride base in the The presence of carbonyldiimidazole in an aprotic solvent for about 8 to about 24 hours at about -30 ° C to room temperature to give compounds 1_0. The hydride base may be, for example, sodium hydride, potassium hydride or lithium hydride and the aprotic solvent may be one as previously defined. The reaction may require cooling or heating from about -20 ° C to about 70 ° C, depending on the conditions used, and preferably from about 0 ° C to about room temperature. The reaction requires approximately 0.5 hours to approximately 10 days, and preferably from approximately 10 hours to 2 days, to complete. The portions of this reaction sequence follow the procedure described by Baker et al. , J. Org. Chem., 1988, 53, 2340, which is incorporated herein by reference. Alternatively, compounds 7 can be treated based on the presence of carbonyldiimidazole, as described above, to give compounds H, which can then be converted to compounds 1 2 or 1 3 in Scheme 3, by forming the cyclic carbamate before the removal of cladinose. Scheme 3 illustrates several routes for the preparation of compounds of the formulas (I) and (I I). An expert in the field will be able to easily decide which approach to use, depending on the product that is desired. In one route, the compound 10 can react with ethylene diamine in a suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF, and become cyclic by treating the intermediate compound (not shown) with dilute acid, such as acetic acid or HCl in a suitable organic solvent such as ethanol or propanol to give the compound 1_2. In another route, the compound 10 can react with aqueous ammonium, which results in the formation of the cyclic carbamate compound 1_3. Scheme 3 also describes representative examples of the further processing of the residue of the 6-position of the compounds of the invention. The desired 6-O-substituted compound can be prepared directly as described above or obtained from the chemical modification of an initially prepared 6-O-substituted compound. <; For example, compound 1 3A where R 1 is 6-O-allyl can be reacted with an aryl halide, a substituted aryl halide, a heteroaryl halide or a substituted heteroaryl halide, under Heck conditions in the presence of (Pd) (II) or (Pd (O), phosphine and amine or inorganic base (see Organic Reactions, 1 982, 27, 345-390), to give compound 1_4, wherein Y is aryl, substituted aryl, heteroaryl and substituted heteroaryl Alternatively, compound 1 3A, where R 1 is 6-O-allyl, can be reacted with an unsaturated halide reagent selected from the group having the formula halogen-CH = CH-aryl, halogen-CH = CH-substituted aryl, halogen-CH = CH-heteroaryl and halogen-CH = CH-substituted heteroaryl under Heck conditions in the presence of (Pd (II) or Pd (0), phosphine and amine or inorganic base, to give the compound 1_4, 'wherein Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, -CH = CH-aryl, -CH = CH-substituted aryl, -CH = CH-het eroaryl or -CH = CH-substituted heteroaryl. In other alternating processes, the compound wherein R1 is 6-O-CH2-CH = CH-CH = H2 can be prepared through Scheme 1 by the use of 1-bromo-2,4-pentadiene in place of allyl bromide. This allows the preparation of compounds 1_4 wherein R1 is - CH2-CH = CH-CH = H2. In turn, these compounds can be reacted with an aryl halide, a substituted aryl halide, a substituted aryl halide, a heteroaryl halide or a substituted heteroaryl halide, under Heck conditions to give the compound 14, wherein Y is -CH = CH-aryl, -CH = CH-substituted aryl, -CH = CH-heteroaryl or -CH = CH-substituted heteroaryl. Also in Esq. 3, compound 1 3B, wherein R 1 is propargyl, can be treated with an aryl halide, a substituted aryl halide, a heteroaryl halide, a substituted heteroaryl halide, or a non-halogen reactive. saturated selected from the group having the formula halogen-CH = CH-aryl, halogen-CH = CH-substituted aryl, halogen-CH = CH-heteroaryl and halogen-CH = CH-substituted heteroaryl in the presence of Pd (triphenylphosphine) 2Cl2 and Cu l in the presence of an organic amine, such as triethylamine, to give compound 1_5, wherein Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, -CH = CH2, -CH = CH -aryl, -CH = substituted CH-aryl, -CH = CH-heteroaryl or -CH = CH-substituted heteroaryl. Compound 1_5 can be further selectively reduced to the corresponding c / s-olefin compound 14 by catalytic hydrogenation in ethanol at atmospheric pressure in the presence of 5% Pd / BaSO and quinoline (Rao et al., J. Org. Chem., (1986), 5J_: 41 58-41 59). Also in Scheme 3, compound 1 3B, wherein R 1 is propargyl, can be optionally substituted with an optionally substituted heteroaryl acid halide or an aryl acid halide substituted by using the conditions discussed above to provide compound 1 5 wherein Y is (aryl) oil or substituted or unsubstituted (heteroaryl) oil. Alternatively, compound 13B can also be treated with a boronic acid derivative HB (ORzz), wherein Rzz is H or dd-alkyl, in an aprotic solvent at 0 ° C to room temperature to give boronic ester compounds (not shown) which can then be treated with Pd (triphenylphosphine) 4 and an aryl halide, a substituted aryl halide, a heteroaryl halide or a substituted heteroaryl halide under Suzuki reaction conditions to give additional substituted compounds 14. Also in the Scheme 5, Compound 1 3B, wherein R 1 is propargyl, can be treated with an optionally substituted heteroaryl acid halide or an aryl acid halide optionally substituted to provide the compound 1_5 wherein Y is aryl (oil) or (heteroaryl) substituted or unsubstituted oil.

Scheme 1 Scheme 2 Scheme 3 Scheme 4 Scheme 4 illustrates the procedure by which compounds 12, 1_3,] 4 and 15 can be converted to compounds of formulas (I) and (I I) by treatment with a halogenating reagent. This reagent acts to replace a hydrogen atom with a halogen atom at the C-2 position of the macrolite. Various halogenating reagents may be suitable for this process. 28 Fluorination reagents include, but are not limited to, ? / - fluorobenzenesulfonimide in the presence of the base, 1.0% F2 in formic acid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2) 2NF, N -fluoro-N-methyl-p-toluenesulfonamide in the presence of the base, N-fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presence of the base. Chlorination reagents include, but are not limited to, hexachloroethane in the presence of the base, CF3CF2CH2ICI2, SO2CI2, SOCI2, CF3SO2CI in the presence of the base, Cl2, NaOCI in the presence of acetic acid. The bromidation reagents include, but are not limited to, Br2 »pyridine» HBr, Br2 / acetic acid,? / -bromosuccinimide in the presence of the base, LDA / BrCH2CH2Br or LDA / CBr4. A suitable iodine-impregnation reagent is N-iodosuccinim in the presence of the base, or 12, for example. Suitable bases for the halogenating reactions they require are compounds such as alkali metal hydrides, such as NaH and KH, or amna bases, such as LDA or triethylamine, for example. The different reagents may require different types of base, but this is well known within the subject. A preferred halogenation reagent is N-fluorobenzenesulfonimide in the presence of sodium hydride. The foregoing can be better understood in relation to the following examples which are presented as an illustration and do not limit the scope of the inventive concept.

Example 1 Compound of Formula (I), Rp is H, R is methyl, X is F Step 1a: Compound of Formula (I), R ° is benzoyl, R1 is methyl, X is F To a solution of compound 12 of Scheme 3, wherein Rp is benzoyl and R1 is methyl (1.00 g, 1.35 mmol, prepared according to the US Patent. 5,631,355) in DMF (10 mL) at 0 ° C, NaH (60% in oil, 108 mg, 2.70 mmol) was added and the mixture was stirred for 30 minutes. To this solution was added N-fluorobenzenesulfonimide (510 mg, 1.62 mmol, Aldrich) and the mixture was stirred at 0 ° C for 3 hours. The mixture was taken in 2-propyl acetate and the solution was rinsed with aqueous sodium bicarbonate and saline, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (levigation with 2: 1 hexanes: acetone) gave the main compound (615 mg).

