MXPA05014064A - Lincomycin derivatives possessing antibacterial activity - Google Patents

Abstract

Novel lincomycin derivatives are disclosed. These lincomycin derivatives exhibit antibacterial activity. As the compounds of the subject invention exhibit potent activities against bacteria, including gram positive organisms, they are useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.

Description

LINCOMYCIN DERIVATIVES THAT HAVE ANTIBACTERIAL ACTIVITY CROSS REFERENCES WITH RELATED REQUESTS This application is a continuation in part of the U.S. patent application. No. 07 / 777,455, filed February 11, 2004, which is a continuation in part of the US patent application. No. 10 / 642,807, filed August 15, 2003, which claims the benefit of 35 U.S.C. §119 (e) of the US provisional application. No. 60 / 403,770 filed on August 15, 2002, and which also claims the benefit of the US provisional application. No. 60 / 479,502, filed June 17, 2003, the descriptions of which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to lincomycin derivatives that exhibit antibacterial activity.

STATE OF THE ART Lincomycin is a biosynthetic product that adversely affects the growth of different microorganisms, particularly Gram-negative bacteria. The characteristics and preparation of lincomycin are described in U.S. Pat. 3,086,912. A variety of lincomycin derivatives have been prepared, which also have antibacterial activity. These derivatives include, for example, clindamycin, which is described in U.S. Pat. 3,496,163. Lincomycin derivatives remain attractive targets for discovering antibacterial drugs. Accordingly, lincomycin derivatives having antimicrobial activity are desired as potential antibacterial agents.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides lincomycin derivatives having antibacterial activity. In one of its aspects of the composition, the invention is directed to a compound of formula (I): wherein: R1 is alkyl; R2 and R3 are independently H, alkyl, hydroxy, fluoro, or cyanoalkyl, or one of R2 and R3 is = NOR7 and the other is absent, or one of R2 and R3 is = CH2 and the other is absent, with the conditions that neither R2 nor R3 are H; when one of R2 and R3 is fluorine, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not fluorine, hydrogen or hydroxy; R6 is selected from the group consisting of H, alkyl, hydroxyalkyl, -C (0) -O-alkylene-cycloalkyl, -C (O) -O- (substituted alkylene) -cycloalkyl, -C (O) -O-alkyl , -C (O) -0- (substituted alkyl), -C (O) 0-aryl, -C (O) -0- (substituted aryl), -C (0) O-heteroaryl, -C (0) -O- (substituted heteroaryl), - [C (0) 0] p-alkylene-heterocycle, - [C (O) Ojp-alkylene- (substituted heterocycle), wherein p is 0 or 1; R7 is H or alkyl; R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen , substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2), -OH, - (CH2) n-NR4R5, -alkylen-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the branched chain isomers of the same, wherein n is an integer from 1 to 8 included, and R 4 and R 5 are H or alkyl; and m is 0, 1, 2 or 3; and prodrugs, tauomers or pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula I has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Strepfococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile. In one embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment m is 3. In a preferred embodiment, R1 is methyl. In one embodiment, one of R2 and R3 is H, and the other is alkyl. In one embodiment, one of R2 and R3 is H, and the other is methyl. In one embodiment, one of R2 and R3 is H, and the other is cyanoalkyl. In one embodiment, both R2 and R3 are F. In one embodiment, one of R2 and R3 is hydroxy, and the other is alkyl. In one embodiment, R2 and R3 together are hydroxyimino or alkoxyimino. In one embodiment, R2 and R3 together are methylene (= CH2).In a preferred embodiment, R6 is H, alkyl, or hydroxyalkyl. In a preferred embodiment, R6 is selected from the group consisting of H, methyl, ethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, and 3-hydroxypropyl. In another embodiment, R6 is not one of the following: In one embodiment, each R9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH , - (CH2) n-NR4R5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the branched chain isomers thereof, wherein n is an integer from 1 to 8 inclusive, R4 and R5 are H or alkyl. In one embodiment, R9 is a substituted alkyl, and wherein the one or more substituents on the alkyl group are selected from the group consisting of halogen, oxygen, hydroxy, amine (primary), amine (secondary amine substituted with alkyl as above) ), amine (tertiary amine substituted with alkyl as above), sulfur, -SH, and phenyl. In a preferred embodiment, each R9 is independently selected from the group consisting of halogen, alkyl, substituted alkyl, alkoxy, alkoxyalkoxy, substituted alkoxy, and cycloalkyl. In another preferred embodiment, each R9 is independently selected from the group consisting of H, alkyl, and substituted alkyl. In one embodiment, R9 is selected from the group consisting of 1-ethylpropyl; 2- (4-fluorophenyl) ethyl; 2,2-difluoroethoxymethyl / fluoro; 2,2-difluoropentyl; 2-cyclobutyl-ethyl; 2-cyclopropyl-ethyl; 2-fiuoroethoxy; 2-methoxyethoxy; 2-propoxy-ethyl; 3- (2-fluoro-eioxy) -propyl; 3- (3-fluoro-propoxy) -propyl; 3- (4-chlorophenyl) propyl; 3- (cyclopropyl-methoxy) -propyl; 3,3,3-trifluoropropoxy; 3,3-difluorobutyl; 3,3-difluoropentyl; 3,3-difluoropropyl; 3,3-difluoropropyl / fluoro; 3-cyclobutyl-propyl; 3-cyclopentyl-propyl; 3-cyclopropyl-propyl; 3-ethoxy-propyl; 3-fluoropropoxy; 3-fluoro-propoxymethyl; 3-fluoropropyl; 3-fluoropropyl / fluoro; 3-hydroxy-3-ethylpentyl; 3-methoxypropyl; 3-propoxy-propyl; 4,4-difluorobutyl; 4,4-difluoropentyl; 4-fluorobutoxy; 4-fluorobutyl; 4-methoxy-butyl; 5,5-difluoropentyl; 5-fluoropentyl; butoxy; butyl; cyclobutyl-methyl; cyclohexyl; cyclohexyl-methyl; cyclopropyl-methoxy; cyclopropyl-methyl; ethyl; ethyl / fluoro; fluoro / butyl; fluoro / propyl; isobutyl; isopentyl; iso-propyl; methoxy; n-butyl; n-pentyl; pentoxy; pentyl; propoxymethyl; and propyl. In another embodiment, R9 is propyl. In one embodiment, R9 is selected from the group consisting of 1-ethylpropyl; 2- (4-fluorophenyl) ethyl; 2,2-difluoropentyl; 2-cyclobutyl-ethyl; 2-cyclopropyl-ethyl; 2-methoxyethoxy; 3- (2-fluoro-ethoxy) -propyl; 3- (4-chlorophenyl) propyl; 3,3-difluorobutyl; 3,3-difluoropentyl; 3,3-difluoropropyl; 3-cyclobutyl-propyl; 3-cyclopentyl-propyl; 3-cyclopropyl-propyl; 3-ethoxy-propyl; 3-fluoropropyl; 3- hydroxy-3-ethylpentyl; 3-methoxypropyl; 3-propoxy-propyl; 4,4-difluorobutyl; 4-fiuorobutyl; 5,5-difluoropentyl; 5-fluoropentyl; butoxy; butyl; cyclobutyl-methyl; cyclohexyl; cyclohexyl-methyl; propyl-methoxy cycle; cyclopropyl-methyl; ethyl; isobutyl; isopentyl; iso-propyl; methoxy; n-butyl; n-pentyl; pentoxy; pentyl; propoxymethyl; and propyl. In one embodiment, R9 is not 2,2-difluoroethoxymethyl / fluoro; 2-fluoroethoxy; 2-propoxy-ethyl; 3- (3-fluoro-propoxy) -propyl; 3- (cyclopropy-methoxy) -propyl; 3,3,3-trifluoropropoxy; 3,3-difluoropropyl / fluoro; 3-fluoropropoxy; 3-fluoro-propoxymethyl; 3-fluoropropyl / fluoro; 4,4-difluoropentyl; 4-fluorobutoxy; 4-methoxy-butyl; ethyl / fluoro; fluoro / butyl; or fluoro / propyl. In one of its aspects of the composition, the invention is directed to a prodrug compound of formula (IV): wherein R1, R2, R3, and R9 are as defined for Formula I; in which R 6 is as defined for Formula I, or is a suitable prodrug group that can be cleaved in vivo, and wherein R 11 is H or a suitable prodrug group that can be cleaved in vivo. , In one embodiment, the compound is a prodrug wherein R6 is selected from the group consisting of hydrogen; 1 - (acetyloxy) -ethyl-oxycarbonyl; 1-amino-2-methyl-butyl-carbonyl; 1-amino-2-methyl-butyl-carbonyl-oxy-methyl-oxycarbonyl; 1-amino-2-methyl-propyl-carbonyl; 1-amino-2-phenyl-ethyl-carbonyl; 1-amino-ethyl-carbonyl; 1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl-oxycarbonyl; 1-methyl-1,4-dihydro-pyridin-3-yl-carbonyl; 1-methyl-3-oxo-but-1-enyl; 5-methyl- [1, 3] dioxol-2-on-4-yl-methoxy-carbonyl; 5-methyl- [1, 3] dioxol-2-on-4-yl-methyl; ethoxy carbonyl; ethyl-carbonylamino-methyl; Fluorenyl-methylene-oxycarbonyl; phenoxycarbonyl; piperidin-4-yl-carbonyl-oxy-methyl-oxycarbonyl; and pyridin-3-yl-carbonylamino-methyl. In another embodiment, the compound is a prodrug wherein R6 is selected from the group consisting of hydrogen; 1- (acetyloxy) -ethyl-oxycarbonyl; 1-amino-2-methyl-buyl-carbonyl; 1-amino-2-meityl-butyl-carbonyl-oxy-methyl-oxycarbonyl; 1-amino-2-methyl-propyl-carbonyl; 1-amino-2-phenyl-ethyl-carbonyl; 1-amino-ethyl-carbonyl; 1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl-oxycarbonyl, 1-methyl-1,4-dihydro-pyridin-3-yl-carbonyl; 1-methyl-3-oxo-but-1-enyl; ethyl-carbonylamino-methyl; piperidin-4-yl-carbonyl-oxy-methyl-oxycarbonyl; and pyridin-3-ii-carbonamino-methyl. In another embodiment, the compound is a prodrug wherein R6 is not 5-methyl- [1, 3] dioxol-2-on-4-yl-methoxy-carbonyl; 5-methyl- [1, 3] dioxol-2-on-4-yl-methyl; ethoxy carbonyl; Fluorenyl-methylene-oxycarbonyl; or phenoxycarbonyl.

In another embodiment, the compound is a prodrug wherein R6 is not 5-methyl- [1, 3] dioxol-2-on-4-yl-methoxycarbonium; or 5-methyl- [1, 3] dioxol-2-on-4-yl-methyl. In another preferred embodiment, the compound is a prodrug wherein R11 is selected from the group consisting of hydrogen; 2- (N- (2-morpholin-4-yl-ethyl) -amino-carbonyl) -ethyl-carbonyl; -C (O) CH2CH2COOH; NN-dimethylamino-methylene-carbonyl; pentadecyl-carbonyloxy; and -PO3H2. In a preferred embodiment, this invention provides compounds of formula (II): wherein: R1 is alkyl; R2 and R3 are independently H, alkyl or cyanoalkyl, with the proviso that neither R2 nor R3 are H; R6 is H, alkyl, or hydroxyalkyl, R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, cycloalkyl substituted, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH 2) n-OH, - (CH 2) n-NR 4 R 5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the isomers of branched chain thereof, wherein n is an integer from 1 to 8 included, and R4 and R5 are H or alkyl; and m is 0, 1 or 2; and prodrugs and pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula II has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coii, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile. In a particularly preferred embodiment, this invention provides compounds of formula (III): wherein: R1 is alkyl; R2 and R3 are fluorine; R6 is H, alkyl, or hydroxyalkyl, R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, -cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyle, - (CH 2) n-OH, - (CH 2) n-NR 4 R 5, -alkylene-Ra wherein Ra is selected from monofiuorophenyl and monochlorophenyl, and isomers branched chain thereof, wherein n is an integer from 1 to 8 included, and R 4 and R 5 are H or alkyl; and m is 1 or 2; and prodrugs and pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula 111 has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile. In another preferred embodiment, this invention is directed to compounds of formula (IV): wherein: R1 is alkyl; R2 and R3 are independently H, or alkyl, hydroxy, fluoro, or cyanoalkyl, or one of R2 and R3 is = NOR7 and the other is absent, or one of R2 and R3 is = CH2 and the other is absent, with the conditions that neither R2 nor R3 are H: when one of R2 and R3 is fluorine, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not fluorine, hydrogen or hydroxy; R6 is selected from the group consisting of -C (O) -O-alkylene-cycloalkyl, -C (O) -O- (substituted alkylene) -cycloalkyl, -C (0) -O-alkyl, -C (O) -O- (substituted alkyl), -C (O) O-aryl, -C (O) -O- (substituted aryl), -C (O) O-heteroaryl, -C (O) -O- (substituted heteroaryl ), - [C (O) O] p-alkylene-heterocycle, - [C (O) O] p-alkylene- (substituted heterocycle), wherein p is 0 or 1, with the proviso that -C ( 0) O- (substituted alkyl) does not include the following R7 is H or alkyl; R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen , phenyl, substituted phenyl, - (CH2) n-OH, - (CH2), - NR4R5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the branched chain isomers thereof, wherein n is an integer from 1 to 8 included, and R 4 and R 5 are H or alkyl; and m is 1 or 2; and prodrugs, tautomers or pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula I has a minimum inhibitory concentration of 32 μg / m! or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile. Lincomycin derivatives within the scope of the invention include those set forth in the following Tables I and II: TABLE 1 Includes R and / or S isomers as well as individual isomers or as a mixture TABLE II * includes R and / or S isomers as well as individual isomers or as a mixture. As used below, these compounds are named based on acetamide or amide derivatives, but alternatively, these compounds could be named based on 1-thio-substituted derivatives. 1-threo-β-D-galacto-octopyranoside. Specific compounds within the scope of this invention include the following compounds: [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] 4-ethyl-piperidine-2-carboxylic acid amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; [3-Cyano-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-methyl-4-propyl- pyrrolidine-2-carboxylic acid; [2-Hydroxy-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethyl-piperidine-2-carboxylic acid; [2-Hydroxyimino-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; 1-Methylo-4-propyl-pyrrolidine-2-carboxylic acid [2-methoxyimino-1- (3,4,5-trihydroxy-6-methylsulfanyl-teirahydro-pyrn-2-yl) -propyl] -amide.; 5-Butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-pentyl-pyrrolidine-2-carboxylic acid; [4- (3-methyl-butyl) 4- (3-methyl-butyl) -3- (4,5,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. -pyrrolidine-2-carboxylic acid; 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [2,2-Difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-yl-hydro-pyran-2-yl) -propyl] -amide; 4-Pentyl-pyrrolidine-2-carboxylic acid [2,2-D-fluoro-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (3- (4-fluoro-phenyl) - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide] - propyl] -pyrrolidine-2-carboxylic acid; [4- (3,3-Difluoro-propyl) -pyrrolidine-2-methyl-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (3- (4-Chloro-phenyl) -propyl] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -pyrrolidine-2-carboxylic acid; [2- (Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,2-difluoro-pentyl) -pyrrolidine-2 -amide -carboxy; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine -2-carboxylic; [2-Methyl-1- (3,4,5-trihydro-d-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-hydroxy-propyl) -4-pentyl -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylj-amide of 1- (3-hydroxy-propyl) -4-pentyl-pyrrolidine -2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-hydroxy-ethyl) -4- (3-methyl) -butyl) -pyrrolidine-2-carboxylic acid; [4- (3,3-difluoro-propyl) -1- (2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -hydroxy-ethyl) -pyrrolidine-2-carboxylic acid; [2,2-Difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 1- (2-Hydroxy-ethyl) -4-pentyl -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-pentyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-methoxy-piperidine-2-carboxylic acid; [2-Met.l-1- (3,4,5-ylhydroxy-6-mephsulfanyl-1-yrahydro-pyran-2-yl) -propyl] -amide of 4- (l-efil-propyl) -piperidyl) na-2-carboxylic acid; 4-isopropyl-piperidine-2-carboxylic acid [2-Meyll-1- (3,4,5-ylhydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propyl-amide; 4-Butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Cyclohexyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 4-Ethyl-1- (2-hydroxy-ethyl) -piperidine [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; 2- (2-Hydroxy-ethyl) -4-pentyl-piperidine- [2-Meityl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-hydroxy-ethyl) -4-propyl-piperidine- 2-carboxylic; [4- (4,4-difluoro-pentyl) -pyrrolidine [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [4- (3,3-difluoro-butyl) -pyrrolidine-2-methyl-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (3,3-difluoro-pentyl) -pyrrolidine-2-methyl-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (3,3-difluoro-pentyl) -1 - (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid; [4- (3,3-difluoro-propyl) -piperidine-2-methyl-1- (3,4,5-frihydroxy-6-methylsulfanyl-terahydro-pyran-2-yl) -propyl] -amide of 4 (3,3-difluoro-propyl) -piperidine -carboxylic; [4- (4,4-Difluoro-butyl) -piperidine-2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide carboxylic; [4- (5,5-D-fluoro-pentyl) -piperidine [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [4- (5-Fluoro-pentyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; 4- (4-Fluoro-butyl) -piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-ethyl-3-hydroxy-pentyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-butoxy-piperidine-2-carboxylic acid; 4-Pentyloxy-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 4- (4-Fluoro-butoxy) -piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-tphydroxy-6-methylsulfanii-tetrahydro-pyran-2-yl) -propi] -amide.; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -alyl] -amide of 4-butyl-pyrrolidine-2-carboxylic acid; [4-Diethyl-piperidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide 4- (3-fluoro-propoxy) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3,3,3-trifluoro-propoxy) -piperidine -2-carboxylic; 4-Isobutyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propiij-amide; 4-Propyl-piperidine-2-carboxylic acid [2,2-Difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-ylehydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 4-Butyl-4-fluoro-pyrrolidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (2-Methoxyethoxy) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsufinyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4-Butyl! -pyrrolidin-2-carboxylic acid 2-metp-1- (3J4,5-trihydroxy-6-rnethylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [4- (4,4-difluoro-pentyl) -piperidine- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 2-carboxylic; 4- (3-fluoro-propyl) -3- (3-methyl-3-fluoro-propyl-pyran-2-yl) -propyl] -amide (3,4,5-trihydroxy-6-methylsulfanyl) -amide ) -piperidine-2-carboxylic acid; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [4- (2-Fluoroethoxy) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-ii) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclopropyl-ethyl) -piperidine-2-carboxylic acid; 4-cyclopropylmethyl-piperidine-2-carboxylic acid [2-Meyll-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 4- (2-Cyclobutyl-ethyl) -piperidine [2-Metyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [4-Cyclobutylmethyl-piperidine-2-carboxylic acid [2-methyll-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide; 3-Butyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3-Cyclopropylmethyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3-propyl-azetidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3-butyl-1- (2-hydroxy-ethyl) -zetidine-2-carboxylic acid; 3-Pentyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3- (3-Methyl-butyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; 3- (3-Cyclobutyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3- (2-cyclobutyl-ethyl) -azetidine-2- carboxylic; 3- (2-cyclopropyl-ethyl) -azetidine-2-methyl-3- (2-cyclopropyl-ethyl) -zetidine-2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; 3- (3-Cyclopropyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3-Butyl-1-methyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid; [4- (2-Cyclobutyl-ethyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclopropyl-ethyl) -pyrrolidine- 2-carboxylic; [2-Methyl-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid; 4-Butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Meti-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-cyclopentyl-propyl) -piperidine- 2-carboxylic; [2-Mephyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-meioxy-propyl) - piperidine-2-carboxylic acid; [4- (3-Ethoxy-propyl) -piperidine-2-methyl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 4- (3-propoxy-propyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide 4- (3-Cyclopropylmethoxy-propyl) -piperidine-2 acid -carboxylic; [4- (3- (2-fluoro-ethoxy) -propyl] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -piperidine-2-carboxylic acid; [4- (3- (3-fluoro-propoxy) -propyl] - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide] - piperidine-2-carboxylic acid; [4- (4-methoxy-butyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide]; 4-Propoxymethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-yl-hydroxy-6-methyl-sulfanyl-tetrahydro-pyran-2-yl) -propylamide; [4- (3-Fluoro-propoxymethyl) -piperidine-2-methyl-4- (3-fluoro-propoxymethyl) -piperidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. -carboxylic; 4-Cyclohexylmethyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [4- (2-propyloxyethyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethoxy-piperidine-2-carboxylic acid; 4-Fluoro-4-butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 4-Fluoro-4-ethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-fluoro-4- (3-fluoropropyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide From 4-fluoro-4- (3,3-difluoropropyl) - piperidine-2-carboxylic acid; 4-Fluoro-4- (2,2-difluoroethoxymethyl) -piperidine [2-Metyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; and prodrugs, tautomers and pharmaceutically acceptable salts thereof.

Specific prodrug compounds within the scope of this invention include the following compounds: 2- [2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro) -acetic acid 9H-fluoren-9-ylmethyl ester pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid; Ethyl ester of 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1- acid carboxylic; Phenyl ester of 2- [2-methyl-1- (3,4,5-frihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1 acid -carboxylic; (4,5-Dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propyl] -2-methylsulfanyl-tetrahydrofonyl ester -piran-3-i) of phosphoric acid; Monoester of (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propyl.} -2-methylsulfanyl-tetrahydro-pyran-3 -yl) of succinic acid; 4,5-dihydroxy-6-ester. { 2-meityl-1 - [(4-propyl-p-peridine-2-carbonyl) -aminol-propyl} -2- Methylsulfanyl-tetrahydro-pyran-3-yl of N- (2-morpholin-4-yl-ethyl) -succinnamic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propl} -2-methylsulfanyl-tetrahydro-pyran-3-yl of dimethylaminoacetic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide of 1- (5-methyl-2-oxo- [1, 3ldioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2- L) -propylcarbamoyl-4-propyl-piperidine-1-carboxylic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propyl} -2-methylsulfanyl-tetrahydro-pyran-3-yl of hexadecanoic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-1-hydra-pyrn-2-yl) -propyl-amide of 1- (1-methyl-3-oxo-but- 1-enyl) -4-propyl-piperidine-2-carboxylic acid; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-acetoxy-ethyl ester -carboxylic; 2-Methyl-3-methyl-pentanoyloxymelyl ester of 2- [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-piperidine-4-carbonyloxymethyl ester -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide of 1- (propionylamino-methyl) -4-propyl- piperidine-2-carboxylic; N-. { 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl-4-propyl-piperidin-1-ylmethyl} -nicotinamide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide 1- (2-Amino-propionyl) -4-propyl acid -piperidine-2-carboxylic acid; [2-Methoxy-3-phenyl-propionyl] 2- (3-amino-3-phenyl-propionyl) [2-methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide] ) -4-propyl-piperidine-2-carboxylic acid; [2-Amino-3-methyl-pentanoyl] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -propyl-piperidine-2-carboxylic acid; 1- (2-Amino-3-methyl-butyryl) -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide ) -4-propyl-piperidine-2-carboxylic acid; [1- (1-methyl-1,4-dihydro-pyridine- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] 3-carbonyl) -4-propyl-piperidine-2-carboxylic acid; 1-Methyl-1, 2,3,6-tetrahydro-pyridin-4-yl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro) -piran-2-yl) -propylcarbamoyl-4-propyl-piperidine-1-carboxylic acid; and pharmaceutically acceptable salts and tauomers and the like. In one embodiment, a compound of the group is selected which consists of: [4- (4-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide] 2-cyclopropyl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-cyclopropylmethyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanii-tetrahydro-pyran-2-yl) -propyl-amide of 4- (2-cyclobutyl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-cyclobutylmethyl-piperidine-2-carboxylic acid; 3-Butyl-azetidine-2-carboxylic acid [2-methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3-Cyclopropylmethyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3-Propyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3-Butyl-1- (2-hydroxy-ethyl) -azetidine- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide] 2-carboxylic; 3-Pentyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3- (3-Methyl-butyl) [2-Methyl-1- (3,4,5-trihydroxy-6-methyl-sulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. -zetidine-2-carboxylic acid; 3- (3-Cyclobutyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi] -amide.; 3- (2-Cyclobutyl-ethyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3- (2-cyclopropyl-ethyl) -3- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3- (2-cyclopropyl-ethyl) -zetidine-2-carboxylic acid; 3- (3-Cyclopropyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 3-Butyl-1-methyl-azetidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide -carboxylic; Monoester of (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -aminol-propyl} -2-methylsulfanyl-tetrahydro-pyran- 3-yl) of the phosphoric acid; Monoester of (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -aminol-propyl} -2-methylsulfanyl-tetrahydro-pyran-3- il) of succinic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -aminol-propyl} -2-methylsulfanyl-tetrahydro-pyran-3-yl From N- (2-morpholin-4-yl-ethyl) -succinnamic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -aminol-propyl} -2-methylsulfanyl-tetrahydro-pyran-3-yl of dimethylamino-acetic acid; 4-Cyclopropylmethyl-pyrrolidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-a-ida acid 4- (2-cyclobutyl-ethyl) -pyrrolidine-2) -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4- (2-cyclopropyl-ethyl) -pyrrolidine-2- carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 5-propyl-azepane-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide of 4-butyl-piperidine-2-carboxylic acid; [4- (3-cyclopentyl-propyl) -piperidine] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -2-carboxylic; [2-Met l-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (3-methoxy-propyl) l) -piperidine-2-carboxylic acid; [4- (3-ethoxy-propyl) -piperidine-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4- (3-ethoxy-propyl) -piperidine-2- carboxylic; 4- (3-Propoxy-propyl) -piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [4- (3-Cyclopropylmethoxy-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; [4- (3- (2-fluoro-ethoxy) -propyl-) 2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide piperidine-2-carboxylic acid; [4- (3- (3-fluoro-propoxy) -propyl-) 2- [methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] piperidine-2-carboxylic acid; [4- (4-methoxy-butyl) -piperidine-2-methyl-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-ii) -propyl-amide] carboxylic; 4-Propoxymethyl-p-pperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-fluoro-propoxymethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 1- (5-methyl-2-oxo- [1, 3-diox -4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; 5-Methyl-2-oxo- [1, 3-dioxol-4-ylmethyl ester] 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) acid) -propylcarbamoyl-4-propyl-piperidine-1-carboxylic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -aminol-propyl} -2-methylsulfanyl-tetrahydro-pyran-3-yl of hexadecanoic acid; [1- (1-Methyl-3-oxo-but-1-enyl) -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide ) -4-propyl-piperidine-2-carboxylic acid; 1-Acetoxy-ethyl ester 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propylcarbamoyl-4-propyl-piperidine} -1-carboxylic; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl-4-propyl- 2-amino-pentanoyloxymethyl ester piperidine-1-carboxylic acid; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine piperidine-4-carbonyloxymethyl ester -1-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (propionylamino-methyl) -4-propyl-piperidine-2 -amide -carboxylic; N-. { 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylisulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl-4-propyl-piperidin-1-ylmethyl} -nicotinamide; 1- (2-Amino-propionyl) -4-propyl- [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide piperidine-2-carboxylic acid; 1- (2-Amino-3-phenyl-propionyl) -4- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -propyl-? iperidine-2-carboxylic acid; [1- (2-amino-3-methyl-pentanoyl) -4- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide] propyl-piperidine-2-carboxylic acid; [2-amino-3- (3,4-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 1- (2-amino-3-) methyl-butyryl) -4-propyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (1-methyl-1,4-dihydro-) pyridine-3-carbonyl) -4-propyl-piperidine-2-carboxylic acid; 1-Methyl-1, 2,3,6-tetrahydro-pyridin-4-yl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2) acid -l) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid; 4-Cyclohexylmethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (2-propyloxyethyl) -piperidine [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide] -2-carboxylic; 4-Cyclopropylmethoxy-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-butyl-piperidine-2-carboxylic acid; co; 4-Fluoro-4-ethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-fluoro-4- (3-fluoro-propyl) -piperidine-2-propyl-amide] carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-fluoro-4- (3,3-difluoropropyl) -piperidine- 2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-4-fluoro-4- (2, 2-difluoroethoxymethyl) -piperidine-2-carboxylic acid; or a prodrug and / or the pharmaceutically acceptable salts thereof. The compounds, tautomers, prodrugs and pharmaceutically acceptable salts thereof as defined herein, may have activity against bacteria, protozoa, fungi and parasites. In another aspect, this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound defined herein. The pharmaceutical compositions of the present invention may further comprise one or more additional antibacterial agents. One or more of the antibacterial agents may be active against bacteria Gram negative One or more of the antibacterial agents may be active against Gram positive bacteria. In one aspect of the method, this invention is directed to a method for the treatment of a microbial infection in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of this invention. The compound of this invention can be administered to the mammal orally, parenterally, transdermally, topically, rectally or Ntranasa !.

In another aspect of the method, this invention is directed to a method of treating a microbial infection in a mammal comprising administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of this invention. The pharmaceutical compositions of the present invention may further comprise one or more additional antibacterial agents, one of which may be active against Gram-negative bacteria and / or one of which may be active against Gram-positive bacteria. The pharmaceutical composition can be administered to the mammal orally, parenterally, transdermally, topically, rectally or intranasally. In a preferred embodiment, the microbial infection to be treated is an infection by Gram-positive bacteria. In a further embodiment, the infection can be an infection by Gram-negative bacteria.

In a further embodiment, the infection can be a mycobacterial infection, a mycoplasma infection, or a chlamydial infection. In yet another aspect, the present invention provides novel intermediates and methods for preparing the compounds of formula (I), (II), (III) and (IV).

DETAILED DESCRIPTION OF THE INVENTION As described above, this invention relates to lincomycin derivatives that exhibit anti-bacterial activity, in particular Gram-positive antibacterial activity. However, before describing this invention in greater detail, the following terms will be defined first.

Definitions Unless stated otherwise, the following terms and expressions used in the specification and claims have the meanings given below.

"Acyl" means the group -C (0) R wherein R 'is alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. "Acyloxy" means the group -C (O) OR \ in which R 'is alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. "Alkenyl" means a linear unsaturated monovalent hydrocarbon radical of two to eight carbon atoms or a branched monovalent hydrocarbon radical of three to eight carbon atoms, containing at least one double bond (-C = C-). Examples of alkenyl groups include, but are not limited to, allyl, vinyl, 2-butenyl, and the like. "Alkoxy" refers to the group "alkyl-O-" including, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. "Alkoxyalkoxy" refers to the group alkyl-O-alkylene-O-, wherein alkyl is as defined herein. "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms, or a branched saturated hydrocarbon radical of three to eight carbon atoms. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyium, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like. "Alkylene" means a linear divalent hydrocarbon radical of one to eight carbon atoms or a divalent hydrocarbon group branched from three to eight carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, 2-methylpropylene, and the like. "Alkylthio" refers to the group "alkyl-S-" which includes, by way of example, methyl, butylthio, and the like. "Alkynyl" means a linear monovalent hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of three to eight carbon atoms, containing at least one triple bond, (-C = -C-). Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 2-butynyl, and the like. "Amino" or "substituted nitrogen" refers to the group "-NRaRb," wherein Ra and Rb are independently H, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. "Aminocarboxyalkyl" means a group "-RcC (O) NRaRb" wherein Re is an alkylene, as defined above, and Ra and Rb are as defined above.

"Aryl" means a monocyclic or monocyclic monocyclic aromatic carbocyclic group of six to fourteen ring atoms. Examples include, but are not limited to, phenyl, naphthyl and anthryl. The aryl ring may optionally be fused with a non-aromatic, monocyclic, 5-, 6- or 7-membered ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, with the remainder of the ring atoms being C, where one or two C atoms are optionally substituted by a carbonyl. Representative aryl groups with fused rings include, but are not limited to, 2,5-dihydro-benzo [bjoxepinyl, 2,3-dihydrobenzo [1,4] dioxanyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1, 3- dihydroisobenzofuranyl, benzo [1, 3] dioxolyl, 1, 2,3,4-tetrahydroisoquinolinyl, 1, 2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1 H-indolyl, 2,3-dihydro-1 H- isoindolyl, benzimidazol-2-onyl, 2-H-benzoxazol-2-onyl, and the like. "Carbonyl" means the group "C (O)." "Carboxi" means the group "C (O) O." "Cyanoalkyl" refers to an alkyl, wherein alkyl is as defined above, substituted with one or more cyano (-CN) groups with the proviso that if two cyano groups are present, both are not in the same atom of carbon. Examples of cyanoalkyl groups include, for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, and the like. "Cycloalkyl" refers to cyclic alkyl groups of 3 to 20 carbon atoms having one ring or multiple cyclic rings, by way of example, cyclopropylo, cyclobutyl, cyclopentyl, cyclooctyl, adamantanyl, and the like. The cycloalkyl groups of the present invention also include condensed multicyclic rings, in which one or more of the rings in the multicyclic ring system are aromatic, provided that the point of attachment to the core or main chain of the structure is in the non-aromatic ring, e.g. eg, fluorenyl. "Cycloalkylalkyl" means a group -RcRd in which Rc is an alkylene group and R is a cycloalkyl group, as defined above. Examples include, but are not limited to, cyclopropylmethylene, cyclohexylethylene, and the like. "Halogen" means fluorine, chlorine, bromine or iodine. "Halogenoalkyl" means an alkyl, wherein the alkyl is as defined above, substituted with one or more, preferably from one to 6, different or different halogen atoms. Examples of haloalkyl groups include, for example, trifluoromethyl, 3-fluoropropyl, 2,2-dichloroethyl, and the like. "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two or three ring heteroatoms selected from N, O or S, with the remainder of ring C atoms. Representative examples include thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and the like. "Heterocycle" or "heterocyclic" refers to a saturated or unsaturated group having a single ring or multiple fused rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen in the ring, wherein, in the condensed ring systems, one or more of the rings may be aryl or heteroaryl as defined herein. Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine. , quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2,3,4-tetrahydro-isoquinoline, 4,5,6,7-tetrahydrobenzofb-thiophene, thiazole, thiazolidine, thiophene, benzo [bjiothofen , morpholinyl, thiomorpholinyl (also called thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. The heterocycles may be optionally substituted with one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, hydroxyl, carboxy, cyano, oxo, nitro, and alkylthio, as these terms are defined herein. memory. "Hydroxy" or "hydroxyl" means the group -OH.

