MXPA00004227A - 6,11-bridged erythromycin derivatives - Google Patents

Abstract

Novel 6,11-bridged erythromycin compounds 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

ERYTHROMYCIN DERIVATIVES UNITED IN 6.11 This application is a continuation in part of the patent application Serial No. 960,400, filed on October 29, 1997. Field of the Invention This invention relates to novel semi-synthetic macrolides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and a medical treatment method. More particularly, the invention relates to novel derivatives of erythromycin bound in 6,11, methods for preparing the same, compositions containing these compounds and a method for treating bacterial infections with said compositions. Background of the Invention Erythromycins A to D are represented by the formula (E), (E) are well known and potent antibacterial agents, widely used to treat and prevent bacterial infection. They have identified with other antibacterial agents, however, bacterial strains have insufficient resistance or susceptibility to erythromycin. Also, erythromycin A has only weak activity against Gram negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds having improved antibacterial activity, which have less potential for the development of resistance, which have the desired Gram negative activity, or which have unexpected selectivity against target microorganisms. Consequently, numerous researchers have prepared chemical derivatives of erythromycin 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.:187 (1984). Morimoto et al. Also describe derivatives of 6-O-alkyl erythromycin A in J. Antibiotics, 43: 286 (1990) and in U.S. Patent 4,990,602. U.S. Patent 5,444,051 discloses certain 3-O-substituted-3-oxoerythromycin A derivatives. The PCT application WO 97/10251, published on March 20, 1997, describes the intermediates useful for the preparation of erythromycin 3-decladeose 6-O-methyl derivatives. U.S. Patent 5,403,923 discloses certain 6-O-methyl erythromycin A derivatives, and the US Pat.

No. 5,527,780 describes bicyclic derivatives of 6-O-methyl-3-oxoerythromycin A. The PCT application WO 97/17356, published May 15, 1997, describes tricyclic erythromycin A 6-O-methyl derivatives. Certain intermediates of the present invention are described in the U.S. Patent Application. Series Number 08 / 888,350. SUMMARY OF THE INVENTION The present invention provides a novel class of 6,11 erythromycin derivatives having antibacterial activity. In one aspect of the present invention are compounds, or pharmaceutically acceptable salts and esters thereof, having the formula selected from the group consisting of: (I) wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, or 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or is selected from the group consisting of: (1) -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C ^ Ce alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2 ) q-, (3) -C (O) -O- (CH2) q-, (4) -C (O) -NR1- (CH2) q-, wherein R1 is as previously defined, and (5) ) -N = CH- (CH2) q-; [6) -CH (OH) - (CH2) q-, and [7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or selected from the group consisting of X) alkylene, 2) arylene, 3) substituted arylene, [4) heteroarylene, 5) substituted heteroarylene; 6) alkenylene-arylene, 7) arylene-arylene, 8) substituted arylene-arylene, '9) heteroarylene-arylene, 10) substituted heteroarylene-arylene, 11) alkenylene-heteroarylene,' 12) arylene-heteroarylene, 13) arylene -substituted heteroarylene, 14) heteroarylene-heteroarylene, and; 15) heteroarylene-substituted heteroarylene; E is absent or is selected from the group consisting of: 1) - (CH2) r-CH = CH-, [2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , 3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, 4) - (CH2) rC (O) -O-, 5) - (CH2) rN ( R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are absent then m can not be 0, that when E is -CH = CH- and portions A, B and D are absent then m can not be 0, and that B can be -N = CH- (CH2) q- only when a is absent and m is 0. The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound, as defined above, in combination with a pharmaceutically acceptable carrier. The invention further relates to a method for treating bacterial infections in a host mammal in need of such treatment, which comprises 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, processes are provided for the preparation of erythromycin derivatives linked in 6,11 of Formula (I) above. Detailed Description of the Invention Definitions As used throughout this specification and the appended claims, the following terms have the specified meanings. The terms "C, -C3 alkyl," "C, -C6 alkyl" and "0, -0.2" alkyl as used herein, refer to straight or branched chain hydrocarbon radicals, saturated , derived from a portion of hydrocarbon 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 C, -C3 alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of C, -C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, fer-butyl, noepentyl and n-hexyl. Examples of C, -C, 2 alkyl radicals include, but are not limited to, all of the above examples such 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-C12 alkenyl" denotes a monovalent group derived from a hydrocarbon portion containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by the removal of a single hydrogen atom .

Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. The term "C2-C2 alkenylene" denotes a divalent group derived from a hydrocarbon portion containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by the removal of two hydrogen atoms . Alkenylene 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 "C, -Cβ alkoxy," as used herein, refers to an alkyl group of C, -Cβ, as previously defined, attached to a parent molecular moiety through an oxygen atom. Examples of C, -Cβ alkoxy, but are not limited to, methoxy, ethoxy, propoxy, / so-propoxy, n-butoxy, fer-butoxy, neo-pentoxy and n-hexoxy. The term "C, -C3 alkylamino", as used herein, refers to one or two C, -C3 alkyl groups, as previously defined, attached to a parent molecular moiety through a nitrogen atom . Examples of C, -C3 alkylamino 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 protons, that is, 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 will be obvious to those skilled in the art of individual solvents or mixtures thereof, therefore, they may be preferred for specific compounds and reaction conditions, depending on such factors as the solubility of reagents, reactivity of the reagents and preferred temperature scales, for example. Additional discussions of aprotic solvents can be found in textbooks of organic chemistry or in specialized monographs, for example: Oraanic Solvents Phvsical Properties and Methods of Purification. 4th ed., Edited by John A. Riddick et al., Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term "aryl", as used herein, refers to a monocyclic or bicyclic carbocyclic ring system radical, derived from a hydrocarbon portion containing one or two aromatic rings, respectively, by removing a single hydrogen atom. Said aryl radicals include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The term "arylene" denotes a divalent group derived from an aryl moiety, as previously defined, by the removal of two hydrogen atoms. Arylene groups include, for example, 1,2-phenyl, 1,3-phenyl, 1,4-phenyl, 1,2-naphthyl, 1,4-naphthyl, 1,6-naphthyl and the like. The term "C3-C7 cycloalkyl" denotes a monovalent group derived from a carbocyclic, saturated, monocyclic or bicyclic ring compound by 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, refer to an atom selected from fluorine, chlorine, bromine and iodine. The term "alkylamino" refers to a group having the structure -NHR 'wherein R' is alkyl, as previously defined. Examples of alkylamino include methylamino, ethylamino, / so-propylamino and the like. The term "dialkylamino" refers to a group having the structure -NR'R ", wherein R 'and R" independently are 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, dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino and the like. "haloalkyl" denotes an alkyl group, as defined above, having one, two or three halogen atoms attached they are exemplified by said 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 moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like. The term "thioalkoxy" refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a sulfur atom. The term "carboxyaldehyde", 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 "independently are selected from hydrogen or alkyl, or R 'and R" taken together they may optionally be - (CH2) k-, where 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 carbon atoms. ring of which a 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 is bound to the rest of the molecule via any of the ring atoms, such as, by for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl and the like. The term "heteroarylene" denotes a divalent group derived from a heteroaryl moiety, as previously defined, by the removal of two hydrogen atoms. Heteroarylene groups include, for example, 2,3-pyridyl, 2,4-pyridyl, 2,6-pyridyl, 2,3-quinolyl, 2,4-quinolyl, 2,6-quinolyl, 1,4-isoquinolyl, 1,6-isoquinolyl and the like. The term "heterocycloalkyl", as used herein, refers to a ring system of 3 to 10 members, partially unsaturated or fully saturated, non-aromatic, including single rings of 3 to 8 atoms in size and ring systems bi-or tri-cyclics which may include aromatic, six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocycloalkyl rings include those having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom 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 moiety through an alkylene group wherein the alkylene group is one to four carbon atoms . The "hydroxy protecting group", as used herein, refers to an easily removable group that is known in the art to protect a hydroxyl group against an undesirable reaction during synthesis procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art for protecting groups against undesirable reactions during a synthesis process and most of the protecting groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Oraanic Svnthesis. 2a. edition, John Wiley & Sons, New York (1991). Examples of the hydroxy protecting groups include, but are not limited to, methylthiomethyl, urea-dimethylsilyl, urea-butyldiphenylsilyl, ethers such as methoxymethyl and esters including acetyl benzoyl and the like. The term "ketone protecting group", as used herein, refers to an easily removable group that is known in the art to protect a ketone group against undesirable reactions during synthesis procedures and to be selectively removable. The use of ketone protecting groups is well known in the art for protecting groups against undesirable reactions during a procedure of synthesis and most of said protection groups are known, c.f., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Oraanic Svnthesis. 2a. edition, John Wiley & Sons, New York (1991). Examples of ketone protecting groups include, but are not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime and the like. The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group, as defined above, is replaced with a single oxygen atom (ie, a carbonyl group). The term "N-protecting group" or "N-protected", as used herein, refers to those groups intended to protect an amino group against undesirable reactions during the synthesis procedures. The N-protecting groups comprise carbamates, amides including those containing heteroaryl groups, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivatives, mine 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 N-protecting groups are described in T.H. Greene and P.G.M. Wuts, Protective Groups in Oraanic Svnthesis. 2a. edition, John Wiley &; Sons, New York (1991), which is incorporated here as a reference.

The term "protected amino" refers to an amino group protected with an N-protecting group, as defined above, including benzoyl, acetyl, tri-methylamino, triethylsilyl, methoxymethyl groups, for example. The term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc) groups , and benzyloxycarbonyl (Cbz), for example. The term "protogenic organic solvent," as used herein, refers to a solvent that tends 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 such factors as the solubility of reagents. , reactivity of the reagents and preferred temperature scales, for example. Additional discussions of protogenic solvents can be found in organic chemistry textbooks or in specialized monographs, for example: Orqanic Solvents Phvsial Properties and Methods of Purification. 4a. ed., edited by John A. Riddick et al., Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY. 1986 The term "substituted aryl", as used herein, refers to an aryl group, as defined herein, substituted by independently replacing one, two or three of the hydrogen atoms thereof with halo, hydroxy, cyano, C, -C3 alkyl, C, -C6 alkoxy, C, -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. Also, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "substituted arylene", as used herein, refers to an arylene group, as defined herein, substituted by the independent replacement of one, two or three of the hydrogen atoms thereof with halo, hydroxy, cyano, C, -C3 alkyl, C, -C6 alkoxy, C, -C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino alkylamino, dialkylamino, acylamino, mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl or carboxamide . In addition, any substituent can be an aryl, heteroaryl or heterocycloalkyl group. Also, substituted aryl groups 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 thereof with Cl, Br , F, I, OH, CN, C, -C3 alkyl, C, -Cβ alkoxy, C, -C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxyaldehyde, carboxy, alkoxycarbonyl and carboxyamide. In addition, any substituent can be an aryl, heteroaryl or heterocycloalkyl group. Numerous asymmetric centers may exist in the compounds of the present invention. Except where done is otherwise observed, the present invention contemplates the different stereoisomers and mixtures thereof. Consequently, always a joint is represented by a wavy line, it is understood that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of logical medical judgment, suitable for use in contact with the tissues of human or lower animals without undue toxicity., irritation, allergic response and the like, and agree with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. Describe the 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 to react the function of free base with a suitable organic acid. Examples of pharmaceutically acceptable non-toxic 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, acid oxalic, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropionate, 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. The alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. In addition, pharmaceutically acceptable salts include, when convenient, non-toxic ammonium, quaternary ammonium, and amine cations are formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and apisulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters that are hydrolyzed in vivo and include those that readily decompose in the human body to yield the parent compound or 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 alkyl or alkenyl portion advantageously has 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 prodrugs of the compounds in the present invention that are, within the scope of logical medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, according to a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, which are possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to give the parent compound of the above formula, for example by hydrolysis in blood. Through this discussion it is provided in T.