Step 1b: Compound of Formula (I), Rp is H, R1 is methyl, X is F A sample of the compound of Step 1a (600 mg, 0.791 mmol) in methanol (25 mL) was heated to reflux for 24 hours to remove the 2'-benzoyl group. The methanol was removed in vacuo and the crude product was purified by chromatography on silica gel eluted with 3% methanol in dichloromethane to give the main compound (420 mg). MS (DCI / NH3) m / z 656 (M + H) +; 13 C NMR (75 MHz, CDCl 3) d d (203.2 and 202.9), 181.1, d (166.2 and 166.0), 155. 7, 104.2, d (98.5 and 96.4), 81.4, 80.6, 78.9, 77.9, 70.3, 69.5, 65.8, 60. 3, 49.5, 48.5, 42.7, 42.2, 40.5, 40.2, 38.6, 36.1, 28.1, d (25.4 and . 2), 21.9, 21.1, 19.5, 18.6, 15.1, 12.9, 10.9, 10.4; HRMS m / z caled (M + H) + for C33H55FN3? 9: 656.3922. It was found: 656.3914.

Example 2 Compound of Formula (I), Rp is H, R1 is methyl, X is Cl A a solution of compound 12 of Scheme 3, wherein Rp is H and R1 is methyl (130 mg, 0.204 mmol, prepared in accordance to U.S. Patent 5,631,355) in N-methylpyrrolidinone (1.5 mL) was added hexachloroethane (50 mg, 0.214 mmol) and sodium carbonate (43 mg, 0.408 mmol). The mixture was stirred for 3 days at room temperature, additional hexachloroethane (50 mg) and sodium carbonate (50 mg) were added and the mixture was stirred at 60 ° C for 24 hours. The mixture was taken up in 2-propanol and the solution was rinsed with 5% aqueous sodium bicarbonate and saline, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (levigation with acetone) gave the main compound (67 mg). MS m / z 672 (M + H) +; 13C NMR (75 MHz, CDCI3) d 201.3, 181.0, 165.8, 155.9, 104.1, 81.4, 80.7, 79.3, 80.0, 74.2, 69.6, 65.9, 60.5, 49.6, 48.4, 42.8, 42.3, 42.2, 40.2, 38.9, 36.2 , 31.8, 28.2, 22.1, 21.1, 19.7, 18.7, 16.5, 13.0, 11.0, 10.5; HRMS m / z caled (M + H) + for C33H55CIN3? 9: 672.3627. It was found: 672.3624.

Example 3 Compound of Formula (I), Rp is H, R1 is methyl, X is BrA a solution of 0 ° C of compound 12 of Scheme 3, wherein Rp is H and R1 is methyl (500 mg, 0.785 mmol , prepared according to U.S. Patent 5,631,355) in 1: 1 dichloromethane / pyridine (4 mL) was added pyridine-HBr 3 (352 mg, 1.10 mmol). The mixture was stirred overnight at room temperature, additional HBr 3 pyridine (2 equivalents) was added and the mixture was stirred at room temperature for 5 hours. The mixture was cooled with aqueous sodium carbonate and saturated aqueous sodium thiosulfate to pH 10. The mixture was extracted with dichloromethane, which was rinsed with aqueous sodium carbonate and saline, dried over sodium sulfate and concentrated to a empty. Chromatography on silica gel (levigation with 3-5% (2M NH3 in methanol) in dichloromethane gave the main compound (226 mg) MS (DCI / NH3) m / z 716 (79Br (M + H) +) and 718 (81 Br (M + H) +); 13 C NMR (75 MHz, CDCl 3) d 201.6, 181.1, 166.1, 155.8, 103.6, 81.4, 80. 1, 79.8, 78.8, 70.3, 69.4, 66.0, 60.3, 49.4, 48.5, 44.0, 42.8, 42.2, 40. 2, 38.8, 36.0, 32.5, 28.2, 20.0, 21.1, 19.6, 18.8, 17.4, 14.0, 13.0, 10.9, 10.4.

Example 4 Compound of the Formula (II, b.Rp is H. R is -CH? -CH = CH-Y. Y is hydrogen, X is F Step 4a: Compound of Formula (ll) b, Rp is benzoyl, R1 is -CH? -CH = CH-Y, Y is hydrogen To a solution of compound 1_4 of Scheme 4, wherein Rp is acetyl and Y is hydrogen (2.00 g, 1 equivalence) in DMF (20 mL) at 0 ° C, NaH (60% in oil, 235 mg, 2 equivalents) was added and the mixture was stirred at 0 ° C for 30 minutes, to which was added? / -fluorobenzenesulfonimide (1.02 g, 1.1 equivalents) and the mixture was added. stirred at 0 ° C for 3 hours.The mixture was taken in isopropyl acetate and the solution was rinsed sequentially with NaHCO3 and saline, dried (Na2SO4), filtered and concentrated.

Chromatography on residual silica gel with 10-20% acetone in hexanes gave the main compound. MS (DCI / NH3) m / z 699 (M + H) +; 13C NMR (75 MHz, CDCI3) d 217.3, d (203.3 and 203.0), 169.7, d (165.6 and 165.3), 157.4, 135.4, 118.0, 101.5, d (99.3 and 96.6), 83.6, 79.1, 78.7, 78.5, 71.6, 69.2, 64.6, 63.2, 57.6, 44.2, 40.6, 40.5, 38.9, 37.4, 30.6, d (25.1 and 24.9), 22.3, 21.3, 20.9, 20.7, 17.8, 14.9, 13.7, 13.3, 10.6.

Step 4b: Compound of Formula (ll) b, Rp is hydrogen, R1 is -CH? -CH = CH-Y, Y is hydrogen A sample of the compound of Step 4a (400 mg, 0.572 mmol) in methanol (10 mg). mL) was stirred at room temperature for 24 hours to remove the 2'-acetyl group. The methanol was removed in vacuo and the crude product was purified by chromatography on silica gel with 3% methanol in dichloromethane to give 360 mg of the main compound. 13C NMR (100 MHz, CDCI3) d 217.4, d (203.6 and 203.4), d (165.6 and 165. 4), 157.4, 135.4, 117.9, 103.9, d (98.7 and 96.7), 83.6, 79.8, 79.1, 78.4, 70.3, 69.6, 65.8, 64.6, 57.5, 44.2, 40.5, 40.2, 38.7, 37.4, 28.2, d ( 25.3 and 25.1), 22.2, 21.1, 20.7, 17.7, 15.4, 13.8, 13.3, 10.6; HRMS m / z caled (M + Na) + for C33H53N2O10FNa: 679.3576. It was found: 679.3572.

Example 5 Compound of Formula (ll) b, Rp is H, R1 is -CH7-CH = CH-Y, Y is 3-guinolyl-, X is F Step 5a: Compound of Formula (II) b, Rp is benzoyl, R1 is -CH? -CH = CH-Y. And it's 3-quinolyl. X is FA a solution of compound 14 of Scheme 3, wherein Rp is benzoyl and Y is (3-quinolyl) (275 rrig, 0.316 mmol, prepared according to the European Patent Application Serial No. 08 / 888,350) in DMF (2 mL) at 0 ° C, NaH (60% in oil, 25 mg, 0.632 mmol) was added and the mixture was stirred at 0 ° C for 30 minutes. To this solution was added? / - fluorobenzenesulfonimide (119 mg, 0.379 mmol) and the mixture was stirred at 0 ° C for 3 hours and at room temperature for 3 hours. The mixture was taken up in propyl acetate and the solution was rinsed with 10% ammonium hydroxide, aqueous, and saline, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (levigation with 10-20% acetone in hexanes) gave the main compound (141 mg). MS m / z 888 (M + H) +.