"Hydroxyalkyl" refers to an alkyl, wherein the alkyl is as defined above, substituted with one or more -OH groups, with the proviso that if two hydroxy groups are present they are not both on the same carbon. Examples of hydroxyalkyl groups include, for example, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and the like. "Mammal" refers to all mammals including humans, livestock, and pets. "Optional" or "optionally" means that the event or circumstance described below may occur, but is not necessary, and that the description includes cases in which the event or circumstance occurs and cases in which it is not given. For example, "aryl group optionally mono or disubstituted with an alkyl group" means that alkyl may be present, but is not necessary, and the description includes situations in which the aryl group is mono or disubstituted with an alkyl group and situations in which that the aryl group is not substituted with the alkyl group. "Pharmaceutically acceptable carrier" means a vehicle that is useful for preparing a pharmaceutical composition that is generally safe, non-toxic and is not biologically undesirable or otherwise, and includes a vehicle that is acceptable for veterinary use as well as for human pharmaceutical use . "A pharmaceutically acceptable vehicle" as used in the specification and claims, includes one and more than one such vehicle.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. Said salts include, but are not limited to, (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, maleic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-eneodisulfonic acid, 2-hydroxybenzan sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid) ), 3-phenylpropionic acid, trimethylacetic acid, acetic acid (tertiary butyl), lauryl-sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylgiucamine, and the like. "Prodrugs" means any compound that releases a drug of active origin according to a compound of the present invention, in vivo, when said prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in a compound of the present invention, such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs include compounds of the present invention in which a hydroxyl, sulfhydryl or amino group in the compound is linked to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), carbamates (eg, N, N-dimethylaminocarbonyl) or hydroxy functional groups in compounds of the present invention, and the like. Specific examples include -C (0) -alkylene-cycloalkyl, -C (0) -alkylene- (substituted cycloalkyl), -C (0) -alkyl, -C (0) 0- (substituted alkyl), -C (O) O-aryl, -C (O) O- (substituted aryl), -C (O) O-heteroaryl, -C (0) 0- (substituted heteroaryl), - [C (0) 0] p-alkylene-heterocycle, - [C (O) O] p-alkylene- (substituted heterocycle), wherein p is 0 or 1. In one embodiment, -C (0) O- (substituted alkyl) does not include the following: "Substituted alkyl" means an alkyl group, as defined above, in which one or more of the hydrogen atoms has been replaced by a halogen (ie, Cl, Br, F, or I) , oxygen, hydroxy, amine (primary), amine (substituted secondary amine, alkyl as above), amine (tertiary amine substituted with alkyl as above), sulfide, -SH, phenyl, substituted phenyl, cycloalkyl, alkoxy, substituted alkoxy. Examples of substituted alkyl groups include, but are not limited to, 1-fluoroethyl, 1-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 1-bromopropyl, 2-iodopropyl, 1-chlorobutyl, 4-flurobutyl, 4-chlorobutyl, -cyclopropyl-ethyl, 3-cyclobutyl-propyl, 4-cyclopentyl-butyl, and 4-cyclohexyl-butyl. "Substituted alkoxy" means (substituted alkyl) -O-, wherein the substituted alkyl is as defined herein. "Substituted aryl" means an aryl ring substituted with one or more substituents, preferably one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio , and thioalkyl. The aryl ring may optionally be fused with a 5-, 6- or 7-membered monocyclic non-aromatic ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, the remainder of the carbon ring atoms being the that one or two carbon atoms are optionally substituted by a carbonyl. "Substituted cycloalkyl" means a cycloalkyl substituted with an alkyl group, wherein the alkyl is as defined above, or a group as defined above for substituted alkyl. "Substituted heteroaryl" means a heteroaryl ring, wherein the heteroaryl is as defined above, substituted with one or more substituents, preferably one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio, and thioalkyl, wherein said substituents are as defined herein. "Substituted oxygen" refers to the group "-0-Rd" wherein Rd is alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituents are as defined in this memory. "Substituted phenylene" means a phenyl ring in which one or more of the hydrogen atoms have been replaced by a halogen, hydroxy, alkyl, amine (primary, secondary and tertiary, the last two substituted by alkyl), -SH, and phenyl. Representative examples include, but are not limited to, p-bromophenyl, m-iodophenium, o-chlorophenyl, p-ethylphenyl, m-propylphenyl, o-methylphenium, and p-octylphenyl. "Thioalkyl" refers to an alkyl, wherein the alkyl is as defined above, substituted with one or more -SH groups, with the proviso that if two hydroxy groups are present, they are not both in the same carbon. Examples of thioalkyl groups include, but are not limited to, thiomethyl, 2-thioaryl, 2-thiopropyl, and the like. "Therapeutically effective amount" means the amount of a compound or composition, which when administered to a mammal to treat a disease, is sufficient to perform said treatment for the disease. The "therapeutically effective amount" will vary depending on the compound or composition, the disease and its severity and the age, weight, etc., of the mammal that is to be brought. "Treating" or "treating" a disease includes: (1) preventing the disease, that is, causing the clinical symptoms of the disease not to develop in a mammal that may be exposed or predisposed to the disease, but not yet experience or present symptoms of the disease, (2) inhibit the disease, that is, stop or reduce the development of the disease or its clinical symptoms, or (3) alleviate the disease, that is, bring about the regression of the disease or your clinical symptoms "Tautomer" refers to an isomer in which the migration of a hydrogen atom results in two or more structures. The compounds of the present invention are named, in general, according to the IUPAC or CAS nomenclature system. Abbreviations can be used which are known to the person skilled in the art (p. eg, "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "Bn" for benzyl, "h" for hour and "t.a." for room temperature).

General Synthetic Schemes The compounds of this invention can be prepared by the methods depicted in the reaction schemes shown below. The starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Toronto Research Chemicals (North York, ON Canada), Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California). , USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or prepared by methods known to those skilled in the art, following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry or Carbon Compounds, volumes 1-5 and supplementary (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991 ), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Orqanic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and different modifications of these schemes can be made and will be suggested by the person skilled in the art with reference to this specification. As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from suffering unwanted reactions. The protective groups suitable for different functional groups, as well as the suitable conditions for protecting and deprotecting particular functional groups; they are known in the art. For example, they describe numerous functional groups T.W. Greene and G.M. Wuts, in Protecting Groups in Orga'nic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. The starting materials and reaction intermediates can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. The compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, said compounds can be prepared or isolated in the form of pure stereoisomers. All said stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of said compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

Preparation of compounds of formula (I) In general, to prepare the compounds of formula (I) of the present invention, a suitably substituted lincosamine is condensed at intermediate 7 and a pyrrolidinyl or piperidinyl carboxylic acid, suitably substituted, under reactive conditions , preferably in an inert organic solvent, in the presence of a coupling agent and an organic base. This reaction can be carried out with any of a series of coupling reagents, such as O- (7-aza-benzotriazol-1-yl) -NNN'.N'-tetramethyluronium hexafluorophosphate (HATU), hydrate from the -hydro-xibenzotriazole (HOBT) with carbodiimides, isobutyl chloroformate, diphenylphosphoryl azide (DPPA), and the like. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methyl-morpholine, and the like. Suitable inert organic solvents that may be used include, for example, N. N-dimethylformamide, acetonitrile, dichloromethane, and the like. This reaction is typically carried out using an excess of carboxylic acid relative to lincosamine at temperatures in the range of about 0 ° C to about 50 ° C. The reaction is continued until complete, which typically occurs from about 2 to 12 h.

Lincosamines suitably substituted in 7 intermediates, as defined in the present invention (ie, R2 / R3), are synthesized by methods known to the person skilled in the art, starting from 6-amino-6,8-dideoxy-1. -thio-erythro-β-D-galacto-octopyranoside, which can be prepared as described by Hoeksema, et al., Journal of the American Chemical Socíety, 1967, 89 2448-2452. Illustrative syntheses of the suitably substituted lincosamines are shown in 7 below in Schemes 1-5. Suitable substituted pyrrolidinyl or piperidinyl carboxylic acids, as defined in the present invention (ie, R9), are also synthesized by methods known to those skilled in the art from prolines and pyridines. The prolines and pyridines that can be used in the synthesis of the intermediate carboxylic acids of the present invention include, for example, 4-oxoprolines and pyridines substituted in 4. The prolines and pyridines used in the synthesis are commercially available from suppliers such as like Aldrich and Sigma. Alternatively, these prolines and pyridines can be prepared by methods known in the art. Illustrative syntheses are shown for the suitably substituted pyrrolidinyl or piperidinyl carboxylic acids intermediate below in Schemes 6-10. The following Scheme 1 illustrates a general synthesis of an intermediate lincosamine 1 c wherein P is a protecting group of N, preferably Cbz or Boc, and R1 is as defined for formula (I).

SCHEME 1 General synthesis of intermediate lincosamine 1c (a) Protection of N (Boc, Cbz); (b) O-silyl protection (TMS); (c) Swern oxidation. As shown in Scheme 1, methyl-6-amino-6,8-dideoxy-1-thio-erythro-β-D-galacto-octopyranoside, 1 a, is prepared as described by Hoeksema, et al., Journal of the American Chemical Society, 1967, 89-2448-2452. The amino functional group and the hydroxy functional groups of the product are then protected with suitable protecting groups. Suitable N-protecting groups can be formed by the addition of di-t-butyl dicarbonate, N- (benzyloxycarbonyloxy) -succinimide, and the like. The hydroxy groups can be protected as silyl ethers. The hydroxyl group can be converted to trimethylsilyl ethers (TMS) by reaction with N, 0-bis- (trimethylsilyl) trifluoroacetamide in the presence of a suitable organic base such as triethylamine (TEA) or trimethylsilyl chloride in the presence of an organic base such as triethylamine. The protection of N is typically carried out before the protection of the O. Chromatography of the crude product on silica after evaporating the solvent gives the protected product 1 b.

The 7-O-trimethylsilyl group of 1 b is chemoselectively deprotected and oxidized to provide the 7-keto-lincosamine 1c derivative. This selective transformation is carried out by addition of the protected product 1b to dimethyl sulfoxide and oxalyl chloride, in an inert organic solvent such as dichloromethane, followed by a suitable organic base such as triethylamine. Alternatively, the transformation can be carried out by addition of 1b to dimethylsulfoxide and a suitable activating agent such as trifluoroacetic anhydride in an inert organic solvent. The reaction is typically carried out at temperatures in the range of about -70 ° C to 80 ° C. The resulting reaction mixture is stirred at the low temperature and then allowed to warm to about -50 ° C. The reaction is maintained at this second low temperature for about 1 h to 3 h. A suitable organic base, such as TEA, pyridine, and the like, is added to the reaction mixture. The reaction mixture is suitably treated to provide the product 1c. The general class of conditions used for the transformation of 1b to 1c is known in the art as conditions of Swern oxidation. The following scheme 2 illustrates a general synthesis of an intermediate lincosamine 2b wherein P is a protecting group of N, preferably Cbz or Boc, R1 is as defined for formula (I), and one of R2 and R3 is hydrogen and the other is how it has been defined for the formula (i) - SCHEME 2 General synthesis of intermediate lincosamine 2b. (a) Wittig olefination (R2PPh3% R2PO (OEt) 2, base, solvent); (b) and (c) H2 / Pd, overall deprotection As shown in Scheme 2, an intermediate keto-lincosamine 1c is reacted to form an alkene, using the Wittig or Homer-Wadsworth-Emmons reaction. In this reaction, a suitable phosphonium or phosphate salt is deprotonated using a strong base to form a phosphorus ylide. Suitable phosphonium salts which can be used are alkyltriphenylphosphonium halides, which can be prepared by reaction of the triphenylphosphine and an alkyl halide. Suitable phosphorus compounds include, for example, methyltriphenylphosphonium bromide, diethyl (cyano-methyl) phosphonate, and the like. Suitable strong bases that can be used to form the ylide include organolithic reagents, potassium tert-butoxide, and the like. The formation of the phosphorus ylide is typically carried out in an inert atmosphere, such as N2, in an inert organic solvent such as toluene, THF, and the like, at low temperatures. After forming the phosphorus ylide, the product 1c is added to the reaction. The reaction can be conveniently carried out at temperatures between -40 ° C and room temperature and stirred until complete, typically 1 to 4 h. The resulting organic solution was evaporated and chromatography of the crude product on silica provided the product alkene 2a. Optionally, the product 2a can be purified using conventional techniques, such as chromatography, and said purified product can be used in the subsequent coupling reaction to give vinyl-lincosamine derivatives of the present invention. The product 2a is then hydrogenated to give the saturated product 2b. The hydrogenation is typically carried out in a polar organic solvent such as methanol, ethanol and the like, using 10% palladium on carbon in a Parr bottle. The bottle is purged, and charged with H2 to about 3.5 to 4.9 kg / cm 2 and stirred until complete, typically about 12 to 24 h. The resulting reaction mixture is filtered, e.g. g., through celite, and rinsed with a polar organic solvent such as methanol. The organic solution is treated by transfer to a funnel with resin containing Dowex 50w-400x form H + washed and dried, and stirred. After washing the resin with methanol and water, the product 2b is eluted from the resin by washing with TEA in 5% MeOH. The product can also be purified by chromatography on a silica gel column. Scheme 3 illustrates a general synthesis of an intermediate lincosamine 3b wherein P is a protecting group of N, preferably Cbz or Boc, R1 is as defined for formula (I), and one of R2 and R3 is alkyl and the other is -OH.

SCHEME 3 General synthesis of an intermediate lincosamine 3b. (a) R2M (carbon nucleophile); (b) (i) deprotection of TMS (H + or F ") and (ii) N-deprotection. As shown in Scheme 3, suitable carbon nucleophiles are added to the intermediate 7-cetolincosamine 1c in inert organic solvents suitable for provide an intermediate 7-hydroxy-lincosamine 3b Suitable carbon nucleophiles include methylmagnesium chloride, diethyl zinc, sodium acetylide and the like, and suitable inert organic solvents that may be used include, THF, diethyl ether, toluene and the like. The reaction is typically carried out at reduced temperatures, at about 0 ° C, for about 3 to 5 hours, then the reaction is quenched with an aqueous saturated acid solution, as saturated aqueous solution of NH 4 Cl / H 20. inactivated is treated and can be purified by chromatography to provide the product 3b The following Scheme 4 illustrates a general synthesis of an intermediate lincosamine 4b wherein P is a p-group. Rotector of N, preferably Boc, R1 is as defined for formula (1), and R2 / R3 is an oxime (= NOR7), wherein R7 is as defined for formula (I).

SCHEME 4 General synthesis of 7-oxime-lincosamines 4b.

As shown in Scheme 4, intermediate lincosamine 1c is converted to the oxime by agitation in the presence of a suitable reagent such as O-trimethylsilylhydroxylamine, O-alkylhydroxylamine hydrochloride. (e.g., O-methylhydroxylamine hydrochloride), and the like. The reaction is typically carried out in a polar organic solvent such as methanol. The reaction can be conveniently carried out at t.a. in approximately 8 a 24 h. The solvent is removed to provide the N-protected product 4a. The elimination of the proviral group can be carried out with acids, such as trifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid, and the like, in an inert organic solvent such as dichloromethane, dichloroethane, dioxane, THF and the like. The removal is typically carried out at low temperatures, e.g. ex. TC, and then allowed to warm gradually to room temperature to provide the product 4b.

The following Scheme 5 illustrates a general synthesis of an intermediate lincosamine 5b wherein R2 and R3 are both fluorine, P is a protecting group of N, preferably Cbz or Boc, and R1 is as defined for formula (I).

SCHEME S General synthesis of 7-deoxy-7.7-difluoro-lincosamines 5b. (a) F; (b) AC20, pyridine, DMAP; (c) DAST; (d) TFA As shown in Scheme 5, the intermediate lincosamine 1 c is contacted with a suitable fluoride in an inert organic solvent. Suitable fluorides that can be used include tetrabutylammonium fluoride, Amberlite resin form A-26F, HF-pyridine, and the like. Suitable organic solvents include THF, acetonitrile, dichloromethane, dioxane, and the like. The reaction can be conveniently carried out at t.a. in about 1 to 2 h. The product (not shown) can be purified on a column of silica gel. The protecting groups of O in the product obtained from the column are converted by contact with anhydride, acetic acid and dimethylaminopyridine (DMAP) in a suitable mixture of an inert organic solvent and an organic base, such as, for example, dichloromethane and pyridine. The reaction can be conveniently carried out at t.a. in approximately 6 to 12 h. The product can be purified on a silica gel column to provide the product 5a. The product 5a is contacted with a suitable fluorination reagent and then the protecting group of N is removed to provide the product 5b. Suitable fluorination reagents that can be used include, for example, dimethylaminosulfur trifluoride, [bis (2-methoxyethyl) aminolazuffer trifluoride, and the like. The reaction is typically carried out in an inert organic solvent such as dichloromethane, ethyl acetate, THF, and the like, at room temperature, in about 6 to 12 h. Removal of the protecting group can be carried out with acids, such as trifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid, and the like, in an inert organic solvent such as dichloromethane, dioxane, THF, and the like. The removal is typically carried out at low temperatures, e.g. ex. 0 ° C, and then allowed to warm gradually to room temperature to provide the product 5b. The following Scheme 6 illustrates a general synthesis of an intermediate proline 6c wherein R9 is as defined for formula (I).

SCHEME 6 General synthesis of cis / trans mixtures of intermediate R9-proline 6c. (a) R9CH2Br + Ph3P, NaH, DMSO; (b) H2 / Pt As shown in Scheme 6, the product 6c is prepared as described by Birkenmeyer, et al., Journal of Medicinal Chemistry 1972, 15, 1255-1259. Compound 6a is available commercially from distributors such as RSP (Scientific Research Consortium, Inc.). Alternatively, the Product 6a can be prepared from commercially available protected hydroxy prolines by methods known in the art. See, p. eg, Demange, et al., Tetrahedron Letters 1998, 39.1169-1172. The following Scheme 7 illustrates a general synthesis of trans-R9-prolines intermediate 7d, wherein R9 is alkyl or substituted alkyl.

J "y - CcOo-_82n • - '•, i ./> •« * * -!., > - «SCHEME 7 General synthesis of trans-alguilprolines 7d. (a) (i) LiHMDS, THF -78 ° C, (ii) bromoalkene; (b) (i) LiBHEt3, THF -78X, (ii) BF3OEt2, Et3SiH; (c) H2 Pd / C. As shown in Scheme 7, the enolate is formed from a Protected 4-oxoproline, 7a, with a suitable enolate-forming agent and then alkylated with a suitable alkylating agent in an inert organic solvent to provide the lactam 7b (wherein R9 is alkenyl), as described in the process of the bibliography of Zhang, et al., JAC.S. 1998,120 3894-3902. The compound 7a is available commercially from distributors such as Bachem. Allynaily, 7a can be prepared by methods known in the art. Suitable enolate forming agents include LiHMDS, LiM (iPr) 2, and the like, and suitable alkylating agents include allylic and benzylic bromides, for example, 4-bromo-2-methyl-2-butene and cis-1-bromo -2-pentene, allyl bromide and the like. Lactam 7b is reduced using a suitable reducing agent to provide a pyrrolidine 7c, wherein R9 'is alkenyl. The reduction is carried out by a sequence of two stages that involve the reduction with superhydride of the lactam to the hemiaminal and the subsequent reduction of the hemiaminal. Suitable reducing agents that can be used include Et3SiH / BF3 * OEt2, Et3SiH / TiCl and the like. Then the pyrrolidine 7c is hydrogenated to simultaneously eliminate the unsaturation in the substituent R9 'and remove the benzyl protecting group from the carboxylic acid, to give the product 7d. The hydrogenation is typically carried out in a polar organic solvent such as methanol, ethanol and the like, using 10% palladium on carbon in a Parr bottle. The bottle is purged, charged with H2 to about 3.5 to 4.9 kg / cm 2 and stirred until complete, typically about 5 to 24 h. The reaction mixture is filtered, for example, through a pad of celite, and washed with a polar organic solvent, such as methanol. Evaporation of the combined washings and filtrates gives the product 7d, wherein R9 is an alkyl or substituted alkyl. The following Scheme 8 illustrates a general synthesis of the intermediate trans-R9-prolines 8c, in which R9 is alkyl or substituted alkyl. you" SCHEME 8 General synthesis of substituted trans-R9-prolines 8c, in which R9 is alkyl or substituted alkyl. (a) O3, DCM, -78 ° C, DMS; (b) salt of P + Ph3, Base; (c) H2, Pd / C. As shown in Scheme 8, the product 7d is ozonolized to provide the aldehyde 8a. The ozonolysis reaction is typically carried out in an inert anhydrous organic solvent, such as dichloromethane, dioxane, THF, and the like, at low temperatures, e.g. eg, -78 ° C, followed by inactivation of the reaction with a reducing agent such as DMS, Ph3P. The aldehyde 8a is reacted with a suitable phosphonium salt in the presence of a strong base in an inert organic solvent. Suitable phosphonium salts that can be used include, for example, fluorobenzyl phosphonium chloride, 4-chlorobenzyl phosphonium chloride, dibromo-fluoromethane and triphenylphosphine. Suitable bases that can be used include potassium t-butoxide, organolithic reagents, and activated zinc. Suitable organic solvents that can be used include toluene, THF, dimethylacetamide, and the like. The reaction is carried out typically in an inert atmosphere, such as nitrogen, with vigorous stirring. The reaction is typically carried out at t.a. at approximately 110 ° C, for 1 to 2 h. The resulting reaction mixture is treated adequately and can be adequately purified by chromatography to provide product 8b (wherein R9 is alkenyl). Then, the product 8b is hydrogenated to provide the product 8c. The hydrogenation is typically carried out in a polar organic solvent such as methanol, ethanol and the like, using 10% palladium on charcoal in a Par bottle. The bottle is purged and charged with H2 to about 2.8 to 4.9 kg / cm 2 and stirred until complete, typically about 4 to 24 h. The reaction mixture is filtered, for example, through a celite pad and washed several times with a polar organic solvent, such as methanol. Evaporation of the combined washings and filtrates gives the product 8c, wherein R9 is an alkyl or substituted alkyl. The following Scheme 9 illustrates a general synthesis of the intermediate R9-prolines 9d, in which R9 is alkyl, substituted and in which X is halogen.

SCHEME 9 Example of synthesis of trans- (alkyl substituted with halogen) -prolines 9d. (a) Tetraalyltin, BF3 * Et2O; (b) DMSO, (COCI) 2, TEA; (c) DAST (d) 10% Pd / C, H2. As shown in Scheme 9, aldehyde 8a is reduced and alkylated using a suitable reagent in an inert organic solvent to provide a proline subsituted with hydroxyalkenyl, 9a. Suitable reagents for reducing and alkylating the aldehyde include tetraalyltin / boron trifluoride etherate, aliITMS / boron trifluoride etherate, and suitable inert organic solvents that can be used include THF, dichloromethane, and the like. The reaction is carried out typically at low temperatures, e.g. eg, 0 ° C, for about 1 to 2 h. To the reaction mixture is added a solution of a suitable fluoride salt in water, for example, potassium fluoride in water, followed by the addition of methanol. The reaction mixture is filtered, for example, on celite. The product can be purified by chromatography to provide 9a. The proline substituted with hydroxyalkenyl, 9a, is oxidized to the ketone by contact with a suitable oxidizing agent in an inert organic solvent. Suitable oxidizing agents include oxaliium chloride / DMSO, Dess Martin periodinane, and the like. Suitable inert organic solvents include dichloromethane, and the like. The reaction is typically carried out at reduced temperatures, e.g. eg, from -72 ° C to -50 ° C, for approximately 30 min to 2 h. A suitable organic base, such as triethylamine, is added to the reaction mixture. The reaction mixture is treated to provide product 9b. The product substituted with keto 9b is halogen by contact with a suitable halogenating agent in an inert organic solvent. Suitable halogenating agents that can be used include dimethylaminosulfur trifluoride, [bis (2-methoxyethyl) trifluoride sulfur, and the like. Suitable inert organic solvents that can be used include dichloromethane, ethyl acetate, THF and the like. The reaction is typically carried out at low temperatures in the range of about -30 ° C to -78 ° C. The reaction mixture is allowed to warm gradually to t.a. and stir at a.t. until completed, typically 6 to 12 h. The reaction mixture is treated and can be purified by chromatography to provide product 9c. Then, the product 9c is hydrogenated to provide the product 9d. The hydrogenation is typically carried out in a polar organic solvent such as methanol, ethanol and the like, using 10% palladium on charcoal in a Par bottle. The bottle is purged and charged with H2 to about 2.8 to 4.9 kg / cm 2 and stirred until complete, typically about 4 to 24 h. The reaction mixture is filtered, for example, through a pad of celite and washed several times with a polar organic solvent, such as methanol. Evaporation of the combined washings and filtrates gives the product 9d. The following Scheme 10 illustrates a general synthesis, as described by Shuman, Journal of Organic Chemistry. 1990, 55, 741-750, of substituted pyridine carboxylic acids intermediate 10b, wherein R9 is as defined for formula (I). .fe m > SCHEME 10 General synthesis of substituted pyridin-2-yl-carboxylic acids 10b As shown in Scheme 10, an appropriately substituted pyridine is contacted with a suitable oxidizing agent in an inert solvent. The suitably substituted starting pyridines are available commercially from distributors such as Aldrich and Sigma. Alternatively, these pyridines can be prepared by methods known in the art. Suitable oxidizing agents that can be used include hydrogen peroxide, MCPBA, and the like. The reaction is typically carried out at reflux for 6 to 12 h. Then, the reaction mixture is contacted with a suitable cyanide reagent to provide the substituted cyano-pyridine 10a. Suitable cyanide reagents that can be used include trimeylsilyl cyanide, HCN, and the like. Suitable inert organic solvents include dichloromethane, dioxane, THF, and the like. The reaction can be conveniently carried out at t.a. in approximately 6 to 12 h. The reaction mixture is treated to provide the substituted cyano-pyridine, 10a. The substituted cyano-pyridine, 10a, is then hydrolyzed to provide the pyridin-2-yl-carboxylic acid 10b by contact with a suitable acid. Suitable acids for hydrolyzing the cyano group to the carboxylic acid group include hydrochloric acid, aqueous sulfuric acid, and the like. The reaction is typically carried out at reflux in 6 to 12 h.

The following Scheme 11 illustrates the coupling reaction of an intermediate lincosamine, prepared as described above in Schemes 1-5, and pyrrolidinium or piperidinyl carboxylic acid, prepared as described above in Schemes 6-10, that R1, R2, R3, R6 and R9 are as defined for formula (I) and P1 is a suitable protecting group of O and P2 is a suitable protecting group of N.

SCHEME 11 General methods of coupling and deprotection.

As shown in Scheme 11, an appropriately substituted lincosamine is condensed in intermediate 7 (prepared, for example, according to any one of Schemes 1-5), and a suitably substituted pyrrolidinyl or piperidinyl carboxylic acid, (prepared, for example, according to any one of Schemes 6-10) under reactive conditions, preferably in an inert organic solvent, in the presence of a coupling reagent and an organic base. This reaction can be carried out with any of a series of known coupling reagents, such as O- (7-aza benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU). ), 1-hydroxy-benzotriazole hydrate (HOBT) with carbodiimides, isobutyl chloroformate, diphenylphosphoryl azide (DPPA), and the like. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methylmorpholine, and the like. Suitable inert organic solvents that may be used include, for example, N, N-dimethylformamide, acetonitrile, dichloromethane, and the like. This reaction is typically carried out using an excess of carboxylic acid relative to lincosamine at temperatures in the range of about 0 ° C to about 50 ° C. The reaction is continued until complete, which typically occurs in about 2 to 12 h. The removal of the protecting groups can be carried out with acids, such as trifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid, and the like, in an inert organic solvent such as dichloromethane, dichloroethane, dioxane, THF, and the like. . The removal is typically carried out at low temperatures, e.g. eg, 0 ° C, and then allowed to warm gradually to room temperature to provide the product. As also shown in Scheme 11, an appropriately substituted lincosamine is condensed into intermediate 7 (prepared, for example, according to any one of Schemes 1-5), and an appropriately substituted pyridyl-2-carboxylic acid, (prepared , for example, according to Scheme 10) under reactive conditions, preferably in an inert organic solvent, in the presence of a coupling reagent and an organic base, as described above. The pyridine 11 b is hydrogenated to provide the piperidyl product. The hydrogenation is typically carried out in a polar organic solvent such as methanol, ethanol and the like, using platinum (N) oxide in the presence of an acid such as HCl, acetic acid and the like, in a Parr bottle. The bottle is purged and charged with H 2 at about 2.8 to 4.9 kg / cm 2 and stirred until complete, typically about 24 h. The reaction mixture is filtered, e.g. g., through a celite pad, and washed several times with a polar organic solvent such as methanol. Evaporation of the combined washings and filtrates gives the piperidyl product. The coupling of pyridine carboxylic acids and lincosamines to pyridine 11 b followed by reduction to the piperidyl product can also be carried out as described by Birkenmeyer, et al., Journal of Medicinal Chemistry 1984, 27, 216-223. The following Scheme 12 illustrates the alkylation of the pyrrolidinyl or piperidinyl ring nitrogen, wherein R6 is alkyl, hydroxyalkyl, heterocycle substituted with alkylene, or alkylene heterocycle, and R1, R2, R3, and R9 are as defined for the formula (I).

SCHEME 12 General synthesis of 1'-N-substituted lincosamines. to. alkylating agents As shown in Scheme 12, lincosamine 12a can be substituted at N by contact with an alkylating agent in the presence of a suitable base to provide a product 12b. Suitable alkylating agents that can be used include epoxides, alkyl bromides, and the like. Suitable bases that can be used include potassium carbonate, cesium carbonate, triethylamine, and the like. The alkylation reaction is typically carried out in a polar organic solvent such as methanol or DMF. The alkylation reaction is typically carried out at low temperatures in the range of 0 ° C to -10 ° C, for 10 to 20 h. The following Scheme 13 illustrates the acylation of the nitrogen of the pyrrolidinyl or piperidinyl ring, wherein R6 is -C (0) 0-alkylep-cycloalkyl, -C (O) O-alkylene- (substituted cycloalkyl), -C (O ) O-alkyl, -C (O) O- (substituted alkyl), -C (0) O-aryl, -C (0) 0- (substituted aryl), -C (0) 0-heteroaryl, -C ( 0) 0- (substituted heteroaryl), - [C (0) Oj-alkylene-heterocycle, - [C (0) Oj-alkylene- (substituted heterocycle), and R1, R2, R3, and R9 are as defined for the formula (I).

SCHEME 13 General synthesis of 1'-N-substituted lincosamines As shown in Scheme 13, lincosamine 12a can be substituted at N by contact with an acyl chloride 101, such as R6"X, wherein X is a suitable leaving group, and preferably is halogen, even more preferably chloride in the presence of a suitable base to provide a product 102. Examples of compound 101 include bromofluorenyl, CI-C (O) O-alkyl, CI-C (O) O-aryl, and the like. use include DCC, TEA, and the like The reaction is typically carried out in a polar organic solvent such as methanol or DMF The reaction is typically carried out at low temperatures in the range of -10 ° C to 20 ° C. The following Scheme 16 illustrates the general synthesis of trans-alkylazetidine carboxylic acids.

: I6f. 16g SCHEME 16 General synthesis of trans-alkylazetidine-carboxylic acids The following reaction scheme can be used in the synthesis of the trans-alkylazetidine carboxylic acids, wherein R9 is as defined herein: (a) (i) LDA, THF, 0 ° C, (ii) bromoalkane or bromoalkene; (b) TMSCHN2, MeOH, 23 ° C; (c) (i) TMSCHN2, MeOH, 23 ° C, (i) H2, Pd / C, EtOAc, 23 ° C; (d) Et3N.3HF, THF, 23 ° C; (e) LiAIH4, THF, 68 ° C; (f) Boc2O, CH2Cl2, 23 ° C; (g) RuCI3.xH20, NalO4, acetone, H20, 23 ° C. The following Scheme 17 illustrates the general synthesis of trans-alkylazetidine carboxylic acids via the aldehyde. 17c 17f SCHEME 17 General synthesis of trans-algalazetidine-carboxylic acids via the aldehyde.

The following reaction scheme can be used in the synthesis of trans-alkylazetidine carboxylic acids: (a) TBSCI, imidazole, DMF, 23 ° C; (b) (i) ozone, CH2Cl2, -78 ° C, (ii) PPh3; (c) olefination: P + Ph3 salt, base, solvent; (d) H2, Pd / C, EtOAc, 23 ° C or K02CN = NC02K, AcOH, dioxane, 23 ° C; (e) TBAF, THF, 23 ° C; (f) RuCI3.xH20, Nal04, acetone, H20, 23 ° C.

The following Scheme 18 illustrates a general synthesis of ester prodrugs substituted in 2.

SCHEME 18 General synthesis of esters substituted in 2 The following representative reaction scheme can be used in the synthesis of substituted prodrug compounds in 2 of the invention: a. (Boc) 2O, ac. KHC03 THF b. dimethylacetal of p-anisaldehyde, PPTS, c. acylating agent R11, base, d. TFA, DCE, water. The following Scheme 19 illustrates a general method for synthesizing 4,5-disubstituted-2,3,6,7-tetrahydro-azepine-2-carboxylic acid derivatives.

SCHEME 19 The following general reaction scheme can be used to prepare 4,5-disubstituted-2,3,6,7-tetrahydro-azepine-2-carboxylic acid derivatives: a. 2,2-dimethoxypropane, catalytic HCl, MeOH b. 2-Nitrobenzenesulfonium chloride, 2,4,6-collidine, dichloroethane c. CS2C03, TBABr, DMF, tosylates or homoalilic halides d. Benzylidene [1, 3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro- (tricyclohexylphosphine) ruthenium, e. 7-methyl-1, 5,7-triazabicyclo [4.4.0] dec-5-ene, thiophenol f. (Boc) 20, TEA, g. LiOH ac, Dioxane. The following Scheme 21 illustrates the synthesis of 4,4-disubstituted pyrrolidine and piperidine carboxylic acids, wherein R 9 is a suitable substituent and the other substituent is fluorine.

SCHEME 21 Synthesis of intermediate 21 d in which R > 9 is as defined in this specification The following representative reaction scheme can be used in Scheme 21: (a) Tetraalyltin, BF3 * Et20 or R9M (R9 or R9 'carbon nucleophile) (b) H2 / Pd (c) DAST (d) LiOH aq. or deprotection conditions of suitable carboxylate ester.

Pharmaceutical Formulations When used as pharmaceuticals, the compounds of the present invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, parenteral, transdermal, topical, rectal and intranasal. These compounds are effective both as injectable and oral compositions. Said compositions are prepared in a manner known in the pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions containing, as an active ingredient, one or more compounds of the present invention associated with pharmaceutically acceptable carriers. When the compositions of this invention are prepared, the active ingredient is usually mixed with an excipient, diluted with an excipient or enclosed in said vehicle which may be in the form of a capsule, seal, paper or other container. The excipient used is typically an excipient suitable for administration to human subjects or other mammals. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, excipient or medium for the active ingredient. Therefore, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, seals, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in the form of a solid or in a liquid medium), ointments, which they contain, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. When preparing the formulation it may be necessary to grind the active compound to provide the appropriate particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size smaller than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in water. the formulation, p. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, algae, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , sterile water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as hydroxy benzoates of mephyl and propyl; sweetening agents; and flavor agents. The compositions of the invention can be formulated to thereby provide rapid, sustained or delayed release of the active ingredient after administration to the patient, using methods known in the art. The amount of active component, which is the compound according to the present invention, in the pharmaceutical composition and the unit dosage form thereof, can be varied or adjusted broadly depending on the particular application, the potency of the particular compound and the desired concentration. The compositions are preferably formulated in a unit dosage form, and each dosage contains from about 5 to about 100 mg, more usually from about 10 to about 30 mg of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, which contain, each unit, a predetermined quantity of active material, calculated to produce the desired therapeutic effect, associated with a pharmaceutically suitable excipient. Preferably, the above compound of the present invention is used with no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, the remainder being pharmaceutically carrier (s). ). The active compound is effective over a broad dosage range, and is generally administered in a pharmaceutically or therapeutically effective amount. However, it must be understood that the amount of compound actually administered will be determined by the physician, in light of important circumstances, including the condition to be treated, the severity of the bacterial infection to be treated, the chosen route of administration, the exact compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. In the therapeutic use for treating or combating bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, topically, transdermally, and / or parenterally with a dosage to obtain and maintain a concentration, it is say, a quantity, or level in the blood of the active component in the animal subjected to the treatment, which will be effective as antibacterial. In general, said dosage amounts of the active component (ie, an effective dosage) antibacterially or therapeutically effective will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg / kg of body weight / day. . To prepare solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of a compound of the present invention. When these preformulation compositions are mentioned as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, so that the composition can be easily subdivided into the same effective unit dosage forms, such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, from 0.1 to about 500 mg of active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise formed to provide a dosage form that provides the advantage of a prolonged action. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter being in the form of a coating on top of the first. The two components can be separated with an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact to the duodenum or to be released with delay. A variety of materials can be used for said enteric coatings or coatings, said materials including a series of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention can be incorporated for administration orally or by injection, include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as tall oil. corn, cottonseed oil, sesame oil, coconut oil, peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered orally or by nasal airway for a local or systemic effect. The compositions preferably in pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solutions can be inhaled directly from the nebulization device or the nebulization device can be attached to a mask, or a breathing machine with intermittent positive pressure. The solutions, suspensions or powder compositions can be administered, preferably orally or nasally, with devices that release the formulation in a suitable manner. The following formulation examples illustrate pharmaceutical compositions of the present invention.

EXAMPLE OF FORMULATION 1 Hard gelatine capsules containing the following ingredients are prepared: Ingredient Quantity (mq / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and loaded into hard gelatin capsules in amounts of 340 mg EXAMPLE OF FORMULATION 2 A tablet formulation is prepared using the following ingredients: Ingredient Quantity (mg / capsule) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

EXAMPLE OF FORMULATION 3 A dry powder inhaler formulation is prepared which contains the following components: Ingredient Weight% Active ingredient 5 Lactose 95 The active ingredient is mixed with the lactose, and the mixture is added to a dry powder inhalation apparatus.

EXAMPLE OF FORMULATION 4 Tablets are prepared as follows, each containing 30 mg of active ingredient: Inquired Quantity (mg / capsule) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as a solution in % sterile water) Carboxymethyl-sodium starch 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active principle, the starch and the cellulose are passed through a U.S. Standard No. 20 mesh, and mix well. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a U.S. standard No. of mesh 16. The granules thus produced are dried from 50 ° C to 60 ° C and passed through a U.S. standard No. 16 mesh. Then, the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a U.S. sieve, are added. Standard No. 30 mesh, to the granules, which after mixing are compressed in a tablet machine to give tablets weighing, each, 120 mg.

EXAMPLE OF FORMULATION 5 Capsules each containing 40 mg of medicament are prepared as follows: Ingredient Quantity (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active principle, starch and magnesium stearate are mixed, passed US standard sieve No. 20 mesh, and hard gelatine capsules are loaded in amounts of 150 mg.

EXAMPLE OF FORMULATION 6 Suppositories each containing 25 mg of active ingredient are prepared as follows: Ingredient Quantity Active ingredient 25 Fatty acid glycerides 2,000 mg saturated The active ingredient is passed through a U.S. standard or 60 mesh, and is suspended in glycerides of saturated fatty acids previously melted, using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE OF FORMULATION 7 Suspensions containing, each, 50 mg of drug per 5.0 ml of dose are prepared as follows: Ingredient Quantity Active ingredient 50 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Benzoate sodium 10.0 mg Aroma and color cv Purified water up to 5.0 ml The active principle, sucrose and xanthan gum are mixed, passed through a U.S. standard No. 10 mesh, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl starch in water. The sodium benzoate, aroma and color are diluted with some water and added with agitation. Then enough water is added to produce the required volume.