Higuchi and V. Stella, Pro-druas as Novel Deliverv Svstems. Vol. 14 of A. C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drua Desian. American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

Preferred Modalities In a first embodiment of the invention is a compound having the formula (I). In a preferred embodiment of the formula (I), E is -CH = CH- and n is 1. In a second embodiment of the invention is a compound having the formula (II). In a preferred embodiment of formula (II), E is -CH = CH- and n is 1. Representative compounds of the invention are those selected from the group consisting of: Compound of Formula (I), 2'- Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1,3-phenylene, E is - (CH2 ) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 3-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (0) - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is absent, B is -N = CH-, D is 1, 2-phenylene, E is - (CH 2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is NH, B is - (CH2) q-, q is 1, D is 1, 2-phenylene , E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is NH, B is - (CH2) q-, q is 1, D is 1, 3-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is - (CH2) q-, q is 1, D is 1,3-phenylene , E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is - (CH2) q-, q is 1, D is 1, 3-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (II), Rp is H, m is 2, A is -O-, B is - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is acetyl, m is 2, A is -O-, B is absent, D is 3,4-quinoline, E is - (CH2) r-CH = CH-, r is 0 , n is 1; Compound of Formula (I), Rp is acetyl, m is 1, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 3, A is absent, B is absent, D is absent, E is absent, n is 1; Compound of Formula (II), Rp is H, m is 1, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 2, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (II), Rp is H, m is 2, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CHOH- (CH2) q-, q is 1, D is absent, E is - (CH2) r-CH = CH -, r is 0, n is 1; Compound of Formula (I), Rp is acetyl, m is 1, A is absent, B is -C (O) - (CH2) q-, q is 1, D is absent, E is - (CH2) r- CH = CH-, r is 0, n is 1; Compound of Formula (II), Rp is H, m is 2, A is -NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CH (OH) -CH2) q-, q is 0, D is absent, E is absent, n is 3; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CH (O) -CH (OH) - (CH2) q-, q is 0, D is absent, E is absent , n is 1; and Compound of Formula (I), 2-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH2) r-CH = CH-, r is 1, n is 1.

Antibacterial Activity The representative Compounds of the present invention were analyzed in vitro for antibacterial activity in the following manner: twelve petri dishes containing successive aqueous dilutions of the test compound were prepared, mixed with 10 ml of Heart Brain Infusion agar (BHI) , for its acronym in English) (Difco 0418-01-5). Each plate was inoculated with 1: 100 (or 1:10 for slow-developing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 microorganisms different, using a Steers replicator block. The inoculated boxes were incubated at 35-37 ° C for 20 to 24 hours. In addition, a control box, using BHI agar containing the unproven compound, was prepared and incubated at the beginning and end of each test. An additional box containing a compound having the known susceptibility patterns for organisms to be tested and belonging to the same class of antibiotics as the test compound was also prepared and incubated as an additional control, as well as to provide test comparison for test. Erythromycin A was used for this purpose. After incubation, each box was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lower concentration of the drug yield without development, a light mist, or colonies isolated separately on the site of the inoculum compared to the control of development. The results of this analysis are shown in the following Table 1 demonstrating the antibacterial activity of the compounds of the invention.

Table 1 Antibacterial Activity (MIC) of the Selected Compounds Microorganism Code of the Eri.A Organism Staphylococcus aureus ATCC 6538P AA 0.2 Staphylococcus aureus A5177 BB 3.1 Staphylococcus aureus A-5278 CC > 100 Staphylococcus aureus CMX 642A DD 0.39 Staphylococcus aureus NCTC10649M EE 0.39 Staphylococcus aureus CMX 553 FF 0.39 Staphylococcus aureus 1775 GG > 100 Staphylococcus epidermidis 3519 HH 0.39 Enterococcus faecium ATCC 8043 II 0.05 Streptococcus bovis A-5169 JJ 0.02 Streptococcus agalactiae CMX 508 KK 0.05 Streptococcus pyogenes EES61 LL 0.05 Streptococcus pyogenes 930 MM > 100 Streptococcus pyogenes PIU 2548 NN 6.2 Micrococcus luteus ATCC 9341 OO 0.05 Micrococcus luteus ATCC 4998 PP 0.2 Escherichia coli JUHL QQ > 100 Escherichia coli SS RR 0.78 Escherichia coli DC-2 SS > 100 Candida albicans CCH 442 TT > 100 Mycobacterium smegmatis ATCC 114 UU 3.1 Nocardia Asteroids ATCC9970 VV 0.1 Hemophilis Influenzae DILL AMP R WW 4 Streptococcus Pheumoniae ATCC6303 XX 0.06 Streptococcus Pheumoniae GYR 1171 YY 0.06 Streptococcus Pheumoniae 5979 ZZ > 128 Streptococcus Pheumoniae 5649 ZZA 16 Table 1. Continued Anti Bacterial Activity (MIC) of the Selected Compounds Example Code Example Example Example Example Example Example Organization 4 6 10 11 12 13 AA 1.56 0.78 6.2 3.1 0.78 1.56 BB 25 12.5 25 50 0.78 6.2 CC > 100 > 100 100 > 100 > 100 > 100 DD 1.56 1.56 6.2 3.1 0.78 1.56 EE - 1.56 6.2 - 0.78 1.56 FF 1.56 0.78 6.2 3.1 0.78 1.56 GG > 100 > 100 > 100 > 100 > 100 > 100 HH 1.56 0.78 6.2 3.1 1.78 1.56 II 0.39 0.39 0.78 0.2 0.1 0.2 JJ 0.2 0.1 0.39 0.1 0.05 0.1 KK 0.2 0.1 0.39 0.1 0.1 0.39 LL 0.39 0.2 0.78 0.2 0.05 0.2 MM > 100 > 100 25 > 100 50 25 NN 12.5 12.5 6.2 12.5 0.39 12.5 OO 0.2 0.1 0.39 0.2 0.2 0.2 PP 1.56 0.78 1.56 3.1 0.39 1.39 QQ 100 100 > 100 > 100 > 100 > 100 RR 6.2 3.1 6.2 6.2 1.56 25 SS > 100 > 100 > 100 > 100 > 100 > 100 TT > 100 > 100 > 100 > 100 > 100 > 100 uu 3.1 0.39 0.39 0.2 0.78 0.2 vv 0.2 0.39 1.56 0.2 0.78 0.78 ww 16 8 64 32 16 16 XX 0.03 0.03 0.12 0.12 0.25 0.5 YY 0.03 0.03 0.25 0.25 0.125 0.5 ZZ > 128 > 128 64 > 128 128 64 ZZA 16 16 8 32 1 4 * The data i Falt before: are indicated by "-" Table 1. Continued Antibacterial Activity (MIC 'I of Selected Compounds) Eji Code Example Example Example Example Example Example Organization 14 15 16 17 18 19 AA 0.2 0.39 0.39 0.1 0.78 1.39 BB 3.1 3.1 0.39 6.2 0.78 3.1 CC > 100 > 100 100 > 100 > 100 > 100 DD 1.2 0.39 0.39 0.2 0.78 0.78 EE 0.39 0.78 0.39 0.2 0.78 0.78 FF 0.2 0.39 0.39 0.1 0.78 0.78 GG > 100 > 100 > 100 > 100 > 100 > 100 HH 0.2 0.39 0.39 0.2 1.56 0.78 II 0.1 0.1 0.2 0.05 0.39 0.1 JJ 0.05 0.05 0.2 0.01 0.2 0.02 KK 0.05 0.05 0.2 0.11 0.2 0.05 LL 0.05 0.1 0.2 0.02 0.2 0.05 MM > 100 > 100 > 100 > 100 > 100 > 100 NN 6.2 6.2 0.39 25 1.56 12.5 OO 0.05 0.05 0.2 0.02 0.39 0.05 PP 0.39 0.39 0.39 0.1 0.78 0.78 QQ 50 > 100 > 100 > 100 > 100 25 RR 0.78 3.1 0.78 0.78 1.56 0.78 SS > 100 > 100 > 100 > 100 > 100 > 100 TT > 100 > 100 > 100 > 100 > 100 > 100 UU 0.78 1.56 6.2 0.2 12.5 0.39 VV 0.05 0.1 0.39 0.02 0.78 0.05 WW 0 32 32 8 128 8 XX 0.03 0.03 0.25 0.015 1 0.03 YY 0.03 0.03 0.25 0.015 0.5 0.03 ZZ > 128 > 128 > 128 > 128 > 128 > 128 ZZA 16 16 0.25 8 2 16 * The data falt before; je indicate by "-" Table 1. Continued Antibacterial Activity (MIC) of Selected Compounds Axis Code p I E. empl Exempl Example Agency or 20 or 21 or 22 or 24 AA 3.1 1.56 0.78 BB 12.5 1.56 1.56 25 ce > 100 > 100 > 100 DD 3.1 3.1 12.5 1.56 EE 3.1 3.1 > 100 1.56 FF 3.1 3.1 1.56 0.78 GG > 100 > 100 1.56 > 100 HH 3.1 1.56 1.56 1.56 II 0.2 0.2 > 100 02 JJ 0.2 0.1 1.56 0.1 KK 0.39 0.1 0.2 0.1 LL 0.2 0.1 0.05 0.1 MM > 100 > 100 0.1 > 100 NN 25 0.78 0.1 OO 0.2 0.2 > 100 12.5 PP 0.78 0.39 12.5 0.1 QQ 100 > 100 0.1 1.56 RR 3.1 1.56 0.39 100 SS > 100 > 100 100 6.2 TT > 100 > 100 0.78 > 100 UU 0.39 6.2 > 100 > 100 VV 0.2 0.39 > 100 0.39 WW 8 64 0.78 0.1 XX 0.25 0.25 0.1 16 YY 0.25 0.25 4 0.03 ZZ 128 > 128 0.06 0.03 ZZA 1 2 0.06 128 > 128 16 16 Missing data are indicated by "- Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid, or liquid filler, diluent or auxiliary material of any type. Some examples of materials that serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and wax suppositories, oils such as peanut oil, cottonseed oil, sunflower 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; regulatory agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavors and fragrances, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments or drops), buccally, or as an oral or nasal spray. Liquid dosage forms for 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 carbonate, acetate. of ethyl, benzyl alcohol, benzyl benzoate, propylene glycols 1, 3-butyl lignol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofuryl, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfume agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can 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 solvent that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile and fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil including mono or synthetic diglycerides can be employed. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter or by incorporating sterilization agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effect of a drug, it is often convenient to decrease the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline material or amorphous with water solubility scarce. The rate of absorption of the drug then depends on its rate of dissolution which in turn may depend on the size of the crystal and crystalline form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. The forms of injectable deposit are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug to polymer and the nature of the particular polymer employed, 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 trapping the drug in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a wax suppository which are solid at room temperature or liquids at room temperature. body temperature and, therefore, melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In said solid dose forms, the active compound is mixed with, so less, an inert pharmaceutically acceptable excipient or vehicle such as sodium citrate or dicalcium phosphate and / or to) fillers or expanders such as starches, lactose, sucrose, glucose, mannitol, silicic acid, b) binders such as, for example, carboxymethylcellulose , alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, 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 kaolin and bentonite clay, and ) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene 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 fillings in soft and hard filled gelatin capsules using such excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings or shells such as enteric coatings and other coatings. well known in the pharmaceutical formulation art. These may optionally contain opacifying agents and may also have a composition that releases only the active ingredients, or preferably in a certain part of the intestinal tract, optionally, in a delayed form. Examples of embedded compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillings in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar as well as with high molecular weight polyethylene glycols and the like. The active compounds may also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, coatings, pills and granules can be prepared with coatings and shells such as enteric coatings., release controlled coatings and other coatings well known in the pharmaceutical formulating art. In such solid dose forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tablet lubricants and other auxiliaries to form tablets such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms also they can comprise opacifying agents. Optionally they may contain opacifying agents and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can 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, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer that may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated 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, silicates, bentonites, silicic acid. , talc and zinc oxide or mixtures thereof. The powders or sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The sprinklers additionally they may contain traditional propellants such as chlorofluorohydrocarbons. Transdermal patches have the additional advantage of providing controlled release of a compound in the body. Said dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound that crosses the skin. The increase can be controlled either by providing an increase in control membrane or by dispersing the compound in a polymer matrix or gel. According to the methods of the treatment of the present invention, bacterial infections are treated or prevented in a patient such as in a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in said amounts and for such time as necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit / risk ratio applicable to any medical treatment. It should be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical-logical judgment. The specific, therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder that will be treated and the severity of the disorder, the activity of the specific compound employed; the specific composition 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 compound employed, the duration of the treatment; the drug used in combination or coincidental with the specific compound employed; and similar factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other mammal in a single dose or in divided doses may be in amounts, for example, from 0.01 to 50 mg / kg of body weight or more usually 0.1 to 25 mg / kg of body weight. The single dose compositions may contain said amounts or submultiples thereof to form the daily dose. In general, treatment regimens in accordance with the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound of this invention per day in a single dose or multiple doses. The process for preparing a compound having the formula (I) or (II) wherein m, n, Rp, A, B and D are as previously defined and E is absent or is -CH = CH- comprising: ( a) treat a compound that has the formula 1_0 wherein U is 4"-Rp-O-cladinose and U 'is H, or U is U' taken together with the carbon atom to which they are attached to form a carbonyl group, with a reactive compound having the formula H2N- (CH2) mABD-X1, wherein m, A, B are as previously defined, D is as previously defined, and X1 is a leaving group, to prepare an intermediate compound having the formula (b) optionally cylindrizing and reducing the compound of Step (a). In a preferred method of the process described above, m, n, Rp, A, B, and D are as previously defined and E is absent or is -CH = CH- U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I) .In another preferred method of the process described above, m, n, Rp, A, B and D are as previously defined and E is absent or is -CH = CH-, U and U "are taken together with the carbon atom to which they are attached to form a carbonyl group, and the product is a compound of the formula (II) . In a more preferred version of this process, the reagent of Step (a) is 2 - ((- 2-iodophenyl) methoxy) ethylamine. Another method for preparing a compound having the formula (I) or (II) wherein m, n, Rp, A, B and D are as previously defined and E is absent or is -CH = CH-, is the method which comprises: (a) treating a compound of formula 10. wherein U is 4"-Rp-O-cladinose and U 'is H, or U and U' taken together with the carbon atom to which they are attached form a carbonyl group, with a first reactive compound having the formula H2N- (CH2) mA-X2, wherein m and A are as previously defined and X2 is H, to prepare an intermediate compound having the formula (b) treating the intermediate compound of Step (a) with a reactive compound having the formula B'-D-X1, wherein X1 is a leaving group, B 'is a B-precursor portion, and D is as defined previously, to prepare a second intermediate compound that has the formula (b) cyclizing and optionally reducing the compound of Step (b). In a preferred example of the method described immediately above, U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I) In a more preferred method of this process the reagent of Step (a) has the formula H2N- (CH2) mA-X2 is selected from the group consisting of hydrazine and ethylenediamine Still another method for preparing the compound having the formula (I) or (II), wherein m, n, Rp , A, B and D are as previously defined and E is absent or is -CH = CH-, is the method that comprises (a) treating a compound of formula 10, wherein U is 4"-Rp-O-cladinose and U 'is H, or U and U' taken together with the carbon atom to which they are attached form a carbonyl group, with a first reactive compound having the formula H2N- (CH2) mA-X2, wherein m and A are as previously defined and X2 is an N-protecting group, to prepare an intermediate compound having the formula: (b) treating the intermediate compound of Step (a) with a reactive compound having the formula B'-D-X1, wherein X1 is a leaving group, B 'is a B-precursor portion, and D is as defined previously, to prepare a second intermediate compound that has the formula (b) cyclizing and optionally reducing the compound of Step (b). In a preferred method of the process described immediately above, U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I). Yet another example of the process of the invention comprises preparing a compound selected from group consisting of the formula (I) and (II), where A, B and D are as defined above, and E is restricted to the previously defined options (2) - (8) thereof, which comprises ( a) treat a compound that has the formula wherein U is 4"-Rp-O-cladinose, Rp is a hydroxy protecting group, and U 'is H, or U and U' taken together with the carbon atom to which they are attached to form a carbonyl group, with a first reactive compound having the formula H2N- (CH2) mABD-X3, wherein m, A, B, D are as previously defined to prepare a first intermediate compound having the formula (b) treating the first intermediate compound of Step (a) with double-ligating modifying reagents to prepare a second intermediate compound having the formula where E 'is a precursor E; and (c) cyclizing the compound of Step (b). In a preferred method of the latter process, U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I). Abbreviations The abbreviations used in the descriptions of the scheme and the examples are as follows DMF for dimethylformamide, DMSO for dimethylsulfoxide, EtOH for ethanol, HOAc for acetic acid, MeOH for methanol, NaN (TMS) 2 for sodium bis (trimethylsilyl) amide, and THF for tetrahydrofuran Synthesis Methods The compounds and processes of the present invention will be better understood in connection with Schemes 1-5 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 above.The groups A, B, D , E, m, n and Rp are as previously defined Schemes 1-5 are shown in the following section below The preparation of the compounds of the invention of the formula (I) - (V) of erythromycin A is esume in Scheme 1-5. The preparation of protected erythromycin A is described in the following U.S. Patents, US 4,990,602; US 4,331,803, US 4,680,368 and US 4,670,549 which are incorporated by reference. Also incorporated by reference is European Patent Application EP 260,938.