Step 5b: Compound of Formula (I), RP is H, R1 is methyl, X is F A sample of the compound of Step 5a (140 mg, 0.158 mmol) in methanol (30 mL) was heated to reflux for 24 hours to remove the 2'-benzoyl group. The methanol was removed in vacuo and the crude product was purified by chromatography on silica gel eluted with 3% methanol in dichloromethane to give the main compound (114 mg). MS (DCI / NH3) m / z 784 (M + H) +); 13C NMR (75 MHz, CDCI3) d 217.8, d (204.3 and 203.9), d (165.8 and 165.5), 157.1, 149.6, 147.6, 132.6, 130.1, 129.5, 129.1, 129.0, 128.1, 128.0, 126.7, 104.0 , d (99.3 and 96.6), 83.4, 79.5, 79.3, 79.0, 70.3, 69.9, 65.8, 64.2, 58.0, 44.1, 40.7, 40.2, 39.0, 37.4, 28.1, d (25.4 and 25.1), 22.3, 21.1, 20.8 , 17.6, 15.4, 13.7, 13.2, 10.6; HRMS m / z caled (M + H) + for C42H59FN3O10: 784.4184. It was found: 784. 4196.

General experimental procedure A: by using the Heck reaction for the preparation of compounds of Formula (ll) b, wherein Y is different from hydrogen, R is hydrogen, X is F Step a: Compounds of Formula ll (b), Y is different from hydrogen, Rp is -C (O) CH3 or -C (O) CfiHs, X is F A mixture comprising a compound of Formula II is degassed ( b), where Y is hydrogen, X is F, and Rp is -C (O) CH3 or -C (O) C6H5 (1 equivalence), Pd (OC (O) CH3) 2 (0.2 equivalences), tri- o-tolylphosphine (0.4 equivalents) in acetonitrile, flooded with nitrogen, treated sequentially with triethylamine (2 equivalents) and aryl halide (2 equivalents), heated at 90 ° C for 24 hours, diluted with ethyl acetate. ethyl acetate, sequentially rinsed with aqueous NaHCO3 and saline, dried (Na2SO4), filtered and concentrated. The residue was chromatographed on silica gel to provide the 2'-protected master compound.

Step b: Compounds of Formula (ll) b, Y is different from hydrogen, Rp is hydrogen, X is F The conversion of compounds of Formula II (b), wherein Y is different from hydrogen, Rp is -C (O) CH3 or -C (O) C6H5 and X is F for the compounds of Formula II (b), wherein Y is different from hydrogen, Rp is hydrogen and X is F, was carried out by stirring the compounds of Formula II (b), wherein Y is different from hydrogen, X is F, and Rp is -C (O) CH3 or -C (O) C6H5 at reflux or at room temperature in methanol overnight, to give the Main compound after purification by column chromatography on silica gel.

Example 6 Compound of Formula ll (b). Rp is H, R1 is -CH, -CH = CH-Y, Y is 6-nitro-3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step aya Step b of General Experimental Procedure A. 13C NMR (100Mhz, CDCl 3) d 218.0, d (204.4 and 204.1), d (166.0 and 165.8), 157.1, 153.0, 149.3, 145.8, 133.9, 131.4, 131.3, 131.0, 128.9, 127.0, 124.7, 122.4, 104.0, d (99.0 and 96.9), 83.4, 79.5, 79.4, 79.0, 70.3, 69.7, 65.8, 64.0, 58.0, 44.1, 40.8, 40.2, 38.9, 37.4, 28.2, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.7, 13.2, 10.7; HRMS m / z caled (M + H) + for C42H58N4O12F: 829.4035. It was found: 829.4044.

Example 7 Compound of Formula (ll) b. Rp is H, R1 is -CH, -CH = CH-Y, Y is phenyl-. X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. MS (DCI / NH3) m / z 733 (M + H) +; 13C NMR (100 MHz, CDCI3) d 217.7, d (204.0 and 203.8), d (165.7 and 165.5), 156.9, 136.4, 133.7, 128.7, 127.8, 126.5, 126.1, 104.0, d (98.9 and 96.8), 83.4, 79.7, 79.2, 79.0, 70.3, 69.6, 65.8, 64.2, 58.1, 44.2, 40.6, 40. 2, 38.9, 37.4, 28.1, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.7, 15.4, 13. 3, 10.8.

Example 8 Compound of Formula (ll) b. Rp is H, R1 is -CH7-CH = CH-Y. And it is 6- erf butoxycarbonylamino-3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of the Procedure Experimental General A. 13C NMR (100 MHz, CDCI3) d 217.7, d (204.2 and 203.9), d (165.8 and 165.2), 157.1, 152.6, 148.0, 144.4, 136.7, 132.0, 130.1, 129.9, 129.8, 129.1, 128.6 , 122.2, 114.1, 104.0, d (98.9 and 96.9), 83.4, 80.7, 79.6, 79.3, 78.9, 70.3, 69.6, 65.8, 64.3, 58.1, 44.1, 40.7, 40.2, 39.0, 37.4, 28.3, 28.2, d ( 25.3 and 25.1), 22.3, 21.1, 20.7, 17.6, 15.4, 13.8, 13.2, 10.6; HRMS m / z caled (M + H) + for C47H68N4O10F: 899.8412. It was found: 899.4816.

Example 9 Compound of Formula (ll) b, Rp is H, R is -CH7-CH = CH-Y. Y is 6-amino-3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13 C NMR (100 MHz, CDCl 3) d 217.7, d (204.1 and 203.9), d (165.7 and 165.5), 157.1, 145.9, 144.9, 142.7, 130.5, 130.5, 130, 129.6, 129.4, 128.4, 121.2, 107.7, 104.0, d (98.7 and 97.1), 83.4, 79.5, 79.2, 79.0, 70.3, 69.6, 65.7, 64.2, 58.0, 44.1, 40.7, 40.1, 38.9, 37.3, 28.2, d (25.2 and 25.0), 22.2, 21.0, 20J, 17.5, 15.3, 13.7, 13.1 , 10.6; HRMS m / z caled (M + H) + for C42H60N4O10F: 799.4288. It was found: 799.4274.

Example 10 Compound of Formula (ll) b. R is H. R1 is -CH, -CH = CH-Y, Y is 6-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of the Procedure Experimental General A. 13C NMR (100 MHz, CDCI3) d 127.8, d (204.2 and 203.9), d (165.7 and 165.5), 156.9, 149.9, 148.0, 136.1, 134.7, 132.8, 129.6, 128.4, 127.9, 127.4, 126.1 , 121.2, 103.9, d (98.8 and 96.8), 83.3, 79.4, 79.1, 79.0, 70.3, 69.5, 65J, 64.1, 58.0, 44.1, 40.6, 40.1, 38.9, 37.3, 28.2, d (25.3 and 25.1), 22.2 , 21.0, 20.7, 17.5, 15.4, 13.7, 13.2, 10.6; HRMS m / z caled (M + H) + for C42H59N3? 10F: 784.4184. It was found: 784.4172.

Example 11 Compound of the Formula (II.b. Rp is H. R1 is -CH, -CH = CH-Y. Y is 3- (1,8-naphthyridinyl, - .X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13 C NMR (125 MHz, CDCl 3) d 218.0, d (204.3 and 204.0), d (165.9 and 165.6), 157.2, 152.9, 137.4, 133.3, 131.5, 130.6, 130.4, 129.2, 125.4, 122.7, 122.4, 104.0, d (99.3 and 96.5), 83.5, 79.4, 79.4, 78.9, 70.3, 69.6, 65.7, 64.0, 58.0, 44.1, 40.7, 40.2, 38.9 , 37.3, 28.2, d (25.4 and 25.1), 22.2, 21.1, 20.8, 17.5, 15.4, 13.7, 13.1, 10.6, HRMS m / z caled (M + H) + for C4? H58N4O10F: 785.4132. Found: 785.4132 .