EXAMPLE OF FORMULATION 8 Ingredient Quantity (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active principle, starch and magnesium stearate are mixed, passed through a U.S. Standard No. 20 mesh, and hard gelatin capsules are loaded in amounts of 425.0 mg.

EXAMPLE OF FORMULATION 9 A subcutaneous formulation can be prepared as follows: Ingredient Quantity Active ingredient 5.0 mg Corn oil 1.0 ml EXAMPLE OF FORMULATION 10 A topical formulation can be prepared as follows: Ingredient Quantity Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin up to 100 g White soft paraffin is heated until melted. The liquid paraffin and wax emulsifiers are incorporated and stirred until they dissolve. The active ingredient is added and stirring is continued until dispersion. Then the mixture is cooled until it is solid.

EXAMPLE OF FORMULATION 1 An intravenous formulation is prepared as follows: Ingredient Quantity Active ingredient 250 mg Isotonic saline 1000 mg Another preferred formulation used in the methods of the present invention uses transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches to release pharmaceutical agents is known in the art. See, for example, U.S. Pat. 5,023,252, issued June 11, 1991, incorporated herein by reference. Said patches can be constructed for continuous release, pulsed, or as required by pharmaceutical agents. Frequently, it will be convenient or necessary to introduce the pharmaceutical composition into the brain, directly or indirectly. Direct techniques usually involve the placement of a drug delivery catheter into the ventricular system of the host to bypass the blood-brain barrier. One of said implantable delivery systems used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. 5,011, 472, which is incorporated herein by reference. Indirect techniques, which are usually preferred, usually involve formulating the compositions to provide the latent drug by conversion of hydrophilic drugs into lipophilic drugs. Latency is generally achieved by blocking the hydroxy, carbonyl, sulfate and primary amine groups present in the drug to make the drug more soluble in lipids and transportable through the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs can be enhanced by intraarterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.

Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). As indicated above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo half-life in the serum of the administered compound, the compounds can be encapsulated, introduced into the liposome lumen, prepared in the form of a colloid, or other conventional techniques can be used that provide a prolonged half-life of the compounds in the serum. There are a variety of methods available for preparing liposomes, as described, for example Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501, 728 and 4,837,028, each of which is incorporated herein by reference. As indicated above, the compounds administered to a patient are in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or they can be sterilized by filtration. The resulting aqueous solutions can be packaged for use as such, or lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparations will typically be between 3 and 11, more preferably 5 to 9, and more preferably 7 to 8. It will be understood that the use of the above excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents having similar uses. The toxicity and therapeutic efficacy of said compounds can be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, for example, to determine the LD50 (the lethal dose for 50% of the population) and the ED50 (the therapeutically effective dose). in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the DL5o / ED50 ratio. Compounds that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of said compounds preferably is in the range of concentrations in the circulation that include ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used. For any compound used in the method of the invention, the therapeutically effective dose can be calculated initially from cell culture assays. A dose can be formulated in animal models to achieve a concentration range in the circulating plasma that includes the IC 50 (the concentration of the test compound that achieves half of the maximum inhibition of symptoms) determined in the cell culture. This information can be used to more accurately determine useful doses for humans. The levels in the plasma can be measured, for example, by high efficiency liquid chromatography.

Utility The compounds, prodrugs and pharmaceutically acceptable salts thereof, as defined herein, may have activity against a variety of bacteria, protozoa, fungi and parasites. By way of example, the compounds, prodrugs and their pharmaceutically acceptable salts can be active against Gram positive and Gram negative bacteria. The compounds, prodrugs and their pharmaceutically acceptable salts can be active against a variety of fungi, including fungi of the genus Mucor and Candida, p. eg, Mucor racemosus or Candida albicans. The compounds, prodrugs and their pharmaceutically acceptable salts can be active against a variety of parasites, including the malaria parasite and cyptosporidium. The compounds of the present invention exhibit activity against a variety of bacterial infections, including, for example, infections by Gram-positive bacteria, infections by Gram-negative bacteria, mycobacterial infections, mycoplasma infections, and chlamydial infections.

Since the compounds of the present invention exhibit potent acidity to a variety of bacteria, such as Gram-positive bacteria, the compounds of the present invention are useful antimicrobial agents and can be effective against a number of human and veterinary pathogens, including Gram positive bacteria. Gram positive organisms against which the compounds of the present invention are useful include Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaioiaomicron, and Clostridium. difficile, and the like. The compounds of the present invention can be combined with one or more additional antibacterial agents. One or more of the additional antibacterial agents may be active against Gram negative bacteria. Additionally, one or more of the additional antibacterial agents may be active against Gram positive bacteria. The combination of the compounds of the present invention and one or more of the additional antibacterial agents can be used to treat an infection by Gram-negative bacteria. Additionally, the combination of the compounds of the present invention and one or more of the additional antibacterial agents can be used to treat infection by Gram positive bacteria. The combination of compounds of the present invention and one or more of the additional antibacterial agents can also be used to treat mycobacterial infection, mycoplasma infection, or chlamydial infection. The in vitro activity of the compounds of the present invention can be evaluated by standard assay methods such as the determination of the minimum inhibitory concentration (MIC) by dilution in agar as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests during Bacteria that Grow Aerobically, "P ed., Published 1993, by the National Clinical Laboratory Standards Committee, Villanova, Pennsilvania, USA. The amount administered to the mammalian patient will depend on what is administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially stop the symptoms of the disease and its complications. A suitable amount to accomplish this is defined as "therapeutically effective dose". The amounts effective for this use will depend on the condition of the disease to be treated as well as on the judgment of the treating physician, depending on factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like. . The compositions administered to a patient are in the form of pharmaceutical compositions described above. The compositions can be sterilized by conventional sterilization techniques, or they can be sterilized by filtration. The resulting aqueous solutions can be packaged for use as such, or lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparations will typically be between 3 and 11, more preferably from 5 to 9, and more preferably from 7 to 8. It will be understood that the use of some of the above excipients, carriers or stabilizers, will result in the formation of pharmaceutical salts. The therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment has been made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the attending physician. it prescribes it. For example, for intravenous administration, the dose will typically range in the range of about 20 mg to about 500 mg per kilogram of body weight, preferably from about 100 mg to about 300 mg per kilogram of body weight. Suitable dosage ranges for intranasal administration, in general, are from about 0.1 mg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from the dose-response curves obtained from in vivo assay systems or from animal models. The following synthetic and biological examples are offered to illustrate this invention, and are not to be construed as limiting the scope of this invention in any way.

EXAMPLES In the above discussion and the following examples the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning 7-methyl / MTL = 1-methylthio-7-deoxy-7-methyl-lincosamine t ap = apparent triplet atm = atmospheres Bn = benzyl Boc = tert-butoxycarbonyl protecting group s width = broad singlet BSTFA = N, 0-bis (tri- methylsilyl) trifluoroacetamide Cbz = carbonyloxybenzyloxy protecting group CDCI3 = chloroform deduced CD3OD = deuterated methanol ufe = colony forming units d = doublet DAST = dimethylaminosulfur trifluoride dd = doublet doublets dddd = doublet of doublets of doublets of doublets dt = doublet of triplets DCC = dicyclohexylcarbodiimide DCE = dicoloroethane DCM = dichloromethane DIEA = diisopropylethylamine DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide DE50 = therapeutically effective dose in 50% of the population EDC = 1- (3-dimethylamopropyl) -3-ethylcarbodiamide HCl Equiv = equivalents EM-ES = electrospray mass spectrometry Et = ethyl EtOAc = ethyl acetate Et20 = diethyl ether g = grams. h = hours HATU = 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate HBTU = 0- (Benzotriazol-1-yl) -N, N, N hexafluorophosphate N'-tetramethyluronium HOBT = 1-hydroxybenzotriazole hydrate NMR 1H = Hydrogen nuclear magnetic resonance HPLC = high pressure liquid chromatography Hz = Hz CI5o = concentration of the test compound that reaches half of the maximum inhibition of symptoms J = constant coupling in hertz L = liters LD50 = lethal dose for 50% of the population LDA = lithium diisopropylamide LiHMDS = lithium hexamethyldisilazide LiN (iPr) 2 = lithium diisopropylnitride m = multiplet M = molar MCPBA = 2- (4 -chloro-o-tolyloxy) acetic Me = methyl MeCN = acetonitrile MeOH = methanol mg = milligrams MHz = megahertz Min = minutes ml = milliliters mm = millimeters mm = millimoles EM (SPOS) = mass spectrometry by electrospray ionization in a positive way EM (ESNEG) = mass spectrometry by positive electrospray ionization MTL = 1-methylthiolincosamine (6-amino-6,8-dideoxy-1-thio-erythro-β-D-galacto-octopyranoside) N = normal NMR = nuclear magnetic resonance OBz = protective group benzyloxy OtBu = tert-butoxy Pd / C = palladium / carbon pg = picograms Ph = phenyl PPTS = pyridinium p-toluenesulfonate Pro = L-proline kg / cm2 = kilograms per square centimeter PTFIE = polytetrafluoroethylene q = quartet cv = quantitative Rf = Retention factor t.a. = room temperature s = singlet sat = saturated t = triplet TBAF = tetrabutylammonium fluoride TBS = tert-butyldimethylsilyl TEA = triethiamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl μg = micrograms μl = microliters μm = micromolar v / v = volume at volume p / p = weight to weight Additionally, the term "Aldrich" indicates that the compound or reagent used in the following processes is commercially available from Aldrich Chemical Company, Inc., 1001 West St. Paul Avenue, Milwaukee, Wl 53233 EE. UU; the term "Fluka" indicates that the compound or reagent is commercially available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA; the term "Lancaster" indicates that the compound or reagent is commercially available from Lancaster Synthesis, Inc., PO Box 100 Windham, NH 03087 USA, the term "Sigma" indicates that the compound or reagent is available in the trade in Sigma, P.O. Box 14508, St. Louis MO 63178 US; the term "Chemservice" indicates that the compound or reagent is available commercially from Chemservice Inc., Westchester, PA, USA; the term "Bachem" indicates that the compound or reagent is commercially available from Bachem Bioscience Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA.; the term "Maybridge" indicates that the compound or reagent is commercially available from Maybridge Chemical Co. Trevillett, Tintagel, Comwall PL34 OHW United Kingdom; the term "RSF indicates that the compound or reagent is commercially available from RSP Amino Acid Analogs, Inc., 106 South St., Hopkinton, MA 01748, USA, and the term" TCI "indicates that the compound or reagent is commercially available from TC1 America, 9211 North Harborgate St., Portland, Oregon, 97203, OR, USA, the term "Toronto" indicates that the compound or reagent is commercially available from Toronto Reasearch Chemicals, Inc., 2 Brisbane Rd., New York, ON, Canada M3J2J8; the term "Alpha" indicates that the compound or reagent is commercially available from Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 018350747; and the term Nova Biochem "indicates that the compound or reagent is commercially available in NovaBiochem USA, 10933 North Torrey Pines Road, PO Box 12087, La Jolla CA 92039-2087. In the following examples, all temperatures are in degrees Ceisius (unless otherwise indicated) and the following general procedures are used to prepare the compounds as indicated. One skilled in the art will note that the following general procedures are intended to be illustrative only and that the methods may be extended to synthesize other compounds of the present invention.

GENERAL PROCEDURES METHOD A Methyl-6-amino-6,8-dideoxy-1-thio-erythro-β-D-galacto-octopyranoside 1 a (R 1 = Me) (MTL) was prepared as described by Hoeksema, H. et al., J. Am. Chem. Soc, 1967, 89, 2448-2452. The N- (benzyloxycarbonyloxy) succinimide (5.8 g 23.1 mmol) and the product were suspended (5.0 g, 19.7 mmol) in pyridine (40 ml) and stirred under N2 36 h. The reaction mixture was cooled to 0 ° C, and then bis-N, O-trifluoroacetamide (15.7 ml, 59.0 mmol) was added with syringe in 2 min. The reaction mixture was allowed to warm to t.a. and stirred for 42 h. Toluene (100 ml) was added and the reaction mixture was evaporated to dryness. The residue was taken up in ethyl acetate (400 ml). The organic solution was washed rapidly with 10% citric acid (200 ml), H20 (3 x 100 ml), saturated NaHCO3 solution (100 ml), and brine (2 x 100 ml), and dried over Na2SO4 and evaporated to dryness. Chromatography of the crude product in silica with EtOAc / Hexanes containing 0.2% TEA, at 10%, provided, after coevaporation with toluene (100 ml) and cyclohexane (2 x 100 ml), the protected product 1 b (IP = Cbz, R1 = Me) (7.2 g , 54%) in the form of a colorless oil. 1 H NMR (300 MHz, CD3SOCD3) d 7.34-7.31 (m, 5), 7.05 (d, J = 8.2, 1), 5.19 (d, J = 5.8, 1), 5.01 (d, J = 1.6, 2), 3.99 (t ap dt, J = 5.5, 9.3, 9.3, 2), 3.93-3.86 (m, 3), 3.49 (dd, J = 2.5, 9.6, 1), 2.01 (s, 3), 1.03 (d, J = 6.3, 3), 0.10 (s, 9), 0.09 (s, 9), 0.04 (m, 18). To dimethylsulfoxide (413 μL, 5.82 mmol) in DCM (1.5 mL) cooled to -72 ° C was added 2M oxalyl chloride in DCM (1.49 mL, 2.98 mmol) in 1 min. After 25 min the probiged product 1b (1.92 g, 2.84 mmol) in DCM (4.0 ml) was added via a cannula. The resulting reaction mixture was stirred for 25 min and then allowed to warm to -50 ° C (dry ice acetonitrile) and kept at this temperature for 2 h. TEA (1.29 mL, 3.30 mmol) was added to the reaction mixture. After 25 min the reaction mixture was diluted with EtOAc (300 mL). The resulting organic solution was washed rapidly with 5% citric acid (300 ml), H20 (2 x 300 ml), saturated NaHCO3 solution (100 ml), brine (100 ml), dried over Na2SO4 and evaporated to dryness with the help of toluene (100 ml) to provide the product 1c. The product lie (P = Cbz, R1 = Me) was obtained as a colorless crystalline solid (1.60 g, 94%) after coevaporation with n-pentane and removal of the residual solvent with high vacuum. 1 H NMR (300 MHz CDCl 3) d 7.37-7.33 (m, 5), 5.60 (m, 1), 5.21 (d, J = 5.2, 1), 5.17 (d, J = 12.4, 1), 5.08 (d, J = 12.4, 1), 4.74 (m, 1), 4.16-4.12 (m, 2), 3.87 ( d, J = 2.2, 1), 3.69 (dd, J = 2.5, 9.3, 1), 2.01 (s wide, 3), 1.90 (s, 3), 0.19 (s, 9), 0.16 (s, 9) , 0.15 (s, 9).

METHOD B The product protected with Boc 1c (P = Boc, R1 = Me) can be prepared in general as indicated above. The product was suspended (R1 = Me) (MTL) (dried at 50 ° C under high vacuum) (21.8 g, 86 mmol) in methanol (200 ml) and TEA (26 ml) and cooled to 0 ° C with ice. To this mixture was added di-t-butyl dicarbonate (57.0 g, 0.26 moles). Then the reaction mixture was stirred overnight at t.a. Toluene (100 ml) was added to the reaction mixture. The solvents were removed to a total volume of 100 ml, leaving a thick slurry to which cyclohexane (300 ml) was added. The resulting solid precipitate was triturated, then filtered and washed with cyclohexane, ether and pentane, and dried to constant weight. The product protected with crude Boc was used without further purification (87%). TLC Rf = 0.75 (MeOH / 10% DCM); MS (ESPOS): 354 [M + H] 1 H NMR (300 MHz, CD3OD) d 0.14 (d, J = 6.3, 3), 1.43 (s, 9), 2.07. (s, 3), 3.55 (dd, J = 3.3, 10.43, 1), 3.84-4.08 (m, 3), 4.10-4.15 (m, 2), 5.25 (d, J = 5.5, 1). To N-Boc-1-methylthiolincosamide (240 mg, 0.68 mmol) in DMF (5 mL), BSTFA (0.52 mL, 2.0 mmol) and triethylamine (0.14 mL, 1.42 mmol) were added at 0 ° C and then stirred all night at ta The DMF was separated and the crude product was rapidly passed through a column of silica gel (pretreated with TEA in 2% ethyl acetate) eluting with ethyl acetate in 10% hexane to stop the product 1b (P = Boc)., R1 = Me) (350mg, 95%). Oxalyl chloride (0.16 mL, 0.78 mmol) in dichloromethane (5 mL) was added slowly at -60 ° C, dimethylsulfoxide (0.22 mL, 0.78 mmol), and then stirred for 15 min. After which, product 1b (370 mg, 0.65 mmol) in DCM (5 ml) was slowly added. The reaction mixture was stirred for 45 min, and during this time the temperature of the reaction was raised to -40 ° C. Then triethylamine (0.70 ml, 3.25 mmol) was added and stirring was continued for an additional 15 min at -40 ° C. It was then extracted with DCM (100 ml) and washed with 10% citric acid (50 ml). The residue obtained by removing the solvent was then purified on a column of silica gel using ethyl acetate in hexanes ai 10% as eluent to give the product 1c (P = Boc, R1 = Me) as a colorless oil (289 mg , 78%). TLC: Rf = 0.60 (EtOAc / 10% Hexanes); MS (ESPOS): 590 [M + Na] +; 1 H NMR (300 MHz, CDCl 3) d 0.11 (s, 18), 0.17 (s, 18), 1.40 (s, 9), 1.84 (s, 3), 2.26 (s, 3), 3.63 (dd, J = 2.7, 9.34, 1), 3.82 (d, J = 1.9, 1), 4.01-4.12 (m, 2), 5.15 (d, J = 5.5, 1).

METHOD C Triphenylphosphonium bromide (3.29 g, 9.2 mmol) and potassium tert-butoxide (715 mg, 6.4 mmol) were suspended under N2 in toluene (31 mL) with vigorous stirring. After 4 h the protected product 1c (P = Cbz, R 1 = Me) (1.4 g, 2.36 mmol) in toluene (20 ml) was added via a cannula. The resulting reaction mixture was stirred 2 h and then diluted with EtOAc (250 mL). The resulting organic solution was washed rapidly with H20 (2 x 100 ml), brine (1 x 100 ml) dried over Na2SO and evaporated to dryness. Chromatography of the product on silica with EtOAc / 6% Hexanes containing 0.2% TEA gave the product alkene 2a (P = Cbz, R1 = Me, R = CH2) as a colorless oil which crystallized after coevaporation with toluene and cyclohexane (0.65 g, 46%). 1 H NMR (300 MHz CDCl 3) d 7.35-7.27 (m, 5), 6.36 (d, J = 7.1, 1), 5.24 (d, J = 5.5, 1), 5.08 (m, 4), 4.34 (m, 1), 4.16 (m, 2), 3.88 (d, J = 2.2, 1), 3.61 (dd, J = 2.2, 9.3, 1), 2.20 (s, 3), 1.79 (s, 3), 0.17- 0.13 (m, 27). The product 2a (P = Cbz, R1 = Me, R2 = CH2) (490 mg, 0.82 mmol) in ethanol (50 ml) was added to palladium on charcoal 10% (Degussa wet form with 50% water w / w ) (700 mg) in a Parr bottle. The bottle was purged with H2 at 4.55 kg / cm2 and stirred 24 h. The reaction mixture was filtered through celite, and rinsed with methanol. The organic solution was transferred to a funnel with resin containing Dowex 50w-400x form H + (0.8 g) washed and dried and stirred for 10 min. After washing the resin with methanol three times and with water twice, the saturated product 2b was eluted (R1 = Me, R2 = Me from the resin washing with TEA in 5% MeOH (35 ml, x 10 min x 5) The combined filtrates were evaporated to dryness, coevaporated with EtOH twice and lyophilized in 1: 1 MeCN / H20 to give the product as a colorless powder (198.4 mg, 96%). 1 H NMR (300 MHz, D20) d 5.17 (d, J = 5.8, 1), 3.97-3.84 (m, 3), 3.52 (dd, J = 3.0, 10.0, 1), 2.82 (dd, J = 4.4, 8.5, 1), 1.94 (s, 3), 1.89-1.81 (m, 1), 0.82 (d, J = 6.9, 3), 0.72 (d, J = 6.9, 3). MS (ESPOS): 252.2 [M + Hf, (ESNEG): 250.4 [M-H] ".

METHOD D Alternatively when the Boc protecting group was used, methyltriphenylphosphonium bromide (12 g, 33.6 mmol) and potassium t-butoxide (3 g, 26.7 mmol) were taken up in THF (70 ml) at 0 ° C, and stirred at.. to. during 4 h. Then the product protected with Boc 1c was added (P = Boc, R1 = Me) (4.7 g, 8.2 mmol) in THF (30 ml) and stirred at r.t. for 2 h. After which it was extracted with EtOAc (300 ml), washed with brine (100 ml) and dried over sodium sulfate. The crude alkene 2a product (P = Boc, R1 = Me, R2 = CH2) was purified by column chromatography on silica gel using EtOAc in 10% Hexane as eluent (4.1 g, 87.6%). TLC: Rf = 0.5 (EtOAc in 10% Hexane): 1 H NMR (300 MHz, CD3OD) d 7.24 (m, 2), 5.22 (d, J = 5.7, 1), 4.21 (m, 1), 4.09 ( m, 2), 3.87 (d, J = 2.4, 1), 3.60 (dd, J = 2.7, 9.3, 1), 1.99 (s, 3), 1.76 (s, 3); 1.43 (s, 9); MS (ESPOS): 444 (M-2TMS + Na). To product 2a (P = Boc, R1 = Me, R2 = CH2) in methanol (30 ml), Dowex H + resin (1 g) was added and stirred at r.t. for 1 h. The resin was filtered and the product was obtained by removing the solvent (2.4 g, 6.8 mmol), and was taken up in MeOH (30 mL). Pd / C (2.5 g) was added and hydrogenated at 3.85 kg / cm2 overnight. The crude product obtained by filtering and removing the solvent was purified by silica gel column chromatography using MeOH in 10% DCM to provide the Boc protected 7-Methyl-MTL as a white solid (2.06 g, 86% ). TLC Rf = 0.5 (MeOH in 10% DCM). 1 H NMR (300 MHz, CD3OD) d 5.23 (d, J = 5.4, 1), 4.11 (m, 1), 3.97 (d, J = 10.2, 1), 3.84 (m, 1), 3.52 (m, 1 ), 2.08 (s, 3), 1.44 (s, 9), 1.14 (m, 1), 0.93 (d, J = 6.9, 3), 0.85 (d, J = 6.9, 3); MS (ESPOS): 351 [M + Hf. To the 7-methyl-MTL protected with Boc (150 mg, 0.43 mmol) in dichloroethane (6 ml), dimethyl sulfide (0.16 ml, 2.5 mmol) was added, followed by TFA (2 ml), water (0.16 ml) and stirred to ta for 1 h. The solvent was removed to obtain the crude product 2b (R1 = Me, R2 = Me). After purification by silica gel column chromatography, using MeOH in 30% DCM as eluent, product 2b was obtained (R1 = Me, R2 = Me) identical in all respects to the material obtained by Method C.

METHOD E Sodium hydride (80 mg, 3.3 mmol) was suspended under N2 in THF (4 mL) with vigorous stirring. The suspension was cooled to -30 ° C and diethyl (cyanomethyl) phosphonate (805 μL, 5.0 mmol) was added. After 30 min the protected product 1c (P = Cbz, R1 = Me) (1.0 g, 1.7 mmol) in THF (3 ml) was added via a cannula. The resulting reaction mixture was stirred 4 h and then diluted with EtOAc (250 mL). The resulting organic solution was washed rapidly with saturated aqueous solution of NaHCO 3 (1 X 100 ml), brine (1 x 50 ml) dried over Na 2 SO 4 and evaporated to dryness. Chromatography of the crude product on silica with EtOAc / 6% Hexanes to EtOAc / 10% Hexanes containing 0.2% TEA gave the protected alkene product 2a (P = Cbz, R1 = Me, R2 = CHCN) in the form of a colorless oil (0.38 g, 37%). MS (ESPOS): 625.5, 2 [M + H] +, ES (NEG): 659.5 [M + CI].

Product 2a was added (P = Cbz, R1 = Me, R2 = CHCN) (180 mg, 0. 29 mmoles) in ethanol (15 ml) with 10% palladium on carbon (Degussa wet form in 50% w / w water) (300 mg) in a Parr bottle and concentrated HCl (29 μl) was added. The bottle was purged, and charged with H2 at 4.55 kg / cm2 and stirred for 24 h. The reaction mixture was filtered through celite, and rinsed with methanol. The organic solution was transferred to a funnel with resin, which contained Dowex 50w-400x form H + washed and dried (1 g) and stirred 10 min. After washing the resin with methanol twice and with water, the saturated product 21 b (R = Me, R2 = CH2CN) was eluted from the resin by washing with TEA in 5% MeOH (20 ml x 20 min x 3) and MeCN (20 ml x 20 min). The combined organic filtrates were evaporated to dryness and lyophilized from MeCN / H20) 1: 1 to give product 2b (R1 = Me, R2 = CH2CN) as a colorless solid (70 mg, 91%). ES (NEG): 275.3 [M-H] \ METHOD F To protected product 1c (P = Cbz, R1 = Me) (0.75 g, 1.3 mmol) in THF (7.3 ml) was added MeMgCl (3M) in THF (7.0 ml 2.1 mmol) at 0 ° C. At 30 min the reaction mixture was heated to 4 ° C and after 4 h the reaction mixture was quenched with saturated aqueous solution of NH CI / H20 1: 3 (10 ml). The inactivated mixture was diluted to 100 ml with water and extracted with DCM (4 x 50 ml). The combined organic phases were dried and evaporated. He The residue was dissolved in H20 / HOACITHF 124 (100 ml) and stirred for 20 h, and then evaporated with toluene (2 x 100 ml). Chromatography with DCM / MeOH from 10: 1 to 10: 2 gave the product 3a (P = Cbz, R1 = Me, R2 = Me) (153 mg, 31%). (ESNEG): 399.5 [M-HT. Product 3a (P = Cbz, R1 = Me, R2 = Me) (79 mg, 0.2 mmol) in ethanol (10 ml) was added to 10% palladium on charcoal (Degussa wet form in 50% w / w water ) (400 mg) in a Parr bottle. The bottle was charged with H2 at 4.55 kg / cm2 and stirred 6 h. The reaction mixture was filtered through celite, and rinsed with methanol. The combined filtrates were evaporated to dryness and lyophilized from 1: 1 MeCN / H20 to give the product 3b (R1 = Me, R2 = Me) as a colorless powder (42 mg, 80%). 1 H NMR (300 MHz, D20) d 5.33 (d, J = 5.8, 1), 4.83-4.06 (m, 3), 3.65-3.60 (m, 1), 3.06-3.03 (m, 1), 2.18 (s) , 3), 1.30 (s, 3), 1.23 (s, 3). MS (ESPOS): 268.4 [M + Hf, MS (ESNEG): 266.2 [M-H ".

METHOD G To the product protected with Boc 1c (P = Boc, R1 = Me) (100 mg, 0.18 mmol) in methanol (3 ml), O-trimethylsilylhydroxylamine (0.10 ml, 0.88 mmol) was added and stirred overnight at r.t. The solvent was removed to obtain the product protected with crude Boc 4a (P = Boc, R1 = Me, R7 = H). To the gross product 4a (95 mg, 0.15 mmole), trifluoroacetic acid in 30% dichloroethane (10 ml) and dimethyl sulfide (0.5 ml) was added and stirred for 1 h. The solvent was removed and the product 4b (R1 = Me, R7 = H) was collected as it was for the next step. TLC: Rf = 0.35 (10% MeOH / DCM); MS (ESPOS): 267 [M + H] +; 1 H NMR (300 MHz, CD3OD) d 1.96 (s, 3), 2.09 (s, 3), 3.58 (dd, J = 3.3, 10.2, 1), 3.90 (s, 1), 4.11 (dd, J = 5.7 , 10.20, 1), 4.19 (d, J = 5.4, 1), 4.50 (d, J = 5.1, 1), 5.36 (d, J = 5.7, 1).

METHOD H To the product protected with Boc 1c (P = Boc, R1 = Me) (100 mg, 0.176 mmol) in methanol (4 ml) and water (1 ml), 0-alkylhydroxylamine hydrochloride (for example, O-hydrochloride) was added. methylhydroxylamine) (60 mg, 0.70 mmol) and sodium acetate (57 mg, 0.70 mmol) and heated at 80 ° C for 3 h and then stirred at rt. all night. The solvent was removed under high vacuum to obtain the product protected with crude Boc 4a (P = Boc, R1 = H, R7 = Me). "The crude product 4a was taken up in trifluoroacetic acid in 30% dichloroethane (10 ml), dimethyl sulphide (0.5 ml) and stirred for 1 h at rt The solvent was removed and the residue was kept under high vacuum for 1 h and the product 4b (R1 = Me, R7 = Me) was collected as it was for the next step. TLC: Rf = 0.63 (MeOH / 10% DCM); MS (SPOS): 281 [M + Hf. 1 H NMR (300 MHz, CD3OD) d 1.95 (s, 3), 2.08 (s, 3), 3.60 (dd, J = 3.3, 10.20, 1), 3.92 (s, 3), 4.13 (dd, J = 4.8 , 10.20, 1), 4.49 (d, J = 1.2, 1), 5.38 (d, J = 5.4, 1).

METHOD I To the product protected with Boc 1c (P = Boc, R1 = Me) (500 mg, 0.88 mmol) in THF (10 ml), tetrabutylammonium fluoride (2.5 mmol, 1 M in THF) was added and the reaction mixture was stirred a ta for 1 h. The solvent was removed and the residue was purified on a silica gel column using methanol in 5% dichloromethane as eluent. The product (111 mg, 0.31 mmol) obtained from the column was then taken up in a mixture of dichloromethane (3 ml) and pyridine (3 ml) to which were added acetic anhydride (0.5 ml, 10.6 mmol) and dimethylaminopyridine (80 mg). , 1.7 mmol) and stirred at rt all night. The solvent was removed and the crude product was purified on a silica gel column using 30% ethyl acetate in hexanes as eluent to give the product 5a (P = Boc, R1 = Me) (58 mg, 38%).

TLC: Rf = 0.73 (EtOAc / 50% Hexanes); MS (ESPOS): 500 [M + Naj +. 1 H NMR (300 MHz, CDCl 3) d 1.38 (s, 9), 1.91 (s, 3), 1.98 (s, 3), 2. 07 (s, 3), 2.18 (s, 3), 4.33 (m, 1), 4.72 (m, 1), 4.94 (m, 1), 5.21 (m, 2), 5.45 (s, 1), 5.57 (m, 1). To product 5a (P = Boc, R1 = Me) (158 mg, 0.331 mmol) in DCM (5 ml), dimethylaminosulfur trifluoride (732 μl, 3.31 mmol) was added and stirred overnight. More DCM was added and the organic part was washed with sodium bicarbonate. The residue obtained by removing the solvent was purified by silica gel column chromatography using 20% ethyl acetate in hexanes as eluent (100 mg, 60%) to provide the protected product (P = Boc, R1 = Me). The Boc-protected product was taken up in trifluoroacetic acid in 30% dichloroethane and dimethyl sulfide and stirred for 1 h at RT. The solvent was removed to give the product 5b (R1 = Me). TLC: Rf = 0.63 (MeOH / 40% Hexanes); EM (SPOS): 522 [M + Naf. 1 H NMR (300 MHz, CDCl 3) d 1.40 (s, 9), 1.69 (t, J = 18.9, 3), 1.98 (s, 3), 2.08 (s, 6), 2.13 (s, 3), 4.22- 4.30 (m, 1), 4.53 (dd, J = 10.9, 25.3, 1), 5.16-5.28 (m, 2), 5.52 (s, 1), 5.63 (d, J = 5.2, 1).

METHOD J Enolization (LiHMDS) and alkylation of product 7a with 4-bromo-2-methyl-2-butenyl provided a mixture of diastereomers of lactam 7b (R9 = 2-methyl-2-butenyl) (61%) according to Bibliography procedure of Zhang, R .; et al., Journal of the American Chemical Society. 1998, 120, 3894-3902. The compound 7a is available commercially from distributors such as Bachem. Alternatively, the product 7a can be prepared by methods known in the art, for example see Baldwin, et al .; Tetrahedron, 1989, 45, 7449-7468. Lactam 7b was reduced to pyrrolidine 7c (R9 = 2-methyl-2-butenyl) (70%) by a two-step sequence involving reduction of lactamic superhydride to the hemiaminal and subsequent reduction of the hemiaminal with Et3S. H / BF3OEt2. Pyrrolidine 7c (R9 = 2-methyl-2-butenyl) (778 mg, 2.08 mmol), 10% palladium on charcoal (230 mg), in anhydrous methanol (25 ml) was subjected to Parr hydrogenolysis at 3.5 kg / cm2 for 5 h. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washes and filtrates were evaporated to dryness, giving, without further purification, a colorless oil 7d (R9 = 2-methylbutyl). TLC: Rf = 0.3 [Solvent system: DCM: hexanes: MeOH (6: 5: 1)]. EM (NEGATIVE): 284.5 [M-H] \ METHOD K Enolization (LiHMDS, 33 mmol, 33 mL, 1.1 equiv) and alkylation of product 7a (9.47 g, 29.7 mmol, 1 equiv) with cis-1-bromo-2-pentene (4.21 mL, 35.6 mmol, 1.2 equiv) ), in anhydrous THF at -78 ° C under a nitrogen atmosphere, gave a mixture of diastereomers of lactam 7b (R9 = 2-pentenyl) (43.2%) after purification on silica gel. Lactam 7b (3.96 g, 10.22 mmol) was reduced to pyrrolidine 7c (R9 = 2-pentenyl) by the two-step sequence involving the reduction of lactamic superhydride to the hemiaminal, at -78 ° C in anhydrous THF, and the subsequent reduction of the hemiaminal with Et3SiH / BF3.OEt2, anhydrous DCM at -78 ° C, yielding the product 7c (R9 = 2-pentenyl) (71%) after purification on silica gel. Pyrrolidine 7c (2.71 g, 7.26 mmol), 10% palladium on charcoal (560 mg), in anhydrous methanol (30 ml) was subjected to Parr hydrogenolysis at 3.5 kg / cm2 for 5 h. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washings and filtrates were evaporated to dryness, giving, without further purification, a colorless oil 7d (R9 = pentyl) (1.68g, 80%). TLC: Rf = 0.3 [Solvent system: DCM: hexanes: MeOH (6:51)]. MS (ESNEG): 284.5 [M-H] ".

METHOD L Ozonolysis of the product 7d (R9 = 2-meitylbutyl) in anhydrous dichloromethane followed by treatment with DMS at -78 ° C provided the aldehyde 8a (77%). 4-Fluorobenzyl-phosphonium chloride (0.87 g, 2.13 mmol) and potassium t-butoxide (0.17 g, 1.48 mmol) were suspended in toluene under nitrogen with vigorous stirring. After 4 h, a solution of the aldehyde 8a (204 mg, 0.59 mmol) in toluene (4.6 ml) was added dropwise. The reaction mixture was stirred at t.a. for 2 h and diluted with ethyl acetate (50 ml). The organic layer was washed with water (2 x 20 ml), and brine, dried and concentrated. The residue was purified by chromatography to give a clear syrup 8b (R9 '= 3- (4-fluorophenyl) prop-2-enyl) (171 mg). To a solution of the product 8b (R9 = 3- (4-f! Uorophenyl) prop-2-enium) (171 mg, 0.39 mmol) in MeOH (25 ml) in a Parr bottle was added 10% palladium on charcoal ( Degussa wet form in water at 50% w / w) (200 mg). The bottle was purged with H2 at 2.8 kg / cm2 and stirred for 4 h. The reaction mixture was filtered through celite, and rinsed with MeOH. The filtrate was concentrated to give a yellow oil 8c (R9 = 3- (4-fluorophenyl) propyl) (120 mg). MS (ESOP): 374.5 [M + Na] +, MS (ESNEG): 350.3 [M-H] \ METHOD M 4-Chlorobenzyl-phosphonium chloride (0.95 g, 2.24 mmol, 3.9 equiv) and potassium t-butoxide (0.17 g, 1.55 mmol, 2.7 equiv) in toluene (7.5 mL) were suspended under nitrogen with vigorous stirring. After 4 h, a solution of the aldehyde 8a (200 mg, 0.58 mmol, 1 equiv) in toluene (4.9 ml) was added dropwise. The reaction mixture was stirred at t.a. for 2 h and diluted with ethyl acetate (50 ml). The organic layer was washed with water (2 x 20 ml), and brine, dried and concentrated. The residue was purified by chromatography to give a clear syrup 8b (R = 3- (4-chlorophenyl) prop-2-enyl) (216 mg, 82%). MS (ESPOS): 478.5 [M + Na] +, MS (ESNEG): 454.4 [MH]. "To a solution of the product 8b (R9 = 3- (4-chlorophenyl) prop-2-enyl) (147 mg, 0.32 mmol) in cyclohexane (50 ml) was added 10% palladium on charcoal (Degussa wet form in 50% w / w water) (80 mg) The reaction mixture was stirred at rt in 1 atm H 2 O. The reaction mixture was filtered through celite, and rinsed with MeOH.The filtrate was concentrated to give an alkane product 8c (R 9 = 3- (4-chlorophenyl) propyl) in the form of a clear oil (131 mg, 89%). To a solution of the alkane (131 mg, 0.29 mmol, 1 equiv) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (60 mg, 1.43 mmol). 5 equiv) The reaction mixture was stirred overnight, THF was removed in vacuo, the residue was diluted with water (5 ml) and washed with ether (10 ml). ethyl acetate (60 ml) and partitioned with 10% citric acid (30 ml) The organic layer was washed with a Brine and brine, dried and concentrated to give a clear syrup 8c (R9 = 3- (4-chlorophenyl) propyl) (105 mg, 100%). MS (ESPOS): 390.4 [M + Na] +, 268.4 [M-Boc + H] +.