As shown in Scheme 1, the carbonyl group of C-9 of compound 1_ is protected with an oxime to give compound 2, wherein V is = NO-Ra or = N-OC (R) (Rc) -O -Ra where Ra is as defined above and Rb and Rc each are independently selected from the group consisting of (a) hydrogen, (b) unsubstituted C, -C12 alkyl, (c) C, -C12 alkyl substituted with aryl, and (d) C, -C12 alkyl substituted with substituted aryl, or Rb or Rc taken together with the carbon to which they are attached form a cycloalkyl ring of C3-C, 2. An especially preferred carbon protecting group V is O- (1-isopropoxycyclohexyl) oxime. The 2'- and 4"-hydroxy groups of 2. are protected by reaction with a hydroxy-protective reagent, such as those described by TW Greene and PGM Wuts in Protective Groups in Oral Synthesis, 2nd edition, John Wiley & Son, Inc., 1991, incorporated by reference, Hydroxy protecting groups 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, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, 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 The aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. The protection of the 2'- and 4"-hydroxy groups of 2. can be achieved sequentially or simultaneously to provide the compound 3. wherein Rp is a hydroxy protecting group Preferred Rp protecting groups include acetyl, benzoyl and tri-methylsilyl. The 6-hydroxy group of compound 3 is then alkylated by reaction with an alkylating agent in the presence of the base to give compound 4. Alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-toluenitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propino, 3-bromo-2 -octin, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, 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 sulfonates 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 dimethyl sulfoxide, diethylsulfoxide, N, N-dimethyl formamide, NN-dimethematamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, acetate ethyl, 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 io-butoxide, potassium isobutoxide and the like. The preferred intermediate compound of this invention is one wherein R is allyl. The deprotection of the 2'- and 4"-hydroxyl groups is then carried out according to the methods described in the literature, for example, by TW Greene and PGM Wuts in Protective Groups in Qraanic Svnthesis, 2nd ed., John Wiley &Sons, Inc., 1991, which is incorporated herein by reference The conditions used for the deprotection of the 2'- and 4"-hydroxyl groups usually results from the conversion of X a = N-OH. (For example, using acetic acid in acetonitrile and water results in the deprotection of the 2'- and 4"-hydroxyl groups and the conversion of x to from = 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 is carried out in a separate step.The deoximation reaction can be carried out according to the methods described in the literature, for example by Greene (op.cit.) and others, examples of the deximation 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, potassium thiosulfate, potassium metabisulfite and the like . Examples of solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the aforementioned 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 the 5_ compound used. In a preferred embodiment, the deoximation is carried out using an organic acid such as formic acid in ethanol and water to give the compound 6_ of 6-O-substituted erythromycin. In the preferred process of this invention, R is allyl in compound 6_. Scheme 2 illustrates the methods used to prepare the intermediary compounds of the invention. The 6_6-O-substituted compound can be converted to a protected 7. hydroxy compound by the procedures referenced previously. Compound 7. is treated with medium aqueous acid hydrolysis or by enzymatic hydrolysis to remove the cladinose portion and give compound 8_. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. The Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. The reaction times are usually from 0.5 to 24 hours. The reaction temperature is preferably -10 to 35 ° C. Compound 8_ can be converted to compound 9_ by oxidation of the 3-hydroxy group to an oxo group using a Corey-Kim reaction with N-chlorosuccinimide-dimethyl sulfide, or with a modified Swern oxidation process using carbodiimide-dimethylsulfoxide. In a preferred reaction, 8. is added in a pre-formed N-chlorosuccinimide complex and dimethyl sulfide in a chlorinated solvent such as methylene chloride at -10 to 25 ° C. After stirring for about 0.5 to about 4 hours, a tertiary amine such as triethylamine or a Hunig base is added to produce the ketone 9_. Compounds 7 and 9 can then be treated with an excess of sodium hexamethyldisilazide or a hydride base in the presence of carbonyldiimidazole in an aprotic solvent of from about 8 to about 24 hours at about -30 ° C at room temperature to give the compounds 10a and 10b, respectively. The hydride base can be, for example, sodium hydride, potassium hydride or lithium hydride, an aprotic solvent can 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 about 0.5 hours to about 10 days, and preferably about 10 hours to 2 days, to complete. 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. Scheme 3 illustrates several routes for the preparation of the compounds of the formula (I) and (II). A person skilled in the art will be able to easily decide which approach is used, depending on the product that is desired. In a preferred route, when a H2N- (CH2) m-A-B-D precursor can be conveniently prepared, compounds 10a and 10b can be reacted with a precursor in the presence of a suitable base to give compounds 12a and 12b. respectively. A suitable H2N- (CH2) m-A-B-D precursor compound is one such as H2N- (CH2) m-A-B-D-X1, wherein A, B, D and m are as previously defined and X1 is a suitable leaving group. Suitable bases include, for example, triethylamine and Hunig's base, and suitable leaving groups include, but are not limited to Cl, Br, I and trilfluoromethanesulfonate. When D is selected from options (6) - (15) as previously defined, the precursor or precursors of portion D may be commercially available or prepared by standard methods known to those skilled in the art.