Example 12 Compound of Formula (ll) b. Rp is H. R1 is -CH, -CH = CH-Y. Y is 6-quinoxalinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13 C NMR (125 MHz, CDCl 3) d 217.8, d (204.1 and 203.9), d (165.9 and 165.7), 156.9, 145.1, 144.3, 143.4, 142.8, 138.5, 132.0, 129.9, 129.7, 127.8, 127.3, 104.1, d (98.7 and 97.0), 83.3, 79.6, 79.5, 78.9, 70.3, 69.6, 65.8, 64.0, 58.0, 44.2, 40.7, 40.1, 38.9, 37.4, 28.1, d (25.3 and 25.2), 22. 3, 21.1, 20.8, 17.6, 15.4, 13.7, 13.2, 10.7; HRMS m / z caled (M + H) + for C41H58N4O? 0F: 785.4131. It was found: 785.4133.

Example 13 Compound of Formula (ll) b. R p is H, R 1 is -CH? -CH = CH-Y, Y is 6- (dimethylamino) -3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of the Procedure Experimental General A. 13 C NMR (125 MHz, CDCl 3) d 217.8, d (204.2 and 203.9), d (165.7 and 165. 6), 157.2, 148.8, 145.6, 141.9, 130.8, 130.6, 129.6, 129.5, 129.5, 128.2, 119.2, 105.6, 104.0, d (98.8 and 97.1), 83.4, 79.6, 79.3, 79.0, 70. 4, 69.6, 65.8, 64.4, 58.1, 44.2, 40.7, 40.7, 40.2, 39.0, 37.4, 28.2, d (25.3 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.8, 13.2, 10.7; HRMS m / z caled (M + H) + for C44H64N4O10F: 827.4601. It was found: 827.4605.

Example 14 Compound of Formula (ll) b, Rp is H, R1 is -CH.-CH = CH-Y. Y is 6- (aminosulfonylmethyl) -3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13C NMR (125 MHz, CDCI3) d 217.6, d (204.3 and 204.1), d (165.8 and 165.6), 157.8, 148J, 144.9, 135J, 132.8, 130.7, 130.4, 130.1, 128.8, 128.6, 123.2, 116.1, 104.0, d (98.8 and 97.2), 83.8, 79.3, 79.3, 79.1, 70.4, 69.7, 65.8, 64.2, 58.4, 44.0, 40.8, 40.2, 39.2, 38.9, 37.4, 28.2, d (25.5 and 25.3), 22.4, 21.2, 20.9, 17.6 , 15.4, 13.8, 13.3, 10.8; HRMS m / z caled (M + H) + for C43H62N4O12SF: 877.4063. It was found: 877.4065.

Example 15 Compound of Formula (ll) b, Rp is H, R1 is -CH CH = CH-Y. Y is 6- (aminocarbonyl) -3-quinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13C NMR (125 MHz, CDCI3) d 218.2, d (204.3 and 204.1), 168.9, d (165.5 and 165.3), 157.5, 151.8, 148.8, 132.9, 131.6, 130.5, 129.6, 129.6, 129.6, 128.2, 127.7, 127.1, 104.1, d (98.7 and 97.1), 83.8, 79.5, 79.3, 79.2, 70.4, 69.7, 65.8, 63.8, 58.4, 44.1, 40.7, 40.2, 39.0, 37.4, 28.2, d (25.4 and 25.2), 22.3, 21.1, 21.0, 17.7, 15.5 , 13.9, 13.2, 10.6; HRMS m / z caled (M + H) + for C43H60N4OHF: 827.4237. It was found: 827.4236.

Example 16 Compound of Formula (ll) b, Rp is H, R1 is -CH.-CH = CH-Y. Y is 6- (N-methylamino) -3-guinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13C NMR (125 MHz, CDCI3) d 127.8, d (204.2 and 204.0), d (165.8 and 165.6), 157.2 147.4, 145.4, 142.7, 130.6, 130.6, 129.9, 129.8, 129.7, 128.3, 121.0, 104.1, 103.0, d (98.8 and 97.1), 83.5, 79.7, 79.3, 79.0, 70.4, 69.7, 65.9, 64.4, 58.1 ,. 44.2, 40.8, 40.2, 39.0, 37.4, 30.7, 28.2, d (25.3 and 25.2), 22.3, 21.1, 20.9, 17.7, 15.4, 13.8, 13.3, 10.7; HRMS m / z caled (M + H) + for C43H62N4O10F: 813.4445. It was found: 813.4436.

Example 17 Compound of Formula (ll) b, Rp is H, R1 is -CH CH = CH-Y. Y is 6- (formyl) -3-guinolinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13C NMR (125 MHz, CDCI3) d 218.1, d (204.4 and 204.2), 191.6, d (165.9 and 165.7), 157.2, 152.3, 150.1, 134.6, 134.3, 133.7, 130.7, 130.5, 130.4, 129.5, 127.6, 126.1, 104.1, d (98.8 and 97.2), 83.5, 79.5, 79.4, 79.0, 70.4, 69.7, 65.8, 64.1, 58.1, 44.2, 40.8, 40.2, 39.0, 37.4, 28.2, d (25.4 and 25.2), 22.3, 21.2, 20.8, 17.6, 15.4 , 13.8, 13.2, 10.7; HRMS m / z caled (M + H) + for CísHsgNaOnF: 812.4134. It was found: 812.4128.

Example 18 Compound of Formula (ll) b. R is H. R1 is -CH.-CH = CH-Y. And it is 6-R (hydroxyimino) methyl1-3-quinolinyl-, X is F A sample of Example 17 in methanol at room temperature was treated with hydroxyamine hydrochloride, concentrated, and chromatographed on silica gel to provide the main compound. 13C NMR (125 MHz, CDCI3) d 218.0, d (204.4 and 204.1), d (165.9 and 165.7), 157.4, 150.0, 149.2, 148.0, 132.9, 131.3, 130.2, 129.8, 129.6, 129.6, 128.1, 128.0, 126.3 , 104.0, d (98.8 and 97.2), 83.6, 79.5, 79.4, 79.1, 70.4, 69.6, 65.8, 64.2, 58.2, 44.2, 40.8, 40.2, 39.0, 37.4, 28.3, d (25.4 and 25.2), 22.3, 21.1 , 20.8, 17.6, 15.4, 13.8, 13.2, 10.7; HRMS m / z caled (M + H) + for CísHeo ^ OnF: 827.4237. It was found: 827.4228.

Example 19 Compound of Formula (ll) b, R is H. R1 is -CH? -CH = CH-Y. And it is 6-faminoimino (methyl) j-3-guinolinyl-, X is F A sample of Example 17 in methanol at room temperature was treated with hydrazine, concentrated, and chromatographed on silica gel to provide the main compound. 13 C NMR (125 MHz, CDCl 3) d 217.9, d (204.3 and 204.1), d (165.8 and 165. 6), 157.2, 149.7, 147.9, 142.2, 133.8, 132.6, 130.0, 130.0, 129.6, 129.3, 128.0, 126.4, 126.2, 104.1, d (98.8 and 97.2), 83.5, 79.6, 79.4, 79.0, 70.4, 69.7, 65.8, 64.3, 58.1, 44.2, 40.8, 40.2, 39.0, 37.4, 28.2, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.4, 13.8, 13.2, 10.7; HRMS m / z caled (M + H) + for C43H6? N5? 10F: 826.4397. It was found: 826.4395.