METHOD N To a solution of aldehyde 8a (406.5 mg, 1.17 mmol, 1 equiv) in dimethyl acetamide (0.25 ml) at 0 ° C was added dibromodifluoromethane (0.21 ml, 2.34 mmol, 2 equiv). To the stirred mixture was added a solution of triphenylphosphine (0.61 g, 2.34 mmol, 2 equiv) in dimethyl acetamide (0.5 ml) over a period of 20 minutes under nitrogen atmosphere. The reaction mixture was heated to t.a. and stirred for 30 minutes, and then activated zinc (0.25 g, 3.82 mmol, 3.3 equiv) was added with the help of dimethyl acetamide (0.3 ml). The resulting reaction mixture was stirred at 110 ° C for 1 h and cooled to t.a. and filtered with the aid of dimethylacetamide (7 ml). The filtrate was poured into ice water (100 ml) and extracted with ether (150 ml). The ether layer was washed with brine, dried and concentrated. The residue was purified by chromatography to give a clear oil 8b (R9 '= 3,3-difluoroprop-2-enyl) (182 mg, 41%). MS (Spores): 282.4 [M-Boc + H] +. To a solution of the product 8a (R9 '= 3,3-difluoroprop-2-enyl) (126 mg, 0.33 mmol) in MeOH (35 ml) was added 10% palladium on charcoal (Degussa wet form in 50% water) p / p) (120 mg). The reaction mixture was stirred at t.a. in a hydrogen atmosphere (1 atm) overnight and filtered through celite with the aid of MeOH. The filtrate was concentrated to give a clear syrup 8c (R9 = 3,3-difluoropropyl) (97 mg, 100%). MS (ESPOS): 194.4 [M-Boc + H] +, MS (ESNEG): 292.4 [M-H] ".

METHOD OR To a solution of the aldehyde 8b (258 mg, 0.74 mmol, 1 equiv) in THF (3 ml) at 0 ° C was added tetraalyltin (178 μl, 0.74 mmol, 1 equiv), followed by the addition to the weight of the boron trifluoride (94.3 μl, 0. 74 mmoles, 1 equiv) in a period of 15 min. The reaction mixture was stirred at 0 ° C for 1.5 h. Then a solution of potassium fluoride (125 mg) in water (1.25 ml) was added. The resulting mixture was heated to t.a. and stirred at t.a. for 20 min. This was followed by the addition of meianol (10 ml) and the resulting mixture was stirred at r.t. for another 20 min. The reaction mixture is filtered through celite. The filtrate was evaporated to dryness. The residue was diluted with dichloromethane (100 ml), washed with water (50 ml), dried, concentrated and purified by chromatography to give a clear oil 9a (R9 = 2-hydroxypent-4-eny!) (261). mg, 90%): MS (SPOS): 412. 5 [M + Na] +, 290.4 [M-Boc + H] +. To a solution of dimethyl sulfoxide (0.17 ml, 2.42 mmol, 3 equiv) in dichloromethane (0.5 ml) at -72 ° C was added a solution of 2 M oxalyl chloride in dichloromethane (0.61 ml, 1.21 mmol, 1.5 equiv) in a 1 min period The mixture was stirred at -72 ° C for 25 min, followed by the dropwise addition of a solution of alcohol 9a (314 mg, 0.81 mmol, 1 equiv) in dichloromethane (1.4 ml) over a period of 2 min. The mixture of. The reaction was stirred at -72 ° C for 25 min, and then warmed to -50 ° C and stirred for an additional 2 h. Triethylamine (0.56 ml, 4.04 mmol, 5 equiv) was added and stirred at -50 ° C for 25 min. The mixture was diluted with ethyl acetate (100 ml), washed with 5% citric acid (100 ml), water, saturated aqueous solution of NaHCO 3 and brine, dried, evaporated and coevaporated with anhydrous toluene to give a clear syrup. 9b (R9 = 2-propenylcarboxymethyl) (287 mg, 92%). MS (ESPOS): 288.5 [M-Boc + H] +; MS (ESNEG): 386.2 [MH]. "To a solution of the ketone 9b (225.1 mg, 0.58 mmol, 1 equiv) in dichloromethane (2 ml) at -78 ° C was added diethylaminosulfur trifluoride (0.46 ml, 3.49 ml , 6 equiv.) The reaction mixture was warmed to rt and stirred at rt for 3 h, followed by an addition of additional (diethylamine) sulfur trifluoride) 0.46 ml, 3.49 ml, 6 equiv.) At -78 ° C. The mixture was warmed to rt and stirred overnight, then the mixture was diluted with dichloromethane (60 ml), washed with saturated aqueous NaHCO 3 solution (1 x), brine (1 x), dried and evaporated. The residue was purified by chromatography to give a yellow oil 9c (X, X = fluoro, fluoro) (75 mg, 32%). MS (Spores): 310.5 [M-Boc + H] +. To a solution of 9c (R9 = 2,2-difluoropent-4-enyl) (85 mg, 0.21 mmol) in MeOH (20 ml) was added 10% palladium on charcoal (Degussa wet form in 50% water p / p) (100 mg). The reaction mixture was stirred at t.a. under a hydrogen atmosphere (1 atm) overnight, it was filtered through celite with the aid of MeOH (10 ml). Palladium on charcoal 10% (Degussa wet form in 50% w / w water) (130 mg) was added to the filtrate. The reaction mixture was stirred at t.a. under a hydrogen atmosphere (1 atm) overnight, it was filtered through celite with the aid of MeOH (10 ml). The filtrate was concentrated to give the halogen-alkyl-N-Boc-amino acid 9d (X, X = fluoro, fluoro) (67.7 mg, 100%) as a clear syrup. MS (ESPOS): 344.4 [M + Na] +, 222.4 [M-Boc + H] + MS (ESNEG): 320.2 [M-H] '.

METHOD P To the 4-propylpyridine (2.5 g, 20 mmol), 30% hydrogen peroxide (2.4 g) was added and the mixture was heated to reflux overnight. The solvent was removed and the resulting residue was taken up in DCM (30 ml). Trimethylsilyl cyanide (2.6 g, 26 mmol) was added to the above solution followed by dimethylcarbamyl chloride (2.8 g, 26 mmol), and the reaction mixture was stirred at r.t. all night. Potassium carbonate (10%, 100 ml) was added. The organic layer was separated, dried over sodium sulfate and then concentrated to obtain 4-propyl-2-cyanopyridine (2.5 g, 93%). It was then heated to reflux in hydrochloric acid (6 N, 60 ml) overnight. The 4-propyl-2-pyridinecarboxylic acid 10b (R9 = propyl) was obtained after crystallization from acetonitrile (2 g, 71%). MS (ESPOS): 166 [M + Hf; 1 H NMR (300 MH2, CD3OD) d 8.75 (dd, J = 9.0, 3.0, 1), 8.42 (s, 1), 8.08 (dd, J = 9.0, 3.0, 1), 3.00 (t, J = 7.5, 2), 1.82 (m, 2), 1.05 (t, J = 7.2, 3). 13b METHOD Q A mixture of picolinic acid (Aldrich) (20 g, 162 mmol, 1 equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 ml) was heated to reflux for 5 h. The solvent was removed in vacuo. Absolute methanol (160 ml) was added and the mixture was stirred at r.t. for 30 min. The solvent was evaporated, and the residue was taken up in 5% sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers were combined and dried over MgSO4 and evaporated. The residue was purified by chromatography to give the methyl ester of 4-chloropicolinic acid as a white solid (19.9 g, 72%): 1 H NMR (300 MHz, CDCl 3) d 8.63 (d, J = 5.4, 1) , 8.13 (d, J = 2.1, 1), 7.48 (dd, J = 2.0, 5.3, 1), 4.00 (s, 3). A mixture of the methyl ester of 4-chloropicolinic acid (2.4 g, 14. 1 mmol), 57% hydroiodic acid (13.3 ml) and 50% aqueous hypophosphorous acid (0.66 ml) was stirred at 85% for 2 h and then stirred at 107 ° C overnight. The mixture was cooled to 95 ° C. At this temperature, 10 M aqueous sodium hydroxide solution (4.2 ml) was added in 30 min, followed by the addition of water (15.2 ml). The mixture was cooled to t.a. and stirred at t.a. for 1 h. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, 66%): 1 H NMR (300 MHz, DMSO d6) d 8.39 (d, J = 5.1, 1), 8.35 (d, J = 1.8, 1), 8.07 (dd, J = 1.7, 5.2, 1); MS (ESPOS): 250.2 [M + H] +. To a mixture of the HCl salt of 7-Me-MTL 2b (R1 = Me, R2 = Me) (200 mg, 0.69 mmol, 1 equiv) in dry DMF (1.8 ml) at 0 ° C was added triethylamine (0.50 ml, 3.61 mmol, 5.2 equiv), followed by the addition of BSTFA (0.28 ml, 1.04 mmol, 1.5 equiv. ). The reaction mixture was stirred at 0 ° C for 10 min, and then stirred at r.t. for 50 minutes. To the reaction mixture was added 13a acid (341 mg, 0.90 mmol, 1.3 equiv) and HATU (423 mg, 1.11 mmol, 1.6 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with water (1 x), saturated NaHCO 3 solution (1 x) and brine. The organic layer was dried over Na S0 and evaporated to give a yellow residue which was dissolved in methanol (20 ml) and to which dry Dowex resin (250 mg) was added. The reaction mixture was stirred at t.a. for 1 h. The resin was filtered off and the crude product was eluted with ammonia in 2M methanol. The methanolic eluent was evaporated, and the resulting residue was purified by chromatography to give a white solid 13b (R1 = Me, R2 = Me, R3 = H) (250 mg, 75%): 1 H NMR (300 MHz, CD3OD) d 8.46 (d, J = 11.8, 1), 8.30 (d, J = 5.4, 1), 7.98 (dd, J = 1.8, 5.1 , 1), 5.25 (d, J = 6.0, 1), 4.32-4.23 (m, 2), 4.09 (dd, J = 5.7, 10.2, 1), 3.87 (d, J = 3.0, 1), 3.54 ( dd, J = 3.3, 10.2, 1), 2.24-2.15 (m, 1), 2.11 (s, 3), 0.99-0.96 (m, 6); MS (ESPOS): 483.5 [M + H] +; MS (ESNEG): 481.4 [M-H] '. The product 13b (R1 = Me, R2 = Me, R3 = H) (133.9 mg, 0.28 mmol) was added to a dry flask., 1 equiv), triphenylphosphine (46.7 mg, 0.18 mmol, 0.64 equiv), copper iodide (1) (33.9 mg, 0.18 mmol, 0.64 equiv), palladium acetate (20 mg, 0.09 mmol, 0.32 equiv) and triethylamine ( 1.6 ml). The mixture was degassed with nitrogen, followed by the addition of 3-prop-2-ynyl-cyclopentane (120 mg, 1.11 mmol, 4 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = Me, R9 = 3-cyclopentyl-prop-1-inyl, R2 = Me, R3 = H) as a yellow solid (106 mg, 83%): 1 H NMR (300 MHz, CD3OD) d 8.55 (d, J = 4.8, 1), 7.98 (s, 1), 7. 47 (dd, J = 1.7, 5.0, 1), 5.26 (d, J = 5.4, 1), 4.33-4.22 (m, 2), 4.10 (dd, J = . 5, 10.4, 1), 3.86 (d, J = 3.3, 1), 3.55 (dd, J = 3.3, 10.5, 1), 2.49 (d, J = 6.9, 2), 2. 26-2.12 (m, 2), 2.11 (s, 3), 1.93-1.82 (m, 2), 1.73-1.55 (m, 4), 1.43-1.31 (m, 2), 1.00-0.96 (m, 6 ); MS (ESPOS): 463.6 [M + H] +; MS (ESNEG): 461.5 [M-H] \ METHOD R To a solution of the product 13a prepared in the method Q (5 g, 13.26 mmol) in methanol (500 ml) were added one drop of concentrated sulfuric acid. The reaction mixture was heated to reflux overnight. The solvent was evaporated and the residue was purified by chromatography to give the methyl ester of 4-iodopipecolinic acid 14a as a yellow solid (3.0 g, 86%): 1 H NMR (300 MHz, CDCl 3) d 8.49 (d, J = 1.5, 1), 8.37 (d, J = 5.4, 1), 7.85 (dd, J = 1.6, 5.2, 1), 4.00 (s, 3); MS (SPOS): 264.3 [M + Hf. The product 14a (1 g, 3.8 mmol, 1 equiv), triphenylphosphine (79.7 mg, 0.3 mmol, 0.08 equiv), copper iodide (1) (57.9 mg, 0.3 mmol, 0.08 equiv), acetate were added to a dry flask. of palladium (34.1 mg, 0.15 mmol, 0.04 equiv) and triethylamine (14 ml). The mixture was degassed with nitrogen, followed by the addition of 3-butyn-1-ol (0.53 g, 7.6 mmol, 2 equiv).

The mixture was stirred at t.a. for 3 h. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give product 14b (R9 = 3-hidoxy-but-1-inyl) as a yellow oil (0.78 g, 100%): 1 H NMR (300 MHz, CDCl 3) d 8.66-8.63 (m, 1), 8.09-8.08 (m, 1), 7. 43-7.40 (m, 1), 3.99 (s, 3), 3.88-3.82 (m, 2), 2.72 (t, J = 6.3, 2). EM (SPOS): 206.4 [M + H] +. To a solution of the above product 14b (R9 '= 3-hidoxy-but-1-ynyl) (0.78 g, 3.8 mmol) in methanol (40 ml) was added 10% palladium on charcoal (0.4 g). The flask containing the reaction mixture was purged and charged with hydrogen (1 atm) and stirred at r.t. All night long. The palladium was removed by filtration and the filtrate was concentrated to give the product 14c (R9 = 3-hydroxybutyl) in the form of an oil (0.77 g, 97%): 1 H NMR (300 MHz, CDCl 3) d 8.60 (d, J = 4.5, 1), 7.97 (d, J = 1.2, 1) , 7.29 (dd, J = 1.6, 5.0, 1), 3.99 (s, 3), 3.67 (t, J = 6.3, 2), 2.72 (t, J = 7.7, 2), 1. 81-1.69 (m, 2), 1.62-1.54 (m, 2); MS (ESPOS): 210.4 [M + H] +.

METHOD S To 4-hydroxypyridine-2-carboxylic acid 10b (R9 = hydroxy) (200 mg, 1.4 mmol) in DMF (2 ml), potassium carbonate (397 mg, 2.8 mmol) was added followed by n-bromobutane (197 mg, 1.4 mmoles), and heated up to 60 ° C all night. The solvent was removed to obtain the crude ester product. The crude ester (360 mg, 1.4 mmol) was dissolved in THF (4 ml), lithium hydroxide (72 mg, 1.7 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The residue obtained by removing the solvent was purified by chromatography on silica gel using MeOH in 10% DCM to provide 4-butoxypyridine-2-carboxylic acid 15a (R9 '= butyl) (100 mg, 43%). 1 H NMR (300 MHz, CD3OD) d 8.37 (d, J = 6.0, 1), 7.63 (d, J = 2.7, 1), 7.07 (dd, J = 2.7, 6.0, 1), 4.15 (t, J = 6.6, 2), 1.82 (m, 2), 1.54 (m, 2), 1.01 (t, J = 7.5, 3). MS (ESNEG): 194 [M-H] -. To 4-butoxypyridine-2-carboxylic acid 15a (R9 '= Butyllum) (100 mg, 0.5 mmol) in DMF (2 ml), 7-methyl-ce-thiolyl-assosimide 2b (R1 = Me, R2 = Me) was added ( 147 mg, 0.5 mmol) followed by HBTU (214 mg, 0.55 mmol) and DIEA (132 mg, 1 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed, and purification of the crude material was carried out by chromatography on silica gel to obtain compound 15b (R1 = Me, R2 = Me, R9 = butyl) (201 mg, 91%): 1H NMR ( 300 MHz, CD3OD) d 8.42 (m, 1), 7.96 (s, 1), 7.09 (m, 1), 5.27 (d, J = 5.4, 1), 4.10-4.87 (m, 3), 3.85 (d , J = 3.3, 1), 3.76 (m, 1), 2.11 (m, 4), 1.81 (m, 2), 1.49 (m, 4), 0.99 (m, g). MS (+ -IS METHOD): 428 [M + H] +. To a solution of pyridine 15b (R1 = Me, R2 = Me, R9 '= butyl) (200 mg, 0.46 mmol) in water (10 ml), AcOH (3 ml) and MeOH (2 ml), Pt02 (200 mg) was added and the resulting reaction mixture was stirred at 3.85 kg / cm2 of hydrogen overnight. The residual catalyst was removed by filtration through celite, and the solvent was removed to obtain the crude product. Purification was carried out by silica gel column chromatography using MeOH in 20% DCM to obtain the lincosamide 1 analogue (R 1 = Me, R 2 = Me, R 3 = H, R 9 = butoxy) (12 mg, %). 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.4, 1), 4.22 (dd, J = 10.2; 3.3, 1), 4.08 (m, 2), 3.81 (d, J = 3.0, 1), 3.70 (m, 1), 3.54 (m, 4), 3.43 (m, 2), 2.90 (m, 1) , 2.41 (m, 1), 2.19 (m, 1), 2.10 (s, 3) 1.45 (m, 6), 0.92 (m, 9); MS (ESPOS): 435 [M + H] +.

METHOD T Following the general method found in scheme 16, to a solution of P-lactam 16a (2.92 g, 12.8 mmoles) 1 equiv; prepared from (S) - (-) - 4-oxo-2-azetidine-benzylated carboxylate (Aldrich) described by Baldwin et al, Tetrahedron, 1990, 46, 4733 in THF (30 ml) at 0 ° C added a solution of LDA (2.0 M, 14.0 ml, 28.1 mmoles, 2.2 equiv) by a syringe pump 20 min. The reaction was stirred at 0 ° C for 30 min, crotyl bromide (85%, 2.89 ml, 28.1 mmol, 2.2 equiv) was added dropwise in about 1.5 min, and the mixture was stirred for 2 h at 0 °. C, and then partitioned between aqueous KHS0 1.0 M solution (100 ml) and EtOAc (100 ml). The organic layer was separated and washed with 1.0 M aqueous KHSO4 solution (100 ml), brine (100 ml), dried (MgSO), filtered and concentrated to give the product 16b (R9 '= 2-butenyl) 3.65 g (100%) of a yellow-green solid. This material was used without further purification. MS (ESNEG): 282.2 [M - H] \ Add (trimethylsilyl) diazomethane (2.0 M in Et20, . 0 ml, 50 mmol, 3.9 equiv) to a solution of 16b acid (R9 = 2-butenyl) (3.65 g, 12.9 mmol, 1 equiv) in methanol (70 ml) at 0 ° C. The solvent was removed in vacuo to give 3.53 g (11.9 mmol, 92%) of the desired ester product as a yellow oil. This material was used in the next reaction without further purification. To a solution of the alkene 16c (R9 '= 2-butenyl) (3.53 g, 11.9 mmol, 1 equiv) in EtOAc (40 mL) at 23 ° C was added Pd / C (10% by weight, 482 mg). The reaction vessel was charged with hydrogen (balloon), and the mixture was stirred vigorously. After 2.5 h, the reaction mixture was filtered through a pad of celite. The celite was washed with EtOAc (200 ml) and the filtrate was concentrated to give 3.51 g (11.7 mmol, 99%) of product 16c (R9 = butyl) as a yellow oil. This material was used without further purification. MS (ESPOS): 300.4 [M + H] +. To a solution of N-TBS-β-lactam 16c (R9 = butyl) (3.51 g, 11.7 mmol, 1 equiv) in THF (50 mL) at 23 ° C was added Et3N »3HF (0.95 mL, 5.85 mmol, 0.5 equiv). After stirring for 60 min at 23 ° C, the reaction mixture was partitioned between 90% safed brine (150 ml) and EOAc (200 ml). The organic layer was separated and washed with brine (150 ml), dried (MgSO), filtered and concentrated. The product was purified by column chromatography on silica gel using 50% EtOAc in hexane as eluent to give 1.48 g (8.0 mmol, 68%) of product 16d (R9 = butyl) as one of a clear oil. MS (ESPOS): 578.3 [3M + H] +. To a solution of ß-lactam 16d (R9 = butyl) (2.06 g, 11.1 mmol, 1 equiv) in THF (150 mL) at 23 ° C was added a solution of LiAIH4 (1.0 M in THF, 22.9 mL, 22.9 mmol , 2.06 equiv) by syringe in the course of 2 min. After stirring for 10 min at 0 ° C, the reaction was heated to 23 ° C, stirred for 15 min, and then heated to reflux for 3 h. The mixture was then cooled to 0 ° C and quenched by careful addition of H20 (1.0 ml), followed by 15% aqueous NaOH (1.0 ml), and then H20 (2.5 ml). The resulting suspension was stirred at 23 ° C for 1.5 h, diluted with Et20 (250 mL), and filtered through Celite, washing with Et20 (250 ml). The filtrate was concentrated to provide 1.42 g of the desired product 16e (R9 = butyl) (9.93 mmol, 89%) as a clear oil. The product was used without further purification. MS (ESPOS): 287.4 [2M + H] +. To a solution of the amino alcohol 16e (R9 = butyl) (1.41 g, 9.86 mmol, 1 equiv) in dichloromethane (50 ml) at 23 ° C was added Boc20 (2.59 g, 11. 9 mmol, 1.2 equiv). After stirring for 2 h at 23 ° C, the reaction mixture was concentrated. The product was purified by flash column chromatography on silica gel using EOM in 33% hexane as eluent to give 1.53 g (6.31 mmol, 64%) of product 16f (R9 = butyl) as a clear oil. MS (ESPOS): 266.0 [M + Na] +. To a solution of Nal04 (8.81 g, 41.2 mmol, 10 equiv) in H20 (60 ml) at 23 ° C was added RuCI3"xH20 (350 mg, catalytic amount) followed by a solution of the alcohol 16f (R9 = butyl) (1.00 g, 4.12 mmol, 1 equiv) in acetone (60 ml). The biphasic mixture was stirred for 30 min at 23 ° C, then extracted with EtOAc (250 mL), decanting the organic phase The aqueous residue was extracted with two more portions of EtOAc (2 x 150 mL). were treated with 2-propanol (75 ml) and stirred at 23 ° C. After stirring for 2 h, the mixture was filtered through Celite, washing with EtOAc (300 ml) The filtrate was concentrated to give 0.78 g of the desired product 16g (R9 = butyl) (3.04 mmol, 74%) as a dark oil The product was used without further purification MS (ESPOS): 280.0 [M + Na] +.

METHOD U Following the method shown in the general scheme 17, a solution of the alcohol 16f (R9 '= 2-methyl-2-buyenyl) (3.31 g, 13.0 mmol, 1 equiv) in DMF (100 ml) at 23 ° C was added imidazole (2.21 g, 32.5 mmol, 2.5 equiv) followed by TBSCI (2.93 g, 19.5 mmol, 1.5 equiv). The reaction was stirred for 35 min, and then quenched with MeOH (2.0 mL). After stirring for 5 min, the resulting mixture was partitioned between Et20 (500 ml) and H20 (400 ml). The organic layer was separated and washed with H20 (400 ml), brine (200 ml), dried (MgSO), filtered and concentrated to give the product 17a (R9 '= 2-methyl-2-butenyl), 4.13 g (11.2 mmol, 86%) of the desired product in the form of a clear oil. MS (ESPOS): 392.4 [M + Na] +.

A solution of intermediate 17a (R9 = 2-methyl-2-butenyl) prepared as described in method T (2.03 g, 5.50 mmol, 1 equiv) in dichloromethane (80 ml) at -78 ° C was treated with ozone (1.2 l / min) introduced through a gas dispersion tube until a blue color was observed (20 min). Then an oxygen stream (1.2 l / min) was passed through the reaction mixture to discharge the excess ozone. After 15 min, the oxygen flow was stopped and PPf.3 (2.16 g, 8.25 mmol, 1.5 equiv) was added. The reaction mixture was stirred at -78 ° C for 30 min, and then at 0 ° C for 15 min, and then heated to 23 ° C. After stirring for 10 min at 23 ° C, silica gel was added, and the resulting mixture was concentrated to dryness under vacuum to provide a fluid powder that was directly loaded onto a column of silica gel. Flash column chromatography using EOM in 30-33% hexane as eluent gave 1.52 g (4.42 mmol, 80%) of product 17b as a clear oil. MS (ESPOS): 398.0 [M + MeOH + Na] +. To a suspension of the Wittig salt (cyclopropylmethyltriphenyl phosphine) (1216 g, 3.06 mmol, 1.5 equiv) in THF (10 mL) at 0 ° C was added dropwise a solution of NaHMDS (1.0 M in THF, 3.06 ml, 3.06 mmol, 1.5 equiv) by syringe in the course of 1 min. The resulting solution was stirred for 20 min at 0 ° C and then treated with a solution of aldehyde 17b (700 mg, 2.04 mmol, 1 equiv) in THF (3.0 ml; 2 x 1.0 ml washout) transferred by cannula. After 15 min at 0 ° C, the reaction was heated to 23 ° C, stirred for a further 10 min and then quenched with saturated NH CI solution (30 ml). The resulting mixture was partitioned between Et20 (120 ml) and H20 (50 ml). The organic layer was separated and washed with brine (50 ml), dried (MgSO 4), filtered and concentrated. Flash column chromatography using 10% EtOAc in hexanes as eluent gave 588 mg (1.54 mmol, 76%) of product 17c (R9 '= 2- (3-cyclopropyl) -propen-1-yl) as an oil transparent. MS (Spores): 404.3 [M + Na] +. To a solution of TBS 17c ether (R9 '= 2- (3-cyclopropyl) -propen-1-yl) (190 mg, 0.50 mmol, 1 equiv) in THF (10 mL) at 23 ° C was added a solution of TBAF (1.0 M in THF, 0.55 ml, 0.55 mmoles, 1.1 equiv). The resulting solution was stirred for 40 min at 23 ° C and then partitioned between Et20 (50 ml) and H20 (50 ml). The organic layer was separated and washed with brine (50 ml), dried (MgSO 4), filtered and concentrated to give 133 mg (0.50 mmol)., 100%) of the product 17c (R9 '= 2- (3-cyclopropyl) -propen-1-yl) in the form of a clear oil. MS (ESPOS): 290.2 [M + Naf. To a solution of alkene 17c (R9 '= 2- (3-cyclopropyl) -propen-1-yl) (191 mg, 0.50 mmol, 1 equiv) in dioxane (5.0 ml) at 23 ° C was added dipotassium azodicarboxylate ( 973 mg, 5.01 mmol, 10 equiv) followed by the slow addition of an AcOH solution (573 μl, 10.0 mmol, 20 equiv) in dioxane (5.0 ml) over the course of 16 h by a syringe pump. After the addition was complete, the reaction was stirred an additional 6 h and then filtered through a sintered glass with the aid of Et20 (150 ml) to separate the precipitate. The resulting solution was washed with saturated aqueous NaHCO3 solution (2 x 100 ml), brine (80 ml), dried (MgSO), filtered and concentrated. The above procedure was repeated three times in the raw material obtained to give complete conversion to the alkene, yielding 183 mg (0.48 mmol, 96%) of the saturated product 17d (R9 = 3-cyclopropyl-propyl) in the form of a clear oil. MS (ESPOS): 406.0 [M + Na] +.

METHOD V Following the general method of Scheme 18, to a solution of the hydrochloride of compound 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-cis-n-Pr, and m = 2) (4.00 g, 9.90 mmol, 1 equiv) in THF (70 mL) at 23 ° C was added H20 (70 mL) followed by KHC03 (1.29 g, 12.9 mmol, 1.3 equiv), followed by (Boc) 20 (2.81 g, 12.9 mmoles, 1.3 equiv). After stirring for 5 h, the reaction mixture was partitioned between brine (200 ml) and EtOAc (300 ml). The organic layer was separated and washed with brine (150 ml), and dried (MgSO). The solvent was removed in vacuo and the crude product was purified using the Biotage® column chromatography system (40 + M cartridge, 40 mm ID x 150 mm) using a linear gradient (75% EtOAc / hexanes-100% EtOAc ) with 1.2 total liters of eluent at 50 ml / min to give 4.49 g of crude carbamate 18a (where R1 = R2 = Me, R3 = H, R9 = 4-cis-n-Pr, and m = 2) (8.91 mmoles, 90%). To a solution of carbamate 18a (in which R1 = R2 = Me, R3 = H, R9 = 4-cis-n-Pr, and m = 2) (7.99 g, 15.9 mmol, 1 equiv) in benzene (300 ml) at 23 ° C was added p-anisaldehyde dimethyl acetal (4.06 ml, 23.8 mmol, 1.5 equiv. ), followed by PPTS (199 mg, 0.79 mmol, 0.05 equiv). The reaction mixture was heated to reflux. After 4 h, a second portion was added of dimethylacetal of p-anisaldehyde (2.0 ml, 11.7 mmol, 0.74 equiv). After an additional 17 h, a third portion of p-anisaldehyde dimethylacetal (2.0 ml, 11.7 mmol, 0.74 equiv) was added. After the final addition, the reaction was refluxed an additional 3 h, and then cooled to 23 ° C and partitioned between EtOAc (300 ml) and H20 (300 ml). The organic layer was washed with saturated aqueous NaHC 3 solution (300 ml), brine (150 ml), dried (MgSO 4), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using 40% EtOAc in hexane as eluent to give acetal 18b (wherein R 1 = R 2 = Me, R 3 = H, R 9 = 4-cis-n- Pr, and m = 2), 7.00 g (11.3 mmol, 71%) of the desired product in the form of a white foam (ratio of diastereomers 1: 1). A small portion of the product was purified in a Biotage® column chromatography system (40 + S cartridge, 40 mm ID x 75 mm) using a linear gradient (5% EtOAc / hexanes-90% EtOAc / hexanes) with 1 , 2 liters of total eluent at 50 ml / min to separate the two diastereoisomers for characterization.

Diastereoisomer with high Rf: MS (ESPOS): 623.0 [M + H] +. Diastereoisomer with low Rf: MS (ESPOS): 623.0 [M + H] +. To a solution of alcohol 18b (in which R1 = R2 = Me, R3 = H, R9 = 4-cis-n-Pr, and m = 2) (3.00 g, 4.82 mmol, 1 equiv) in trimethyl-phosphate (60 ml) at 0 ° C was added pyridine (3.90 ml, 48.2 mmol, 10 equiv), followed by POCI3 (0.88 ml, 9.65 mmoles, 2 equiv) added over the course of 60 s. After the addition the reaction was maintained at 0 ° C for 2 h, and then triethylammonium bicarbonate buffer (1.0 M, pH 8.5, 40 ml) was carefully added to inactivate the reaction. Then H20 (60 ml) was added and the resulting mixture was stirred at 0 ° C for 30 min and then heated to 23 ° C. After stirring the inactivated reaction mixture for 2 h at 23 ° C, the volatiles were removed in vacuo with the aid of moderate heating with a water bath (40-45 ° C). The resulting product was dried azeotropically by coevaporation with DMF (3 x 100 ml), and then toluene (150 ml, bath temperature = 40-45 ° C) to provide 9.4 g of white solid. The crude product 18c (in which R1 = R2 = Me, R3 = H, R9 = 4-cis-n-propyl, R11 = PO (OH) 2 and m = 2) was substantially contaminated with triethylammonium salts, but was continued with it without purification. MS (ESNEG): 701.2 [M - H] -. To a solution of the protected phosphate 18c (in which R1 = R2 = Me, R3 = H, R9 = 4-cis-n-propyl, R11 = PO (OH) 2 and m = 2) prepared as described above (9.4 g, crude from the previous step, approximately 4.8 mmol) in 1, 2- Dichloroethane (600 ml) at 0 ° C was added H20 (25 ml) followed by TFA (200 ml). After the additions, the reaction was maintained at 0 ° C for 5 min and then heated to 23 ° C. After stirring for 25 min at 230 ° C, the volatiles were removed in vacuo to give 16.2 g of oil. The crude product was dissolved in H20 / MeOH 1: 1 (70 ml), filtered and the solution The resulting product was purified by preparative HPLC (Aguas Nova-Pak® HR C? 8, particle size 6 μm, pore size 60 A, 40 mm ID x 200 mm, acetonitrile at 5-60% H20 / 0.1% AcOH). 30 min, flow 75 ml / min) to give 1497 g of the desired phosphate 5 (where R1 = R2 = Me, R3 = H, R9 = 4-cis-n-propyl, R11 = PO (OH) 2) ( 3.10 mmole, 64% from free alcohol) in the form of a white solid.

METHOD W Following the general method indicated in Scheme 19, amino acid 19a (R12 = H) (Aldrich) (1.0 g, 8.7 mmol) suspended in MeOH (5 ml) and 2,2-dimethoxypropane (15 ml) was added concentrated HCl ( 1.0 ml), and the mixture was stirred 12 ha The solvents were removed in vacuo, and the residue was triturated with Et20 and coevaporated with dry toluene to give the crude methyl ester as a bone-colored solid which was used without further purification. To a suspension of the methyl ester of 1-allyl glycine in dichloroethane (32 ml) at 0 ° C was added 2,4,6-collidine (2.3 ml, 19.1 mmol, 2.2 equiv) and solid 2-nitrobenzenesulfonyl chloride. The reaction was stirred for 3 h at t.a. The solvent was removed in vacuo and the residue was partitioned between EtOAc (200ml) and saturated aqueous NH 4 Cl solution. The organic layer was washed with 1 M aqueous KHSO 4 solution, saturated aqueous solution of NaHC03, brine, and dried (MgSO), and concentrated to give a residue which was purified by column chromatography on silica (10 to 20% EtOAc / hexanes gradient) to give the desired product 19b (R12 = H) 0.70. g (26%) in the form of a yellow oil. 1 H NMR (300 MHz, CDC13) d 8.10-8.06 (m, 1), 7.95-7.92 (m, 1), 7.76-7.73 (m, 2), 6.08 (d, J = 8.2, 1), 5.74-5.60 (m, 1), 5.17-5.12 (m, 2), 4.33-4.26 (m, 1), 3.52 (s, 3), 2.58 (dd, J = 6.0, 6.0, 1), 3.44-3.30 (m, 2), 2.25-2.10 (m, 2), 2.11 (s, 3), 2.00-1.88 (m, 1), 1.86-1.70 (m, 1), 1.44-1.25 (m, 6), 0.98-0.88 ( m, 9 H). MS (ESNEG): 313.0 [M-H] ". To a stirred suspension of sulfonamide 19b (R12 = H) (685 mg, 2.18 mmol), CS2C03 (710 mg, 2.18 mmol), and tetrabutylammonium bromide (702 mg , 2.18 mmoles), in DMF (5.0 ml) was added a solution of 3-methylenehex-1-yl-toluenesulfonate (702 mg, 2.61 mmol, prepared as described by Kelvin H. Yong et al., Journal of Organic Chemistry, 2001, 66 , 8248) in DMF (1.0 ml), the reaction mixture was heated at 60 ° C overnight, the reaction solvent was removed by evaporation, the resulting residue was taken up in EtOAc and washed with aqueous citric acid solution. to 10% and brine, the organic phase was dried over MgSO4, concentrated to give a residue which was purified by chromatography on a silica column (17% -20% EtOAc / hexanes) to give the desired product 19c (R12 = H, R13 = propyl), (0.38 g, 42%) in the form of an oil EM (SPOS): 433 [M + Naf. To a solution of 19c (R12 = H, R13 = propyl) (0.38 g, 0.92 mmol) in anhydrous DCM (40 ml) was added benzylidene [1,3-bis (2,4,6-dimethyl-phenyl) -2-imidazolidinylidene] dichloro- (idricylohexylphosphine) ruenium (23.3 mg, 0.0276 mmol). The resulting reaction mixture was heated under reflux under N2 for 2.5 h, cooled to room temperature and concentrated. The product was purified by flash column chromatography on silica gel (35% ethyl acetate / hexanes) to give the desired compound 19d (R12 = H, R13 = propyl) (0.29 g, 81%). MS (ESPOS): 383 [M + Na] +. To a stirred solution of thiophenol (183 μl, 1.79 mmol) and 7-methyl-1, 5,7-triazabicyclo- [4,4,0] -dec-5-ene (214 μl, 1.49 mmol) in anhydrous DMF ( 3 ml) was added a solution of alkene 19d (R12 = H, R13 = propyl) (228 mg, 0.596 mmol) in anhydrous DMF (3.0 ml) via a cannula. After mixing the solutions a color change to yellow was observed, the resulting reaction mixture was stirred under N2 for one hour and then concentrated to a residue. The residue was taken up in ether, stirred with 1 N aqueous HCl (15.0 ml) for 5 min. The aqueous phase was washed with ether and then made basic with solid potassium carbonate. The resulting basic aqueous phase was extracted three times with ether. The combined organic layers were washed with brinewere dried with anhydrous sodium sulfate, concentrated, cooled to 0 ° C, treated with HCl in 2M ether (0.8 ml), and the mixture was stirred for 5 min. and then evaporated to dryness to give the product. desired 19d (R12 = H, R13 = propyl) in the form of the hydrochloride salt (144 mg, 103%). MS (ESPOS): 198 [M + H] +. To a solution of the 19d amine (R12 = H, R13 = propyl) (143 mg, 0.61 mmol) in anhydrous dichloromethane (2.0 ml) was added triethylamine (170 μl, 1.22 mmol) and di-t-butyl dicarbonate (350 mg, 1.6 mmol). The resultreaction mixture was stirred overnight at room temperature under N2 and then evaporated to dryness and purified by flash column chromatography on silica gel us20% ethyl acetate in hexanes as eluent to give the compound desired 19e (R12 = H, R13 = propyl) (176 mg, 86%). MS (Spores): 320 [M + Na] +. To a solution of ester 19e (R12 = H, R13 = propyl) (175 mg, 0.59 mmol) in dioxane / water (61) (4 mL) was added 1M aqueous lithium hydroxide (0.65 mL, 0.648 mmol). The resultreaction mixture was stirred overnight at room temperature under N2 and the solvent was removed under reduced pressure. The residue was taken up in water and washed with ether. The aqueous layer was acidified with 10% citric acid and extracted with ether. The organic layer was washed with brine, dried with sodium sulfate, and evaporated to dryness to give the desired protected cyclic amino acid 19f (R12 = H, R13 = propyl) (175 mg, 105%).