To prepare the compounds (I) and (II) wherein m is 0 and A is -O-, the reagent H2N- (CH2) mABD-X1 is a hydroxylamine compound H2N-OBD-X1, where m is 0 and B, D and X1 are as previously described. These compounds can be prepared by the two step reaction which involves reacting the N-hydroxyphthalimide with an appropriate alcohol and separating the intermediate with hydrazine, as described by Grochowski and Jurezak, Synthesis, 682-683, (1976), for example . The preparation of the intermediates and precursors for the desired hydroxylamine reagent from normal starting materials and reactions will be readily accomplished by those skilled in the art. To prepare the compounds (I) and (II) wherein m is 0 and A is -O-, the reagent H2N- (CH2) mABD-X1 is an amino ether compound having the formula H2N- (CH2) mOBD- X1, where m is not 0 but is otherwise as previously defined, and B, D and X are as previously defined. These compounds can be prepared from an amino alcohol by a two-step reaction (see Grochowski and Jurezak, op.cit.) Which involves first converting the amino group of an amino alcohol compound to a phthalimide derivative. The free hydroxyl group of the derivatized molecule is then reacted with an appropriate reagent to form the desired portion B, and the phthalimide protecting group is removed by treatment with hydrazine to give the desired amino ether compound. For example, the reactants H2N- (CH2) m-A-B-D-X1 is that they have the formulas H2N- (CH2) m -O- (CH2) q-D-X1, H2N- (CH2) m-O- C (O) - (CH2) qDX \ H2N- (CH2) mOC (O) -O- (CH2) qDX \ H2N- (CH2) -OC (O) -NR1- (CH2) qD-X1 and H2N- ( CH2) mOC (O) -NR1- (CH2) qD-X1 can be prepared in this way. The preparation of the desired compound can be achieved without undue effort by those skilled in the art. Also shown in Scheme 3 is an alternate route for the preparation of intermediate compounds 12a and 12b. This multi-step approach is preferred when a compound of the precursor H2N- (CH2) m-A-B-D can not be conveniently prepared in advance. This can occur, for example in the case where A is -O- or -N (R1) - and B is desired to be -C (O) - (CH2) q-, -C (O) -O- ( CH2) q-, or-C (O) -NR1- (CH2) q-. In an example of this alternate route, compounds 10a and 10b are treated with a reactive compound having the formula H 2 N- (CH 2) mA-X 2, wherein m and A are as previously defined and X 2 is H or when A is - NH-, can also be an N-protector group, to give intermediate compounds 11a and 11b. For example, when m is 0 and A is -N (R1) -, where R1 is H, this reagent is hydrazine and produces intermediates 11a and 11b. wherein m is 0, A is -NH- and X2 is H. Intermediates 11a and 11b, wherein m is 0, A is -NH- and X2 is H can then be reacted with a reagent having the formula B ' -D-X1, wherein B 'is a precursor of portion B. For example, when B'-D-X1 is an aldehyde having the formula HC (O) - (CH2) qDX \ B' is HC (O ) yq and D are as defined previously, and the reaction produces compounds 12a and 12b where m is 0, A is absent and B is -N = CH- and q and D are as previously defined. The reduction of the mine function of these intermediary compounds with a borohydride reducing agent provides the compounds 12a and 12b wherein m is 0, A is -NH-, B is -NH- (CH2) q-, q is at least 1 and D is as previously defined. In another example is this route, when the compounds 10a and 1_0b. are treated with a diamine reagent compound having the formula H2N- (CH2) mA-X2, where m is not 0, A is -N (R1) - and X2 is H or an N-protecting group, intermediates 11a and 11b wherein m is not 0, A is -N (R1) and X2 and H or an N-protected group are prepared. If the protected N of these intermediates can be deprotected by normal reactions to give compounds wherein X2 is H. These compounds 11a and 11b, wherein X2 is H, can then be reacted with the reagents of the formula B'-D-X1, wherein B 'is a precursor of portion B and X1 is as previously defined, to give compounds 12a and 12b. wherein A is -N (R1) - and B- is -C (O) - (CH2) q-. Examples of said B'-D-X1 reagents include acylation reagents, for example, acid halides having the formula halogen-C (O) - (CH2) q-D-X1. Other acylating agents can be anhydride of acids of the formula O (C (O) -D-X1) 2, or free acids of the formula HO-C (O) - (CH2) qD-X1 in the presence of an activation such as carbodiimide. A Suitable carbodiimide reagent is 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride. Other reagents of B'-D-X1 include carbonation reagents of the halogen type-C (O) -O- (CH2) qD-X1 or O (C (O) -O- (CH2) qD-X1) 2, which give the compounds 12a and 12b wherein A is -NH- and B is -C (O) -O- (CH2) q-. Still other B'-D-X1 reagents include carbamation reagents of the halogen-C (O) -N (R1) - (CH2) qDX \ type which result in compounds 12a and 12b wherein A is -N (R1) ) - and B is -C (O) -N (R1) - (CH2) q-. Intermediates 11a and 11b, wherein m is 0, A is -NH- and X2 is H, prepared as described herein, can also be reacted with appropriate B'-D-X1 acylating agents, the carbonation or carbamylation agents to give the desired intermediate compounds 12a and 12b wherein m is 0, A is -NH- and B is -C (O) - (CH2) q-, -C (O) -O- (CH2 ) q-, or -C (O) -NR1- (CH2) q-. In yet another example of this multi-step route, compounds 10a and 10b are treated with amino alcohol H2N- (CH2) m-OH, where m is 2-7, to give intermediates 11a and 11b. wherein m is 2-7, A is -O- and X2 is H. The freshly introduced free hydroxyl group of these intermediates can then be subjected to various reactions in order to prepare additional intermediates. For example, the free hydroxyl group can be reacted with acylation reagents, carbonation reagents or carbamation reagents as previously described to provide the compounds where A is O- and B is -C (O) - (CH2) q-, -C (O) -O- (CH2) q- or -C (O) -N (R1) - (CH2) q-, respectively. The hydroxyl group can also be converted by the use of normal reactions to a sulfonate, which are then converted to an azide, which can in turn be reduced to an amino compound. These newly formed compounds 11 a and 11 b, wherein A is now -NH- and X 2 is H, can be treated with appropriate acylation reagents B'-D-X1, carbonation reagents or carbamation reagents as previously described to provide the compounds wherein B is -C (O) - (CH2) q-, -C (O) -O- (CH2) q- or -C (O) -N (R1) - (CH2) q-, respectively. Once the compounds 12a and 12b have been prepared it is possible to close the ring and prepare the compounds 14a and 14b. In the examples where D is present and E is -CH = CH-, this is generally achieved by the Heck reaction media in the presence of (Pd (ll) or Pd (O), phosphine, and amine or inorganic base ( see Organic Reactions, 1982, 27, 345-390.) When D is alkenylene, an olefin metastasis reaction can be used to close the ring (cf, R. H. Grubbs, S. J. Miller, and G. G. Fu, Acc. Chem. Res., 28., 446 (1995)). Alkenylene can be oxidized to a glycol (-CH (OH) -CH (OH) -) with reagents such as osmium tetroxide and morpholine N-oxide. Another route for the preparation of the compounds of the formula (I) and (II) is also shown in Scheme 3. According to this method, the compounds 11a and 11b are treated with a reagent of B'-D-X1, where D is present and B 'is as previously defined, by means of a Heck reaction, as described above, to give compounds 13a and 12b. At this point, ring closure is achieved by a reaction at portions X2 and B 'of 13a and 13b. When A is O and X2 is H, then the ring is closed to give compounds 14a and 14b where B is OC (O) - (CH2) q-, -C (O) -O- (CH2) q-, or -C (O) -NR1- (CH2) q-, can be more easily achieved when B 'is part of the selected acylation reagents, carbonation reagents or carbamation reagents as previously described. The carbonyl group of -C (O) - (CH2) q- can be reduced to -C (OH) - (CH2) q- with reducing agents such as NaBH4, NaBH3CN and the like. Optional deprotection of compounds 14a and 14b as previously described gives 15a and 15b, in which are compounds of formula (I) and (II) of the invention, respectively, wherein E is -CH = CH-. This is possible to reduce the double bond of the compounds 15a and 15b to give the corresponding compounds -CH 2 -CH 2 -, which are structures of the formula (I) and (II), where E is absent and n is at least 2, when said compounds are desired. Scheme 4 illustrates the preparation of the additional compounds of the invention, wherein E is different from -CH = CH-. In order to prepare these compounds, it is necessary to modify a double of an intermediate compound of the invention. This is more easily achieved by the first reaction compound 10a or 10b with a new H2N- (CH2) m-A-B-D-X3 reagent where m is as previously defined and X3 is - (CH2) rY, where r is 0, 1, 2, 3 or 4 and Y can be a precursor N, an acyl precursor, hydroxyl portion or -CH2-I , to prepare the new intermediate compounds 16a v 16b. An acyl precursor may be a portion such as C (O) -X *, wherein X * is H or a leaving group, or the acyl precursor may be an acyloxy group. Suitable N-precursor portions are N-protected amino groups, such as acylamino groups that can be deprotected for a free amino group or groups such as -N3 and -NO2, which can be reduced to amino groups. After the Heck reaction has been carried out, it is possible to reduce the double ligand of -CH = CH- by using hydrogen in the presence of a Pd / C catalyst. This reduction allows the preparation of the compounds of the invention wherein E is arylene-CH2-CH2- or arylene-CH2-CH2. Showing in the middle of the lower part of Scheme 4 are further reactions that can be carried out with a double-binding modification reagent when E is -CH = CH-. The portion M 'is an abbreviated representation of the macrolide portion in which the portion 6-O- (CH2) n-CH = CH2 is attached. Examples of the double-ligation modification reagents are the following. For example, compounds 16a and 16b can be treated with perchloric acid to convert the -CH = CH- portion to an epoxy portion to give compounds 17a and 17b, respectively. The Compounds 16a and 16b can be treated with ozone, or OsO4 and NalO4 to give the aldehyde compounds 18a and 18b. respectively. The aldehyde compounds 18a and 18b can then be reduced to the alcohol compounds 19a and 19b. respectively, by treatment with a borohydride reducing agent, such as sodium borohydride or potassium borohydride. Alternatively, the compounds 18a and 18b can be converted to the amine compounds 20a and 20b, respectively, by reductive amination with an amine of the formula R1NH2 in the presence of a reducing agent such as NaBH3CN or H2 and Pd / C. Or, the aldehyde compounds 18a and 18b can be converted to the carboxy 21 a and 21 b compounds, respectively, by oxidation with the Jones reagent. Scheme 5 further illustrates the conversion of compounds 18a. 18b. 19a. 19b. 20 a. 20b, 21a. or 21b. prepared in Scheme 4, for the compounds (I) or (II) of the invention. The variable E 'represents a portion of the precursor E, such as the groups described in Scheme 4, for example -CH (O), -OH, -NH 2 -C (O) OH, or an epoxy ring of the compounds. In compounds 16a and 16b. X3 is - (CH2) rY, where r and Y are as defined above. Suitable N-precursor portions are N-protected amino groups, such as acylamino groups that can be deprotected for a free amino group, or groups such as -N3 and -NO2, which can be reduced to amino groups. The amino group can then be used as a reactant to react with the epoxy group just formed of the compounds 17a and 17b to form the compounds of the formula (I) or (II), wherein E is - (CH2) r-NR1-CH2-CH (OH) -. The amino group can also be used as a reagent to react with the newly formed aldehyde group of compounds 18a and 18b to form imine compounds which are subsequently reduced with hydrogen in the presence of a Pd or Pt catalyst to give the compounds of the formula ( I) or (II) where E is - (CH2) r) -N (R1) -. The amino group can also be used as a reagent to react with the newly formed carboxyl group of compounds 21a and 21b to form the compounds of formula (I) or (II) wherein E is (CH2) rN (R1) - CO)-. In some cases it is possible to react the N-protected acylamino moieties with the desired newly formed functional groups to give the desired compounds of the formula (I) or (II).

Scheme 1 & Scheme 2 Scheme 3 =? H, Scheme 4 _u U - > 4"-0-RP-cl_dinose, U" = H 16a: O = 4 ** - 0-RP-clad? Nose. U "= H b: U + U'asO 16b: U + U- = 0 19a 21. 19b 2ih An acyl precursor may be a portion such as -C (O) -X *, wherein X is H or a leaving group, or the acyl precursor may be an acyloxy group. These precursors can react with the hydroxyl group of the newly formed compounds 19a and 19b to form the compounds of the formula (I) or (II), wherein E is - (CH2) rC (O) -O-, or they can react with the compounds 20a and 20b newly formed to form the compounds of the formula (I) or (II), wherein E is - (CH2) rC (O) -N (R1) -. When Y of the group X3 is a hydroxyl group it can be reacted with the carboxyl group of the newly formed compounds 21a and 21b to form the compounds of the formula (I) or (II) wherein E is - (CH2) rOC (O) -. When Y of the group X3 is a group -CH2-I, it can be reacted with the hydroxyl group of the newly formed compounds 19a and 19b to form the compounds of the formula (I) or (II) wherein E is - (CH2) - OR-.

Scheme 5 It should be appreciated by one skilled in the art that the decision of when to carry out certain of the reactions described above, may depend on the presence of reactive portions within the molecule. Therefore, adequate protection and deprotection steps may be required from time to time, as is well known and applied within the art. The foregoing will be better understood by reference to the following examples which are presented for illustration and not to limit the scope of the inventive concept. Example 1 Compounds of the Formula (I). 2'-Rp is H. 4"-Rp is acetyl, m is 2, A is NH, B is -C (0) - (CH2) 2-, q is 0. D is 1, 3-phenylene, E is - (CHz) r- C = CH-, r is 0. n is 1.