Example 20 Compound of Formula (ll) b, R is H, R 1 is -CH, -CH = CH-Y. And it is 6-rr (1-Methylethylidene) amino-minolmethylol-3-quinolinyl-, X is F A sample of Example 19 was treated with acetone at room temperature, concentrated, and chromatographed on silica gel to provide the main compound. 13C NMR (125 MHz, CDCI3) d 217.9, d (204.3 and 204.1), 167.9, d (165.9 and 165.7), 157.1, 156.8, 150.5, 148.8, 133.3, 132.9, 130.2, 129.9, 129.8, 129.7, 129.6, 127.9 , 127.1, 104.0, d (98.8 and 97.2), 83.4, 79.5, 79.4, 79.0, 70.4, 69.7, 65.8, 64.3, 58.1, 44.2, 40.8, 40.2, 39.0, 37.4. 28.2, 25.4, d (25.4 and 25.2), 22.3, 21.1, 20.8, 18.7, 17.6, 15.4, 13.8, 13.2, 10.7.

Example 21 Compound of Formula (ll) b. Rp is H. R1 is -CH CH = CH-Y. Y is 3- (5-cyano) pyridinyl-, X is F The main compound was prepared from Example 4 (Step 4a) according to Step a and Step b of General Experimental Procedure A. 13 C NMR (125 MHz, CDCl 3 ) d 218.1, d (204.4 and 204.2), d (166.1 and 165.9), 157.2, 151.2, 150.8, 135.9, 132.6, 132.1, 127.4, 116.5, 110.1, 104.0, d (98.8 and 97.2), 83.4, 79.5, 79.3 , 79.0, 70.4, 69.7, 65.8, 63.9, 58.0, 44.1, 40.9, 40.2, 38.9, 37.4, 28.1, d (25.4 and 25.2), 22.3, 21.1, 20.8, 17.6, 15.3, 13.7, 13.2, 10.8; HRMS m / z caled (M + H) + for C39H56N4O10F: 759.3579. It was found: 759.3573.

Example 22 Compound of Formula (ll) b, Rp is hydrogen, R1 is -CH? -CH = CH- Y, Y is hydrogen, X is F Step 22a: Compound of Formula (II). Rp is -C (O) CH3, R1 is -CH? -CH = CH-Y, Y is hydrogen. X is F The compound 1_5 of Scheme 3, wherein Rp is acetyl and Y is hydrogen, was processed as described in Step 4a to provide the main compound. MS (DCI / NH3) m / z 697 (M + H) +; 13C NMR (75 MHz, CDCI3) d 216.2, d (203.6 and 203.2), 169.7, d (165.8 and 165.5), 157.4, 101.6, d (99.2 and 96.4), 83.5, 80.4, 80.2, 78.8, 78.6, 74.0, 71.6, 69.3, 63.2, 57.6, 50.3, 44.1, 40.6, 40.4, 38.1, 37.4, 30.8, 30.5, d (25.2 and 24.9), 22.2, 21.3, 20.9, 20.1, 17.8, 14.8, 13.7, 13.3, 10.6; Step 22a: Compound of Formula (II), Rp is hydrogen, R1 is -CH, -CH = CH-Y, Y is hydrogen. X is F The compound described in Step 22a is processed as described in Step 4b to provide the main compound. General experimental procedure B: using the Sonogashira reaction for the preparation of compounds of Formula II (c), wherein Y is different from hydrogen, Rp is hydrogen, X is F A mixture of a compound of Formula II (c), where Y is hydrogen, Rp is -C (O) CH3 and X is F (1 equivalence) and Pd (PPh3) 2CI2 (0.02 equivalences) in 5: 1 acetonitplo: triethyl amine was degassed and filled with nitrogen, treated sequentially with Cul (0.01 equivalences) and an aryl halide or arylacyl halide (2-3 equivalences), it was stirred at room temperature for 10 minutes, heated at 70 ° C for 6-24 hours, diluted with ethyl acetate or isopropyl acetate, sequentially rinsed with water and saline, dried and chromatographed on silica gel to give protected 2'-protected compound of Formula II (c), wherein Y is different from hydrogen H and Rp -C (O) CH3. Step b: Compound of Formula (II), Rp is hydrogen, R1 is -CH? -CH = CH-Y, Y is different from hydrogen, X is F The conversion of the compounds of Formula II (c), where Y is different from hydrogen, Rp is -C (O) CH3 and X is F in compounds of Formula II (c), wherein Y is different from hydrogen, Rp is hydrogen and X is F, was carried out by agitation of the compounds of Formula II (c), wherein Y is different from hydrogen, X is F and Rp -C (O) CH 3 reflux or at room temperature in methanol overnight to give the main compound after the purification by column chromatography on silica gel.

Example 23 Compound of Formula (II), R is hydrogen. R is -CH, -CH = CH-Y, Y is phenylcarbonyl-, X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of General Experimental Procedure B. 13C NMR (75 MHz, CDCI3) d 215.9, d (204.3 and 203.9), 177.8, d (166.2 and 166.9), 157.5, 136.4, 134.1, 129.9, 128.5, 104.1, d (98.9 and 96.1), 91.3, 84.1, 83.2, 80.8, 80.7, 78.9, 70.2, 69.5, 65.8, 58.2, 50.3, 44.0, 40.3, 40. 1, 38.2, 37.7, 31.5, d (25.5 and 25.2), 22.2, 21.2, 20.3, 17.7, 15.5, 14.1, 13.8, 13.3, 10.5; HRMS m / z caled (M + H) + for CíoHseNsOnF: 759.3868. It was found: 759.3888.

Example 24 Compound of Formula (II). R is hydrogen. R1 is -CH.-CH = CH-Y, Y is 2-thienylcarbonyl-, X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of General Experimental Procedure B. 13 C NMR (125 MHz, CDCl 3) d 216.1, d (204.3 and 203.9), 169.5, d (166.2 and 166.9), 157.4, 144.4, 135.8, 135.4, 128.2, 104.2, d (98.9 and 96.1), 89.6, 83.5, 83.2, 80.9, 80.6, 78.9, 70.3, 69.8, 65.8, 58.2, 50.3, 44.0, 40.3, 40. 2, 38.2, 37.7, 28.2, d (25.5 and 25.2), 22.2, 21.2, 20.3, 17.7, 15.5, 13.8, 13.3, 10.5; HRMS m / z caled (M + H) + for CssHs ^ OnFS: 765.3427. Found: 765.3429.

Example 25 Compound of Formula (II), Rp is hydrogen, R1 is -CH? -CH = CH-Y, Y is (6-chloro-3-pyridinyl) carbonyl-, X is F The main compound was prepared from of Example 22 (Step 22a) according to Step a and Step b of General Experimental Procedure B. MS (DCI / NH3) m / z 794 (M + H) +; 13 C NMR (125 MHz, CDCl 3) d partial 217.7, d (203.3 and 202.9), d (172.8 and 172.5), 157.4, 144.5, 132.8, 124.1, 104.8, d (92.2 and 87.6).

Example 26 Compound of Formula (II). R p is hydrogen, R 1 is -CH, -CH = CH-Y, Y is 3-guinolinyl-, X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of the Procedure Experimental General B. 13 C NMR (125 MHz, CDCl 3) d 216.7, d (204.1 and 203.8), d (166.0 and 165.8), 157.3, 152.3, 146.9, 138.5, 129.9, 129.2, 127.8, 127.3, 127.0, 117. 1, 104.1, d (98.5 and 96.8), 89.4, 83.5, 82.9, 80.3, 80.0, 78.6, 70.3, 69. 7, 65.7, 58.0, 51. or, 44.2, 40.6, 40.2, 38.5, 37.4, 29.2, 28.1, d (25.2 and 25.0), 22.2, 21.2, 20.2, 17.6, 15.4, 13.7, 13.2, 10.6; Anal. Caled for C42H56FN3O10: C, 64.52, H, 7.22, N, 5.37. Found: C, 64.26, H, 7.37, N, 5.04; HRMS m / z caled (M + H) + for C42H57N3O10FS: 782.4028. It was found: 782.4003.