MS (ESNEG): 292 [M-H] ".

METHOD X As shown in the following Scheme 20, suitable amino esters 209 n = 1.2 can be coupled with pseudoephedrine which serves as a chiral auxiliary, allowing stereospecific alkylation of carbon a with a suitable allyl bromide 20e. Protection of the secondary amine followed by the olefin metathesis and cleavage of the chiral auxiliary leads to N-protected 4,5-unsaturated cyclic amino acids 201. The reduction of 2-carboxylic acid to a hydroxymethyl allows stereospecific trans-reduction of unsaturation in 4.5, which leads to 20n. Reoxidation of the hydroxymethyl to a carboxylic acid in which R12 or R13 can be R9 as defined in Formula I. 2 ° * 20b 20c 20C "^ OH - _.Br 20m 2 &20o SCHEME 20 Stereospecific general synthesis of trans-alkylpiperidine-2-carboxylic acids (n = 1) and trans-algalazapine-2-carboxylic acids (n = 2) The following reaction scheme can be used to prepare trans-alkylpiperidine-2-carboxylic acids and trans-alkylazapine-2-carboxylic acids: (a) NaH, DMF; R-Br, 65 ° C; (b) 1M aqueous KOH, EtOH, 80 ° C; (c) CH20, piperidine, EtOH, 80 ° C; (d) DIBALH, CH2Cl2, -50 ° C; (e) PBr3, pyridine, Et20, 0 ° C; (f) ethyl bromoacetate, Et20, 23 ° C; (g) 4.0 M HCl in dioxane, Et20, hexane, 23 ° C; (h), (1R, 2R) - (+ pseudoephedrine, t-BuOLi, THF, 23 ° C; (i) LiHMDS, LiCl, THF, 0 ° C; G) (Boc) 20, Et3N, CH2Cl2, 23 ° C; (k) benzylidene [1, 3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro- (1-cyclohexylphosphine) -ruthenium, CH 2 Cl 2, 23 ° C; (1) NaOH aq. 1 M, MeOH, 70 ° C; (m) (i) sobutyl chloroformate, 4-methylmorpholine, DME, -15 ° C, (ii) NaBH4, H20, 0 ° C; (n) H2, lrCODIPyPCy3.PF6, CH2Cl2, 23 ° C; (o) RuCI3.xH20, Nal04, acetone, H20, 23 ° C. As shown in Scheme 20, suitable amino esters 20g n = 1.2 can be linked with pseudoephedrine which serves as a chiral auxiliary allowing stereospecific alkylation of carbon a with an allylic bromide 20e. Protection of the secondary amine followed by the olefin metathesis and cleavage of the chiral auxiliary leads to N-protected 4,5-unsaturated cyclic amino acids 201. The reduction of 2-carboxylic acid to a hydroxymethyl allows stereospecific trans-reduction of the unsaturation in 4.5, which leads to 20n. The reoxidation of the hydroxymethyl to a carboxylic acid in which R12 or R13 may be R9 as defined in the general structure.

METHOD AND Following the general reaction scheme 21, a rapidly stirred solution of the 1-tert-butyl ester of 4-oxo-piperidine-1,2-dicarboxylic acid 21a (m = 2, P = H, P2 = Boc) (16.0 g , 0.066 moles) (prepared by the method described by Bousquet et al., Tetrahedron, 1997, 53, 15671) in DMF (200 ml) was treated with solid cesium carbonate (10.7 g, 0.033 moles) and methyl iodide (4.5 ml. , 0.072 moles). The reaction mixture was stirred 5 h, diluted with EtOAc and extracted with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and brine, the organic layer was separated and dried over sodium sulfate, filtered and evaporated to dryness. The product obtained by removing the solvent was dried azeotropically by evaporation with benzene to give 14.8 g (98%) of the desired product 1-tert-butyl ester and 2-methyl ester of 4-oxo-p-perid Na-1,2-dicarboxylic acid 21a (m = 2, P = Me, P2 = Boc) as an oil: TLC Rf 0.53 (Hexanes / EtOAc, 1: 1): 1 H NMR (300 MHz, CDCl 3) d 5.33 (broad m, 0.5) rotamer, 5.06 (broad m, 0.5) rotamer, 4.31-4.19 (m, 1), 3.95 (s, 3), 3.95-3.70 (m, 1), 3.16-2.97 (m, 2) ), 2.71 (m, 2), 1.68 (broad s, 9). A solution at 0 ° C of the ester of 1-tert-butyl ester and 2-methyl ester of 4-oxo-piperidine-1,2-dicarboxylic acid 21a (m = 2, P = Me, P2 = Boc) (5.17 g , 0.02 mole) in DCM (60 ml) was treated with tetraalyl-tin (Aldrich) (5.3 ml, 0.022 mole) followed by the dropwise addition of BF3 * OEt2 (2.5 ml, 0.02 mole). The reaction mixture was stirred 1 h, and then 1 M potassium fluoride (38.0 ml) and celite (5 g) were added and the reaction mixture was stirred 3 h. The reaction mixture was filtered and concentrated drynessThe residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and evaporated to dryness. The obtained residue was purified by silica gel column chromatography (100% DCM to DCM: acetone 9: 1) to provide 3.85 g (64%) of the desired product 1-tert-butyl ester and ethyl ester. 2-methyl 4-allyl-4-hydroxy-piperidine-1,2-dicarboxylic acid 21 b (m = 2, P = Me, P2 = Boc, R9 '= allyl) in the form of an oil. or 1 H NMR (300 MHz, CDCl 3) d 6.11-5.97 (m, 1), 5.42-5.32 (m, 2), . 06 (broad d, J = 6.0, 0.5) rotamer, 4.87 (broad d, J = 6.0, 0.5) rotamer, 4.18-4.03 (m, 1), 3.93 (s, 3), 2.48-2.37 (m, 2) , 1.98-1.43 (m, 11); MS (ESPOS): 322.0 [M + Na] +. A stirred suspension of product 21b (m = 2, P = Me, P2 = Boc, R9 '= allyl) (3.80 ml, 1.27 mmole) and 10% Pd / C (Degussa wet form at 50% w / w) (1.35 g, 1.3 mmol) in MeOH (80 ml) was stirred 6 h with 1 atm of hydrogen. The reaction mixture was filtered through celite and evaporated to dryness and dried azeotropically by evaporation with toluene, and the obtained residue (3.15 g) was used in the next step without further purification. To a stirred solution at -78 ° C of DAST (1.7 mL, 1.3 mmol) in DCM (50 mL) was added 1-tert-butyl ester and 2-methyl ester of 4-hydroxy-4-propyl- piperidine-1, 2-dicarboxy in DCM (30 ml). Then, the reaction mixture was stirred for 1 h, and then allowed to warm to -40 ° C for 5 h. Additional DAST (0.4 ml) was added and the reaction mixture was stirred an additional 2 h, saturated aqueous K2C03 solution (20 ml), and water (60 ml) were added followed by diethyl ether (500 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to dryness. The crude fluorinated product was purified by column chromatography on silica gel (hexanes-EtOAc 9:11). The residue obtained by chromatographic purification was dissolved in dioxane (65 ml) and water (26 ml), cooled to 0 ° C, and treated with OS04 (0.65 ml, 4% strength aqueous solution) and 30% H202 ( 10 ml). The reaction mixture was stirred overnight and concentrated to dryness. The residue was dissolved in DCM and the organic layer was washed with water (100 ml), ac solution. Na2SO3 to 25% (2x 100 ml), and brine (100 ml), dried over Na2SO4 and evaporated to dryness. The obtained residue was purified by silica gel column chromatography (hexanes-EtOAc 9: 1) to provide (1.08 g, 34%) of the desired product, the 1-tert-butyl ester and 2-methyl ester of the acid 4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid 21c (m = 2, P = Me, P2 = Boc, R9 = H-propyl) in the form of an oil. 1 H NMR (300 MHz, CDCl 3) d 4.59 (dd, J = 6.0, 6.0, 1), 3.82-3.69 (m, 1), 3.74 (s, 3), 3.28 (m, 1), 3.29-2.04 (m , 2), 1.91-1.71 (m, 3), 1.60-1.31 (m, 6), 1.45 (s, g), 0.92 (t, J = 7.1, 3); MS (ESPOS): 204.1 (M + H-Boc), 326.3 [M + Na] +. A stirred solution of the product 21c (m = 2, P2 = Boc, R9 = n-propyl) (1.06 g, 3.47 mmol) in dioxane-water 6: 1 (42 ml) was treated with lithium hydroxide aq. 1.0 M (5.3 ml, 5.3 mmol). The reaction mixture was stirred at room temperature overnight, treated with aq. 1. 0 M (1.5 ml), and the resulting reaction mixture was stirred 5 h. The reaction solvent was removed, the residue was taken up in ethyl acetate (500 ml), washed with 10% citric acid and brine and dried over MgSO4.

The concentration of the organic solution gave the desired product the 1-tert-butyl ester of 4-fluoro-4-propyl-p-peridine-1,2-dicarboxylic acid 21 d (m = 2, P2 = Boc, R9 = n-propyl) (0.88 g, 87%) as a white solid. 1 H NMR (300 MHz, CDCl 3) d 4.59 (dd, J = 6.0, 6.0, 1), 3.82-3.69 (m, 1), 3.74 (s, 3), 3.28 (m, 1), 3.29-2.04 (m , 2), 1.91-1.71 (m, 3), 1.60-1.31 (m, 6), 1.45 (s, 9), 0.92 (t, J = 7.1, 3); MS (ESNEG): 288.4 [M-H] ".

EXAMPLE 1 Preparation of 4-ethyl-piperidine-2-carboxylic acid r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -prop-p-amide The HCl salt of 4-ethyl-pyridine-2-carboxylic acid (Toronto) (117 mg, 0.64 mmol) was suspended in dry acetonitrile (4 mL). Triethylamine (180 μL, 1.28 mmol) was added and the reaction mixture was cooled to 0 ° C. Isobutyl chloroformate (129 μL, 0.62 mmol) was added and the reaction mixture was heated to 4 ° C. After 1.5 h the activated ester solution was transferred to a solution of product 2b (R1 = Me, R2 = Me), prepared as in Method C, in acetone / water 1: 1 (2 ml), and heated to 30 ° C for its dissolution. Then triethylamine (80 μl) was added, 0.057 mmole) to the reaction mixture. The reaction mixture was stirred for 10 h at rt, and then evaporated to dryness and chromatographed on silica with dichloromethane: ammonia in 0.25% methanol 94: 5 to give the product 111b (R1 = Me, R2 = Me R3 = H , R9 = ethyl) (167 mg 69.7%). MS (ESPOS): 385.2 [M + H] +. A solution of pyridine 11b (m = 2, R1 = Me, R2 = Me R3 = H, R9 = ethyl) (167 mg, 0.435 mmoies) in methanol / water 3: 2 (20 ml) was added to platinum oxide (IV) (339 mg, 0.521 mmol) in a Parr bottle. Concentrated HCl (52 μL, 0.52 mmol) was then added. The bottle was purged and charged with H2 at 4.55 kg / cm2 and stirred for 24 h. The reaction mixture was filtered through celite and rinsed with methanol. The combined filtrates were evaporated to dryness and chromatographed on silica with dichloromethane: ammonia in 0.25% methanol from 88:12 to 80:20 to give 43 mg of a high Rf product and 49 mg of a mixed fraction. Chromatography of the low Rf fraction in fluorosil with dichloromethane: ammonia in 0.25% methanol from 84:16 to 80:20 gave [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan! 4-ethyl-piperidine-2-carboxylic acid tetrahydro-pyrn-2-yl) -propyl] -amide (21.9 mg, 12.9%), which was taken up in acetonitrile: water 1: 1 (50 ml ), filtered with Millipore of 0.2 μ, and cooled to 0 ° C. 1 N HCl (67 μl) in water (20 ml) was added and re-lyophilized to give the HCl salt (24.0 mg) as a colorless powder. 1 H NMR (300 MHz, D20) d 5.32 (d, J = 5.8, 1), 4.14-4.06 (m, 1), 4.12 (s, 2), 3.85 (d, J = 3.30, 1), 3.60 (dd) , J = 3.3, 10.4, 1), 3.30 (dd, J = 2.5, 11.8, 1), 3.09 (m, 1), 2.56 (ddd, J = 2.8, 12.9, 15.7, 1), 2.14 (s, 3 ), 2.14-2.05 (m, 1), 1.96-1.90 (m, 1), 1.74-1.69 (m, 1), 1.45-1.35 (m, 1), 1.33-1.23 (m, 2), 1.08-0.98 (m, 2), 0.86 (m, g); MS (ESOP): 391.4 [M + H] +, 803.5.4 [2M + Na], (ESNEG): 389.5 [M-H] \ EXAMPLE 2 Preparation of the 1-methyl-4-propyl-pyrrolidine-2- r 2 -methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-p-amide carboxylic The 4-n-propylhydric acid prepared by the method of Hoeksema, H. et. to the. Journal of the American Chemical Society, 1967, 89-2448-2452 (157 mg, 0.76 mmol) was suspended in dry acetonitrile (5 ml).

Triethylamine (421 μL, 3.02 mmol) was added and the reaction mixture was cooled to 0 ° C. Isobutyl chloroformate (98 μL, 0.76 mmol) was added and after 10 min the reaction was allowed to warm to 4 ° C. After 1.5 h, a solution of the product 21 b (R1 = Me, R2 = Me), of Method C (190 mg, 0.76 mmol) in acetone: water 1: 1 (5 ml) was added and the reaction mixture stirred for 10 ha The reaction mixture was evaporated to dryness and chromatographed on silica with dichloromethane: ammonia in 0.25% methanol 94: 6. Fractions 14-18 contained the product as a colorless oil (50.2 mg, 16.5%). 1 H NMR (300 MHz, D20) d 5.33 (d, J = 6.0, 1), 4.27-4.22 (m, 1), 4.18 (s, 1), 4.09 (dd, J = 5.8, 10.2, 1), 3.92 -3.81 (m, 1), 3.92-3.81 (m, 1), 3.64-3.59 (m, 1), 2.92 (s, 3), 2.92-2.85 (m, 1), 2.35-2.28 (m, 3) , 2.13 (s, 3), 1.46-1.41 (m, 2), 1.40-1.28 (m, 2), 0.89-0.84 (m, g); MS (ESPOS): 405.5 [M + H] \ EXAMPLE 3 Preparation of 1-methyl-4-propyl-3-methyl-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide pyrrolidine-2-carboxylic acid Lincosamine 2b (R1 = Me, R2 = CH2CN) (54.2 mg, 0.20 mmol) prepared by Method E was dissolved in DMF (0.7 ml). The reaction mixture was cooled to 0 ° C and triethylamine (170 μL, 1.2 mmol) and BSTFA (96 μL, 0.36 mmol) were added. The reaction mixture was allowed to warm to t.a., and was stirred at t.a. for 1 h. 4-n-propylhydric acid prepared by the method of Hoeksema, et al., J. Am. Chem. Soc, 1967, 89 2448-2452 (66.4 mg, 0.32 mmol) and HATU (149 mg, 0.39 mmol) were added. , and the mixture was stirred at for 3 h. The DMF was removed and the residue was dissolved in DCM (100 ml), washed with saturated NaHC 3 solution (30 ml) and brine (30 ml), and dried over sodium sulfate. The residue obtained by removing the solvent was dissolved in methanol (20 ml) and treated with Dowex H + resin (300 mg) for 15 min. The crude material was eluted from the resin by washing with TEA in 5% MeOH (25 ml x 15 min x 2) and TEA in 5% MeCN (25 ml x 15 min). The combined eluates were evaporated to dryness and purified by silica gel column chromatography using NH3 in 0.25M methanol in 7% dichloromethane as eluent (24 mg, 28%). 1 H NMR (300 MHz, D20) d 5.61 (d, J = 5.8, 1), 4.59 (d, J = 10.2, 1), 4.46 (d, J = 10.2, 1), 4.46 (dd, J = 6.0, 10.4, 1), 4.05 (d, J = 3.0, 1), 3.84 (dd, J = 3.3, 10.4, 1), 3.48 (dd, J = 5.8, 8.0, 1), 3.34 (dd, J = 5.2, 10.2, 1) 2.81-2.61 (m, 2), 2.65 (s, 3), 2.43 (s, 3), 2.31-2.10 (m, 2), 1.32 (d, J = 6.0, 1), 1.18 (t , J = 7.1, 3); MS (ESPOS): 430.5 [M + H] + MS (Spores): 428.5 [M-H] ".

EXAMPLE 4 Preparation of 4-ethyl-piperidine-2-carboxylic acid r2-hydroxy-2-methyl-1- (314,5-trihydroxy-6-methylsulfanyl tetrahydro-pyran-2-yl) -propin-amide 3b (R1 = Me, R2 = Me) prepared by Method F (54.2 mg, 0.20 mmol) was dissolved in DMF (1.0 ml). The reaction mixture was cooled to 0 ° C and triethylamine (178 μL, 1.3 mmol) and BSTFA (85 μL, 0.32 mmol) were added. The reaction mixture was allowed to warm to t.a., and was stirred for 1 h. The HCl salt of 4-ethyl pyridine-2-carboxylic acid (Toronto) (55.3 mg, 0.29 mmol) and HATU (122 mg, 0.32 mmol) were added, and the mixture was stirred at t.a. for 3 h. The DMF was separated and the residue was dissolved in THF (10 ml) and treated with Amberlite A-26 form F "(600 mg) and catalytic TBAF for 5 h.The crude product was obtained by separation of the resin and evaporation of the resin. solvent to dryness and purified by silica gel column chromatography using NH3 in 0.25 M methanol in 10% dichloromethane as eluent to give the pyridine product 11 b (m = 2, R = Me, R2 = Me R3 = OH , R9 = ethyl) (26 mg, 33%). MS (ESNEG): 399.5 [MH] ".

A solution of pyridine 11b (m = 2, R1 = Me, R2 = Me R3 = OH, R9 = ethyl) (26 mg, 0.065 mmol) in methanol: water 3: 2 (10 ml) was added to platinum oxide (IV) (51 mg) in a Parr bottle. Then concentrated HCl (6.0 μl, 0.072 mmol) was added. The bottle was purged and charged with H2 at 4.55 kg / cm2 and stirred for 24 h. The reaction mixture was filtered through celite and rinsed with methanol. The combined filtrates were evaporated to dryness and chromatographed on silica with dichloromethane: ammonia in 0.25% methanol 80:20 to give a product with high Rf and the title compound (5.8 mg, 21.8%). 1 H NMR (300 MHz, D20) d 5.37 (d, J = 6.0, 1), 4.41 (d, J = 9.6, 1), 4.32 (d, J = 9.3, 1), 4.08 (dd, J = 6.6, 11.0, 1), 3.93-3.90 (m, 2), 3.59 (dd, J = 3.0, 10.7, 1), 3.93 -3.90 (m, 2), 3.04 (t ap dt, J = 7.1, 14.6, 14.6, 1), 2.24-2.18 (m, 1), 2.20 (s, 3), 1.70-1.60 (m, 1), 1.42-1.13 (m, 1), 0.88 (dd, J = 6.0, 7.4, 1); MS (ESPOS): 407.4 [M + H] +.

EXAMPLE 5 Preparation of the f-hydroxyimino-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide of 1-methyl-4-propyl-pyrrolidine-2-acid carboxylic Triethylamine (0.041 ml, 0.28 mmol) and BSTFA were added (0.24 ml, 0.94 mmole) to the crude oxime 4b (R1 = Me, R7 = H) prepared by the Method G (50 mg, 0.19 mmol) in DMF (3 mL) at 0 ° C and the mixture was stirred at r.t. all night. Then, 4-n-propylhydric acid (63 mg, 0.37 s mmoles) and HATU (142 mg, 0.37 mmoles) were added and the mixture was stirred at t.a. for 4 h. The DMF was separated and the residue was extracted with dichloromethane (100 ml) and washed with saturated bicarbonate solution (20 ml) and brine (20 ml). The residue obtained by removing the dichloromethane was then treated with TFA in 10% dichloroethane (10 ml) and dimethyl sulfide (0.5 ml) for 1 h. Then 0 the solvent was removed to obtain the crude product, which was purified by silica gel column chromatography using 20% methanol in dichloromethane as eluent to give the title compound (20 mg, 25%). TLC: Rf = 0.67 (methanol in 20% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 0.93 (t, J = 6.8, 3), 1.31-1.44 (m, s 4), 1.88 (s, 3), 1.99 (s, 3), 2.09 (m, 2) , 2.11 (m, 1), 2.62-2.98 (m, 3), 2.76 (s, 3), 3. 60 (m, 2), 4.10 (dd, J = 5.7, 10.20, 1), 4.27 (d, J = 9.6, 1), 5.23 (d, J = 5.5, 1), MS (SPOS): 420 [M + H] '.

EXAMPLE 6 Preparation of the 1-methyl-4-propyl-pyrrolidine-r2-methoxyimino-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-p-amide 2- carboxylic The title compound was prepared from the oxime product Crude 4b prepared by the method H (R1 = Me, R7 = Me), as in Example 5 (10 mg, 47%). TLC: Rf = 0.55 (methanol in 10% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 0.91 (m, 3), 1.32 (m, 4), 1.88 (s, 3), 1.98 (s, 3), 1.78-2.04 (m, 2), 2.34 (s, 3), 2.90 (dd, J = 5.1, 6.30, 8.10, 1), 3.21 (dd, J = 6.3, 10.2, 1), 3.57 (dd, J = 3.3, 10.2, 1), 4.23 (dd, J = 5.4, 10.2, 1), 5.25 (d, J = 5.7, 1); MS (ESPOS): 434 [M + H.

EXAMPLE 7 Preparation of 5-butyl-piperidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide The intermediate lincosamine 2b (R1 = Me, R2 = Me), prepared by ei Method C, was dissolved in DMF (2 ml). Triethylamine (80 mg, 1 mmol) and BSTFA (307 mg, 1.1 mmol) were added, and the reaction mixture was stirred at r.t. for 1.5 h. Then fusaric acid (143 mg, 0.7 mmol) was added and HATU (184 mg, 0.5 mmol), and the reaction mixture was stirred at r.t. for 3 h. The DMF was separated and the residue was dissolved in EtOAc (50 ml), washed with sodium bicarbonate (10%, 30 ml) and brine (30 ml), and dried over sodium sulfate. The residue obtained by removal of the solvent was dissolved in methanol and treated with Dowex H + resin for 1 h. The crude product obtained by filtering the resin and removing the solvent was purified by column chromatography on silica gel using 10% methanol in dichloromethane as eluent to give the title compound (100 mg, 61%). TLC Rf = 0.6 (methanol in 10% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 8.47 (s, 1), 8.02 (d, J = 8.1, 1), 7.80 (d, J = 8.1, 1), 5.27 (d, J = 5.4, 1), 4.31 (m, 2), 4.12 (dd, J = 5.7, 4.2, 1), 3.85 (d, J = 3.0, 1), 3.56 (dd, J = 3.3, 6.9, 1), 2.80 (m, 2), 2.24 (m, 1), 2.11 (s, 3), 1.67 (m, 2), 1.41 (m, 2), 1.00 (m, 9); MS (ESPOS): 413 [M + H] +. Pt02 (50 mg, 0.22 mmol) was added to compound 11b (m = 2, R1 = Me, R2 = Me, R3 = H, R9 = butyl), (70 mg, 0.16 mmol) in methanol (2 ml), water (10 ml), and acetic acid (3 ml), and the mixture was hydrogenated at 3.5 kg / cm2 overnight. The product obtained after filtering the catalyst and removing the solvent was purified by silica gel column chromatography using 30% methanol in dichloromethane as eluent to give the title compound (16 mg, 46%). TLC Rf = 0.7 (methanol in 30% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.16 (m, 3), 3. 82 (d, J = 3.3, 1), 3.53 (m, 2), 2.93 (m, 2), 2.09 (s, 3), 1.93 (m, 1), 1.76 (m, 2), 1.50 ( m, 1), 1.30 (m, 7), 0.92 (m, 9); MS (ESPOS): 419 [M + H] +.

EXAMPLE 8 Preparation of 4-pentyl-pyrroMdine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide Triethylamine (0.2 ml, 1.44 mmol, 3.6 equiv) was added, followed by BSTFA (0.2 ml, 0.76 mmol, 1.9 equiv), to a stirred suspension of product 2b (R1 = Me, R2 = Me) prepared by Method C ( 100.4 mg, 0.4 mmol, 1 equiv) in anhydrous DMF (2 ml) at 0 ° C and under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The resulting solution was cooled to 0 ° C and a solution of the product 6c (R9 = pentyl) was added (Scheme 6) prepared as described by Birkenmeyer, R. D; et al; Journal of Medicinal Chemistry 1972, 15, 1255-1259, (144 mg, 0.51 mmol, 1.2 equiv) in anhydrous DMF (1.5 ml), followed by HATU solid. The reaction mixture was allowed to warm to t.a. and after 2 h the reaction solution was evaporated to dryness in vacuo. The residual oil obtained was diluted with EtOAc (150 ml), washed sequentially with 10% citric acid (2 x 30 ml), saturated aqueous solution of NaHC 3, water 1: 1 (2 x 30 ml), and brine (30 ml), dried over Na2SO4, and evaporated to dryness. 1,2-Dichloroethane (8 ml) was added, followed by dimethyl sulfide (180.3 μl), TFA (2.7 ml), and water (180.3 μl) to the crude product (267.5 mg) obtained above. The resulting mixture was stirred at t.a. for 1 h and evaporated to a minimum volume, diluted with DCE (3 x 30 ml), and evaporated to dryness. The obtained residue was purified by chromatography on silica gel, with an eluent with gradient of ammonia in 8-10% methanol in dichloromethane. The desired fractions were combined, evaporated to dryness, and lyophilized to provide the title compound as a white fluffy powder (35.6 mg, 21.2%).

TLC, Rf = 0.15 (ammonia in 0.25 M methanol in 16% dichloromethane). H-NMR (300MHz, D20) d 5.4 (d, J = 5.8, 1), 3.91 (s, 1), 3.69-3.66 (m, 3), 2.1 (s, 3), 1.32-1.15 (m, 3.37) , 0.93-0.87 (m, 9.8); MS (ESPOS): 419.5 [M + H] +, (ESNEG): 417.45 [M-H] ".

EXAMPLE 9 Preparation of 4- (3-Methyl-butyl) -pyrrolidine- [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydropyran-2-yl-propylamide of 4- (3-Methyl-butyl) -pyrrolidine- 2- carboxylic Triethylamine (0.13 ml, 0.96 mmol, 3.2 equiv) was added, followed by BSTFA (0.12 ml, 0.45 mmol, 1.5 equiv), to a solution of product 2b (R1 = Me, R2 = Me) prepared by Method C (75 mg, 0.30 mmol, 1 equiv) in dry DMF (0.8 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. To the reaction mixture was added 7d (R9 = 2-methylbutyl), prepared by Method J (160 mg, 0.56 mmol, 1.9 equiv), in a 25 ml round bottom flask. Then, HATU (227 mg, 0.60 mmol, 2 equiv) was added. The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (100 ml), washed with 10% citric acid (2 x 60 ml), water (60 ml), half-saturated solution of NaHCO 3 (60 ml), and brine. The organic layer was dried over Na 2 SO and evaporated to give a yellow syrup. Trifluoroacetic acid (5 ml) and water (0.33 ml) were added to a solution of the above syrup in dichloromethane (15 ml) with dimethyl sulfide. (0.33 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give the title compound (75 mg, 60%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.4, 1), 4.18-3.99 (m, 4), 3.75 (d, J = 2.4, 1), 3.51 (dd, J = 3.3, 10.5, 1), 3.38-3.31 (m, 1), 2.68 (dd, J = 8.2, 10.6, 1), 2.23-2.05 (m, 3), 2.10 (s, 3), 1.97-1.87 (m, 1), 1.59-1.47 (m, 1), 1.46-1.34 (m, 2), 1.25-1.16 (m, 2), 0.92-0.88 (m, 12). MS (ESPOS): 419.5 [M + H] +, MS (ESNEG): 417.5 [M-H]. " EXAMPLE 10 Preparation of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide Triethylamine (0.6 ml, 4.33 mmol, 3.6 equiv) was added, followed by BSTFA (0.6 ml, 2.27 mmol, 1.9 equiv), to a stirred suspension of product 2b (R1 = Me, R2 = Me) prepared by Method C ( 298.8 mg, 1.19 mmol, 1 equiv) in anhydrous DMF (5 ml) at 0 ° C and under a nitrogen atmosphere.

The resulting reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The resulting solution was cooled to 0 ° C and a solution of the product 7d (R9 = n-pentyl) prepared by the K method (400.1 mg, 1. 40 mmoles, 1.2 equiv) in anhydrous DMF (5 ml), followed by solid HATU (678.7 mg, 1.79 mmol, 1.5 equiv). The reaction mixture was allowed to warm to t.a. and after 2 h the reaction solution was evaporated to dryness in vacuo. The residual oil obtained was diluted with EtOAc (400 ml), washed sequentially with 10% citric acid (2 x 100 ml), saturated aqueous solution of NaHCO 3, water 1: 1 (2 x 100 ml), and brine (100 ml). ml), dried over Na2SO4, and evaporated to dryness. 1,2-Dichloroethane (35 ml) was added, followed by dimethyl sulfide (768 μl), TFA (11.5 ml), and water (768 μl) to the crude product (1.14 g) obtained above. The resulting mixture was stirred at t.a. for 1 h, evaporated to a minimum volume, diluted with DCE (3 x 90 ml), and evaporated to dryness. A third part of the obtained residue was purified by chromatography on silica gel, with an eluent with gradient of ammonia in 8-12% methanol in dichloromethane. The desired fractions were combined, evaporated to dryness, treated with anhydrous deuterium oxide / acetonitrile, and lyophilized to yield a fluffy white powder (68.2 mg, 41.1%); TLC, Rf = 0.15. { ammonia in 0.25 M methanol in 16% dichloromethane). 1 H NMR (300 MHz, D20) d 5.41 (d, J = 5.8, 1 H), 4.55 (m, 1), 4.24 (s, 2), 4.14 (m, 1), 3.91 (d, J = 3.3, 1), 3.70-3.66 (m, 2), 3.15 (m, 1), 2.36-2.27 (m, 2), 2.19 (s, 5), 1.59-1.13 (m, 9), 0.93-0.88 (m, 9); 13 C NMR (D20,): d 170.4, 119.4, 88.4, 70.9, 69.3, 68.8, 68.2, 60.0, 53.4, 51.4, 37.3, 36.7, 31.3, 27.9, 27.2, 22.3, 20.1, 14.8, 13.7, 13.3; MS (ESPOS): 419.6 [M + H] +; (ESNEG): 417.5 [M-H] ".

EXAMPLE 11 Preparation of 1-methyl-propyl-pyrrolidine-2-carboxylic acid r2.2-difluoro-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide % trifluoroacetic acid in dichloroethane (10 ml) and sulfur, dimethyl or (0.5 ml) were added to intermediate lincosamine 5b (R1 = Me), prepared by method H (100 mg, 0.20 mmol). The mixture was stirred at t.a. for 1 h. The solvent was removed and the residue was kept under vacuum for 1 h. N-Methyl-4-trans-propylproline (53 mg, 0.4 mmol) and HATU (114 mg, 0.30 mmol) were added to the dry compound in DMF (3 mL), and the mixture was stirred at r.t. all night. The DMF was removed and the residue obtained was then extracted with ethyl acetate (100 ml) and washed with saturated bicarbonate solution (50 ml). Then the organic part was dried using magnesium sulfate and the solvent was removed to obtain the crude product. The crude product was purified on a silica gel column using ethyl acetate as eluent (50 mg, 46%). Then, the product (50 mg, 0.09 mmol) was taken up in methanol (2 ml) and water (1 ml), to which solid potassium carbonate (124 mg, 0.90 mmol) was added and the mixture was stirred at r.t. for 24 h. Then, the solvents were removed and the crude product was purified by column on silica gel using methanol in 20% dichloromethane as eluent (20 mg, 52%). TLC: Rf = 0.57 (methanol in 20% dichloromethane); EM (SPOS): 427 [M + H] +. 1 H NMR (300 MHz, CD3OD) d 0.91 (m, 3), 1.34 (m, 4), 1.69 (t, J = 19.8, 3), 1.98 (s, 3), 2.20 (m, 2), 2.46 (s, 3), 3.18 (dd, J = 5.1, 10.20, 1), 3.93 (d, J = 3.0, 1), 4.08 (dd, J = 3.3, 10.20, 1), 4.40-4.70 (m, 2), 5.28 (d, J = 5.4, 1).

EXAMPLE 12 Preparation of 4-pentyl-pyrrolidine-2-carboxylic acid r2.2-difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide Boc-4-trans-pentylproline 7d (R9 = n-pentyl) (179 mg, 0.631 mmol), HATU (299 mg, 0.789 mmol), and diethylisopropylamine (182 mg, 1.2 mmol) were added to intermediate lincosamine 5b (R1). = Me) prepared by method H (210 mg, 0.526 mmol) in DMF (3 ml) at 0 ° C. The mixture was stirred at t.a. all night. After removing the DMF, the residue was taken up in ethyl acetate and washed with saturated bicarbonate solution (30 ml).

Then the organic part was dried over sodium sulfate and the solvent was removed to obtain the crude product. The crude product was purified by column chromatography using 30% ethyl acetate in hexanes as eluent (200 mg, 57%). Potassium carbonate (450 mg, 3.0 mmol) s was added to the product (200 mg, 0.30 mmol) of the above reaction in methanol (3 mL) and water (1 mL), and the reaction mixture was stirred at t.a. for 2 h. The solvent was removed and the obtained residue was taken up in trifluoroacetic acid in 30% dichloroethane (10 ml) and dimethyl sulfide (0.5 ml) and stirred for 1 h. After removing the solvent, the crude product obtained was purified by column using methanol in 10% dichloromethane as eluent (10 mg, 90%). TLC: Rf = 0.56 (methanol in 20% dichloromean); 1 H NMR (300 MHz, CD3OD) d 0.90 (m, 3), 1.31 (m, 7), 1.44 (m, 20), 1.73 (t, J = 19.5, 3), 2.02 (m, 1), 2.08 ( s, 3), 2.24 (m, 2), 2.89 (t, J = 9.9, 1), 3.56 (m, 2), 3.86 (s, 1), 4.07 (dd, J = 6.0, 9.6, 1), 4.37 (m, 2), 4.63 (m, 1), 5.28 (d, J = 5.4, 1); MS (ESPOS): 441 [M + H] +.