Step 1a: Compound 4 of Scheme 1: V is N-OM-isopropoxycyclohexyl), R is allyl. Rp is trimethylsilyl To a solution at 0 ° C of 2 ', 4"-jb / sO-trimethylsilylethyromycin A 9- [O- (1-isopropoxycyclohexyl) oxime (1032 g, 1.00 mmol, prepared according to the method of US Patent No. 4,990, 602) in 5 ml) of DMSO and 5 ml of THF was added freshly distilled allyl bromide (0.73 ml, 2.00 mmol). After about 5 minutes, a solution of ferrous-butoxide was added. potassium (1M 2.0 ml, 2.0 ml) in 5 ml of DMSO and 5 ml of THF was added dropwise over 4 hours.The reaction mixture was taken up in ethyl acetate and washed with water and brine.The organic phase was concentrated vacuum to give the desired compound (1.062 g) as a white foam Step 1b: Compound 5 of Scheme 1: V is NOH R is allyl A solution of the compound from Step 1a (1.7 g) in 17 ml of acetonitrile and 8.5 ml of water was added 9 ml of acetic acid at room temperature After several hours, the reaction mixture was diluted with 200 ml of toluene and concentrated to the The residue obtained was found to contain unreacted starting material, so that additional acetonitrile (15 ml), water (70 ml) and acetic acid (2 ml) were added. After 2 hours, an additional 1 ml aliquot of acetic acid was added. After about three more hours, the reaction mixture was placed in the freezer overnight. The reaction mixture was allowed to warm to room temperature, diluted with 200 ml of toluene and It was concentrated in vacuo. The residue was washed twice with toluene and dried to constant weight (1524 g). Step 1c: Compound 6 of Scheme 1: R is allyl The compound of Step 1b (1225 g) in 16 ml of ethanol-water 1: 1 was treated with NaHSO 3 (700 mg) and formic acid (141 μL) at 86 ° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with 5-6 ml of water, basified with 1N NaOH to pH 9-10 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The crude material was purified by column chromatography, eluting with 1% MeOH in methylene chloride containing 1% ammonium hydroxide, to give 686 mg (57%) of the title compound 13C NMR (CDCl 3) d 219.3 (C-). 9), 174.8 (C-1), 135.5 (C-17), 116.3 (C-18), 101.9 (C-1 '), 95.9 (C-1"), 79.7 (C-5), 78.8 (C -6), 78.5 (C-3), 74.1 (C-12), 72.4 (C-3"), 70.6 (C-11), 68.1 (C-5 '), 65.5 (C-16), 65.1 ( C2 '), 49.0 (C-3"O-CH3), 45.0 (C-2), 44.1 (C-8), 39.7 (NMe2), 37.9 (C-4), 37.1 (C-10), 34.6 ( C-2"), 28.4 (C-4 '), 21.0, 20.6 (C-3" CH3, C-6' CH3), 20.8 (C-14), 18.3 (C-6"), 18.1 (C- 8 CH3), 15.7, 15.6 (C-2 CH3> C-6 CH3), 11.9 (C-10 CH3), 10.1 (C-15), 8.9 (C-4 CH3). MS (FAB) + m / e 774 [M + H] \ 812 [M + K] +. Step 1d. Compound 7 of Scheme 2. Rp is acetyl To a solution of the compound of Example 1c (80 g, 103 mmol and DMAP (4.0 g, 32.7 mmol) in dichloromethane (200 ml) was added acetic anhydride (40 ml, 400 mmol). The solution was stirred for 5 hours at room temperature, and the mixture was diluted with dichloromethane (800 ml). The organic phase was washed with Na2CO3, 5% saturated NAHCO3 and brine, dried over MgSO4. The solvent was removed in vacuo, and the residue was dried. The residue was crystallized from acetonitrile to give the title compound (60.0 g). MS (APCI) m / z 858 [M + H] +. Step 1e. Compound 10a of Scheme 3. Rp is acetyl To a solution of the compound of Step 1d (42.85 g, 50 mmol) in THF (250 ml) cooled to -40 ° C in a dry ice-acetonitrile bath was added bis (trimethylsilyl) sodium amide (65.0 ml, 1 M in THF, 65.0 mmol) for 30 minutes. After 45 minutes a solution of 32.43 g (200 mmoles) of carbonidiimidazole in 150 ml of THF and 100 ml of DMF was added. The mixture was stirred for 2.5 hours at -40 ° C and 18 hours at room temperature. The reaction was cooled by adding a 0.5 M NaH2PO4 solution (500 mL). The product was isolated by extracting the reaction mixture with ethyl acetate. The extract was dried with MgSO 4 and concentrated to give the crude product, which was purified by flash chromatography using 40-60% acetone / hexanes, giving 46 g (100%) of the title compound. MS (APCI) m / z 934 [M + H] +. Step 1f. Compound 11a of Scheme 3. Rp is acetyl, m is 2. A is NH. X2 is H The compound of Step 1e (25 g, 26.8 mmol) and ethylenediamine (18 ml, 10 eq., 0.27 mol) in 60 ml of CH3CN, 10 ml of THF and ml of water was heated at 70 ° C for 6 hours. The solvents were evaporated, and the residue was taken up in ethyl acetate, which was washed with NaHCO3, brine, dried over MgSO4 and concentrated. This material was used without further purification. MS (ESI) m / z 926 [M + H] +. Step 1a. Compounds 12a of Scheme 3. Rp is acetyl. m is 2. A is NH. B is -C (O) - (CH: L): L-. or is 0. D is 1,3-phenylene. X1 is iodine A sample of the compound from Step 1f (3.0 g, 3.19 mmole), 3-iodobenzoic acid (1.20 g, 4.81 mmole), 1-hydroxybenzotriazole hydrate (HOBT, 0.65 g, 4.81 mmole), and N-methylmorpholine ( 0.71 g, 7.02 mmol) were dissolved in CH2Cl2 (5.0 mL). To the stirred solution at 0 ° C was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.95 g, 4.81 mmol). After stirring at 0 ° C at room temperature for 3 hours, the mixture was diluted with CH2Cl2, and the organic layer was washed with water, NaHCO3 and brine. The solvent was removed, and the crude product was purified by chromatography on silica gel with acetone / hexanes 1: 2 to 1.1 to give 2.50 g of the product as a white foam (67.0%). MS (APCI) m / z 1156 [M + H] +. Step 1h. Compound of Formula (I). Rp is acetyl. m is 2. A is NH. B is -C (Q) - (CH2): L-. q is 0. D is 1,3-phenylene. E is - (CH-Zir-CH = CH-. R is 0. n is 1 To a solution of the compounds from Step 1g (1.16 g, 1.0 mmol) in acetonitrile (100 ml) were added palladium acetate (67.5 mg, 0.30 mmole), tri- (o-tolyl) phosphine (137 mg, 0.45 mmole) and triethylamine (0.278 ml, 2.0 mmol). The mixture was degassed with N2 for 30 minutes, sealed in a tube under nitrogen, and heated at 60 ° C for 1 hour, and 70 hours at 80 ° C. The solvent was evaporated, the residue was taken up in ethyl acetate, which was washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel eluting with acetate / hexanes (1: 2 to 2: 1) to give 0.799 g of the product as a pale yellow foam. MS (APCI) m / z 1028 [M + H] +. Step 1i. Compound of Formula (I), 2'-Rp is acetyl. m is 2. A is NH. B is -C (O) - (CH 1) 1-. q is 0. D is 1, 3-phenylene, E is - (CH ^) r-CH = CH-, r is 0. n is 1 A sample of the compound from Step 1h (50 mg, 0.049 mmol) in methanol ( 5 ml) was heated to reflux for 4 hours to remove the 2'-acetyl group. The methanol was evaporated, and the crude product was purified by chromatography on silica gel eluted with CH 2 Cl 2 / MeOH / NH 4 OH (15: 1: 0.05) to give the title compound (43 mg, 89%). MS (APCI) m / z 989 [M + H] +. Example 2 Compound of Formula (I). 2'-Rp is H. 4"-Rp is H. m is 2. A is NH.B is -C (O) - (CH- L-. Or is 0. D is 1,3-phenylene. CH1) r-CH = CH-, r is 0. n is 1 A sample of the product from Example 1 (0.15 g, 0.146 mmol) was treated with 1 N LiOH (1.0 mL, ca. 7 eq.) In methanol (5 mL). ) at room temperature for 8 hours. 1N hydrochloric to bring the neutral near pH. After the partial removal of methanol, the reaction mixture was diluted with CH2Cl2. The two layers were separated, and the organic layer was dried over MgSO 4, filtered and concentrated. The crude product was purified by chromatography on silica eluted with CH2Cl2 / MeOH / NH4OH (10: 1: 0.05) to give the title compound MS (APCI) m / z 944 [M + H] +. Example 3 Compound of Formula (I), 2'-Rp is H. 4"-Rp is acetyl.m is 2. A is NH.B is -C (O) - (CH-L): L-. is 0, D is 1,2-phenylene, E is -fCH) r-CH = CH-. r is 0. n is 1 The title compound was obtained following the procedures of Example 1, Steps g and h, except that the 2-iodobenzoic acid by 3-iodobenzoic acid from Step 1g, and the intermediate is purified by chromatography, two intermediates are obtained (Compounds A and B) Compound A was treated according to step i of Example 1. MS (APCI) m / z 986 [M + H] +. Example 4 Compound of Formula (I), 2'-Rp is H. 4"-Rp is H, m is 2, A is NH. B is -C (Q) - (CHt) 1-, q is 0. D is 1,2-phenylene. E is - (CH ,, r-CH = CH-. R is 0. n is 1 The title compound was prepared following the procedures of Example 2, except that the compound of Example 3 is replaced by the compound of Example 1, Step 1i.

MS (APCI) m / z 944 [M + H] +. HRMS C50H78N3O14: Calculated. 944.5478; Measured 944.5484.

Example 5 Compound of Formula (I). 2'-Rp is H. 4"-Rp is acetyl.m is 2. A is NH.B is -C (O) - (CH ^) rL-. Q is 1. D is 1, 2-phenylene. is - (CHI) r-CH = CH-, r is 0. n is 1 The title compound was prepared following the procedures of Example 1, steps g, hei, except that the 2-bromophenylacetic acid is replaced by the acid 3 -iodobenzoic acid from Step 1g MS (APCI) m / z 1000 [M + H] + Example 6 Compound of Formula (I) 2'-Rp is H. 4"-Rp is H. m is 2. A is NH, B is -C (O) - (CH-) -. or is 1. D is 1,2-phenylene. E is - (CH1) r-CH = CH-, r is 0. n is 1 The title compound was prepared following the procedures of Example 2, except that the product of Example 5 is replaced by the product of Example 1, Step 1i. MS (APCI) m / z 958 [M + H] +. Example 7 Compound of Formula (I), 2'-Rp is H. 4"-Rp is acetyl.m is 0, A is absent B is -N = CH-, D is 1, 2-phenylene. (CHI) r-CH = CH-, r is 0. n is 1 Step 7a; Compound 11a of Scheme 3. 2'-Rp is H. 4"-Rp is acetyl, m is 0, A is NH. X2 is H To a solution of the compound of Example 1, Step 1e (15 g, 16.1 mmol) in acetonitrile (100 mL) was added hydrazine (2.54 mL, 80.9 mmol)., and the solution was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give 15.4 g of the yellow foam. The residue was purified by column chromatography (95: 5: 1 dichloromethane: methanol: ammonium hydroxide) followed by recrystallization from acetonitrile to give a white foam. Step 7b: Compound 11a of Scheme 3. 2'-Rp is H. 4"-Rp is acetyl.m is 0. A is absent, B is -N = CH-, D is 1, 2-phenylene, X1 is iodine The compounds of Step 7a (0.25 g, 0.292 mmol), 4Á molecular sieves of 4A (1 g) and 2-iodobenzaldehyde (2.92 mmol) were dissolved in toluene (5 ml) and heated with nitrogen at 90 ° C for 10 days The slurry was filtered and purified by column chromatography (94: 5.1 CH2Cl2: MeOH: NH4OH) to give 0.138 g (44%) of white foam Step 7c: Compound of Formula (I) .2'-Rp is H. 4"-Rp is acetyl. m is 0. A is absent. B is -N = CH-. D is 1, 2-phenylene. E is -ÍCH1) r-CH = CH-. r is 0. n is 1 To a solution of the compound from Step 7b (0.20 g, 0.175 mmol) in acetonitrile (18 ml) were added palladium acetate (12 mg, 0.053 mmol), tri- (o-tolyl) phosphine ( 16 mg, 0.053 mmol) and triethylamine (30 mg, 0.35 mmol). The mixture was degassed with N2 for 30 minutes, sealed in a tube with nitrogen, and heated at 60 ° C for 1 hour and 70 hours at 80 ° C. The solvent was evaporated, and the residue was taken up in ethyl acetate, which was washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel eluting with acetone / hexanes (1: 2 to 2: 1) to give the pure product (56.6%) as a pale yellow foam. MS (APCI) m / z 942 [M + H] +.