Example 27 Compound of Formula (II), Rp is hydrogen. R1 is -CH? -CH = CH-Y, Y is 8-sulfonylamino-3-guinolinyl-, X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of the Procedure Experimental General B. 13C NMR (125 MHz, CDCI3) d 216.9, d (204.2 and 203.9), d (166.0 and 165.8), 157.4, 153.3, 141.6, 139.1, 138.6, 132.9, 129.3, 127.9, 126.2, 118.5, 104.1 , d (98.5 and 96.8), 91.1, 83.6, 81.9, 80.4, 79.8, 78.6, 70.3, 69.7, 65.7, 58.0, 51.0, 44.2, 40.6, 40.1, 38.3, 37.4, 28.1, d (25.3 and 25.1), 22.2 , 21.2, 20.3, 17.6, 15.3, 13.7, 13.2, 10.6; HRMS m / z caled (M + H) + for C42H58N4O12FS: 861.3756. It was found: 861.3751.

Example 28 Compound of Formula (II), Rp is hydrogen. R1 is -CH? -CH = CH-Y, Y is (2,2'-bistiene) -5-yl-. X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of General Experimental Procedure B. 13 C NMR (125 MHz, CDCl 3) d 216.6, d (204.1 and 203.8), d (165.8 and 165.6), 157.2, 138.9, 136.8, 133.3, 127.8, 124.7, 124.3, 123.5, 121.5, 104.1, d (98.4 and 96.8), 90.8, 83.5, 80.1, 79.0, 78.8, 70.3, 69.7, 65.8, 58.1 , 51.2, 44.2, 40.5, 40.2, 38.4, 37.4, 28.2, d (25.3 and 25.2), 22.3, 21.1, 20.3, 17.7, 15.4, 13.8, 13.3, 10; HRMS m / z caled (M + H) + for C? H56N2O10FS2: 819.3360. It was found: 819.3353.

Example 29 Compound of Formula (II), Rp is hydrogen, R1 is -CH CH = CH-Y, Y is r5- (2-pyridyl) -2-thienylol-. X is F The main compound was prepared from Example 22 (Step 22a) according to Step a and Step b of the Procedure Experimental General B. 13C NMR (125 MHz, CDCI3) d 216.3, d (203.9 and 203.7), d (165.8 and 165.6), 157.2, 152.0, 149.5, 145.9, 136.5, 133.3, 124.5, 124.4, 122.0, 118.9, 104.1 , d (98.4 and 96.8), 91.2, 83.4, 80.1, 80.1, 79.3, 78.7, 70.3, 69.6, 65.8, 58.1, 51.1, 44.1, 40.4, 40.1, 38.3, 37.4, 28.2, d (25.3 and 25.1), 22.2 , 21.1, 20.2, 17.6, 15.3, 13.7, 13.2, 10.6. Examples 30 to 97 can be prepared according to the procedures described in Examples 1 to 29 and the synthetic schemes and discussions discussed herein.