EXAMPLE 13 Preparation of the 4-r3- (4-fluoro-phenyl) -propin-pyrrolidine-2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide) 2- carboxylic Triethylamine (0.13 ml, 0.96 mmol, 3.2 equiv) was added, followed by BSTFA (0.12 ml, 0.45 mmol, 1.5 equiv), to a solution of product 21 b (R1 = Me, R2 = Me) prepared by Method C ( 75 mg, 0.30 mmol, 1 equiv) in dry DMF (0.8 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The reaction mixture was added to the acid 8c (R9 = 3- (4-fluorophenyl) propyl) prepared by Method L (120 mg, 0.34 mmol, 1.1 equiv) in a 25 ml round bottom flask, followed by HATU ( 160 mg, 0.42 mmol, 1.4 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (100 ml), and washed with 10% citric acid (2 x 60 ml), water (60 ml), half saturated NaHCO 3 solution (60 ml) , and brine. The organic layer was dried over Na 2 SO and evaporated to give a yellow syrup. Trifluoroacetic acid (5 ml) and water (0.33 ml) were added to a solution of the above syrup in dichloromethane (15 ml) with dimethyl sulfide (0.33 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [ 3- (4-Fluoro-phenyl) -propyl] -pyrrolidine-2-carboxylic acid (90 mg, 62%) as a white solid. 1 H NMR (300 MHz, CDCl 3) d 7.94 (broad s, 1), 7.11-7.06 (m, 2), 6.97-6.90 (m, 2), 5.31 (d, J = 5.4, 1), 4.10 (dd, J = 5.7, 9.9, 1), 3.96-3.82 (m, 3), 3.68-3.52 (m, 2), 3.10-3.20 (m, 1), 2.70-2.60 (m, 1), 2.56 (dd, J = 7.4, 7.4, 2), 2.36-2.24 (m, 1), 2.13 (s, 3), 2.10-1.93 (m, 2), 1.85-1.73 (m, 1), 1.64-1.50 (m, 2) , 1.40-1.30 (m, 2), 0.92-0.85 (m, 6). MS (ESPOS): 485.5 [M + H] + EM (ESNEG): 483.5 [M-H] ".

EXAMPLE 14 Preparation of 4- (3,3-difluoro-propyl) f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide of 4- (3,3-difluoro-propyl) - pyrrolidine-2-carboxylic acid Triethylamine (0.13 ml, 0.96 mmol, 3.2 equiv) was added, followed by BSTFA (0.12 ml, 0.45 mmol, 1.5 equiv), to a solution of product 2b (R1 = Me, R2 = Me) prepared by Method C (75 mg, 0.30 mmol, 1 equiv) in dry DMF (0.8 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min., and then to t.a. for 50 min. The reaction mixture was added to acid 8c (R9 = 3,3-difluoropropyl) prepared by method N (97 mg, 0.33 mmol, 1.1 equiv) in a 25 ml round bottom flask, followed by HATU (170 mg, 0.45 mmoles, 1.5 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (100 ml), and washed with 10% citric acid (2 x 60 ml), water (60 ml), semi-saturated NaHCO3 solution (60 ml) , and brine. The organic layer was dried over Na2SO4 and evaporated to give a yellow syrup. Trifluoroacetic acid (5 ml) and water (0.33 ml) were added to a solution of the above syrup in dichloromethane (15 ml) with methyl sulfide (0.33 ml). The reaction mixture was stirred at t.a. for 1 h. the solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3, 3-difluoro-propyl) -pyrrolidine-2-carboxylic acid (81 mg, 64%) as a white solid. 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, J = 8.1, 1), 5.80 (dddd, J = 4.2, 4.2, 57, 57, 1), 5.31 (d, J = 5.7, 1), 4.11 ( dd, J = 5.4, 9.9, 1), 3.96-3.82 (m, 3), 3.64-3.52 (m, 2), 3.21-3.10 (m, 1), 2.73-2.60 (m, 1), 2.36-2.23 (m, 1), 2.13 (s, 3), 2.18-1.95 (m, 2), 1.90-1.73 (m, 3), 1.56-1.43 (m, 2), 0.93-0.85 (m, 6). MS (ESPOS): 427.5 [M + H] +, MS (ESNEG): 425.5 [MH] \ EXAMPLE 15 Preparation of r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2 4-r3- (4-chloro-phenyl) -propi-pyrrolidine-2-carboxylic acid-yl-propylamide Triethylamine (88.3 μL, 0.64 mmol, 3.2 equiv) was added, followed by BSTFA (79.2 mL, 0.30 mmol, 1.5 equiv), to a solution of product 21 b (R1 = Me, R2 = Me) prepared by Method C ( 50 mg, 0.20 mmol, 1 equiv) in dry DMF (0.5 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The reaction mixture was added to product 8c (R9 = 3- (4-chlorophenyl) propyl) prepared by Method M (97.3 mg, 0.26 mmol, 1.3 equiv) in a 25 ml round bottom flask, followed by HATU ( 123 mg, 0.32 mmol, 1.6 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (60 ml), and washed with 10% citric acid (2 x 40 ml), water (40 ml), half-saturated solution of NaHCO3 (40 ml). , and brine. The organic layer was dried over Na2SO4 and evaporated to give a yellow syrup. Trifluoroacetic acid (3 ml) and water (0.2 ml) were added to a solution of the above syrup in dichloromethane (9 ml) with dimethyl sulfide (0.2 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (4-chloro-phenyl) -propyl] -pyrrolidine-2-carboxylic acid (41.6 mg, 42%) as a white solid. 1 H NMR (300 MHz, CDCl 3) d 7.26-7.21 (m, 2), 7.17-7.12 (m, 2), . 23 (d, J = 5.7, 1), 4.10-4.00 (m, 3), 3.83-3.75 (m, 1), 3.74-3.70 (m, 1), 3.54- 3.48 (m, 1), 3.25-3.18 (m, 1), 2.63-2.50 (m, 3), 2.20-2.00 (m, 3), 2.09 (s, 3), 1. 85-1.74 (m, 1), 1.68-1.55 (m, 2), 1.42-1.33 (m, 2), 0.95-0.85 (m, 6). MS (ESPOS): 501.5 [M + H] + MS (ESNEG): 499.4 [M-H] ".

EXAMPLE 16 Preparation of 4- (2,2-difluoro-penti-pyrrolidine- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide of 4- (2,2-difluoro-penti-pyrrolidine- 2- carboxylic Triethylamine (88.3 ml, 0.64 mmol, 3.2 equiv) was added, followed by BSTFA (79.2 ml, 0.30 mmol, 1.5 equiv), to a solution of product 2b (R1 = Me, R2 = Me) prepared by Method C (50 mg, 0.20 mmol, 1 equiv) in dry DMF (0.5 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The reaction mixture was added to acid 9d (R9 = 2,2-difluoropentyl) prepared by Method O (67.7 mg, 0.21 mmol, 1.1 equiv) in a 25 ml round bottom flask, followed by HATU (101 mg, 0.27 mmoles, 1.3 equiv). The reaction mixture was stirred at t.a. for 3h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (60 ml), and washed with 10% citric acid (2 x 40 ml), water (40 ml), half-saturated solution of NaHCO3 (40 ml). , and brine. The organic layer was dried over Na2SO4 and evaporated to give a yellow syrup. Trifluoroacetic acid (3 ml) and water (0.20 ml) were added to a solution of the above syrup in dichloromethane (9 ml) with dimethyl sulfide (0.20 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2.2. -difluoro-pentyl) -pyrrolidine-2-carboxylic acid (56 mg, 62%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.17-4.04 (m, 3), 3.98 (dd, J = 3.3, 9.3, 1), 3.77 (d, J = 3.1) , 3.51 (dd, J = 3.4, 10.3, 1), 3.40 (dd, J = 6.9, 10.5, 1), 2.71 (dd, J = 10.2, 10.2, 1), 2.42-2.33 (m, 1), 2.23 -2.11 (m, 2), 2.10 (s, 3), 2.08-1.73 (m, 5), 1.56-1.42 (m, 2), 0.99-0.89 (m, 9). MS (ESPOS): 455.5 [M + H] +; MS (ESNEG): 453.5 [M-H] ".

EXAMPLE 17 Preparation of 4-propyl-piperidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide Triethylamine (0.18 ml, 1.26 mmol) and BSTFA (0.549 ml, 2.1 mmol) were added to intermediate lincosamine 2b (R1 = Me, R2 = Me) prepared by Method D (102 mg)., 0.42 mmol) in DMF (5 ml) at 0 ° C, and the mixture was stirred at r.t. for 3 h. The 10b acid (R9 = propyl) prepared by Method P (200 mg, 0.84 mmol) and HATU (319 mg, 0.84 mmol) was added and the mixture was stirred for 4 h at RT. The DMF was separated and the residue was extracted with ethyl acetate (100 ml) and washed with saturated bicarbonate solution (40 ml). The product obtained by removing the solvent was taken up in methanol and treated with Dowex H + resin for 1 h. After filtering the resin, the methanol was removed to obtain the crude product. Then, the crude product was purified on a column of silica gel using 10% methanol in dichloromethane as eluent to give pyridine 11 b (R 1 = Me, R 2 = Me, R 3 = H, R 9 = propyl) (117 mg, 58 %). TLC: Rf = 0.81 (methanol in 10% dichloromethane); 1 H NMR (300 MHz, CDCl 3) d 1.20 (t, J = 6.3, 6H), 2.19 (m, 2), 2.32 (s, 3), 2.43 (m, 1), 2.84-2.97 (m, 4), 3.74 (m, 1), 4.06 (m, 1), 4.31 (m, 1), 4.52 (m, 2), 5.42 (d, J = 5.7, 1), 7.33-7.61 (m, 5), 780 ( m, 1), 8.15 (s, 1), 8.69 (d, J = 4.8, 1); MS (ESPOS): 475 [M + H] +. Pt02 (100 mg, 0.44 mmol) was added to pyridine 11 b (R1 = Me, R2 = Me, R3 = H, R9 = propyl), (150 mg, 0.37 mmol) in methanol (2 ml), water (10 ml), and acetic acid (3 ml), and the mixture was hydrogenated at 3.5 kg / cm2 all night. The product obtained after filtering the catalyst and removing the solvent was purified by silica gel column chromatography using 30% methanol in dichloromethane as eluent to give the title compound (20 mg, 14%). TLC: Rf = 0.7 (methanol in 50% dichloromethane); 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 6.9, 1), 4.86 (m, 1), 4.13 (m, 2), 3.79 (d, J = 3.3, 1), 3.52 (dd, J = 3.3, 9.9, 1), 3.32 (m, 1), 3.17 (m, 1), 2.67 (m, 1), 2.17 (m, 1), 2.10 (s, 3), 1.97 (m, 1), 1.74 (m, 1), 1.54 (m, 1), 1.38 (m, 2), 1.31 (m, 2), 1.14 (m, 2), 1.02 (m, 9). MS (ESPOS): 405 [M + H] +.

EXAMPLE 18 Preparation of 1- (2-hydroxy-ethyl) -4-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydropyran-2-ip-propylamide) -pentyl-pyrrolidine-2-carboxylic acid DIEA (0.1 ml, 0.57 mmol) and liquid ethylene oxide (3 ml) were added to a stirred solution of [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran 2-yl) -propyl] -amide of crude 4-pentyl-pyrrolidine-2-carboxylic acid, prepared as in Example 10 (237.4 mg), in anhydrous methanol (10 ml), at 0 ° C and under nitrogen . The resulting solution was stirred at -4 ° C for 18 h and evaporated to dryness. The obtained residue was purified by chromatography on silica gel with an eluent of ammonia in methanol in 5% dichloromethane. The desired fractions were evaporated and lyophilized (deuterium oxide / anhydrous acetonitrile, 1: 1, v / v, 10 ml) to give the title compound as a white fluffy powder (50.1 mg, 30.2%); TLC, Rf = 0.68 (ammonia in methanol in 14% dichloromethane); 1 H NMR (300 MHz) d 5.40 (d, J = 5.8, 1), 4.55 (m, 1), 4.24 (s, 1), 4.17-4.11 (m, 1), 3.99-3.89 (m, 4), 3.69-3.65 (m, 1), 3.47 (d, J = 4.4, 2), 3.01 (m, 1), 2.33 (s wide, 4), 2.18 (s, 4), 1.57-1.32 (m, 9) , 0.94-0.87 (m, 9). MS (ESPOS): 464 [M + H] +; (ESNEG): 497.5 [M-H + HCl].

EXAMPLE 19 Preparation of the 1- (2-hydroxy-propyl) -4- r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide of the acid pentyl-pyrrolidine-2-carboxy DIEA (0.1 ml, 0.58 mmol, 1 equiv) and R (+) - propylene oxide (3 ml) were added to a stirred cold solution of [2-methyl-yl- (3,4,5-trihydroxy-6 4-pentyl-pyrrolidine-2-carboxylic acid (4-pentyl-pyridin-2-yl) -propyl] -amide (307.6 mg, 0.58 mmol, 1 equiv), prepared as in Example 10, in anhydrous methanol ml), at 0 ° C and under nitrogen atmosphere. The resulting solution was stirred at -4 ° C for 18 h and evaporated to dryness. The obtained residue was purified by chromatography on silica gel, with an eluent of ammonia in methanol in 6% dichloromethane. The desired fractions were evaporated and lyophilized (deuterium oxide / anhydrous acetonitrile, 1: 1, v / v, 20 ml) to give the title compound as a white fluffy powder (91 mg, 48%).

TLC, Rf = 0.7 (ammonia in methanol in 14% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 5.44 (d, J = 5.5, 1), 4.31 (s, 2), 4.26-4.11 (m, 1), 3.97 (d, J = 3.3, 1.1, 1), 3.75 (dd, J = 3.3, 3.3, 1), 3.39 (dd, J = 3.8, 3.8, 1), 2.31 (s, 3), 1.5-0.95 (m, 12), 1.34 (d, J = 6.0, 4 ), 1.17-1.10 (m, 13); MS (ESPOS): 477.6 [M + H] \ (ESNEG): 475.6 [M-H] ".

EXAMPLE 20 Preparation of 1- (2-hydroxy-propyl) [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -prop-p-amide] -4-pentyl-pyrrolidine-2-carboxylic acid Dimethyl sulfide (62 μl), TFA (1 ml), and water (62 μl) were added to a stirred solution of [2-methyl-1- (3,4,5-trihydroxy-6-met. 1,4-pentyl-pyrrolidine-2-carboxylic acid substituted sulfonyl-tetrahydro-pyrn-2-yl) -propyl] -amide (92 mg, 0.18 mmol), prepared as in Example 10 , in anhydrous dichloroethane (3 ml). The resulting solution was stirred at t.a. for 1 h and evaporated to dryness. Anhydrous methanol (8 ml) and DIEA (31 μl, 0. 18 mmoles) to the obtained residue. The mixture was cooled to -4 ° C and S - (+ propylene oxide (2 ml) was added.The resulting solution was stirred at -4 ° C for 18 h, evaporated to dryness, and purified by gel chromatography. of silica, with an eluent of ammonia in methanol in 6% dichloromethane The desired fractions were evaporated and lyophilized (deuterium / acetonitrile anhydrous, 1: 1, v / v, 8 ml) to give the title compound as a fluffy white powder (29.8 mg, 31.2%) TLC, Rf = 0.7 (ammonia in methanol in 12% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 5.44 (d, J = 5.5, 1), 4.35-4.19 (m, 4), 4.02 (d, J = 3.3, 2), 2.75 (d, J = 6.3, 2.2, 3), 2.3 (s, 3), 1.50 (m, 11), 1.4 (d, J = 6.0, 3.5, 3), 1.16-1.10 (m, 12) .MS (SPOS): 477.6 [M + H] +; (ESNEG) 475.4 [MH] ".

EXAMPLE 21 Preparation of the 1- (3-hydroxy-propyl) r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide of the acid 4-pentyl-pyrrolidine-2-carboxylic acid Triethylamine (0.2 ml, 1.38 mmol, 3 equiv) was added, followed by 3-bromo-1-propanol (60 μl, 0.69 mmol, 1.5 equiv), to a stirred solution of [2-Methyl-1- (3, 4,5-Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of crude 4-pentyl-pyrrolidine-2-carboxylic acid (192.5 mg, 0.46 mmol, 1 equiv), prepared as in Example 10, in anhydrous acetonitrile (2 ml), under a nitrogen atmosphere. The resulting mixture was stirred at t.a. for 18 h and evaporated to dryness. The obtained residue was purified by chromatography on silica gel with an eluent of ammonia in methanol in 5% dichloromethane. The desired fractions were combined, evaporated to dryness and lyophilized to give the title compound as a white fluffy powder (13.5 mg, 6%). TLC, Rf = 0.75 (ammonia in methanol in 14% dichloromethane); 1 H NMR (300 MHz, CD3OD) d 5.44 (d, J = 5.8, 1), 4.33-4.26 (m, 4), 4.01 (d, J = 2.7, 1), 3.85-3.74 (m, 6), 2.29 (s, 3), 2.1 (m, 4), 1.54 (m, 8), 1.16-1.08 (m, 12); MS (ESPOS): 477.6 [M + H] +.

EXAMPLE 22 Preparation of 1- (2-hydroxyethyl) -4- (2-hydroxy-ethyl) f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide (3-Methyl-butyl) -pyrrolidine-2-carboxylic acid Ethylene oxide (0.6 ml) was added to a solution of [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -am 4- (3-Methyl-butyl) -pyrrolidine-2-carboxylic acid (35.1 mg, 0.084 mmol), prepared as in Example 9, in methanol (3 ml), at 0 ° C. The reaction mixture was stirred at 4 ° C overnight. Additional ethylene oxide (0.6 ml) was added and stirred at 4 ° C overnight. The reaction mixture was concentrated and purified by chromatography to give a white solid, [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. 1- (2-hydroxy-ethyl) -4- (3-Methyl-butyl) -pyrrolidine-2-carboxylic acid (24.1 mg, 62%). 1 H NMR (300 MHz, CDCl 3) d 7.68 (d, J = 9.0, 1), 5.32 (d, J = 5.4, 1), 5.24 (d, J = 3.0, 1), 4.13-4.07 (m, 1), 4.01 (ddd, J = 2.8, 9.9, 9.9, 1), 3.86 (d, J = 10.8, 1), 3.78 -3.68 (m, 2), 3.61-3.57 (m, 1), 3.56-3.48 (m, 1), 3.36-3.32 (m, 1), 3.27-3.21 (m, 1), 2.94-2.85 (m, 1), 2.76-2.70 (m, 1), 2.55 (ddd, J = 3.6, 3.6, 12.6, 1), 2.41-2.37 (m, 1), 2.36-2.27 (m, 1), 2.15 (s, 3 ), 2.03-1.95 (m, 2), 1.93-1.81 (m, 1), 1.54-1.42 (m, 1), 1.39-1.26 (m, 2), 1.22-1.10 (m, 2), 0.99-0.92 (m, 6), 0.90-0.84 (m, 6). MS (ESPOS): 463.5 [M + H] + MS (ESNEG): 461.5 [M-H] ".

EXAMPLE 23 Preparation of the 4- (3 -3-difluoro-propyl) -1- (2-hydroxy) 2- (3-3-difluoro-propyl) -1- (2-hydroxy) - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propip-amide of 4- (3 -3-difluoro-propyl) -1- (2-hydroxy) -ethyl) - pyrrolidine-2-carboxylic acid Ethylene oxide (0.4 ml) was added to a solution of [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propyl] -amide of the 4- (3,3-difluoro-propyl) -pyrrolidine-2-carbopylic acid, prepared as in Example 14 (29.7 mg, 0.07 mmol), in methanol (2 ml), at 0 ° C. The reaction mixture was stirred at 4 ° C overnight. Additional ethylene oxide (0.4 ml) was added and stirred at 4 ° C overnight. The reaction mixture was concentrated and purified by chromatography to give a white solid, 1- [2- (S) -4- (R) - (3-methylbut-1-yl) -N- (2-hydroxyethyl-1- il) pyrrolidin-2-yl] -N-. { 1- (R) - [2- (S) -3- (S), 4- (S), 5- (R) -trihydroxy-6- (R) - (methylthio) tetrahydropyran-2-l ] -2-metilprop-1-il} Acetamida (19.3 mg, 59%). 1 H NMR (300 MHz, CDCl 3) d 5.86 (dddd, J = 4.3, 4.3, 57, 57, 1), 5.23 (d, J = 5.7, 1), 4.13-4.04 (m, 3), 3.75 (d, J = 3.3, 1), 3.73-3.57 (m, 2), 3.53 (dd, J = 3.3, 10.2, 1), 3.42-3.36 (m, 1), 3.26-3.18 (m, 1), 2.88-2.78 (m, 1), 2.62- 2.55 (m, 1), 2.17- 2.00 (m, 4), 2.10 (s, 3), 1.94-1.73 (m, 3), 1.55-1.45 (m, 2), 0. 98-0.91 (m, 6). MS (ESPOS): 471.5 [M + H] +, MS (ESNEG): 469.4 [MH] \ EXAMPLE 24 Preparation of r2,2-difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro) 1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid-pyran-2-yl) -propyl-amide Ethylene oxide (1 ml, excess) was added to the title compound of Example 12 (60 mg, 0.136 mmol) in methanol (5 ml) at 0 ° C, and the mixture was stirred at 4 ° C overnight. The solvent was removed and the crude product was purified by column chromatography on silica gel using dichloromethane in methane! 10% as eluent (25 mg, 38%). TLC: Rf = 0.76 (methanol in 5% dichloromethane); 1 H NMR (300 MHz, CD 3 OD) d 0.89 (m, 3), 1.30 (m, 8), 1.68 (t, J = 19.4, 3), 1.78 (m, 1), 1.99 (m, 2), 2.07 ( s, 3), 2.63 (m, 1), 2.73 (m, 1), 3.19 (m, 1), 3.58 (m, 3), 3.95 (m, 1), 4.08 (dd, J = 6.0, 9.90, 1), 4.44-4.60 (m, 2), 5.26 (d, J = 5.4, 1); MS (ESPOS): 485 [M + H] +.

EXAMPLE 25 Preparation of 4-pentyl-piperidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide 4-Pentylpyridine-2-carboxylic acid, (10b) (R9 = penylyl) was prepared using Method P. To 4-pentylpyridine (3 g, 20 mmol) in acetic acid (30 ml), hydrogen peroxide was added. (0.7 g, 30%, 20 mmol) and heated to reflux overnight. Removal of the solvent resulted in a residue which was dissolved in DCM (100 ml), dried over MgSO 4 and filtered. Separation of the DCM resulted in a brown liquid, the N-oxide of 4-pentylpyridine (3.3 g, 100%). To trimethylsilyl cyanide (2.37 g, 24 mmol), the 4-pentylpyridine N-oxide (3.3 g, 20 mmol) in DCM (10 ml) was added followed by the dropwise addition of dimethylcarbamoyl chloride (2.56 g). , 24 mmol) in DCM (10 ml). After stirring at room temperature overnight, sodium bicarbonate (100 ml, 10%) was added and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 ml) and the organic layer was dried over magnesium sulfate. Removal of the solvent resulted in compound 10a (R9 = pentyl) (4.1 g, 100%). 1 H NMR (300 MHz, CD3OD) d 8.52 (m, 1), 7.46 (s, 1), 7.27 (m, 1), 3.00 (m, 2), 2.60 (m, 2), 1.60 (m, 2) , 1.27 (m, 2), 0.86 (m, 3). MS (ESPOS): 175 [M + H] +. The 4-pentyl-2-cyanopyridine (10a) (R9 = pentyl) (3.4 g, 19.5 s mmoles) from the previous step was dissolved in HCl (6 N, 100 ml) and heated to reflux overnight. The residue obtained by removing the HCl was purified by column chromatography using MeOH in 20% DCM ai (3.7 g, 100%) to give compound 10 (b). 1 H NMR (300 MHz, CD3OD) d 8.74 (d, J = 6.3, 1), 8.39 (s, 1), 8.06 0 (d, J = 6.3, 1), 2.98 (t, J = 7.2, 2), 1.77 (m, 2), 1.39 (m, 4), 0.95 (t, J = 7.2, 3H). MS (ESNEG): 192 [M-H] -. Then, to the 7-methyl-α-iiolincosaminide 21 b (R1 = Me, R2 = Me) (90 mg, 0.35 mmol) in DMF (2 ml), TEA (72 mg, 0.7 mmol), BSTFA (276 mg) were added. , 1.05 mmole) at 0 ° C and stirred at ambient temperature 5 for 1.5 h. Then the acid (10b) (R9 = pentyl) (138 mg, 0.7 mmol) and HATU (165 mg, 0.53 mmol) were added to the reaction mixture, and it was stirred at room temperature overnight. The DMF was completely removed, the residue was taken up in EtOAc (50 ml), washed with sodium bicarbonate (10%, 50 ml), brine (50 ml). The product obtained after drying over magnesium sulfate and concentrating was taken up in methanol (10 ml) and treated with NR-50 resin (150 mg) for 3 h. The resin was filtered and the solvent was removed. Purification of the crude product was carried out by silica gel column chromatography using MeOH in 3% DCM as eluent to obtain compound 11b (R1 = Me, R2 = Me R3 = H, R9 = pentyl) (90 mg, 59%): 1 H NMR (300 MHz, CD 3 OD) d 8.50 (d, J = 5.11, 1), 7.95 (s, 1), 7.11 (m, 1), 5.25 (d, J = 5.7, 1) , 4.20-4.87 (m, 3), 3.85 (d, J = 3.3, 1), 3.55 (dd, J = 3.3, 7.2, 1), 2.72 (m, 2), 2.16 (m, 4), 1.67 ( m, 2), 1.35 (m, 4), 0.96 (m, 9). MS (ESPOS): 427 [M + H] +. To pyridine 11 b (R1 = Me, R2 = Me R3 = H, R9 = pentyl) (90 mg, 0.7 mmol) in water (10 ml), AcOH (3 ml) and MeOH (2 ml), Pt02 was added (100 mg) and hydrogenated at 3.85 kg / cm2 overnight. The solvent was separated for get the gross product. Purification of the crude product was carried out by silica gel column chromatography using MeOH in 20% DCM to obtain the title compound (35 mg, 38%) 1 H-NMR (300 MHz, CD3OD) d 5.23 (d, J = 5.1, 1), 4.17 (m, 3), 3.79 (d, J = 3.3, 1), 3.52 (m, 1), 3.38 (m, 1), 3.07 (m, 1), 2.68 (m, 1), 2.14 (m, 4), 1.88 (m, 1 ), 1.71 (m, 1), 1.52 (m, 1), 1.30 (m, 8), 1.07 (m, 3), 0.90 (m, 9); EM (SPOS): 433 [M + H] +.

EXAMPLE 26 Preparation of the 4-methoxy-piperidine-2-carboxylic acid r2-methyl-1- (314,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-p-amide 4-Methoxypyridine-2-carboxylic acid, compound 10 (b) (R9 = methoxy), was prepared using Method P. To trimethylsilyl cyanide (0.95 g, 9.6 mmol), 4-methoxypyridine N-oxide was added (1 g, 8 mmol) in DCM (10 ml), followed by dimethylcarbamoyl chloride (1.03 g, 9.6 mmol) in DCM (10 ml), dropwise. After stirring at room temperature overnight, sodium bicarbonate (100 ml, 10%) was added and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 ml each time). The combined organic layer was dried over magnesium sulfate and the solvent was removed to obtain the product, compound 10a (0.97 g, 90%). 1 H NMR (300 MHz, CD 3 OD) d 8.52 (m, 1), 7.22 (m, 1), 7.01 (m, 1), 3.92 (s, 3 H); MS (ESPOS): 135 [M + H] +. The 4-methoxy-2-cyanopyridine, compound 10a (R9 = methoxy), (0.97 g, 7.2 mmol) was dissolved in HCl (6 N, 50 ml), and heated to reflux overnight. The HCl was evaporated and the resulting product was crystallized from acetonitrile, to give compound 10b (R9 = methoxy) (0.6 g, 60%). 1 H NMR (300 MHz, CD 3 OD) d 8.65 (m, 1), 7.99 (m, 1), 7.68 (m, 1), 4.21 (s, 3H). MS (ESNEG): 152 [M-H] ". To 7-methyl-a-thiolyl-assoside, compound 2b (R1 = Me, R2 = Me), (90 mg, 0.35 mmol) in DMF (2 ml), TEA (72 mg, 0.7 mmol), BSTFA (276 mg, 1.05 mmol) were added at 0 ° C and allowed to stir at room temperature for 1.5 h. Then compound 10b (R9 = methoxy) (109 mg, 0. 7 mmole) and HATU (165 mg, 0.53 mmole) to the reaction mixture, and stirred at room temperature overnight. The DMF was completely removed and the residue was taken up in EtOAc (50 ml), washed with saddic bicarbonate (10%, 30 ml), brine (30 ml), and dried over magnesium sulfate. The solvent was removed to obtain an oil-like brown liquid, which was dissolved in methanol (10 ml) and treated with NR-50 resin for 1 h. The resin was filtered, and the solvent was removed to obtain the crude material. Purification was carried out by column chromatography on silica gel using EtOAc as eluent to obtain compound 11 b (R1 = Me, R2 = Me R3 = H, R9 = methoxy) (100 mg, 72%). 1 H NMR (300 MHz, CD 3 OD) d 8.42 (m, 1), 7.64 (m, 1), 7.07 (m, 1), 5.25 (d, J = 5.4, 1), 4.07-4.87 (m, 3), 3.94 (m, 4), 3.56 (m, 1), 2.99 (m, 2), 2.80 (m, 1), 2.22 (m, 1), 2.11 (s, 3), 0.96 (m, 3). MS (ESPOS): 387 [M + H] +. To compound 11 b (R1 = Me, R2 = Me R3 = H, R9 = meioxy) (100 mg, 0. 26 mmol) in water (10 ml), AcOH (3 ml) and MeOH (2 ml), Pt02 (100 mg) were added and hydrogenated at 3.85 kg / cm2 overnight. The solvent was removed to obtain the crude product. Purification of the crude product was carried out by column chromatography on silica gel using MeOH in 20% DCM to obtain the title compound. (9 mg, 9%). 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.17 (dd, J = 9.9, 3.3, 1), 4.07 (m, 2), 3.79 (m, 1), 3.52 (dd) , J = 10.5, 3.3, 1), 3.35 (s, 3), 3.18 (m, 2), 2.72 (m, 1), 2.16 (m, 1), 2.12 (s, 3) 1.99 (m, 2), 1.50 (m, 1), 1.24 (m, 2), 0.90 (d, J = 6.9, 6); MS (ESPOS): 393 [M + H] +.

EXAMPLE 27 Preparation of the 4- (1-ethyl-propyl-piperidine-2-r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide of the acid -carboxylic 4-Isopentyridine-2-carboxylic acid, compound 10b (R9 = 1-ethyl-propyl), was prepared using the P-MeOH-4- (1-efil-propyl) -pyridine (8.5 g. , 57 mmol) in acetic acid (30 ml), hydrogen peroxide (17.8 g, 30%, 57 mmol) was added. The resulting reaction mixture was heated to reflux overnight. The residue obtained by removing the solvent was dissolved in DCM (100 ml), copper MgS0 was dried. After filtration, the solvent was removed to obtain a brown liquid, 4- (1-ethyl-propyl) -pyridine N-oxide (9 g, 95%).

To a solution of trimethylsilyl cyanide (6.5 g, 65 mmol) and 4- (1-ethyl-propyl) -pyridine N-oxide (9 g, 54 mmol) in DCM (25 mL) was added a solution of dimethylcarbamoyl chloride (7 g, 65 mmol) in DCM (10 ml), dropwise. After stirring at room temperature overnight, sodium bicarbonate (100 ml, 10%) was added, and the organic layer was separated. The aqueous layer was extracted twice with DCM (50 ml). The combined organic layers were dried over magnesium sulfate and the solvent was removed to obtain the product, compound 10a (R9 = 1-ethyl-propyl) (9.6 g, 100%). 1 H NMR (300 MHz, CD 3 OD) d 8.58 (m, 1), 7.46 (m, 1), 7.26 (m, 1), 2.42 (m, 1), 1.77 (m, 4), 0.78 (t, J = 7.5, 6). MS (ESPOS): 175 [M + H] +. Compound 10a (R9 = 1-ethyl-propyl) (9.5 g, 54 mmol) was dissolved in HCl (6 N, 50 mL) and heated to reflux overnight. HCl was evaporated and the resulting product, compound 10b (R 9 = 1-ethyl-propyl), was crystallized from acetonitrile (10 g, 100%). 1 H NMR (300 MHz, CD 3 OD) d 8.86 (m, 1), 8.45 (m, 1), 8.20 (m, 1), 2.92 (m, 1), 1.87 (m, 4), 0.84 (t, J = 7.5, 6). MS (ESNEG): 192 [MH]. "To the acid 10b (77 mg, 0.4 mmol) in DMF (2 ml), 7-methyl-α-thioi-zincosaminide, compound 2b (R 1 = Me, R 2 = Me), was added. (100 mg, 0.4 mmol), followed by HBTU (166 mg, 0.44 mmol) and DIEA (205 mg, 0.8 mmol) The mixture was stirred at room temperature for 2 h.The product was obtained by separating the DMF and purifying by column chromatography on silica gel using ethyl acetate to give the title compound 11 b (R 1 = Me, R 2 = Me R 3 = H, R 9 = 1-ethyl-propyl) (150 mg, 89%)]. 1 H NMR (300 MHz, CD3OD) d 8.42 (d, J = 5.1, 1), 7.37 (s, I), 7.32 (m, 1), 5.27 (d, J = 4.8, 1), 4.21-4.88 (m, 3), 3.85 (d, J = 3.6, 1), 3.56 (dd, J = 3.3, 10.2, 1), 2.48 (m, 1), 2.11 (m, 4), 1.00 (m, 12). MS (ESPOS): 427 [M + H] +. To compound 11b (R1 = Me, R2 = Me R3 = H, R9 = 1-ethyl-propyl) (130 mg, 0.3 mmol) in water (10 ml), AcOH (2 ml) and MeOH (2 ml) were added. , Pt02 (150 mg) and hydrogenated at 3.85 kg / cm2 overnight. The solvent was removed to obtain the crude product. Purification was carried out by column chromatography on silica gel using MeOH in 20% DCM to obtain the title compound. (40 mg, 30%). 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.17 (dd, J = 9.9; 3. 3, 1), 4.10 (m, 2), 3.78 (m, 1), 3.51 (m, 2), 2.81 (m, 2), 2.16 (m, 1), 2.10 (s, 3) 1.90 (m, 2), 1.76 (m, 3), 1.40 (m, 8), 0.91 (m, g); MS (ESPOS): 433 [M + H] +.

EXAMPLE 28 Preparation of 4-isopropyl-piperidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide The 4-isopropylpyridine-2-carboxylic acid, compound (10b) (R9 = isopropyl), was prepared using the P method. To the 4-isopropylpyridine (5 g, 0.041 mol) in acetic acid (60 ml), peroxide was added of hydrogen (30%, 4.7 g, 0.13 mol) and heated to reflux overnight. After removing the solvent, the residue was dissolved in DCM, dried over magnesium sulfate and taken as it was for the next step. To the resulting compound in dichloromethane (10 ml) were added trimethylsilyl cyanide (7.0 ml, 0.07 moles) and dimethylcarbamyl chloride (5.6 ml, 0.05 moles) and stirred at room temperature for 24 hours. Aqueous potassium carbonate (10%, 50 ml) was added and extracted with dichloromethane (100 ml). The crude product obtained by removing the solvent was taken up in hydrochloric acid (6 N, 30 ml) and heated to reflux for 24 h. Separation of the acid followed by crystallization of the crude product in acetonitrile resulted in the acid 10b (R 9 = isopropyl) (5 g, 75%). 1 H NMR (300 MHz, CD3OD): d 8.78 (d, J = 6.1), 8.42 (s, 1), 8.16 (d, J = 6.0, 1), 3.25 (m, 1), 1.33 (d, J = 9.0, 6) MS (ESNEG): 164 [MH] \ To the amine, compound 2b (R1 = Me, R2 = Me), (140 mg, 0.56 mmole) in DMF (3 ml), BSTFA (0.59 ml) was added. , 2.24 mmole) and triethylamine (0.18 ml, 1.26 mmole) at 0 ° C and the reaction mixture was stirred at room temperature for 3 hours. The 10b acid (R9 = isopropyl) (188 mg) was combined, 1.13 mmole) and HATU (319 mg, 0.84 mmole) and allowed to stir for a further 4 hours at room temperature. The DMF was separated and the residue was extracted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (40 ml). The product obtained by removing the solvent was taken up in methanol and treated with Dowex H + resin for 1 hour. After filtering the resin, the methanol was removed to obtain the crude product. It was then purified on a column of silica gel using 10% methanol in dichloromethane as eluent to provide compound 11b (R1 = Me, R2 = Me R3 = H, R9 = isopropyl) (120 mg, 53%). 1 H NMR (300 MHz, CD3OD): 8.42 (d, J = 5.1, 1), 7.37 (s, 1), 7.32. (m, 1), 5.27 (d, J = 4.8, 1), 4.21-4.88 (m, 3), 3.85 (d, J = 3.6, 1), 3.56 (dd, J = 3.3, 10.2, 1), 2.48 (m, 1), 2.11 (m, 1), 2.10 (s, 3), 1.20 (m, 12). MS (ESPOS): 399 [M + H] +. To the product 11 b (R1 = Me, R2 = Me R3 = H, R9 = sopropyl) (100 mg, 0.257 mmol) in methanol (5 ml), water (10 ml) and acetic acid (5 ml) was added Platinum dioxide (100 mg, 0.44 mmol) and hydrogenated at 4.2 kg / cm2 for 16 h. After filtering the cacifier, the solvent was removed by evaporation to obtain the crude product which was then purified by silica gel column chromatography using 10% methanol in dichloromethane as eluent. The compound of minor Rf was the title compound (10 mg, 9%). 1 H NMR (300 MHz, CD3OD): d 5.24 (d, J = 5.7, 1), 4.17 (dd, J = 9.9, 3.3, 1), 4.10 (m, 2), 3.80 (m, 1), 3.51 ( m, 1), 3.16 (m, 1), 2.61 (m, 1), 2.16 (m, 1), 2.10 (s, 3) 1.90 (m, 1), 1.76 (m, 1), 1.50-1.09 ( m, 5), 0.91 (m, 12); MS (ESPOS): 405 [M + H] +.