Example 8 Compound of Formula (I). 2'-Rp is H. 4"-Rp is acetyl, m is 0. A NH B is -ÍCH ^^, q is 1. D is 1,2-phenylene. E is - (CH-) r-CH = CH-, r is 0. n is 1 Step 8a: Compound 11a of Scheme 3, 2'-R is H. 4"-R is acetyl.m is 0. A is NH, B is - (CH ^^, q is 1, D is 1.2-phenylene, X1 is iodine To a solution of the compounds of Example 7, Step 7b (0.109 g) in methanol (5 ml), acetic acid was added ( 0.1 ml) and NaBH3CN (68 mg, 1.08 mmol) The solution was stirred under reflux for 18 hours, cooled with saturated NaHCO3 (20 ml), diluted with ethyl acetate (20 ml), then washed with water ( 20 ml), brine (20 ml), dried over Na 2 SO 4, concentrated in vacuo, and purified by column chromatography (95: 4: 1 CH 2 Cl 2: MeOH: NH 4 OH) to give 0.091 g (78%) of white foam. Step 8b: Compound 14a of Scheme 3. 2'-Rp is H, 4"-Rp is acetyl.m is 0. A is NH, B is - CH ^) ^ -. q is 1. D is 1.2-phenylene The title compound was obtained by following the procedures of Example 7, Step 7, except that the compound of Step 8a is replaced by the compound of Step 7b. Step 8c: Compound 14a of Scheme 3. 2'-Rp is H, 4"-Rp is H. m is 0. A is NH. B is - (CH ^) a-, q is 1. D is 1.2-phenyl- The title compound was prepared following the procedure of Example 2, except that the product of Example 8, Step 8b was replaced by the product of Example 1, Step 1. Example 9 Compound of Formula (I). Rp is H. 4"-Rp is acetyl. m is 0. A is NH. B is - (CH ^^. Or is 1. D is 1, 3-phenylene, E is -ÍCHz) r-CH = CH-. r is 0. n is 1 The title compound was prepared following the procedures of Example 7, Steps 7a and 7b, except that 3-iodobenzaldehyde is replaced by 2-iodobenzaldehyde from Step 7b, and treating the product with NaBH3CN according to with the procedure of Example 8, Step a, then the Heck reaction is carried out as in example 7 Step c MS (APCI) m / z 944 [M + H] +. Example 10 Compound of Formula (I). 2'-Rp is H. 4"-Rp is acetyl.m is 2. A is NH.B is - (CH ^) ^ -. Q is 1. D is 1, 3-phenylene, E is -ÍCH1) r -CH = CH-, r is 0. n is 1 The title compound was prepared following the procedures of Example 7, except that the ethylenediamine by the hydrazine of Step 7a and the 3-iodobenzaldehyde is replaced by 2-iodobenzaldehyde from Step 7b, then the product is treated with NaBH 3 CN according to the procedure of Example 8, Step 8a, and the Heck reaction is carried out. according to the procedures of Example 7, step CE. MS (ESI) m / z 972 [M + H] +. Example 11 Compound of Formula (I), 2'-Rp is H, 4"-Rp is H. m is 2, A is NH. B is - (CH ^^ -. Q is 1. D is 1, 3 phenylene, E is -IChU) r-CH = CH-. r is 0. n is 1 The title compound was prepared by treating the compound of Example 10 according to the procedures of Example 1, Step j, and Example 2 MS (ESI) m / z 930 [M + H] + Example 12 Compound of Formula (II) 2'-Rp is H. m is 2. A is -O- B is - (CH - ^ - q is 1. D is 1,2-phenylene E is - (CH1) r-CH = CH-, r is 0. n is 1 Step 12a: Compound 8 of Scheme 2. Rp is HA a suspension of the compounds prepared in the Example 1, Step 1c (7.73 g, 10.0 mmol) in ethanol (25 ml) and water (75 ml) was added 1M aqueous HCl (18 ml) for 10 minutes.The reaction mixture was stirred for 9 hours at room temperature and Then it was allowed to stand in the refrigerator overnight, 2M aqueous NaOH (9 ml, 18 mmol) which resulted in the formation of a white precipitate, the mixture was diluted with water and filtered.

The solid was washed with water and dried in vacuo to give the des-cladinosyl compound 7 (3.11 g). Step 12b: Compound 8 of Scheme 2. Rp is benzoyl To a solution of the product from Step 12a (2.49 g, 4.05 mmol) in dichloromethane (20 ml) was added benzoic anhydride (98%, 1.46 g, 6.48 mmol) and triethylamine (0.90 ml, 6.48 mmol) and the white suspension was stirred for 26 hours at room temperature. 5% aqueous sodium carbonate was added and the mixture was stirred for 20 minutes. The mixture was extracted with dichloromethane. The organic phase was washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the title compound (2.46 g) as a solid bench. Step 12c: Compound 9 of Scheme 2. Rp is benzoyl To a solution at -10 ° C with N 2 of n-chlorosuccinimide (0.68 g, 5.07 mmol) in dichloromethane (20 ml) was added dimethylsulfide (0.43 ml, 5.92 mmole) during 5 minutes. The resulting white mixture was stirred for 20 minutes at -10 ° C and then a solution of the compound resulting from step 12b (2.43 g, 3.38 mmol) in dichloromethane (20 ml) was added and the reaction mixture was stirred for 30 minutes at room temperature. -10 to -5 ° C. Triethylamine (0.47 ml, 3.38 mmol) was added dropwise over 5 minutes and the reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was extracted with dichloromethane. The organic phase was washed twice with 5% aqueous sodium bicarbonate and once with brine, dried over sodium sulfate and concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the title compound (2.27 g) as a white foam. Step 12d: Compound 10b of Scheme 2. Rp is benzoyl The title compound was prepared following the procedure of Example 1, Step e above, except that the compound of Step 12c is replaced by the compound of Example 1, Step d. Step 12e: Compound 12b of Scheme 3. Rp is benzoyl. m is 2, A is -O-. B is - (CH ^^, q is 1, D is 1, 2-phenylene, X is iodine The compound of Step 12d (1.13 g, 1.42 mmoles) and 2 - ((2-iodophenyl) methoxy) ethylamine (1.18 g (4.26 mmol) were dissolved in 3 ml of 10% aqueous CH3CN and stirred under nitrogen at 60 ° C. for 20 hours, the mixture was diluted with dichloromethane and cooled with 50 ml of 5% KH2PO4. washed with brine and dried over Na 2 SO 4 The solvent was removed, and the residue was separated by chromatography on silica gel, eluting with 25% acetone in hexanes to give the title compound Step 12f: Compound 14b of Scheme 3. Rp is benzoyl, m is 2, A To a solution of the compound from Step 12e (0.75 g, 0.948 mmol) in acetonitrile (50 ml) were added palladium acetate (85 mg, 0.379 mmol), tri- (o-tolyl) phosphine (228 mg, 0.750 mmol) and triethylamine (0.50 ml, 3,687 mmoles). The mixture was degassed with N2 for 30 minutes, sealed in a tube with nitrogen, and heated for 16 hours at 50 ° C. The solvent was evaporated, and the residue was taken up in ethyl acetate, which was washed with saturated NaHCO3 and brine, then dried over MgSO4. The solvents were removed and the crude product was purified by chromatography on silica gel eluting with 1: 4: 1 to 1: 3: 1 acetone / hexanes / t-butanol to give 332 mg of the title compound. Step 12G; Compound of formula (II). Rp is H. m is 2. A is -O-, B is - (CHZ) -, q is 1. D is 1, 2-phenylene. E is - (CH1) r-CH = CH-, r is 0. n is 1 A solution of the compound from Step 12g (50 mg) in methanol was stirred for 2 days. The solvent was removed and the product was purified by chromatography on silica gel, eluting with 50% methanol in dichloromethane containing 0.5% NH4OH to give the title compound (29 mg). MS (APCI) m / z 771 [M + H] +. Example 13 Compound of Formula (I). Rp is acetyl. m is 2, A is-O-, B is absent. D is 3,4-quinoline. E is -fCH ^) r-CH = CH-. r is 0. n is 1 Step 13a: Compound 11a of Scheme 3. m is 2. A is -O-. X2 is H To a solution of imidazolide (compound 10a of Scheme 3, 15 g, 16.6 mmol) in acetonitrile (200 ml) and water (20 ml), 2-amino-ethanol (6.91 g, 113 mmol) was added. The solution was stirred at room temperature for 48 hours. The solvent was removed in vacuo, and the material was purified by FSC (95: 5: 0.1 CH2Cl2: MeOH: NH 4 OH), then recrystallized from acetonitrile to give 8.7 g (56%) of the white foam. MS (ESI) m / z 927 [M + H] +. Step 13b: Compound 12a of Scheme 3, m is 2, A is -O-. B is absent. D is 3,4-quinoline. X1 is IA a mixture of the compounds of Step 13a (2.5 g, 2.70 mmol), 2-iodo-3-hydroxyquinoline (0.74 g, 2.72 mmol) and triphenylphosphine (1.06 g, 4.72 mmol) in THF (40 mL) was added DEAD (0.74 ml, 4.72 mmol). The solution quickly became homogeneous and was stirred for 18 hours. The solution was cooled with saturated sodium bicarbonate and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (74 ml), washed with saturated sodium bicarbonate (50 ml), water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The white foam was purified by MPLC (95: 5: 0.1 CH2Cl2: MeOH: NH4OH). A second purification by MPLC (7: 3: 0.1 Acetone: Hexane: triethylamine) gave 2.96 g (93%) of white foam. (ESI) m / z 1178 [M + H] +. Step 13c: Compound of Formula (I), Rp is acetyl, m is 2, A is -O-, B is absent. D is 3,4-quinoline. E is. - (CH1) r-CH = CH-, r is 0, n is 1 The compound of Step 15b was treated by the method of Example 1, Step g to give the title compound. (ESI) m / z 1010 [M + H] +. Example 14 Compound of Formula (I), Rp is acetyl. m is 1. A is absent, B is absent. D is absent. E is - (CH,) r-CH = CH-. r is 0. n is 1 Step 14a: Compound 11a of Scheme 3. Rp is acetyl, m is 1, is absent. X2 is -CH = CH-H The compound from Step e of Example 1 (compound 10a of Scheme 3, 25 g, 26.8 mmol) and allylamine (15 ml) in 50 ml and 5 ml of water were heated at 70 ° C for 6 hours. The solvents were evaporated and the residue was taken up in ethyl acetate, which was washed with NaHCO3, brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel eluted with acetone / hexanes from 1: 2 to 1: 1 to give the desired product (15, 60.7%). The product was further purified by recrystallization from ethyl acetate. MS (ESI) m / z 926 [M + H] +.

Step 14b: Compound of Formula (I). Rp is acetyl. m is 1. A is absent. B is absent. D is absent. E is - (CH ^) r-CH = CH-, r is 0. n is 1 The solution of the compound of step 14a (2.50 g, 2.71 mmol) and ruthenium dichloride (IV) of Bis (tricyclohexylphosphine) benylidine (Grubss catalyst 0.25 g) in dichloromethane (500 ml) was stirred at room temperature with nitrogen for 24 hours. The solvent was evaporated, the black residual material was purified by chromatography on silica gel eluted with acetone / hexanes from 1: 2 to 2: 1 to give the product (2.36 g, 97.4%).

Step 14c: Compound of Formula (I) Rp is H. m is 1. A is absent. B is absent. D is absent. E is - (CH) r-CH = CH-, r is 0. n is 1 The solution of the compound from Step 14b (75 mg) in methanol (2 ml) was heated to reflux for 3 hours to remove the acetyl group at C2 '. The cooled solution was then treated with LiOH (0.9 ml) at t.a. for 5 hours to remove the acetyl group at the C4 position. "After neutralization with 1N HCl, the mixture was extracted with AcOEt twice.The combined extract was dried over MgSO4, concentrated and purified by gel gravity column. silica, eluting with 10% MeOH in methylene chloride containing 0.5% ammonium hydroxide, to give 55 mg (57%) of the title compound.MS (APCI) m / z 811 [M + H] \ HRMS calculated for C42H7, N2O13: 811486; measured, 811.4968. 13C NMR (CDCl3) d 216.1, 167.8, 17.6, 130.4, 131.1, 103.0, 95.4, 83.9, 80.3, 77.9, 77.2, 75.0, 72.7, 70.6, 69.1, 65.7, 65.6, 56.0, 55.4, 49.5, 45.4, 45.2, 42.3, 40.2, 39.2, 38.7, 38.4, 34.4, 34.4, 30.8, 28.5, 22.9, 21.5, 21.4, 20.2, 18.5, 17.5, 14.2, 13.4, 13.2, 13.2, 11.2, 8.50 Example 15 Compound of Formula (I), Rp is H. m is 3. A is absent D is absent E is absent, n is 1 A sample of the compound of Example 16 (25 mg) was hydrogenated with hydrogen (1 atm) and 10% palladium on carbon (10 mg) in ethanol. The catalyst was removed by filtration, and the filtrate was concentrated and purified by the silica gel gravity column, eluting with 10% MeOH in methylene chloride containing 0.5% ammonium hydroxide to give 24 mg (96%) of the title compound. (APCI) m / z 813 [M + H] +. HRMS Calculated for C42H73N2O, 3, 813.5113; measured, 813.5120. Example 16 Compound of Formula (II), Rp is H. m is 1, A is absent, B is absent. D is absent. E is (CH ^) ^ - CH = CH- r is 0, n is 1 A sample of the compound from Step b of Example 1 4 (1.25 g, 1.40 mmol) was treated with 2 N hydrochloric acid (18 ml) in EtOH (15 ml) for a total of 120 hours. The mixture was neutralized with 2N NaOH, then extracted twice with CH2Cl2. The combined CH2Cl2 extracts were dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel eluted with acetone / hexanes 1: 1 to give 2: 1 to give the hydroxyl compound of intermediate C-3 (0.65 g, 81.2%) together with 0.21 g of starting material without reacting (16.8%). To a solution at -10 ° C with N 2 of N-chlorosuccinimide (0.173 g, 1.30 mmol) in dichloromethane (3 m) was added dimethylsulfide (0.12 ml, 1.63 mmoles) for 5 minutes. The resulting white mixture was stirred for 20 minutes at -10 ° C and then a solution of the intermediate C-3 hydroxyl compound (0.45 g, 0.65 mmol) in dichloromethane (2 ml) was added and the reaction mixture was stirred for 30 minutes. -10 to -5 ° C. Triethylamine (0.23 ml, 1.63 mmol) was added per drop for 5 minutes, and the reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was extracted with dichloromethane. The organic phase was washed twice with 5% aqueous sodium bicarbonate and once with brine, dried over sodium sulfate and concentrated in vacuo to give a white foam (370 mg). This second intermediate was heated in methanol for 4 hours to remove the acetyl group to the C-2 'position. The solvent was evaporated, and the residue was purified by silica gel chromatography, eluting with 5% MeOH in methylene chloride containing 0.5% ammonium hydroxide to give the title compound (301 mg, 71.4% yield for the two steps). MS (API m / z 651 [M + H] +. HRMS Calculated for C34H54N2O, 0 651.3857; measured, 651, 3843. Example 17 Compound of Formula (II) .Rp is H. m is 2. A is absent. B is absent, D is absent, E is (CH) -CH = CH- r is 0, n is 1 Step 17a. Compound 11a of Scheme 3. m is 1. A is absent, X2 is -CH CH = CH-H The cyclic carbamate of 11-N homoalyl was prepared from the compound of Step e Example 1 (compound 10a of Scheme 3, 1.0 g, 0.931 mmol) following the procedures described in step 16a, except that homoaliamine (3-butenamine, 2.0 g, ca. 20 equivalent, prepared as described by Koziara et al., Synthesis, 1984, 202-204) is substituted. by allylamine, in 55% yield, MS (ESI) m / z 937 [M + H] +. HRMS Calculated for C49H8, N2O15, 937.5361; measured, 937.5636.