Example 30 Compound of Formula (ll) b, R is H. R is -CH, -CH = CH-Y. Y is 5- (3-pyridinyl) -2-pyrrolyl-, X is F Example 31 Compound of the Formula (ll.b. R is H. R1 is -CH7-CH = CH-Y, Y is 5- (2 -pyrazinyl) -2-pyrrolyl-, X is F Example 32 Compound of Formula (ll) b. Rp is H, R1 is -CH, -CH = CH-Y. And it is 5- (4-pyridinyl) -2-pyrrolyl-, X is F Example 33 Compound of Formula (ll) b, Rp is H. R1 is -CH, -CH = CH-Y. And it is 5- (2-pyridinyl) -2-pyrrolyl-, X is F Example 34 Compound of Formula (ll) b. Rp is H. R1 is -CH7-CH = CH-Y, Y is 2-guinoxalinyl-, X is F Example 35 Compound of Formula (ll) b. Rp is H. R1 is -CH, -CH = CH-Y, and is - (1-methyl-2-pyridinyl) -2-pyrrolyl-, X is F Example 36 Compound of Formula (ll) b, Rp is H. R1 is -CH CH = CH-Y, Y is - (1-methyl-2-pyrazinyl) -2-pyrrolyl-, X is F Example 37 Compound of Formula (ll) b. Rp is H. R1 is -CH7-CH = CH-Y. And it's 5- (2-pyrazinyl) -2-furanyl-, X is F Example 38 Compound of the Formula (II, b.Rp is H. R1 is -CH? -CH = CH-Y, Y is 5- (3-pyridinyl) -2-furanyl-, X is F Example 39 Compound of Formula (ll) b, Rp is H, R1 is -CH? -CH = CH-Y. And it is 5- (2-pyridinyl) -2-furanl-, X is F Example 40 Compound of Formula (ll) b. Rp is H. R1 is -CH7-CH = CH-Y, and is 7r (methoxyimino) methylol-7-quinoxalinyl-, X is F Example 41 Compound of Formula (ll) b. R is H. R1 is -CH, -CH = CH-Y. And it is 5- (3-pyridinyl) -2-thienyl-, X is F Example 42 Compound of Formula (ll) b. Rp is H, R1 is -CH? -CH = CH-Y. And it is 5- (2-pyrazinyl) -2-thienyl-, X is F Example 43 Compound of Formula (ll) b. Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (4-pyridinyl) -2-thienylol Example 44 Compound of Formula (ll) b. Rp is H. R1 is -CH7-CH = CH-Y. And it is - [5- (aminocarbonyl) -3-pyridinyl1-2-thienyl-, X is F Example 45 Compound of Formula (ll) b. Rp is H, R1 is -CH? -CH = CH-Y. And it is 5- (2-thiazoyl) -2-thienyl-, X is F Example 46 Compound of Formula (ll) b, Rp is H, R1 is -CH? -CH = CH-Y. And it's 5- (5-thiazoyl) -2-thienyl-, X is F Example 47 Compound of Formula (ll) b, Rp is H, R 1 is -CH, -CH = CH-Y. Y is 5- [2- (methyl) -5-thiazoyl-2-thienyl-, X is F Example 48 Compound of Formula (ll) b, Rp is H, R1 is -CH? -CH = CH-Y, Y is 7 - [(hydroxyamino) methylol-7-quinoxalinyl-, X is F Example 49 Compound of Formula (ll) b, Rp is H, R1 is -CH? -CH = CH-Y, Y is 5- (5-pyrimidinyl) -2-thienyl-, X is F Example 50 Compound of Formula (ll) b, Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (2-pyrimidinyl) -2-thienyl-, X is F Example 51 Compound of Formula (ll) b. Rp is H, R1 is -CH CH = CH-Y. And it is -f5- (methoxycarbonyl) -3-pyridinyl) -2-thienyl-, X is F Example 52 Compound of Formula (ll) b, Rp is H, R1 is -CH CH = CH-Y, Y is 5-thienoir-2,3-blpyridinyl-, X is F Example 53 Compound of Formula (ll) b, Rp is H, R1 is -CH, -CH = CH-Y, Y is 1H-pyrrolor2,3-blpyridinyl-, X is F Example 54 Compound of Formula (ll) b, Rp is H, R1 is -CH? -CH = CH-Y, and is 3H-3-methylimidazor4,5-b1pyridinyl-, X is F Example 55 Compound of Formula (ll) b, Rp is H, R1 is -CH CH = CH-Y, Y is 6-carboxy-3-quinolinyl-, X is F Example 56 Compound of Formula (II) b, Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (2-thienyl) -2-t¡azoyl-, X is F Example 57 Compound of Formula (ll) b. Rp is H. R1 is -CH, -CH = CH-Y, Y is 2- (2-thienyl) -5-thiazoyl-, X is F Example 58 Compound of Formula (ll) b. Rp is H, R1 is -CH CH = CH-Y, Y is 2- (3-pyridyl) -5-thiazoyl-, X is F Example 59 Compound of Formula (ll) b. R is H, R1 is -CH CH = CH-Y, Y is 5- (3-pyridyl, -2-thiazoyl-, X is F Example 60 Compound of Formula (ll) b. Rp is H. R1 is -CH CH = CH-Y, Y is 5- (2-pyrazinyl) -3-pyridinyl-, X is F Example 61 Compound of Formula (ll) b, Rp is H. R1 is -CH CH = CH-Y, Y is -f (2-pyridinylamino) carbonylol-3-pyridinyl-, X is F Example 62 Compound of Formula (ll) b. Rp is H. R1 is -CH CH = CH-Y, Y is 5-((3-pyridinylamino) carbonyl1-3-pyridinyl-, X is F Example 63 Compound of Formula (ll) b, Rp is H, R1 is -CH CH = CH-Y, Y is 5-rr (4-chlorophenyl) amino-1-carbonyl-3-pyridinyl-, X is F Example 64 Compound of Formula (ll) c, R is H, R 1 is -CH CH = CH-Y. And it is 5- (3-pyridinyl) -2-pyrrolyl-, X is F Example 65 Compound of Formula (ll) c, Rp is H, R1 is -CH? -CH = CH-Y, Y is 5- (2-pyrazinyl) -2-pyrrolyl-. X is F Example 66 Compound of Formula (ll) c. Rp is H. R is -CH? -CH = CH-Y, Y is 5- (4-pyridinyl) -2-pyrrolyl-, X is F Example 67 Compound of Formula (ll) c, Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (2-pyridinyl) -2-pyrrolyl-, X is F Example 68 Compound of Formula (ll) c, Rp is H, R1 is -CH, -CH = CH-Y, Y is 2- guinoxalinyl-, X is F Example 69 Compound of the Formula (ll.c. Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (1-methyl-2-pyridinyl) -2-pyrrolyl-, X is F Example 70 Compound of Formula (ll) c. Rp is H, R1 is -CH7-CH = CH-Y, Y is 5- (1-methyl-2-pyrazinyl) -2-pyrrolyl-, X is F Example 71 Compound of Formula (ll) c. Rp is H, R1 is -CH, -CH = CH-Y. And it's 5- (2-pyrazinyl) -2-furanyl-, X is F Example 72 Compound of the Formula (ll.c. Rp is H. R1 is -CH, -CH = CH-Y, Y is 5- (3-pyridinyl) -2-furanyl-, X is F Example 73 Compound of Formula (ll) c, R is H. R1 is -CH? -CH = CH-Y. And it is 5- (2-pyridinyl) -2-furanyl-, X is F Example 74 Compound of Formula (ll) c, Rp is H, R1 is -CH? -CH = CH-Y. Y is 7- [(methoxyimino) methylol-7-guinoxalinyl-, X is F Example 75 Compound of Formula (II) c, R is H, R1 is -CH? -CH = CH-Y, Y is 5- ( 3-pyridinyl) -2-thienyl-, X is F Example 76 Compound of Formula (ll) c. Rp is H, R1 is -CH, -CH = CH-Y. And it is 5- (2-pyrazinyl) -2-thienyl-, X is F Example 77 Compound of Formula (ll) c, Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (4-pyridinyl) -2-thienill Example 78 Compound of Formula (ll) c. Rp is H. R1 is -CH CH = CH-Y. Y is 5- [5- (aminocarbonyl) -3-pyridinyl-2-thienyl-, X is F EXAMPLE 79 Compound of Formula (ll) c, Rp is H, R 1 is -CH? -CH = CH-Y, Y is 5- (2-thiazoyl) -2-t¡en¡l-. X is F Example 80 Compound of the Formula (I Me. Rp is H, R is -CH CH = CH-Y, Y is 5- (5-thiazoyl) -2-thienyl-, X is F Example 81 Compound of the Formula (II) ) c, Rp is H. R1 is -CH, -CH = CH-Y. Y is 5- f2- (methyl) -5-thiazoyl1-2-thienyl-, X is F Example 82 Compound of the Formula (I Me Rp is H. R1 is -CH? -CH = CH-Y.) Y is 7- (hydroxyimino) methylol-7-guinoxalinin-, X is F Example 83 Compound of the Formula (Ie, R is H, R1 is -CH, -CH = CH-Y, Y is 5- (5-pyrimidinyl) -2-thienyl-, X is F Example 84 Compound of the Formula (ll.c. Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (2-pyrimidinyl) -2-thienyl-, X is F Example 85 Compound of Formula (ll) c, R is H, R 1 is -CH CH = CH-Y, Y is 5- r 5 - (methoxycarbonyl) -3-pyridinyl) -2-thienyl-, X is F Example 86 Compound of the Formula (I Me. Rp is H, R1 is -CH CH = CH-Y, Y is 5- tienolf2.3-blpiridinyl-, X is F Example 87 Compound of the Formula (IMc, R is H, R1 is -CH.-CH = CH-Y, Y is 1 / - / - pyrrolor2.3-b1pyridinyl-, X is F Example 88 Compound of the Formula (IMc.Rp is H. R1 is -CH, -CH = CH-Y, Y is 3 / - / - 3-methylimidazo [4,5-blpyridinyl-, X is F Example 89 Compound of the Formula (IMc.Rp is H, R1 is -CH.-CH = CH-Y, Y is 6- carboxy-3-guinolinyl-, X is F Example 90 Compound of the Formula (IMc, Rp is H, R1 is -CH, -CH = CH-Y, Y is 5- (2-thienyl) -2-thiazoyl-, X is F Example 91 Compound of the Formula (IMc R is H. R1 is -CH, -CH = CH-Y, Y is 2- (2-thienyl) -5-thiazoyl-, X is F Example 92 Compound of the Formula (IMc, Rp is H, R1 is -CH? -CH = CH-Y.) Y is 2- (3-pyridyl) -5-thiazoyl-, X is F Example 93 Compound of the Formula (IMc.Rp is H. R1 is -CH, -CH = CH-Y. Y is 5- (3-pyridyl) -2-thiazoyl-, X is F Example 94 Compound of the Formula (I Mc, Rp is H, R1 is -CH? -CH = CH-Y, Y is 5- (2-pyrazinyl) -3-pyridinyl-, X is F Example 95 Compound of the Formula (IMc, Rp is H, R1 is -CH? -CH = CH-Y.) Y is 5- f (2-pyridinylamino) carbonyl1-3-pyridinyl-, X is F Example 96 Compound of the Formula (I Mc, Rp is H, R1 is -CH? -CH = CH-Y, Y is 5- f (3-pyridinylamino) carbonylol-3-pyridinyl-, X is F Example 97 Compound of the Formula (l 1) c R is H, R 1 is -CH, -CH = CH-Y, Y is 5- ff (4-chlorophenyl) aminolcarbonyl 1-3-pyridinyl-, X is F

Claims (10)