EXAMPLE 29 Preparation of 4-butyl-piperidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide 4-Butylpyridine was prepared by the addition of potassium t-butoxide (0.68 g, 6 mmol) to propylphosphonium bromide (Aldrich) (2.4 g, 6.0 mmol) in THF (10 mL), at 0 ° C and stirring at room temperature. for 1 hour. Pyridine-4-carbaldehyde (428 mg, 4 mmol) was added and the reaction mixture was stirred for 2 h. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The product obtained after removing the solvent was taken up as it was in methanol (30 ml) and to which palladium on charcoal (10%, 300 mg) was added and hydrogenated at 1 atm pressure overnight. Removal of the solvent and purification by column chromatography using ethyl acetate resulted in 4-butiipyridine (500 mg, 92%): 1 H NMR (CDCl 3): d 8.42 (d, J = 6.0, 2), 7.05 (d , J = 6.0, 1), 2.60 (t, J = 6.5, 2), 1.62 (m, 2), 1.37 (m, 2), 0.93 (t, J = 7.0, 3). MS (Spores): 136 [M + H] +. 4-Butylpyridine-2-carboxylic acid, compound (10b) (R9 = butyl), was prepared using Method P. To 4-butylpyridine (2 g, 0.014 mol) in acetic acid (15 ml), peroxide was added of hydrogen (30%, 5 ml, 0.056 moles) and heated to reflux overnight. After removing the solvent, the residue was dissolved in DCM, dried over magnesium sulfate and taken as it was for the next step. To the compound from the previous step in dichloromethane (10 ml), trimethylsilyl cyanide (3.92 ml, 0.029 mole) and dimethylcarbamoyl chloride (2.67 ml, 0.028 mole) were added and stirred at room temperature for 24 hours. Aqueous potassium carbonate (10%, 50 ml) was added and extracted with dichloromethane (100 ml). The crude product obtained by removing the solvent was taken up in hydrochloric acid (6 N, 30 ml) and heated to reflux for 24 h. Separation of the acid after crystallization of the crude product in acetyloiryl resulted in the acid 10b (R9 = butyl) (1.5 g, 60%). 1 H-NMR (CDCl 3): d 8.92 (d, J = 6.0, 1), 8.65 (s, 1), 8.27 (m, 1), 3. 23 (t, J = 6.5, 2), 1.98 (m, 2), 1.67 (m, 2), 1.20 (t, J = 7.0, 3). MS (ESNEG): 178 [M-H] -. To the amine, compound 2b (R1 = Me, R2 = Me), (140 mg, 0.56 mmol) in DMF (3 mL), BSTFA (0.59 mL, 2.24 mmol) and triethylamine (0.18 mL, 1.26 mmol) were added to 0 ° C and then stirred at room temperature for 3 hours. 10b (R9 = butyl) (203 mg, 1.13 mmol) and HATU (319 mg, 0.84 mmol) were added and the reaction mixture was stirred for a further 4 hours at room temperature. The DMF was separated and the residue was extracted with ethyl acetate (100 ml) and washed with saturated bicarbonate solution (40 ml). The product obtained by removing the solvent was taken up in methanol and treated with Dowex H + resin for 1 hour. After filtering the resin, the methanol was removed to obtain the crude product. The product was then purified on a silica gel column using ethyl acetate as eluent to provide compound 11b (R1 = Me, R2 = Me R3 = H, R9 = butyl) (200 mg, 86%). 1 H NMR (CDCl 3) d 8.40 (d, J = 4.2, 1), 8.01 (s, 1), 7.29 (m, 1), 5.40 (d, J = 5.4, 1), 4.02-4.36 (m, 3) , 4.80 (s, 1), 3.48-3.60 (m, 1), 3.72 (t, J = 6.0, 2), 2.49 (m, 1), 2.20 (s, 3), 1.67 (m, 4), 1.40 (m, 3), 0.98-1.18 (m, 9). Mass 413 [M + F] +. To compound 11 b (R1 = Me, R2 = Me R3 = H, R9 = butyl) (200 mg, 0.49 mmol) in methanol (5 ml), water (10 ml) and acetic acid (5 ml), dioxide was added of platinum (100 mg, 0.44 mmol) and hydrogenated at 4.2 kg / cm2 for 16 h. After filtering the catalyst, the solvent was removed by evaporation to obtain the crude product, which was then purified by silica gel column chromatography using methanol in 20% dichloromethane as eluent. Fractions of lower Rf provided the title compound (60 mg, 29%). 1 H NMR (CDCl 3): d 5.20 (d, J = 3.6, 1), 4.20 (dd, J = 3.0, 4.8, 1), 4. 04 (m, 2), 3.80 (d, J = 3.0, 1), 3.61-3.66 (m, 1), 3.52 (dd, J = 3.3, 10.2), 2.88 (m, 1), 2.17 (m, 1 ), 2.14 (s, 3), 1.87 (m, 2), 1.62 (m, 2), 1.32 (m, 6), 0.89 (m, g); MS (ESPOS): 419 [M + H] +.

EXAMPLE 30 Preparation of 4-cyclohexyl-piperidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -prop-p-amide 4-Phenylpyridine-2-carboxylic acid, compound 10b (R9 = phenyl), was prepared using the P method. To the N-oxide of 4-phenylpyridine (1 g, 5.84 mmol) in dichloromethane (10 ml) was added cyanide of trimethylsilyl (1.5 ml, 11.6 mmol) and dimethylcarbamoyl chloride (1 ml, 11.6 mmol) and the reaction mixture was stirred at room temperature for 24 hours. An aqueous solution of polybasic carbonate (10%, 10 ml) was added and the mixture was extracted with dichloromethane (100 ml). The crude product obtained by removing the solvent was taken up in hydrochloric acid (6 N, 30 ml) and heated to reflux for 24 hours. Removal of the solvent followed by crystallization of the crude product in acetonitrile resulted in the acid 10b (R 9 = phenyle) (1 g, 86%). MS (ESNEG): 198 [M-H] -; NMR (300 MHz, CD3OD) d 7.64-7.67 (m, 3), 8.02-8.06 (m, 2), 8.53-8.56 (m, 1), 8.82 (s, 1), 8.82-8.90 (m, 1) .

To amine 2b (R1 = Me, R2 = Me) (102 mg, 0.42 mmol) in DMF (5 ml), BSTFA (0.549 ml, 2.1 mmol) and triethylamine (0.183 ml, 1.26 mmol) were added at 0% and then it was stirred at room temperature for 3 hours. Acid 10b (R9 = phenyl) (158 mg, 0.80 mmol) and HATU (302 mg, 0.80 mmol) were added and the reaction was stirred for an additional 4 hours at room temperature. The DMF was separated and the residue was extracted with ethyl acetate (100 ml) and washed with saturated bicarbonate solution (40 ml). The product obtained by removing the solvent was taken up in methanol and treated with Dowex H + resin for 1 h. After filtering the resin, the methanol was removed to obtain the crude product. Then, the resulting residue was purified by silica gel column chromatography using 10% methanol in dichloromethane as eluent to provide compound 11b (R1 = Me, R2 = Me R3 = H, R9 '= phenyl) (50 mg, 58%). TLC: Rf = 0.70 (MeOH / 10% DCM); MS (ESPOS): 435 [M + Hf; 1 H NMR (300 MHz, CDCl 3) d 1.01 (t, J = 6.6, 6), 2.12 (s, 3), 2.28 (m, 1), 3.56 (dd, J = 3.3, 10.5, 1), 3.90 (d, J = 3.3, 1), 4.12 (dd, J = 5.4, 10.5, 1), 4.27-4.36 (, 2) , 4.52 (m, 2), 5.26 (d, J = 5.7, 1), 7.48-7.55 (m, 3), 7.77-7.80 (m, 2), 7.83 -., 85 (m, 1), 8.37 ( s, 1), 8.69 (d, J = 5.4, 1). To compound 11 b (R1 = Me, R2 = Me R3 = H, R9 '= phenyl) (40 mg, 0.09 mmol) in methanol (5 ml), water (10 ml) and acetic acid (5 ml) was added Platinum dioxide (100 mg, 0.44 mmol) and the reaction mixture was stirred at 4.2 kg / cm 2 of hydrogen for 16 h. The catalyst was removed by filtration, and the solvent was evaporated to obtain the crude product, which was then purified by silica gel column chromatography using 10% methanol in dichloromethane to provide the title compound (10 mg, 25% ). TLC: Rf = 0.22 (MeOH / 20% DCM); MS (ESPOS): 447 [M + H] +; 1 H NMR (300 MHz, CD3OD) d 0.90 (d, J = 6.8, 6), 0.93-1.05 (m, s 5), 1.20 (m, 6), 1.33-1.47 (m, 4), 1.75 (m, 6), 2.10 (s, 3), 2.18-2.22 (m, 1), 2.97 (t, J = 12.3, 1), 3.39-3.52 (m, 2), 3.70-3.78 (m, 2), 4.05- 4.21 (m, 3), 5.23 (d, J = 5.7, 1).

EXAMPLE 31 o Preparation of f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide of 4-ethyl-1- ( 2-hydroxy-ethyl-piperidine-2-carboxylic acid To the product of Example 1 (28 mg, 0.07 mmol) in methanol (2 ml), ethylene oxide (0.5 ml) was added and stirred at 4 ° C overnight. The solvent was removed and the resulting product was purified by column chromatography using MeOH in 20% DCM as eluent to obtain the title compound (16 mg, 51%) as a white powder. 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 6, 1), 4.27 (m, 1), 4.10 (m, 2), 3.95 (m, 1), 3.79-3.50 (m, 4), 3.85 (m, 1) 3.74 (m, 1), 3.26 (m, 1), 2.91 (m, 2), 2.33 (m, 1), 2.13 (m, 4), 1.92 (m, 1), 1.71 ( m, 1), 1.17 (m, 7), 0.94 (m, 9); MS (ESPOS): 435 [M + H] +.

EXAMPLE 32 Preparation of 1- (2-hydroxyethyl) -4- (2-hydroxy-ethyl) f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide pentyl-piperidine-2-carboxylic acid The title compound was prepared using the procedures of Example 32 with the product of Example 25 as the starting material. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 6.0, 1), 4.19 (m, 3), 3.79 (d, J = 3.3, 1), 3.74 (m, 1), 3.65 (m, 1 ), 3.54 (dd, J = 3.0, 10.2, 1), 3.25 (m, 2), 2.82 (m, 2), 2.14 (m, 4), 1.89 (m, 1), 1.72 (m, 1), 1.28 (m, 12), 0.94 (m, 9); MS (ESPOS): 477 [M + Hf.

EXAMPLE 33 Preparation of the 1- (2-hydroxy-ethylP-4-propyl) 2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) piperidine-2-carboxylic The compound of the invention was prepared using the procedures of Example 32 with the product of Example 17 as a starting material. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 6.0, 1), 4.19 (dd, J = 9.6, 3.3, 1), 4.11 (m, 2), 3.79 (d, J = 3.3, 1) , 3.75 (m, 1), 3.65 (m, 1), 3.54 (m, 1), 3.28 (m, 1), 2.82 (m, 2), 2.27 (m, 5) 1.90 (m, 1), 1.71 (m, 1), 1.36 (, 8), 0.94 (m, 9); MS (ESPOS): 449 [M + H] +.

EXAMPLE 34 Preparation of the 9-fl-oren-9-ylmethyl ester of 2-r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylcarbamoy-4-propyl) piperidine-1-carboxylic To the product of Example 17 (50 mg, 0.123 mmol) in water (3 ml) and dioxane (3 ml), Fmoc-CI (38 mg, 0.197 mmol) and sodium carbonate, (25 mg, 0.246 mmol) were added and the The reaction mixture was stirred overnight at room temperature. The solvents were removed and the crude material was loaded onto a column of silica gel and eluted with ethyl acetate to obtain the title compound as a white solid (3.0 mg, 51%). TLC: Rf = 0.5 (EtOAc). MS (ESPOS): 627 [M + H] \ 649 [M + Na] +; 1 H NMR (CD 3 OD, 200 MHz): 7.79 (d, J = 4.6 Hz, 2), 7.59-7.62 (m, 2), 7.28-7.41 (m, 4), 5.19 (d, J = 3.8 Hz, 1) , 4.45 (m, 2), 4.24 (t, J = 4.2, 1), 3.99-4.15 (m, 4), 3.93 (m, 1), 3.47-3.50 (m, 2), 2.05 (s, 3) , 1.87 (m, 1), 1.67 (s, 2), 1.50 (m, 1), 1.30 (m, 4), 0.86-0.91 (m, 9).

EXAMPLE 35 Preparation of the ethyl ester of 2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-β-P-propylcarbamoyl-4-propyl-piperidine-1-carboxylic acid To the product of Example 17 (50 mg, 0.123 mmol) in water (3 ml) and dioxane (3 ml), ethyl chloroformate (20 mg, 0.147 mmol) and sodium carbonate (25 mg, 0.246 mmol) were added and stirred overnight at room temperature. The solvents were removed and the crude material was loaded onto a column of silica gel and eluted with ethyl acetate to obtain the title compound as a white solid (40 mg, 52%). TLC: Rf = 0.28 (EtOAc). MS (ESPOS): 477 [M + Hf; 499 [M + Naf; 1 H NMR (CD3OD, 200 MHz): 5.22 (d, J = 3.6 Hz, 1), 4.27 (m, 1), 4.03-4.14 (m, 5), 3.96 (broad s, 1), 3.62 (m, 1 ), 3.54 (d, J = 2.2 Hz, 1), 3.52 (d, J = 2.2 Hz, 1), 2.08 (s, 3), 1.93-2.03 (m, 2), 1.75-1.85 (m, 3) , 1.61 (m, 2), 1.33 (m, 4), 1.22-1.28 (m, 3), 0.90-0.94 (m, g).

EXAMPLE 36 Preparation of phenyl ester of 2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-P-propylcarbamoin-4-propyl-piperidine-1-carboxylic acid To the product of Example 17 (50 mg, 0.123 mmole) in water (3 ml) and dioxane (3 ml), phenyl chloroformate (40 mg, 0.246 mmole) and sodium carbonate (25 mg, 0.246 mmole) were added and the mixture of reaction was stirred overnight at room temperature. The solvents were removed and the crude material was loaded onto a column of silica gel and eluted with ethyl acetate to obtain the title compound as a white solid (30 mg, 47%). TLC: Rf = 0.4 (EtOAc). MS (ESPOS): 526 [M + H] +, 548 [M + Na] +; 1 H-NMR (CD3OD, 200 MHz): 7.36 (t, J = 3.8 Hz, 2), 7.17-7.23 (m, 10), 7.10 (d, J = 3.6 Hz, 2), 5.20 (d, J = 3.6 Hz , 1), 4.09 (m, 3), 3.93 (d, J = 2.2 Hz, 1), 3.82 (m, 2), 3.46 (m, 2), 2.01 (s, 3), 2.00 (m, 1) , 1.71 (m, 1), 1.46-1.36 (m, 4), 0.96-0.90 (m, 9).

EXAMPLE 37 Preparation of 4- (4,4-difluoro-pentiP-pyrrolidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propip-amide of 4- (4,4-difluoro-pentiP-pyrrolidine -2- carboxylic acid To a solution of the aldehyde 8a, prepared by the first step of Method L, (510 mg, 1.47 mmol, 1 equiv) in benzene (8 ml) was added 1-triphenylphosphoranylidene-2-propanone (Aldrich) (702 mg, 2.2 mmol, 1.5 equiv.) The reaction mixture was heated to reflux overnight and the solvent was removed in vacuo.The residue was purified by chromatography to give the ester of 1-tert-butyl ester and 2-methyl ester. of 4- (4-oxo-pent-2-enyl) -pyrrolidine-1,2-dicarboxylic acid (237 mg, 42%). MS (ESPOS): 410.2 [M + Na] +, 288.3 [M-Boc + H] +; MS (ESNEG): 386.2 [MH] ". To a solution of the ester of 1-tert-butyl ester and 2-methyl ester of 4- (4-oxo-pent-2-enyl) -pyrrolidine- 1,2-dicarboxylic acid (193 mg, 0.5 mmol, 1 equiv) in benzene (0.9 ml) was added a solution of triphenylphosphine hexamer-hydride of copper (I) in benzene (3.6 ml). The mixture was stirred at t.a. overnight and hexane (13 ml) was added. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography to give the 1- tert -butyl ester and 4- (4-oxo-pentyl) -pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (127 mg, 65%). 1 H NMR (300 MHz, CDCl 3) d 7.35-7.30 (m, 5), 5.25-5.04 (m, 2), 4.42-4.25 (m, 1), 3.77-3.62 (m, 1), 3.00-2.85 (m , 1), 2.39 (t, J = 7.2), 2.34-1.47 (m, 7), 2.10 (s, 3), 1.43 (s, 3H), 1.31 (s, 6H); MS (ESPOS): 412.3 [M + Na] +, 290.3 [M-Boc + H] +; MS (ESNEG): 388.4 [MH] ". To a solution of the ester of 1-tert-butyl ester and 2-methyl ester of 4- (4-oxo-pentyl) -pyrrolidine-1,2-dicarboxylic acid (155 mg 0.40 mmol, 1 equiv) in dichloromethane (1.5 ml) at -78 ° C was added DAST (0.21 ml, 1.60 mmol, 4 equiv.) The reaction mixture was warmed to RT and stirred at RT for 3 h. h, followed by the addition of additional DAST (0.32 ml, 2.4 mmol, 6 equiv) at -78 ° C. The mixture was warmed to rt and stirred overnight, then the mixture was diluted with dichloromethane, washed with solution NaHCO3 (1X), dried and evaporated, The residue was purified by chromatography to give the ester of 1-tert-butyl ester and 2-methyl ester of 4- (4,4-difiuoro-pentyl) - pyrrolidine-1,2-dicarboxylic acid in the form of a yellow oil (88 mg, 54%). MS (ESPOS): 434.2 [M + Na] +, 312.3 [M-Boc + H] +. To a solution of the ester of 1-tert-butyl ester and 2-methyl ester of 4- (4,4-difluoro-pentyl) -pyrrolidine-1,2-dicarboxylic acid (88 mg, 0.21 mmol, 1 equiv) in THF (1.2 ml) and water (0.4 ml) was added lithium hydroxide monohydrate (45 mg, 1.07 mmol, 5 equiv). The reaction mixture was stirred at t.a. all night. The THF was removed in vacuo. The residue was diluted with water and washed with ether. The aqueous layer was taken up in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1x), brine (1x), dried and concentrated to give the 4- (4,4-difluoro-pentyl) -pyrrolidine-1-tert-butyl ester of the acid. , 2-dicarboxylic (66 mg, 96%). 1 H NMR (300 MHz, CDCl 3) d 4.39-4.34 (m, 1), 3.57-3.48 (m, 1), 2. 92-2.83 (m, 1), 2.57-2.50 (m, 1), 2.30-2.18 (m, 1), 1.91-1.73 (m, 3), 1.64-1.36 (m, 7), 1.48 (s, 9) ); MS (ESPOS): 344.3 [M + Na] +, 222.3 [M-Boc + H] +; MS (ESNEG): 320.2 [MH]. "To a solution of compound 21 b (R1 = Me, R2 = Me) (50 mg, 0.20 mmol, 1 equiv) in dry DMF (0.5 ml) at 0 ° C was added triethylamine (88.3 μl, 0. 64 mmoles, 3.2 equiv), followed by the addition of BSTFA (79.2 μl, 0.30 mmoles, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. last 50 minutes. The reaction mixture was added to the acid (66 mg, 0.21 mmol, 1 equiv) in a 25 ml round bottom flask, followed by the addition of HATU (96.8 mg, 0.25 mmol, 1.25 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid, saturated NaHCO 3 solution and brine. The organic layer was dried over Na2SO4 and evaporated and used in the next step without further purification. To a solution of the Boc-protected lincosamide above in DCM (9 ml) with methyl sulfide (0.20 ml) were added trifluoroacetic acid (3 ml) and water (0.20 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was evaporated in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give the title compound (68 mg, 75%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.4, 1), 4.16 (dd, J = 3.3, 9.9, 1), 4.11-4.00 (m, 3), 3.75 (d, J = 3.3, 1), 3.51 (dd, J = 3.3, 10.2, 1), s 3.40-3.32 (m, 1), 2.71 (dd, J = 8.2, 10.6, 1), 2.23-2.05 (, 3), 2.10 (s) , 3), 1.98-1.76 (m, 3), 1.63-1.39 (m, 7), 0.94-0.87 (m, 6). MS (ESPOS): 455.3 [M + H] +.

EXAMPLE 38 Preparation of 4- (3,3-difluoro-butyl) -pyrrolidine-2-methyl-3- (3,4-trihydroxy-6-methylsulfanyl-tetrahydro-0-pyran-2-yl) -propyl-amide of the acid - carboxylic Ethyltriphenylphosphonium bromide (Aldrich) (2.92 g, 7.86 mmol, 3.9 equiv) and potassium t-butoxide (0.61 g, 5.44 mmol, 2.7 equiv) in toluene (26 mL) were suspended under nitrogen with vigorous stirring. After 0 to 4 h, a solution of the aldehyde 8a prepared by the first step of Method L (700 mg, 2.01 mmol, 1 equiv) in toluene (17 ml) was added dropwise. The reaction mixture was stirred at t.a. for 2 h and diluted with ethyl acetate (150 ml). The organic layer was washed with water (2x), brine, dried and concentrated. The residue was purified by chromatography to give a clear oil, 1-tert-butyl ester and 2-mephile ester of 4-but-2-enyl-pyrrolidine-1,2-dicarboxylic acid (360 mg, 50%). MS (ESPOS): 260.3 [M + H - Bocf. To a solution of the 1-tert-butyl ester and 2-methyl ester of 4-but-2-enyl-pyrrolidine-1,2-dicarboxylic acid (149 mg, 0.42 mmol, 1 equiv) in DMF (1.4 ml) and water (0.2 ml) was added palladium (II) chloride (7.4 mg, 0. 042 mmol, 0.1 equiv) and copper (I) chloride (41.1 mg, 0.42 mmol, 1 equiv). The mixture was stirred at 50 ° C overnight with bubbling of oxygen in the mixture. The mixture was filtered and the filtrate was concentrated under high vacuum. The residue was diluted with ethyl acetate, washed with water (1x), brine (1x), dried and concentrated. The residue was purified by preparative TLC to give the 1-tert-butyl ester and 4- (3-oxo-butyl) -pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (110 mg, 71%). 1 H NMR (300 MHz, CDCl 3) d 7.35-7.28 (m, 5), 5.24-5.03 (m, 2), 4. 43-4.25 (m, 1), 3.75-3.61 (m, 1), 3.01-2.87 (m, 1), 2.44-2.35 (m, 2), 2.28-2.15 (m, 1), 2.11 (s, 3 ), 2.09-1.98 (m, 1), 1.91-1.51 (m, 3), 1.43 (s, 3.4 H), 1.31 (s, 5.6 H). MS (ESPOS): 398.3 [M + Na] +, 276.3 [M-Boc + H] +. To a solution of the ester of 1-tert-butyl ester and 2-methyl ester of 4- (3-oxo-butyl) -pyrrolidine-1,2-dicarboxylic acid (110 mg, 0.29 mmol, 1 equiv) in dichloromethane (1.1 ml) at -78 ° C was added DAST (0.16 ml, 1.17 mmol, 4 equiv). The reaction mixture was heated to t.a. for 3 h, followed by the addition of additional DAST (0.23 ml, 1.76 mmol, 6 equiv) at -78 ° C. The mixture was heated to t.a. and it stirred all night. Then the mixture was diluted with dichloromethane, washed with saturated aqueous solution of NaHCO 3 (1X), dried and evaporated. The residue was purified by chromatography to give the 1-tert-butyl ester and 4- (3,3-difluoro-butyl) -pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (92.7 mg, 80%) . MS (ESPOS): 420.3 [M + Na] +. To a mixture of the ester of 1-tert-butyl ester and 2-methyl ester of 4- (3,3-difluoro-butyl) -pyrrolidine-1,2-dicarboxylic acid (92.7 mg, 0.23 mmol, 1 equiv) in THF (1.2 ml) and water (0.4 ml) was added lithium hydroxide monohydrate (49 mg, 1.17 mmol, 5 equiv). The reaction mixture was stirred at t.a. overnight, and the THF was removed in vacuo. The residue was diluted with water, and washed with ether. The aqueous layer was taken up in ethyl acetate, and partitioned with 10% citric acid. The organic layer was washed with water (1x), brine (1x), dried and concentrated to give a white solid, 4- (3,3-difluoro-butyl) -pyrrolidine-1-tert-butyl ester. -1, 2-dicarboxylic (59.7 mg, 83%). 1 H NMR (300 MHz, CDCl 3) d 4.40-4.36 (m, 1), 3.59-3.52 (, 1), 2.94-2.86 (m, 1), 2.55-2.48 (m, 1), 2.33-2.15 (m, 1), 1.92-1.73 (m, 3), 1.66-1.40 (m, 5), 1.47 (s, 9); MS (ESPOS): 330.2 [M + Na] +, 208.2 [M-Boc + H] +; MS (ESNEG): 306.1 [MH]. "To a solution of compound 2b (R1 = Me, R2 = Me) (50 mg, 0.20 mmol, 1 equiv) in dry DMF (0.5 ml) at 0 ° C was added triethylamine (88.3 μl, 0.64 mmol, 3.2 equiv), followed by the addition of BSTFA (79.2 μl, 0.30 mmol, 1.5 equiv.) The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at rt for 50 minutes. minutes The reaction mixture was added to the 4- (3,3-difluoro-butyl) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (59.7 mg, 0.20 mmol, 1 equiv) in a flask. 25 ml round bottom, followed by the addition of HATU (93.3 mg, 0.25 mmol, 1.25 equiv.) The reaction mixture was stirred at RT for 3 h.The reaction mixture was evaporated to dryness, taken up in Ethyl was washed with 10% citric acid, water, saturated NaHCO3 solution and brine, the organic layer was dried over Na2SO and evaporated to give a syrup to a solution of the above syrup in DCM (9 ml) with sodium sulphide. dimeti lo (0.20 ml) were added trifluoroacetic acid (3 ml) and water (0.20 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to give the title compound (63 mg, 72%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.22-4.13 (m, 2), 4.10-4.04 (m, 2), 3.76 (d, J = 2.4, 1), 3.54-3.42 (m, 2), 2.84-2.76 (m, 1), 2.29-1.83 (m, 5), 2.10 (s, 3), 1.67-1.51 (m, 6), 0.95-0.87 (m, 6). MS (SPOS): 441.3 [M + Hf.

EXAMPLE 39 Preparation of 4- (313-difluoro-pentiP-pyrrolidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propip-amide) To a solution of compound 7c (R9 = 2-pentenyl) prepared using the methods of Method K (323.7 mg, 0.87 mmol, 1 equiv) in DMF (2.8 ml) and water (0.4 ml) at 0 ° C was added palladium (II) (15.4 mg, 0.087 mmol, 0.1 equiv) and copper chloride (I) (85.9 mg, 0.87 mmol, 1 equiv). The mixture was stirred at 50 ° C overnight with bubbling of oxygen in the mixture. The mixture was filtered and the filtrate was concentrated under high vacuum. The residue was diluted with ethyl acetate, washed with water (1x), brine (1x), dried and concentrated. The residue was purified by preparative TLC to give the ester of 1-tert-buíilo and 2-methyl ester of 4- (3-oxo-pentyl) -pyrrolidine-1,2-dicarboxylic acid (242 mg, 72%). MS (ESPOS): 412.3 [M + Na] +, 290.3 [M-Boc + H] +. To the ester of 1-tert-butyl ester and 2-methyl ester of 4- (3-oxo-pentyl) -pyrrolidine-1,2-dicarboxylic acid (242 mg, 0.62 mmol, 1 equiv) in dichloromethane (2.3 ml) -78 ° C DAST (0.33 ml, 2.49 mmol, 4 equiv) was added. The reaction mixture warmed to t.a. and stirred at t.a. for 3 h, followed by the addition of more DAST (0.49 ml, 3.73 mmoles, 6 equiv) at -78 ° C. The mixture was heated to t.a. and it stirred all night. Afterwards, the mixture Diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution (1x), dried and evaporated. The residue was purified by chromatography to give the 1-tert-butyl ester and 4- (3,3-difluoro-pentyl) -pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (117 mg, 46%). . 1 H NMR (300 MHz, CDCl 3) d 7.35-7.26 (m, 5), 5.25-5.04 (m, 2), 4. 44_4.27 (m, 1), 3.79-3.64 (m, 1), 3.02-2.89 (m, 1), 2.32-2.17 (m, 1), 2.13-2.02 (m, 1), 1.91-1.68 (m) , 5), 1.57-1.47 (m, 2), 1.44 (s, 3.5H), 1.31 (s, 5.5 H), 0.97 (t, J = 7.5, 3). MS (ESPOS): 434.3 [M + Na] +, 312.3 [M-Boc + H] +. To a solution of the ester of 1-tert-buíilo and ester of 2- (3,3-difluoro-pentyl) -pyrrolidine-1,2-dicarboxylic acid 2-methyl ester (106 mg, 0.26 mmol, 1 equiv) in THF (2.4 ml) and water (0.8 ml) was added lithium hydroxide monohydrate (54 mg, 1.29 mmol, 5 equiv). The reaction mixture was stirred at t.a. overnight, and the THF was removed in vacuo. The residue was diluted with water (10 ml), and washed with ether (20 ml). The aqueous layer was taken up in ethyl acetate (50 ml), and partitioned with 10% citric acid (25 ml). The organic layer was washed with water (1x), brine (1x), dried and concentrated to give the 4- (3,3-difluoro-pentyl) -pyrrolidine-1-tert-butyl ester of the acid, 2-dicarboxylic acid in the form of a clear oil (82.1 mg, 99%). 1 H NMR (300 MHz, CDCl 3) d 4.40-4.36 (m, 1), 3.58-3.51 (m, 1), 2. 94-2.86 (m, 1), 2.57-2.51 (m, 1), 2.30-2.15 (m, 1), 1.92-1.72 (m, 5), 1.62-1.53 (m, 2), 1.48 (s, 9 ), 0.99 (t, J = 7.5, 3); MS (ESPOS): 344.3 [M + Na] +, 222.3 [M-BOC + H] +. To a solution of compound 2b (R1 = Me, R2 = Me) (50 mg, 0.20 mmol, 1 equiv) in dry DMF (0.5 ml) at 0 ° C was added triethylamine (88.3 μl, 5 0.64 mmol, 3.2 equiv) , followed by the addition of BSTFA (79.2 μl, 0.30 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. for 50 minutes. The reaction mixture was added to the 4- (3,3-difluoro-pentyl) -pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester (76.6 mg, 0.24 mmol, 1.2 equiv) in a bottom flask or round 25 ml, followed by the addition of HATU (111.9 mg, 0.29 mmol, 1.5 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (60 ml), washed with 10% citric acid (30 ml), water (30 ml), saturated NaHC 3 solution (30 ml) and brine. The organic layer was dried over Na2SO4 and evaporated to give a yellow oil. To a solution of the above oil in DCM (9 ml) with methyl sulfide (0.20 ml) were added trifluoroacetic acid (3 ml) and water (0.20 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by or chromatography to give the title compound (72 mg, 80%) in the form of a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.20-4.04 (m, 4), 3.76 (d, J = 2.7, 1), 3.51 (dd, J = 3.4, 10.3, 1), 3.43 (dd, J = 6.9, 10.8, 1), 2.77 (dd, J = 8.4, 10.8, 1), 2.30-2.05 (m, 3), 2.10 (s, 3), 2.03-1.76 (m , 5), 1.64- 1.54 (m, 2), 1.03-0.89 (m, 9); MS (ESPOS): 455.4 [M + H] +.

EXAMPLE 40 Preparation of 4- (3,3-difluoro-pentiP-1- (2-hydroxy) f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (3,3-difluoro-pentiP-1- (2-hydroxy) acid -ethyl) - To a solution of the product of Example 42 (17.9 mg, 0.039 mmol) in MeOH (2 mL) at 0 ° C was added ethylene oxide (0.4 mL). The reaction mixture was stirred at 4 ° C overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (8.2 mg, 42%). 1 H NMR (300 MHz, CD3OD) d 5.23 (d, J = 5.7, 1), 4.13-4.05 (m, 3), 3.75 (d, J = 3.6, 1), 3.72-3.57 (m, 2), 3.53 (dd, J = 3.3, 10.2, 1), 3.41-3.36 (m, 1), 3.22 (dd, J = 3.3,10.8, 1), 2.88-2.78 (m, 1), 2.63-2.54 (m, 1 ), 2.18-1.99 or 4), 2.10 (s, 3), 1.93-1.75 (m, 5), 1.57-1.46 (m, 2), 1.01-0.90 (m, 9); MS (ESPOS): 499.6 [M + H] +; MS (ESNEG): 497.5 [M-H] ".