Step 17b. Compound of Formula (I). Rp is acetyl, m is 2. A is absent. B, is absent. D is absent. E is - (CHz) r-CH = CH-, r is 0. n is 1 The solution of the compound from step 17a was treated according to the procedure of Example 14b to give the title compound. MS (ESI) m / z 909 [M + H] +. HRMS Calculated for C47H77N2O, 5: 909.5324; measured, 909.5342.

Step 17c: Compound of Formula (I), Rp is H. m is 2. A is absent. B is absent. D is absent, E is - (CH) r-CH = CH-, r is 0. n is 1 The solution of the compound from step 17b was hydrolyzed according to the procedure of Example 14c to give the title compounds. MS (ESI) m / z 825 [M + H] +.

Example 18 Compound of Formula (II). Rp is H. A is absent. B is absent. D is absent. E is - (CH?) R-CH = CH-, r is 0. n is 1 Step 18a: Compound 12n of Scheme 3. Rp is H, m is 2, A is absent. B is absent. D is absent The portion of cladinose was removed from the compound of Step 17a (265 mg) with 3.0 ml of 2N HCl and 3.0 ml of EtOH following the procedures previously described to give the intermediate compound 3-hydroxy. To a solution at -10 ° C with N 2 of N-chlorosuccinimide (57 mg, 0.427 mmol) in dichloromethane (2 ml) was added dimethylsulfide (37 ml, 0.704 mmole). The resulting white mixture was stirred for 20 minutes at -10 ° C and then a solution of the intermediate 3-hydroxy compound (120 mg, 0.163 mmol) in dichloromethane (1 ml) was added, and the reaction mixture was stirred for 30 minutes -10 ° C to -5 ° C. Triethylamine (71 ml, 0.509 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was extracted with dichloromethane. The organic phase was washed twice with 5% aqueous sodium bicarbonate and once with brine, dried over sodium sulfate and concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the title compound (70 mg, 60.8%) as a white foam. MS (APCI) m / z 735 [M + H] +.

Step 18b: Compound 12b of Scheme 3. Rp is H. m is 2, A is absent, B is absent. D is absent Following the procedure of Step b of Example 16, the compound of Step 18a (70 mg, 0.256 mmol) was treated with the Ruthenium catalyst (15 mg) in CH 2 Cl 2 (40 mL) to give 64 mg of the title compound after the purification. MS (ESI) m / z 707 [M + H] \ Step 18d: Compound of Formula (II), Rp is H. m is 2. A is absent. B is absent. D is absent. E is - (CH) r-CH = CH-, r is 0, n is 1 The compound of Step 18b was treated with a hot methanol followed by purification on the silica gel gravity column, eluting with 5% MeOH. % in methylene chloride containing 0.5% ammonium hydroxide, to give the title compound (36 mg, 60% yield). MS (ESI) m / z 655 [M + H] +. Example 19 Compound of Formula (I). Rp is H, m is 1. A is absent. B is -CHQH- (CH1) 1-, or 1. D is absent. E is - (CH1) r-CH = CH-, r is 0. n is 1 Step 19a: Compound 11a of Scheme 3. m is 1. A is absent. X2 is -C (O) - (CHz) -H. a is 0 To a solution of oxalyl chloride (0.68 ml, 7.85 mmol) in dichloromethane (30 ml) cooled to -78 ° C was added DMSO (1.11 ml, 15.7 mmol) in dichloromethane (10 ml). The solution was stirred for 10 minutes then the compound from Step a of Example 13 (4.85 g, 5.23 mmol) in dichloromethane (30 ml) was added, cooled to -78 ° via a cannula. The solution was stirred at -78 ° C for 3 hours, then cooled with triethylamine (3.65 ml; 26.2) and warmed to room temperature. The solution was diluted with dichloromethane (30 ml), washed with water (75 ml), brine (75 ml), dried over sodium sulfate, and concentrated in vacuo to give 4.7 g of foam white (97%) used without further purification. MS (ESI) m / z 925 [M + H] +. Step 19b; Compound 12a of Scheme 3. m is 1. A is absent, B is absent. D is -CH (OH) -CH2-CH = CH-L. X1 is HA a two phase solution of the compound of Step 19a (1.2 g, 1.30 mmol) and allyl bromide (0.63 g, 5.19 mmol) in THF (10 mL) and saturated ammonium chloride (25 mL) was added powder. zinc (0.35 g, 5.19 mmol) all at once. The solution was stirred vigorously for 4 hours, diluted with ethyl acetate (100 ml), washed with water (2 x 50 ml), brine (5 ml), dried over sodium sulfate, and concentrated in vacuo. The material was purified by FSC (95: 5: 0.1 CH2Cl2: MeOH: NH4OH), to give 0.99 g (78.6%) of white foam. MS (ESI) m / z 967 [M + H] +. Step 19c: Compound of Formula (I). R is H. m is 1. A is absent. B is -CHOH- (CH2) q-, q is 1. D is absent The compound of Step 19b was treated with the Grubbs catalyst according to the procedure of Example 14b, then the acetyl protecting groups were removed by further treatment with hot methanol and LiOH according to the procedures of Example 1, step i and Example 2 to give the title compound. MS (ESI) m / z 855 [M + H] +. HRMS Calculated for C44H7SN2O, 4: 855.5213; measured, 855.5212. Example 20 Compound of Formula (I), Rp is acetyl. m is 1, A is absent. B is C (O) - (CHz): L-. q is 1. D is absent.

E is -ÍCH1) r-CH = CH-, r is O, n is 1 Step 20a: Compound of Formula (I). Rp is acetyl. m is 1. A is absent. B is -C (O) - (CHz) q-, q is 1, D is absent. E is - (CHI) r-CH = CH-, r is 0. n is 1 The compounds of Step 19c were oxidized with Swern reagents according to the procedure of Example 19a to give the title compound. M / z (ESI) m / z 895 [M + H] +. Step 20b: Compound of Formula (I). Rp is H. m is 1. A is absent, B is -C (Q) - (CH1) 1-, q is 1. D is absent, E is - (CHz) r-CH = CH-, r is 0 n is 1 Compound 20a was hydrolyzed by further treatment with hot methanol and LiOH according to the procedures of Example 1, step i and Example 2 to give the title compound. MS (ESI) m / z 853 [M + H] +. Example 21 Compound of Formula (II). Rp is H. m is 2. A is NH. B is -C (O) - (CH ^^ -, q is 1. D is 1, 2-phenylene, E is - (CHz) r-CH = CH-. R is 0. n is 1 A sample of the compound of Example 3 (200 mg, 0.195 mmol) was treated with 2N hydrochloric acid (4 ml) in EtOH (6 ml) for a total of 40 hours.The mixture was neutralized with 2N NaOH, and extracted with CH2Cl2 twice. The combined CH2Cl2 extract was dried over MgSO4 and concentrated, The crude product was purified by flash chromatography on silica gel eluted with CH 2 Cl 2 / MeOH / NH 4 OH (10: 1: 0.05) to give the intermediate C-3 hydroxyl compound (73.5 mg, 45.6%). To a solution at -10 ° C with N 2 of N-chlorosuccinimide (24 mg, 0.211 mmol) in dichloromethane (1 ml) was added dimethisulfide (18.6 μL, 0.254 mmol). The resulting white mixture was stirred for 20 minutes at -10 ° C and then a solution of the intermediate C3 hydroxyl compound (70 mg, 0.0845 mmole) in dichloromethane (1 ml) was added and the reaction mixture was stirred for 30 minutes. -10 to -5 ° C. Triethylamine (35.4 μL) was added dropwise., 0.254 mmole) and the reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was extracted with dichloromethane. The organic phase was washed twice with 5% aqueous sodium bicarbonate and once with brine, dried over sodium sulfate, then concentrated in vacuo to give a white foam. The crude product (30 mg) of the above was heated in methanol for 4 hours to remove the acetyl group at C-2 'to give the title compound (27 mg). MS (ESI) m / z 874 [M + H] +.

Example 22 Compound of Formula (I). Rp is H. m is 1. A is absent, B is -CH (OH) - (CHI) 1-. q is 0. D is absent. E is absent, n is 3 Hydrogenation of the compound of Example 19 with H2 over Pd / C to give the title compound. MS (ESI) m / z 857 [M + H] +.

Example 23 Compound of Formula (I). Rp is H. m is 1, A is absent. B is -CH (OH) -CH (OH) - (CHz) ^ -. or is 0. D is absent. E is absent, n is 1 A to a stirred solution of the acetyl-protected intermediates of Example 14, Step b (900 mg, 0.976 mmol) and N-methyl morpholine (120 mg, 1.02 mmol) in mixed solvents which containing acetone / THF / H2O (5/2/1 ml) at 0 ° C osmium tetraoxide (24 g, 0.094 mmol) was added. The mixture was stirred at 0 ° C to t.a for 5 hours to bring the reaction to completion. After cooling with a NaHSO3 solution, the mixture was partitioned between methylene chloride and water. The organic layer was dried and concentrated to give the acetyl protected intermediate (920 mg, 99.0%). A portion of the acetyl protected intermediate (120 mg, 0. 129 mmole) was heated in methanol (5 ml) for 4 hours under reflux, then the solution was treated with 1 N LiOH (0.8 ml, 7.0 eq.) For 7 hours. The mixture was extracted with methylene chloride twice, the combined organic layer was dried over MgSO 4, and concentrated, The crude product was purified by the silica gel gravity column eluted with CH 2 Cl 2 / MeOH / NH 4 OH (10: 1: 0.05) to give the title compound. MS (ESI) m / z 845 [M + H] +. Example 24 Compound of Formula (I). 2'-Rp is H. 4"-Rp is H, m is s, A is NH, B is -C (O) - (CHz) 1-, or is 0. D is 1, 2-phenylene. - (CH) r-CH = CH-, r is 0. n is 1 A sample of compounds B of Example 3 (85 mg, 0.083 mmol) in methanol (10 ml) was heated to reflux for 4 hours to remove the group 2'-acetyl The reaction mixture was cooled to room temperature, the mixture was treated with 1 N LiOH (1.0 ml, ca. 10 eq.) At room temperature for 7 hours, 1N hydrochloric acid was added to bring the pH close to the After the partial removal of methanol, the reaction mixture was diluted with CH2Cl2, the two layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated, The crude product was purified by chromatography on silica gel. eluted with CH2Cl2 / MeOH / NH4OH (10: 1: 0.05) to give the title compound, 74.5 mg, 96.1% MS (ESI) m / z 944 [M + H] +. HRMS Calculated for C50H78N3O, 4, 944.5478; Measured 944.5479.