1. REVIVAL NAME IS 1. A compound selected from the group consisting of: and pharmaceutically acceptable salts and esters thereof, wherein R p is hydrogen or a hydroxy protecting group; X is F, Cl. Br, or I; and R1 is selected from the group consisting of: (1) d-Cβ-alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c) ), heteroaryl, (d) substituted heteroaryl, (e) -NR3R4 wherein R3 and R4 are independently selected from hydrogen and d -Cs-alkyl, or R3 and R4 are taken together with the atom to which they are attached, to form a 3-7 member integrated ring containing a residue selected from the group consisting of -O-, -NH-, N (C? -C? -alkyl-) -, N (aryl-C? -C-) alkyl-) -, -N (substituted aryl-C? -C6-alkyl-) -, -NIheteroaryl-CT-Ce-alkyl-) -, and -N (substituted heteroaryl-CT-Ce-alkyl-) -; (2) -CH2-CH = CH-Y, wherein Y is selected from the group consisting of: (a) H, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) heteroaryl substituted, (f) -CH = H2, (g) -CH = CH-aryl, (h) -CH = CH-substituted aryl, (i) -CH = CH-heteroaryl, and (j) -CH = CH- substituted heteroaryl, (k) (aryl) oil, (I) (substituted aryl) oil, and (n) (substituted heteroaryl) oil; and (3) -CH2-C = CY, wherein Y is as previously defined, with the proviso that in the compounds of Formula (II) wherein R1 is selected from option (1), the group C? -C6-alkyl must be substituted. 2. A compound according to claim 1, characterized in that it is selected from the group consisting of: Compound of Formula (I), Rp is H, R1 is methyl, X is F Compound of Formula (I), Rp is H, R1 is methyl, X is Cl Compound of Formula (I), Rp is H, R1 is methyl, X is Br Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH- And, Y is hydrogen, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is (3-quinolyl), X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is 6-nitro-3-quinolinyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is phenyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-β-trimethoxycarbonylamino-3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-amino-3-quinolinyl-, X is F; Compound of Formula (II) b > R p is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-quinolinyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 3- (1,8-naphthyridinyl) -, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6-quinoxalinyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6- (dimethylamino) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R 1 is -CH 2 -CH = CH-Y, Y is 6- (aminosulfonylmethyl) -3-quinolinyl-, X is F; Compound of Formula (II) or, Rp is H, R1 is -CH2-CH = CH-Y, Y is 6- (aminocarbonyl) -3-quinolinyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6- (N-methylamino) -3-quinolinyl-, X is F; Compound of Formula (ll) t > , Rp is H, R1 is -CH2-CH = CH-Y, Y is 6- (formyl) -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is 6 - [(hydroxyimino) methyl] -3-quinolinyl-, X is F; Compound of Formula (ll) b, R is H, R 1 is -CH 2 -CH = CH-Y, Y is 6- [aminoimino (methyl)] - 3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is 6 - [[(1-methylethylidene) aminoimino] methyl] -3-quinolinyl-, X is F; Compound of Formula (ll) b, Rp is H, R1 is -CH2-CH = CH-Y, Y is 3- (5-cyano) pyridinyl-, X is F; Compound of Formula (II), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is hydrogen, X is F; Compound of Formula (II), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is phenylcarbonyl-, X is F; Compound of Formula (II), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is 2-thienylcarbonyl-, X is F; Compound of Formula (II), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is (6-chloro-3-pyridinyl) carbonyl-, X is F; Compound of the Formula (I I), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is 3-quinolinyl-, X is F; Compound of the Formula (I I), Rp is hydrogen, R1 is -CH2-CH = CH-Y,
2. Y is 8-sulfonylamino-3-quinolinyl-, X is F; Compound of the Formula (I I), Rp is hydrogen, R1 is -CH2-CH = CH-Y, Y is (2,2'-bistiene) -5-yl-,
3. X is F; and Compound of Formula (II), Rp is hydrogen, R is -CH2-CH = CH-Y, and is [5- (2-pyridyl) -2-thienyl] -, X is F. 3. A com position for treating bacterial infections comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable ester or salt thereof in combination with a pharmaceutically acceptable carrier.
4. 4. A method for treating bacterial infections comprising administering to a mammal in need of such treatment, a pharmaceutical composition containing a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable ester or salt thereof.
5. 5. A compound according to claim 1, characterized in that it has the formula (I)
6. 6. A compound according to claim 5, characterized in that X is F.
7. 7. A compound according to claim 1, characterized in that it has the formula (II)
8. 8. A compound according to claim 7, characterized in that X is F.
9. 9. A compound according to claim 1, characterized in that it has the formula (ll) b
10. 10. A process for preparing a compound having the formula wherein wherein R p is hydrogen or a hydroxy protecting group; X is F, Cl. Br, or I; and R1 is selected from the group consisting of: (1) C? -C6-alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c), heteroaryl, (d) substituted heteroaryl, (e) -NR3R4 wherein R3 and R4 are independently selected from hydrogen and C? -C3-alkyl, or R3 and R4 are taken together with the atom to which unite, to form a ring integrated by 3-7 members containing a residue selected from the group consisting of -O-, -NH-, N (d-C6-alkyl-) -, N (aryl-C? -C6-alkyl-) -, -N (substituted aryl-dd-alkyl-) -, -N (heteroaryl-C? -C6-alkyl-) -, and N (substituted-heteroaryl-d-Cß-alkyl-) -; (2) -CH2-CH = CH-Y, wherein Y is selected from the group consisting of: (a) H, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) heteroaryl substituted, (f) -CH = H2, (g) -CH = CH-aryl, (h) -CH = CH-substituted aryl, (i) -CH = CH-heteroaryl, and (j) -CH = CH- substituted heteroaryl, (k) (aryl) oil, (I) (substituted aryl) oil, and (n) (substituted heteroaryl) oil; and (3) -CH2-C = CY, wherein Y is as previously defined, with the proviso that in the compounds of Formula (II) wherein R1 is selected from option (1), the group d -C6-alkyl must be replaced. , the method comprising (a) treating a compound selected from the group consisting of respectively, with a halogenation reagent, and optionally without protection. eleven . The process according to claim 9, characterized in that the halogenation reagent is selected from the group consisting of? / -fluorobenzenesulfonim in the presence of the base, 1.0% of F2 in formic acid, 3,5-dichloro tetrafluoroborate. -1-fluoropyridinium, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2) 2NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of the base,? / - fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presence of the base, hexachloroethane in the presence of the base, CF3CF2CH2ICI2, SOCI2, CF3SO2CI in the presence of the base, Cl2, NaOCI in the presence of acetic acid, Br2 »pyridinium * H Br, Br2 / acetic acid, N -bromosuccinamide in the presence of the base, LDA / BrCH2CH2Br, LDA / CBr4,? / - Yodosuccinimide in the presence of the base, and l2. The process according to claim 9, characterized in that the product is of the formula (I), X is F and the halogenation reagent is? / -fluorobenzenesulfonimide in the presence of sodium hydride. The process according to claim 9, characterized in that the product is of the formula (I I), X is F and the halogenation reagent is? / -fluorobenzenesulfonimide in the presence of sodium hydride. The process according to claim 13, characterized in that R1 is -CH2-CH = CH-Y and Y is selected from the group consisting of (3-q uinolyl), 6-nitro-3-q quinolinyl-, phenyl-, 6-trimethoxycarbonylamino-3-quinolinyl, 6-amino-3-quinolinyl-, 6-q-quinolinyl-, 3- (1,8-naphthyridinyl) -, 6-quinoxalinyl-, 6- (dimethylamino) -3- quinolinyl-, 6- (aminosulfonylmethyl) -3-quinolinyl-, 6- (aminocarbonyl) -3-quinolinyl-, 6- (N-methanollam) -3-quinolinyl-, 6- (formyl) -3-quinolinyl -, 6- [(hydroxy-amino) methyl] -3-quinolinyl-, 6- [aminoimino (methyl)] - 3-quinolinyl-, 6 - [[(1-methylethylidene) aminoimino] methyl] -3-quinolinyl -, and 3- (5-cyano) pyridinyl-.