Claims (19)

1. CLAIMS 1. A compound selected from the group consisting of wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, or 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or selected from the group consisting of: (1) -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C, -Cß alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2) q-, (3) -C (O) -O- (CH2) q- (4) -C (O) -NR1- (CH2) q-, wherein R is as previously defined, and ( 5) -N = CH- (CH2) q-; (6) -CH (OH) - (CH2) q-, and (7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or selected from the group consisting of (1) alkylene, (2) arylene, (3) substituted arylene, (4) heteroarylene, (5) substituted heteroarylene; (6) alkenylene-arylene, (7) arylene-arylene, (8) substituted arylene-arylene, (9) heteroarylene-arylene, (10) substituted heteroarylene-arylene, (11) alkenylene-heteroarylene, (12) arylene-heteroarylene, (13) arylene-substituted heteroarylene, (14) heteroarylene-heteroarylene, and (15) substituted heteroarylene-heteroarylene; E is absent or is selected from the group consisting of (1) - (CH2) r-CH = CH-, (2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , (3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, (4) - (CH2) rC (O) -O-, (5) - (CH2 ) rN (R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are both absent then m can not be 0, that when E is -CH = CH- and portions A, B and D are all absent then m can not be 0, and that B can be -N = CH- (CH2) q- only when A is absent and m is 0.
2. 2. A compound according to claim 1, which is selected from the group consisting of: Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 3-phenylene, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 3-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-R is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is absent, B is -N = CH-, D is 1, 2-phenylene, E is - (CH 2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is NH, B is - (CH2) q-, q is 1, D is 1, 2-phenylene , E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 0, A is NH, B is - (CH2) q-, q is 1, D is 1, 3-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-Rp is acetyl, m is 2, A is NH, B is - (CH2) q-, q is 1, D is 1,3-phenylene , E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), 2'-Rp is H, 4"-R is H, m is 2, A is NH, B is - (CH2) q-, q is 1, D is 1, 3-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (II), R is H, m is 2, A is -O-, B is - (CH2) q-, q is 1, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is acetyl, m is 2, A is -O-, B is absent, D is 3,4-quinoline, E is - (CH 2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), R is acetyl, m is 1, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 3, A is absent, B is absent, D is absent, E is absent, n is 1; Compound of Formula (II), Rp is H, m is 1, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 2, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (II), Rp is H, m is 2, A is absent, B is absent, D is absent, E is - (CH2) r-CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CHOH- (CH2) q-, q is 1, D is absent, E is - (CH2) r-CH = CH -, r is 0, n is 1; Compound of Formula (I), Rp is acetyl, m is 1, A is absent, B is -C (O) - (CH2) q-, q is 1, D is absent, E is - (CH2) r- CH = CH-, r is 0, n is 1; Compound of Formula (II), Rp is H, m is 2, A is -NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH2) r -CH = CH-, r is 0, n is 1; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CH (O) -CH2) q-, q is 0, D is absent, E is absent, n is 3; Compound of Formula (I), Rp is H, m is 1, A is absent, B is -CH (O) -CH (OH) - (CH2) q-, q is 0, D is absent, E is absent, n is 1; and Compound of Formula (I), 2-R is H, 4"-Rp is H, m is 2, A is NH, B is -C (O) - (CH2) q-, q is 0, D is 1, 2-phenylene, E is - (CH 2) r-CH = CH-, r is 0, n is 1.
3. 3. A pharmaceutical composition for treating bacterial infections comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester 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 salt or ester thereof.
5. 5. A compound according to claim 1, having the formula (I)
6. 6. A compound according to claim 5, wherein E is -CH = CH and n is 1.
7. 7. A compound according to claim 1, having the formula (II)
8. 8. A compound according to claim 7, wherein E is -CH = CH and n is 1.
9. 9. A process for preparing a compound selected from the group consisting of a > wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, or 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or is selected from the group consisting of: (D -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C, -C, alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2) q-, (3) -C (O) -O- (CH2) q- (4) -C (O) -NR1- (CH2) q-, wherein R1 is as previously defined, and ( 5) -N = CH- (CH2) q-; (6) -CH (OH) - (CH2) q-, and (7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or is selected from the group consisting of (1) alkenylene, (2) arylene, (3) substituted arylene, (4) heteroarylene, (5) substituted heteroarylene; (6) alkenylene-arylene, (7) arylene-arylene, (8) substituted arylene-arylene, (9) heteroarylene-arylene, (10) substituted heteroarylene-arylene, (11) alkenylene-heteroarylene, (12) arylene-heteroarylene , (13) substituted arylene-heteroarylene, (14) heteroarylene-heteroarylene, and (15) substituted heteroarylene-heteroarylene; E is absent or is selected from the group consisting of (1) - (CH2) r-CH = CH-, (2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , (3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, (4) - (CH2) rC (O) -O-, (5) - (CH2 ) rN (R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are both absent then m can not be 0, that when E is -CH = CH- and portions A, B and D are all absent then m can not be 0, and that B can be -N = CH- (CH2) q- only when A is absent and m is 0, the method comprises (a) treating a compound having the formula where U is 4"-Rp-O-cladinose and U 'is H, or U and U' taken together with the carbon atom to which they are attached, they form a carbonyl group with a reactive compound having the formula H2N- (CH2) mABDX \ where m, A, B are as previously defined, D is as previously defined, and X1 is a leaving group selected from Cl, Br, I and trifluoromethanesulfonate, to prepare an intermediate compound having the formula (b) cylindrizing and optionally reducing the compound of Step (a).
10. The process of claim 9, wherein U is 4"-Rp-O-cyadinosa, and the product is a compound of the formula (I) 11.
11. The process of claim 9, wherein U and U ' they are taken together with the carbon atom to which they are attached they form a carbonyl group, and the product is a compound of the formula (II) 12.
12. The process of claim 11, wherein the reactant of step (a) is 2. - ((2-iodophenyl) methoxy) ethylamine 13.
13. The process for preparing a compound selected from the group consisting of wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, or 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or is selected from the group consisting of: (1) -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C, -C6 alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2) q-, (3) -C (O) -O- (CH2) q- (4) -C (O) -NR1- (CH2) q-, wherein R1 is as previously defined, and ( 5) -N = CH- (CH2) q-; (6) -CH (OH) - (CH2) q-, and (7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or selected from the group consisting of (1) alkenylene, (2) arylene, (3) substituted arylene, (4) heteroarylene, (5) substituted heteroarylene; (6) alkenylene-arylene, (7) arylene-arylene, (8) substituted arylene-arylene, (9) heteroarylene-arylene, (10) substituted heteroarylene-arylene, (11) alkenylene-heteroarylene, (12) arylene-heteroarylene , (13) substituted arylene-heteroarylene, (14) heteroarylene-heteroarylene, and (15) heteroarylene-substituted heteroarylene; E is absent or is selected from the group consisting of (1) - (CH2) r-CH = CH-, (2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , (3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, (4) - (CH2) rC (O) -O-, (5) - (CH2 ) rN (R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are absent that m can not be 0, that when E is -CH = CH- and portions A, B and D are all absent then m can not be 0, and that B can be -N = CH- (CH2) q - only when A is absent and m is 0, the method comprises (a) treating a compound having the formula where U is 4"-Rp-O-cladinose and U 'is H, or U and U' taken together with the carbon atom to which they are attached, they form a carbonyl group with a first reactive compound having the formula H2N - (CH2) mABD-X1, where m and A are as previously defined, X2 is H, to prepare an intermediate compound having the formula (b) cylindrizing and optionally reducing the compound of Step (b).
14. The process of claim 13, wherein U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I).
15. 15. The process of claim 14, wherein the reagent of step (a) having the formula H2N- (CH2) m-A-X2 is selected from the group consisting of hydrazine and ethylenediamine.
16. 16. A process for preparing a compound selected from the group consisting of wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, or 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or selected from the group consisting of: (1) -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C, -C6 alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2) q-, (3) -C (O) -O- (CH2) q- (4) -C (O) -NR1- (CH2) q-, wherein R1 is as previously defined, and ( 5) -N = CH- (CH2) q-; (6) -CH (OH) - (CH2) q-, and (7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or selected from the group consisting of (1) alkenylene, (2) arylene, (3) substituted arylene, (4) heteroarylene, (5) substituted heteroarylene; (6) alkenylene-arylene, (7) arylene-arylene, (8) arylene-substituted arylene, (9) heteroarylene-arylene, (10) substituted heteroarylene-arylene, (11) alkenylene-heteroarylene, (12) arylene-heteroarylene, (13) arylene-substituted heteroarylene, (14) heteroarylene-heteroarylene, and (15) heteroarylene- substituted heteroarylene; E is absent or is selected from the group consisting of (1) - (CH2) r-CH = CH-, (2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , (3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, (4) - (CH2) rC (O) -O-, (5) - (CH2 ) rN (R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are both absent then m can not be 0, that when E is -CH = CH- and portions A, B and D are all absent then m can not be 0, and that B can be -N = CH- (CH2) q- only when A is absent and m is 0, the method comprises (a) treating a compound having the formula where U is 4"-Rp-O-cladinose and U 'is H, or U and U', taken together with the carbon atom to which they are attached, to form a carbonyl group, with a first reactive compound having the formula H2N- (CH2) mABD-X1, wherein m and A are as previously defined and X2 is an N-protecting group, to prepare an intermediate compound having the formula (b) treating the intermediate compound of Step (a) with a reactive compound having the formula B'-D-X1, wherein X1 is a leaving group selected from Cl, Br, I and trifluoromethanesulfonate, B 'is a portion of precursor B and D is as previously defined, to prepare a second intermediate compound having the formula (b) cyclizing and optionally reducing the compound of Step (b).
17. The process of claim 16, wherein U is 4"-Rp-O-cladinose, and the product is a compound of the formula (I)
18. 18. A process for preparing a compound selected from the group consisting of from wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 0 4; Rp independently is hydrogen or a hydroxy protecting group each time it occurs; A is absent or is selected from the group consisting of: (1) -O-, and (2) -N (R1) -, wherein R1 is hydrogen or C, -C6 alkyl optionally substituted with aryl or heteroaryl; B is absent or is selected from the group consisting of (1) - (CH2) q-, where q is 0, 1, 2, 3, 4, 5 or 6, (2) -C (O) - (CH2) q-, (3) -C (O) -O- (CH2) q- (4) -C (O) -NR1- (CH2) q-, wherein R1 is as previously defined, and ( 5) -N = CH- (CH2) q-; (6) -CH (OH) - (CH2) q-, and (7) -CH (OH) -CH (OH) - (CH2) q-; D is absent or selected from the group consisting of (1) alkenylene, (2) arylene, (3) substituted arylene, (4) heteroarylene, (5) substituted heteroarylene; (6) alkenylene-arylene, (7) arylene-arylene, (8) substituted arylene-arylene, (9) heteroarylene-arylene, (10) substituted heteroarylene-arylene, (11) alkenylene-heteroarylene, (12) arylene-heteroarylene , (13) substituted arylene-heteroarylene, (14) heteroarylene-heteroarylene, and (15) heteroarylene-substituted heteroarylene; E is absent or is selected from the group consisting of (1) - (CH2) r-CH = CH-, (2) - (CH2) rO-, where r is 0, 1, 2, 3 or 4 , (3) - (CH2) r-NR1-CH2-CH (OH) -, where R1 is as previously defined, (4) - (CH2) rC (O) -O-, (5) - (CH2 ) rN (R1) -, (6) - (CH2) rOC (O) -, (7) - (CH2) rC (O) -N (R1) -, and (8) - (CH2) rN (R1) -C (O) -, with the restrictions that the sum of m + q can not be 0, that the sum of m + n + q + r is an integer from 2 to 7, that when portions A and B are both absent then m can not be 0, that when E is -CH = CH- and portions A, B and D are all absent then m can not be 0, and that B can be -N = CH- (CH2) q- only when A is absent and m is 0, the method comprises (a) treating a compound having the formula wherein U is 4"-Rp-O-cladinose Rp is a hydroxy protecting group and U 'is H, or U is U' taken together with the carbon atom to which they are attached, form a carbonyl group, with a first compound reagent having the formula H2N- (CH2) mABD-X1, where m, A, B, D are as previously defined and X3 is - (CH2) rY, where r is as previously defined and Y may be a N-precursor, an acyl-precursor, hydroxyl portion or -CH2-I to prepare a first intermediate compound having the formula (b) treating the first intermediate compound of Step (a) with double-ligating modifying reagents, to prepare a second intermediate compound having the formula wherein E 'is a precursor E having a reactive moiety selected from the group consisting of -CH (O), -OH, -NH2, -C (O) OH, and an epoxy ring; and (c) cylindrizing and optionally reducing the compound of Step (b).
19. 19. The process of claim 18, wherein U is 4"-Rp-O-cladinose and the product is a compound of the formula (I).