EXAMPLE 41 Preparation of 4- (313-difluoro-propiP-piperidine-2-carboxylic acid. 2- methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) Compound 14c (R9 = 2,2-difluoroethyl) is prepared using the methods described in Method R. To a dry flask was added compound 14a (1.4 g, 5.32 mmol, 1 equiv), triphenylphosphine (111.6 mg, 0.43 mmol) , 0.08 equiv), copper iodide (I) (81 mg, 0.43 mmol, 0.08 equiv), palladium acetate (47.7 mg, 0.21 mmol, 0.04 equiv) and triethylamine (20 ml). The mixture was degassed with nitrogen, followed by the addition of diethylacetal of propiolaldehyde (1.36 g, 10.65 mmol, 2 equiv). The reaction mixture was stirred at t.a. for 3 h. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give a yellow oil, compound 14b (R9 '= 3,3-diethoxy-prop-1-ynyl) (1.4 g, 100%). 1 H NMR (300 MHz, CDCl 3) d 8.69 (dd, J = 0.8, 5.0, 1), 8.15 (dd, J = 0.8, 1.4, 1), 7.49 (dd, J = 1.7, 5.0, 1), 5.48 ( s, 1), 3.99 (s, 3), 3.82-3.73 (m, 2), 3.71-3.62 (m, 2), 1.26 (t, J = 7.2, 6). MS (ESPOS): 264.5 [M + H] +. To a solution of product 14b (R9 '= 3,3-diethoxy-prop-1-ynyl) s (1.4 g, 5.32 mmol) in methanol (100 ml) was added palladium on charcoal. % (0.3 g). The mixture was purged and charged with hydrogen (1 atm) and stirred at r.t. all night. The palladium was removed by filtration and the filtrate was concentrated to give the product 14c (R 9 = 3,3-diethoxypropyl) as an oil (1.39 g, 98%). 0 1 H NMR (300 MHz, CDCl 3) d 8.60 (d, J = 5.1, 1), 7.98 (d, J = 0.9, 1), 7.31-7.28 (m, 1), 4.45 (t, J = 5.4, 1), 3.98 (s, 3), 3.72-3.58 (m, 2), 3.52-3.39 (m, 2), 2.79- 2.72 (m, 2), 1.99-1.90 (m, 2), 1.22-1.15 (m, 6). To the mixture of product 14c (R 9 = 3,3-diethoxy-propyl) (0.68 g, 2.55 mmol) in acetic acid (8 ml) and water (2 ml) was added concentrated hydrochloric acid (2 drops). The mixture was stirred at t.a. overnight and the solvent was removed under high vacuum. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution (1x), brine (1x). The organic layer was dried and concentrated to give 4- (3-oxo-propyl) -pyridine-2-carboxylic acid methyl ester as a yellow oil (0.27 g, 55%). To a solution of 4- (3-oxo-propyl) -pyridine-2-carboxylic acid methyl ester (0.27 g, 1.4 mmol, 1 equiv) in DCM (5 mL) at -78 ° C was added DAST (0.91 g). g, 5.6 mmoles, 4 equiv). The mixture was heated to t.a. and it stirred all night. The mixture was diluted with dichloromethane (60 ml), washed with saturated aqueous NaHCO3 solution (1x), dried and evaporated. The residue was purified by preparative TLC (MeOH in 5% DCM) to give 4- (3,3-difluoro-propyl) -pyridine-2-carboxylic acid methyl ester (137 mg, 45%): s NMR 1H (300 MHz, CDCl 3) d 8.64 (d, J = 5.1, 1), 8.00-7.98 (m, 1), 7.33-7.29 (m, 1), 5.85 (dddd, J = 4.1, 4.1, 56.4, 56.4, 1), 3.99 (s, 3), 2.90- 2.83 (m, 2), 2.28-2.09 (m , 2); MS (ESPOS): 216.4 [M + H] +. To a solution of 4- (3,3-difluoropropyl) -pyridine-2-carboxylic acid methyl ester (130 mg, 0.6 mmol) (or compound 14c (R9 = or 2, 2-difluoroethyl) prepared in the previous steps) in MeOH (3 ml) and water (3 ml) were added concentrated HCl (0.25 ml, 3.0 mmol, 5 equiv) and platinum oxide (65 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give a clear syrup. To the previous residue were added 2N NaOH (1.21 ml) and t-butyl alcohol (0.7 ml). The reaction mixture was stirred at t.a. for 2 h. Then di-t-butyl dicarbonate (0.16 g, 0.73 mmol) was added. The mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water (10 ml), washed with ether (20 ml). The aqueous layer was acidified with 2 N HCl until pH = 2.0, and extracted with ethyl acetate (2x). The combined organic layers were dried and concentrated to give the 4- (3,3-difluoro-propyl) -piperidine-1, 2-dicarboxylic acid 1-tert-butyl ester as a clear syrup (163 mg, 88 mg). %) 1 H NMR (300 MHz, CDCl 3) d 5.77 (dddd, J = 4.2, 4.2, 56.6, 56.6, 1), 4.34 (i, J = 6.4, 1), 3.62-3.50 (m, 1), 3.41- 3.30 (m, 1), 2.05-1.96 (m, 1), 1.92-1.73 (m, 4), 1.70-1.60 (m, 1), 1.52-1.32 (m, 3), 1.43 (s, 9); MS (ESPOS): 330.5 [M + Na] +; MS (ESNEG): 306.5 [M-H] ". To a mixture of the HCl salt of compound 2b (R1 = Me, R2 = Me) (140 mg, 0.49 mmol, 1 equiv) in dry DMF (1.2 ml) at 0 ° C was added triethylamine (0.34 ml, 2.43 mmol, 5 equiv), followed by the addition of BSTFA (0.20 ml, 0.74 mmoles, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. for 50 minutes. To the reaction mixture were added the 4- (3,3-difluoro-propyl) -piperidine-1,2-dicarboxylic acid 1-tert-buffyl ester (153 mg, 0.50 mmol, 1.0 equiv) and HATU (235 mg, 0.62 mmol, 1.26 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1x), water (1x), saturated NaHCO3 solution (1x) and brine. The organic layer was dried over Na 2 SO and evaporated to give a pink syrup which was used without purification. To a solution of the above syrup in DCM (15 ml) with methyl sulfide (0.33 ml) were added trifluoroacetic acid (5 ml) and water (0.33 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to provide the title compound (lower isomer, 93 mg, 43%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.90 (dddd, J = 4.2, 4.2, 56.7, 56. 7, 1), 5.24 (d, J = 6.1), 4.21 (dd, J = 3.5, 9.8, 1), 4.11-4.04 (m, 2), 3.84-3.77 (m, 2), 3.51 (dd, J = 3.2, 10.3, 1), 3.45-3.37 (m, 1), 3.07-2.98 (m, 1), 2.23-2.12 (m, 2), 2.11 (s, 3), 1.98-1.66 (m, 4), 1.52-1.26 (m, 4), 0.94-0.88 (m, 6). MS (ESPOS): 441.7 [M + H] +.

EXAMPLE 42 Preparation of 4- (4,4-difluoro-butyl) -piperidine r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (4,4-difluoro-butyl) -piperidine -2- carboxylic To a solution of methyl sulphoxide (0.58 ml, 8.16 mmol, 2.4 equiv) in dichloromethane (1.8 ml) at -72 ° C was added a solution of 2 M oxalyl chloride in dichloromethane (2.04 ml, 4.08 mmol, 1.2 equiv) in a period of 1 minute. The mixture was stirred at -72 ° C for 25 minutes, followed by the dropwise addition of a solution of the alcohol 14c (R9 = 4-hydroxybutyl), prepared using the procedures of Method R, (0.71 g, 3.4 mmol, 1 equiv) in dichloromethane (4.8 ml) over a period of 2 minutes. The reaction mixture was stirred at -72 ° C for 25 minutes, then warmed to -50 ° C and stirred for an additional 2 h. Triethylamine (1.89 ml, 13.6 mmol, 4.0 equiv) was added and stirred at -50 ° C for 25 minutes. The mixture was diluted with ethyl acetate, washed with water (1x), saturated aqueous solution of NaHCO 3 (1x), brine (1x), dried, and evaporated and coevaporated with anhydrous toluene to give the aldehyde, methyl ester of 4- (4-oxo-butyl) -pyridine-2-carboxylic acid in the form of an oil (0.66 mg, 94%). 1 H NMR (300 MHz, CDCl 3) d 9.78 (s, 1), 8.62 (d, J = 5.1, 1), 7.97 (s, 1), 7.29 (d, J = 5.1, 1), 3.99 (s, 3 ), 2.72 (t, J = 7.8, 2), 2.50 (t, J = 7.2, 2), 2.04-1.93 (m, 2); MS (ESPOS): 230.4 [M + Na] +. To a solution of 4- (4-oxo-butyl) -pyridine-2-carboxylic acid methyl ester (0.66 g, 3.19 mmol, 1 equiv) in DCM (12 mL) at -78 ° C was added DAST (1.69 ml, 12.75 mmoles, 4 equiv). The mixture was heated to t.a. and it stirred all night. The mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution (1 x), brine (1 x), dried and evaporated. The residue was purified by chromatography to give the methyl ester of 4- (4,4-difluorobutyl) -pyridine-2-carboxylic acid (0.54 g, 74%). 1 H NMR (300 MHz, CDCl 3) d 8.62 (d, J = 5.1, 1), 7.97-7.95 (m, 1), 7.29-7.26 (m, 1), 5.81 (dddd, J = 3.9, 3.9, 56.6, 56.6, 1), 3.98 (s, 3), 2.74 (t, J 7.2, 2), 1.93-1.77 (m, 4). MS (ESPOS): 230.4 [M + H] +, 252.4 [M + Na] +. To a mixture of 4- (4,4-difluorobutyl) -pyridine-2-carboxylic acid methyl ester (0.54 g, 2.36 mmol, 1 equiv) in MeOH (8 mL) and water (8 mL) was added concentrated HCl (0.59 ml, 7.07 mmol, 3 equiv) and platinum oxide (0.2 g). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give a residue: MS (ESPOS): 236.6 [M + H] +. To the residue prepared above was added 2N NaOH (4.72 ml) and t-butyl alcohol (2.5 ml). The reaction mixture was stirred at t.a. for 2 h. Then di-t-butyl dicarbonate (0.77 g) was added, 3.54 mmol). The mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water (10 ml), washed with ether (20 ml). The aqueous layer was acidified with 2N HCl to pH 2.0, and extracted with ethyl acetate (2x). The combined organic layers were dried and concentrated to give the 4- (4,4-difluoro-butyl) -piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.67 g, 89%). 1 H NMR (300 MHz, CDCl 3) d 5.77 (dddd, J = 4.3, 4.3, 56.8, 56.8, 1), 4.30 (t, J = 6.8, 1), 3.58-3.47 (m, 1), 3.41-3.31 ( m, 1), 2.05-1.96 (m, 1), 1.87-1.68 (m, 4), 1.65-1.56 (m, 1), 1.51-1.30 (m, 5), 1.43 (s, 9); MS (ESPOS): 344.5 [M + Na] +. To a mixture of the HCl salt of compound 2b (R1 = Me, R2 = Me) (153 mg, 0.53 mmol, 1 equiv) in dry DMF (1.3 ml) at 0 ° C was added triethylamine (0.37 ml, 2.66 mmol) , 5 equiv), followed by the addition of BSTFA (0.21 ml, 0.80 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. for 50 minutes. To the reaction mixture were added the ester of 1-tert-butyl 4- (4,4-difluorobutyl) -piperidine-1,2-dicarboxylic acid (196 mg, 0.61 mmol, 1.15 equiv) and HATU (293 mg, 0.77 mmoles, 1.45 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1x), water (1x), saturated NaHC 3 solution (1x) and brine. The organic layer was dried over Na 2 SO and evaporated to give a syrup. The residue was dissolved in methanol (20 ml), and then washed and dried Dowex resin (100 mg) was added. The reaction mixture was stirred at t.a. for 30 minutes, and filtered. The filtrate was concentrated to give a clear syrup, which was purified by chromatography to give a clear syrup (0.25 g, 85%). MS (ESPOS): 555.8 [M + H]. To a solution of the above syrup in DCM (15 ml) with methyl sulfide (0.33 ml) were added trifluoroacetic acid (5 ml) and water (0.33 ml). The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to provide the title compound (lower isomer, 70 mg, 34%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.88 (dddd, J = 4.4, 4.4, 57, 57, 1), 5.24 (d, J = 5.4, 1), 4.20 (dd, J = 3.2, 10.1, 1,) , 4.12-4.03 (m, 2), 3.90-3.80 (m, 2), 3.52 (dd, J = 3.5, 10.3, 1), 3.46-3.39 (m, 1), 3.09-2.98 (m, 1), 2.25-2.12 (m, 2), 2.11 (s, 3), 1.98-1.67 (m, 4), 1.56-1.30 (m, 6), 0.95-0.87 (m, 6); MS (ESPOS): 455.7 [M + Hf.

EXAMPLE 43 Preparation of 4- (5,5-difluoro-pentiP-piperidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) Method R is used to prepare compound 14c (R9, = 5-hydroxy-pentyl) (Compound 14a (2 g, 7.60 mmol, 1 equiv), triphenylphosphine (159.4 mg, 0.61 mmol, 0.08 equiv) was added to a dry maltree, copper iodide (I) (115.8 mg, 0.61 mmol, 0.08 equiv), palladium acetate (68.2 mg, 0.30 mmol, 0.04 equiv) and triethylamine (28 ml) The mixture was degassed with nitrogen, followed by the addition of 4 -pentin-1-ol (1.28 g, 15.21 mmol, 2 equiv.) The mixture was stirred overnight.The solvent was removed in vacuo to give a dark residue.The residue was purified by chromatography to give the product 14b (R9, = 5-hydroxypent-1-ynyl) To a solution of 14b (R9, = 5-hydroxypent-1-ynyl) in methanol (60 ml) 10% palladium on charcoal (0.62 g) was added. The mixture was purged and charged with hydrogen (1 atm) and stirred overnight at t.a. The palladium was removed by filtration and the filtrate was concentrated to give a yellow oil 14c (R9 = 5-hydroxypentyl) (1.34 g, 79%). 1 H NMR (300 MHz, CDCl 3) d 8.62 (d, J = 4.8, 1), 7.97 (s, 1), 7.31 (dd, J = 1.6, 5, 1), 3.99 (s, 3), 3.63 (t , J = 6.5, 2), 2.70 (t, J = 7.7, 2), 1.74-1.53 (m, 4), 1.46-1.34 (m, 2). To a solution of methyl sulphoxide (0.46 ml, 6.42 mmol, 2.6 equiv) in dichloromethane (1.4 ml) at -72 ° C was added a solution of 2 M oxalyl chloride in dichloromethane (1.61 ml, 3.21 mmol, 1.3 equiv) in a period of 1 minute. The mixture was stirred at -72 ° C for 25 minutes, followed by the dropwise addition of a solution of pyridine 14c (R9 = 5-hydroxypentyl) (0.55 g, 2.47 mmol, 1 equiv) in dichloromethane (3.8 ml) in a period of 2 minutes. The reaction mixture was stirred at -72 ° C for 25 minutes, then warmed to -50 ° C and stirred for an additional 2 h. Triethylamine (1.48 ml, 10.7 mmol, 4.33 equiv) was added and stirred at -50 ° C for 25 minutes. The mixture was diluted with ethyl acetate, washed with water (2x), saturated aqueous solution of NaHCO 3 (1X), brine (1x), dried and evaporated and coevaporated with anhydrous toluene to give the methyl ester - (5-oxo-pentyl) -pyridine-2-carboxylic acid (0.48 mg, 88%). 1 H NMR (300 MHz, CDCl 3) d 9.75 (t, J = 1.4, 1), 8.61 (d, J = 5.1, 1), 7.97-7.95 (m, 1), 7.28 (dd, J = 1.7, 5.1) , 3.99 (s, 3), 2.73-2.67 (m, 2), 2.50-2.44 (m, 2), 1.71-1.63 (m, 4). To a solution of the 4- (5-oxo-pentyl) -pyridine-2-carboxylic acid methyl ester oil (0.48 g, 2.19 mmol, 1 equiv) in DCM (8 mL) at -78 ° C was added DAST (1.41 g, 8.74 mmoles, 4 equiv). The mixture was heated to t.a. and it stirred all night. The mixture was diluted with dichloromethane, and washed with saturated aqueous solution of NaHCO 3 (1X), dried and evaporated. The residue was purified by chromatography to give 4- (5,5-difluoro-pentyl) -pyridine-2-carboxylic acid methyl ester (278 mg, 52%) 1 H-NMR (300 MHz, CDCl 3) d 8.61 (dd) , J = 0.6, 4.8, 1), 7.97-7.95 (m, 1), 7.28 (dd, J = 1.5, 4.8, 1), 5.78 (dddd, J = 4.3, 4.3, 57, 57, 1), 3.99 (s, 3), 2.70 (t, J - 7.7, 2), 1.94-1.66 (m, 4), 1.55-1.43 (m, 2). MS (ESPOS): 244.2 [M + H] +. To a mixture of 4- (5,5-difluoro-pentyl) -pyridine-2-carboxylic acid methyl ester (278 mg, 1.14 mmol) in MeOH (5 mL) and water (5 mL) were added concentrated HCl ( 0.286 ml, 3.43 mmoles, 3 equiv) and platinum oxide (140 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give the 4- (5,5-difluoro-pentyl) -piperidine-2-carboxylic acid 2-methyl ester MS (ESPOS): 250.2 [M + H ] +. To the previous residue of the 4- (5,5-difluoro-pentyl) -piperidine-2-carboxylic acid 2-methyl ester were added 2N NaOH (2.3 ml) and t-butyl alcohol (1.2 ml). The mixture was stirred at t.a. for 2 h. Then di-t-butyl dicarbonate (0.37 g, 1.72 mmol) was added. The mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water, and washed with ether. The aqueous layer was acidified with 2 N HCl to pH = 2.0, extracted with ethyl acetate (2x). The organic layers were dried and concentrated to give the 4- (5,5-difluoro-pentyl) -piperidin-1,2-dicarboxylic acid 1-tert-butyl ester (310 mg, 81%). 1 H NMR (300 MHz, CD3OD) d 5.84 (dddd, J = 4.5, 4.5, 57, 57, 1), 4.31 (t, J = 6.3, 1), 3.65-3.56 (m, 1), 3.35-3.25 ( m, 1), 2.03-1.63 (m, 5), 1.48-1.30 (m, 8), 1.43 (s, 9). To a mixture of the HCl salt of compound 2b (R1 = Me, R2 = Me) (223.7 mg, 0.78 mmol, 1 equiv) in dry DMF (1.9 ml) at 0 ° C was added triethylamine (0.54 ml, 3.89 mmol) , 5 equiv), followed by the addition of BSTFA (0.31 ml, 1.17 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. for 50 minutes. To the reaction mixture, 4- (5,5-difluoro-pentyl) -piperidine-1,2-dicarboxylic acid 1-tert-buíyl ester (272 mg, 0.81 mmol, 1.05 equiv) and HATU (391 mg) were added. , 1.03 mmoles, 1.32 equiv). The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1x), water (1x), saturated NaHCO3 solution (1x) and brine. The organic layer was dried over Na 2 SO and evaporated to give a residue. The residue was dissolved in methanol (30 ml), and then washed and dried Dowex resin (150 mg) was added. The mixture was stirred at t.a. for 1 h and filtered. The filtrate was concentrated to give a clear syrup, which was purified by chromatography to give a clear syrup (0.26 g, 72%). To a solution of the above syrup in DCM (15 ml) with methyl sulfide (0.33 ml) were added trifluoroacetic acid (5 ml) and water (0.33 ml).

The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to provide the title compound (lower isomer, 40 mg, 15%) as a white solid. H-NMR (300 MHz, CD3OD) d 5.86 (dddd, J = 4.5, 4.5, 57, 57, 1), 5.24 (d, J = 5.7, 1), 4.21 (dd, J = 3.3, 9.9, 1), 4.11-4.04 (m, 2), 3.86-3.78 (m, 2), 3.51 (dd, J = 3.5, 10.4, 1), 3.47-3.38 (m, 1), 3.07-2.97 (m, 1), 2.23 -2.12 (m, 2), 2.11 (s, 3), 1.98-1.64 (m, 4), 1.50-1.27 (m, 8), 0.94-0.87 (m, 6); MS (ESPOS): 469.4 [M + H] +.

EXAMPLE 44 Preparation of 4- (5-fluoro-pentyl) -piperidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl-amide) To a solution of compound 14c (R9 = 5-hydroxypentyl) (0.66 g, 2.96 mmol, 1 equiv), prepared as described in Method R and in the synthesis of Example 47, in DCM (11 mL) at -78 ° C C was added DAST (1.91 g, 11.85 mmol, 4 equiv). The mixture was heated to t.a. and it stirred all night. The mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution (1x), dried and evaporated. The residue was purified by chromatography to give 4- (5-fluoro-pentyl) -pyridine-2-carboxylic acid methyl ester (254 mg, 38%) 1 H-NMR (300 MHz, CDCl 3) d 8.62 (d, J = 4.8, 1), 7.97 (d, J = 1.2, 1), 7.30 (dd, J = 1.7, 5, 1), 4.50 (t, J = 5.9, 1), 4.34 (t, J = 6, 1 ), 3.99 (s, 3), 2.70 (t, J = 7.7, 2), 1.80-1.62 (m, 4), 1.50-1.41 (m, 2). To a mixture of 4- (5-fluoro-pentyl) -pyridine-2-carboxylic acid methyl ester (254 mg, 1.13 mmol) in MeOH (5 ml) and water (5 ml) was added concentrated HCl (0.28 ml). , 3.39 mmoies, 3 equiv) and platinum oxide (130 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give the 4- (5-fluoro-pentyl) -piperidine-2-carboxylic acid 2-methyl ester. MS (Spores): 232.4 [M + H] +. To the 2-methyl ester of 4- (5-fluoro-pentyl) -piperidine-2-carboxylic acid was added 2N NaOH (2.43 ml) and t-butyl alcohol (1.3 ml). The reaction mixture was stirred at t.a. for 2 h. Then di-t-butyl dicarbonate (0.40 g, 1.82 mmol) was added. The mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water, and washed with ether. The aqueous layer was acidified with 2 N HCl to pH = 2.0, and extracted with ethyl acetate (2x). The combined organic layers were dried and concentrated to give the 4- (5-fluoro-pentyl) -piperidine-1,2-dicarboxylic acid ester-1-tert-buíyl ester in the form of a syrup (254 mg, 71%). ' 1 H NMR (300 MHz, CDCl 3) d 4.52-4.06 (m, 3), 3.55-3.30 (m, 2), 2.03-1.94 (m, 1), 1.81-1.54 (m, 4), 1.45-1.20 (m , 8), 1.43 (s, 9). MS (ESPOS): 218.3 [M + Na-Boc] +. To a mixture of the HCl salt of compound 2b (R1 = Me, R2 = Me) (213.8 mg, 0.74 mmol, 1 equiv) in dry DMF (1.8 ml) at 0 ° C was added triethylamine (0.52 ml, 3.72 mmol) , 5 equiv), followed by the addition of BSTFA (0.30 ml, 1.12 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes, and then stirred at r.t. for 50 minutes. To the reaction mixture were added the ester of 1-tert-butyl 4- (5-fluoro-pentyl) -piperidine-1,2-dicarboxylic acid in the form of a syrup (244 mg, 0.77 mmol, 1.04 equiv) and HATU (370 mg, 0.97 mmol, 1.31 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1x), water (1x), saturated NaHC 3 solution (1x) and brine. The organic layer was dried over Na2SO4 and evaporated to give a residue. The residue was dissolved in methanol (30 ml), and then washed and dried Dowex resin (140 mg) was added. The reaction mixture was stirred at t.a. for 1 h and filtered. The filtrate was concentrated to give a clear syrup, which was purified by chromatography to give a clear syrup (212 mg, 52%). To a solution of the above syrup in DCM (15 ml) with methyl sulfide (0.33 ml) were added trifluoroacetic acid (5 ml) and water (0.33 ml).

The reaction mixture was stirred at t.a. for 1 h. The solvent was removed in vacuo and coevaporated with toluene twice. The residue was purified by chromatography to provide the title compound (lower isomer, 40 mg, 17%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.49 (t, J = . 9, 1), 4.33 (t, J = 6.1), 4.20 (dd, J = 3.5, 10.1, 1), 4.11-4.04 (m, 2), 3.83-3.77 (m, 2), 3.51 (dd, J = 3.3, 10.2, 1), 3.44-3.36 (m, 1), 3.06-2.94 (m, 1), 2.23-2.13 (m, 2), 2.11 (s, 3), 1.98-1.88 (m, 1) , 1.77-1.59 (m, 3), 1.45-1.27 (m, 8), 0.94-0.87 (m, 6). MS (ESPOS): 451.4 [M + H] +.

EXAMPLE 45 Preparation of 4- (4-fluoro-butiP-piperidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propip-amide of 4- (4-fluoro-buty-piperidine -2- carboxylic To a solution of compound 14c (R9 = 4-hydroxybutyl) (0.76 g, 3.62 mmol, 1 equiv), prepared as described in Method R and in the synthesis of Example 47, in DCM (14 mL) at -78 ° C C DAST (1.9 ml, 14.47 mmol, 4 equiv) was added. The mixture was heated to t.a. and it stirred all night. The mixture was diluted with dichloromethane, washed with saturated aqueous solution of NaHCO 3 (1x), brine (1x), dried and evaporated. The residue was purified by chromatography to give 4- (4-fluoro-butyl) -pyridine-2-carboxylic acid methyl ester as a yellow oil (0.24 g, 31%). 1 H NMR (300 MHz, CDCl 3) d 8.57 (d, J = 4.8, 1), 7.92 (d, J = 1.2, 1), 7.27-7.23 (m, 1), 4.49 (t, J = 5.6, 1) , 4.33 (t, J = 5.6, 1), 3.94 (s, 3), 2.69 (t, J = 7.5, 2), 1.79-1.59 (m, 4). To a mixture of 4- (4-fluoro-butyl) -pyridine-2-carboxylic acid methyl ester (0.24 g) in THF (3 ml) and water (1 ml) was added lithium hydroxide monohydrate (71.3 mg). , 1.7 mmoles, 1.5 equiv). The mixture was stirred at t.a. overnight and then diluted with methanol (20 ml). Then H + resin was added and the mixture was stirred for 10 minutes. The resin was washed with methanol (1x), acetonitrile / water 1: 1 (1x), and acetonitrile (1x). The product was eluted with TEA in 5% methanol (4x) and acetonitrile (1x). The combined organic solvents were evaporated and coevaporated with toluene to give 4- (4-fluoro-butyl) -pyridine-2-carboxylic acid (0.22 g, 65%). 1 H NMR (300 MHz, CD3OD) d 8.46 (d, J = 4.8, 1), 7.95 (s, 1), 7. 39-7.35 (m, 1), 4.52 (t, J = 5.6, 1), 4.36 (t, J = 5.9, 1), 3.22 (q, J = 7.3, 2.5H, TEA), 2.77 (t, J = 7.5, 2), 1.84-1.62 (m, 4), 1.28 (t, J = 7.2, 3.8H, TEA).

To a solution of 4- (4-fluoro-butyl) -pyridine-2-carboxylic acid (0.22 g, 0.73 mmol, 1 equiv) in dry acetonitrile (4 ml) at 0 ° C was added triethylamine (74 mg, 0.73 mmol) , 1 equiv), followed by the addition of isobutyl chloroformate (100 mg, 0.73 mmol, 1 equiv). The reaction mixture was stirred at 0 ° C for 15 minutes, and then stirred at 4 ° C for 2 h. A solution of the HCl salt of compound 2b (R1 = Me, R2 = Me) (263 mg, 0.91 mmol, 1.25 equiv) and triethylamine (93 mg, 0.91 mmol, 1.25 equiv) in acetone was added to the reaction mixture. / water 1: 1 (4 ml). The reaction mixture was stirred at 4 ° C overnight. The reaction mixture was evaporated to dryness, taken up in DCM, and washed with saturated NaHCO 3 solution (1x). The organic layer was dried over Na 2 SO and evaporated. The residue was purified by chromatography to give a clear solid (110 mg, 35%). To a solution of the above solid (110 mg, 0.25 mmol, 1 equiv) in MeOH (6 ml) and water (4 ml) was added concentrated HCl (20.2 μl, 0.24 mmol, 0.95 equiv) and platinum oxide (220 mg). . The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give a residue which was purified by chromatography to give the title compound (lower isomer, 33 mg, 30%) as a white solid. 1 H NMR (300 MHz, CD 3 OD) d 5.25 (d, J = 5.4, 1), 4.51 (t, J = 6, 1), 4.35 (t, J = 5.9, 1), 4.21 (dd, J = 3.3, 10.2, 1), 4.10-4.04 (m, 2), 3.93-3.80 (m, 2), 3.52 (dd, J = 3.3, 10.2, 1), 3.46-3.38 (m, 1), 3.11-2.98 (m , 1), 2.26-2.13 (m, 2), 2.11 (s, 3), 2.00-1.92 (, 1), 1.80-1.60 (m, 3), 1.54-1.27 (m, 6), 0.95-0.87 ( m, 6). MS (ESPOS): 437.4 [M + H] +.

EXAMPLE 46 Preparation of 4- (3-ethyl-3-hydroxy-pentyl) r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-d-propyP-amide of 4- (3-ethyl-3-hydroxy-pentyl) -piperidine-2-carboxylic acid In a dry flask, compound 13b was added (R1 = Me, R2 = Me, and R3 = H) prepared using Method Q (130 mg, 0.27 mmol, 1 equiv), triphenylphosphine (45.3 mg, 0.17 mmol, 0.64 equiv), copper iodide (I) (32.9 mg, 0.17 mmol, 0.64 equiv) ), palladium acetate (19.4 mg, 0.086 mmol, 0.32 equiv) and triethylamine (1.5 ml). The mixture was degassed with nitrogen, followed by the addition of 3-ethyl-1-pentin-3-ol (174 μl, 1.35 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = Me, R2 = Me, R3 = H, R9 = 3-Ethyl-3-hydroxy-pent-1-inyl).

MS (ESPOS): 467.7 [M + H] +; MS (ESNEG): 465.5 [MH]. "To a mixture of the above syrup in MeOH (12 ml) and water (8 ml) were added platinum oxide (300 mg) and concentrated HCl (26 μl). and charged with hydrogen (4.55 kg / cm2) and stirred overnight The platinum oxide was removed by filtration and the filtrate was evaporated The residue was purified by chromatography to give the title compound as a white solid (19 mg, 15%). 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.17 (dd, J = 3. 11, 10.0, 1), 4.10-4.02 (m, 2), 3.80 (d, J = 3, 1), 3.53-3.48 (m, 1), 3.42-3.35 (m, 1), 3.23-3.15 (m , 1), 2.75-2.64 (m, 1), 2.22-2.11 (m, 1), 2.10 (s, 3), 2.04- 1.97 (m, 1), 1.80-1.72 (m, 1), 1.50-1.40 (m, 6), 1.31-1.06 (m, 5), 0.94-0.80 (m, 12); MS (ESPOS): 477.8 [M + H] +; MS (ESNEG): 475.6 [M-H] ".

EXAMPLE 47 Preparation of 4-butoxy-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide To trimethylsilyl cyanide (5.2 g, 52 mmol), 1-oxide of 4-benzyloxy-pyridine (8.8 g, 44 mmol) in DCM (20 ml) was added, followed by dimethylcarbamoyl chloride (5.6 g, 52 mmol) in DCM (10 ml), drop by drop, was stirred at room temperature overnight. Sodium bicarbonate (100 ml, 10%) was added, stirred for 10 minutes and extracted twice with DCM (50 ml). The combined organic layers were dried over magnesium sulfate, and the solvent was removed to obtain the product, compound 10a (R9 = Benzyloxy) (10.5 g, 100%). 1 H NMR (300 MHz, CDCl 3) d 8.34 (d, J = 5.7, 1), 7.24 (m, 5), 7.11 (t, J = 2.4, 1), 6.90 (dd, J = 5.7, 2.4, 1) , MS (ESPOS): 21 1 [M + H] +. Compound 10a (R9 = Benzyloxy) (5 g, 23 mmol) was dissolved in HCl (6 N, 70 ml) and heated to reflux overnight. The crude product, 4-hydroxypyridine-2-carboxylic acid, compound 10b (R = hydroxy) obtained by separating the HCl, was crystallized from acetonitrile (2.6 g, 80%). 1 H NMR (300 MHz, CD3OD) d 8.55 (d, J = 6.6, 1), 7.78 (d, J = 3.0, 1), 6.90 (dd, J = 2.7, 6.9, 1), MS (ESNEG): 138 [MH]. "Synthesis of the title compound was completed using the synthetic sequence found in Method S starting from the acid 4. -hydroxypyridine-2-carboxylic acid, as previously prepared.H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.4, 1), 4.22 (dd, J = 10.2; 3.3, 1), 4.08 (m, 2), 3.81 (d, J = 3.0, 1), 3.70 (m, 1), 3.54 (m, 4), 3.43 (m, 2), 2.90 (m, 1) , 2.41 (m, 1), 2.19 (m, 1), 2.10 (s, 3) 1.45 (m, 6), 0.92 (m, 9); MS (ESPOS): 435 [M + H] +.

EXAMPLE 48 Preparation of 4-pentyloxy-piperidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide The title compound was prepared using the synthetic sequence found in Method S, starting from 4-hydroxypyridine-2-carboxylic acid 10b (R9 = hydroxy) substituting n-pentyl bromide as the alkylating agent. Compound 15a (R9 = pentoxy): 1 H NMR (300 MHz, CD3OD) d 8.38 (d, J = 5.1, 1), 7.64 (s, 1), 7.10 (d, J = 3.3, 1), 4.18 (t, J = 6.6, 2), 1.85 (m, 2), 1. 49 (m, 4), 0.96 (t, J = 7.2, 3). MS (ESNEG): 208 [MH] ". Compound 15b (R1 = Me, R2 = Me, R9 = pentoxy): 1 H NMR (300 MHz, CD3OD) d 8.41 (d, J = 5.7, 1), 7.61 (d , J = 2.4, 1), 7.07 (dd, J = 2.4, 5.4, 1), 5.27 (d, J = 5.4, 1), 4.05-4.31 (m, 5), 3.85 (d, J = 3.0, 1 ), 3.57 (dd, J = 3.3, 7.2, 1), 2.11 (m, 4), 1.81 (m, 2), 1.49 (m, 4), 1.00 (m, 9), EM (SPOS): 443 [ M + Hf Compound title (20 mg, 10%): 1H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.22 (dd, J = 9.9; 3.3, 1), 4.10 (m, 2), 3.76 (m, 3), 3.51 (m, 3), 3.39 (m, 1), 3.02 (m, 2), 2.43 (m, 1), 2.15 (m , 1), 2.10 (s, 3) 1.95 (m, 2), 1.69 (m, 2), 1.53 (m, 2), 1.34 (m, 2), 0.93 (m, 9); MS (ESPOS): 449 [M + H] +.

EXAMPLE 49 Preparation of 4- (4-fluoro-butoxy-piperidine-2-carboxylic acid r2-methyl-1- (3A5-tri- hydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) The title compound was prepared using the synthetic sequence found in Method S, starting from 4-hydroxypyridine-2-carboxylic acid 10b (R9 = hydroxy) substituting 4-fluorobutyl bromide as the alkylating agent. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.53 (t, J = 5.7, 1), 4.37 (t, J = 5.7, 1), 4.21 (dd, J = 3.3, 6.6, 1), 4.07 (m, 2), 3.80 (d, J = 3.3, 2), 3.60 (m, 5), 2.88 (m, 1), 2.38 (m, 1), 2.18 (m, 1) , 2.10 (s, 3) 1.33-1.83 (m, 8), 0.92 (m, 6); MS (ESPOS): 453 [M + H] +.

EXAMPLE 50 Preparation of 4-butyl-pyrrolidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iD-al-p-amide To a solution of Boc-7-Methylene-MTL (P = Boc, R1 = Me, R2 = CH2) prepared from compound 2a (P = Boc, R1 = Me) by Method D (391 mg, 1.1 mmol) in a solution of dichloroethane (10 ml) and dimethyl sulfide (0.4 ml, 2.5 mmol) was added TFA (5 ml) containing water (0.4 ml) and the reaction mixture was stirred at rt. for 45min. The solvent was removed and the residue was evaporated twice from the DCE to obtain the crude product. The product was obtained in the form of an HCl salt by precipitation with ethyl acetate (4 ml) at 0 ° C by the addition of 2 M HCl in ether, and dried under vacuum (351 mg, 86%). The white solid product was used in the next reaction without further purification. MS (Spores): 350 [M + H] +. Triethylamine (0.68 ml, 4.9 mmol, 4.0 equiv) was added, followed by BSTFA (0.58 ml, 2.20 mmol, 1.8 equiv), to a stirred suspension of the compound prepared above (351 mg, 1.22 mmol, 1 equiv) in DMF anhydrous (5 ml) at 0 ° C and under nitrogen. The resulting reaction mixture was stirred at 0 ° C for 10 min, and then at t.a. for 50 min. The resulting solution was cooled to 0 ° C and a solution of compound 7d (R9 = n-butyl) prepared by Method K (400 mg, 1.47 mmoles, 1.2 equiv) in anhydrous DMF (5 ml) was added, followed by HATU solid (741 mg, 1.95 mmol, 1.6 equiv). The reaction mixture was allowed to warm to t.a. and after 2 h the reaction solution was evaporated to dryness in vacuo. The residual oil obtained was diluted with EtOAc (200 ml), washed sequentially with 10% citric acid, saturated aqueous solution of NaHCO 3, water 1: 1, and brine, dried over Na 2 SO, and evaporated to dryness. To a 50 mg solution of the crude coupling product in 1,2-dichloroethane (6 ml), dimethyl sulfide (200 μl) was added, followed by TFA (11.5 ml), and water (768 μl). The resulting reaction mixture was stirred at t.a. for 1 h, it was evaporated to a minimum volume, diluted with DCE (3x10 ml), and evaporated to dryness. The residue was purified by column chromatography with ammonia in 0.25 M methanol in dichloromethane from 8% to 12% to provide the title compound (10.0 mg, 25%). 1 H NMR (300 MHz, CD3OD) d 5.22 (d, J = 5.8, 1), 5.00 (s, 1), 4. 95 (s, 1), 4.58 (d, J = 8.8, 1) 4.19 (d, J = 8.8, 1), 4.09 (dd, J = 5.8, 10.1, 1) 3. 85-3.77 (m, 2), 3.57-3.52 (m, 1), 3.26-3.29 (m, 1), 2.59-2.53 (m, 1), 2.10-1.98 (m, 4), 1.80 (s, 3 ), 1.36-1.51-1.11 (m, 7), 0.91 (t "J = 6.9, 3); EM (SPOS): 403. 6 [M + Hf.

EXAMPLE 51 Preparation of 1,4-diethyl-piperidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide To the product of Example 1 (30 mg, 0.07 mmol) in DMF (1 ml), DIEA (43 mg, 0.35 mmol) was added at room temperature and stirred overnight. The solvent was then removed and the resulting product was purified by column chromatography using MeOH in 20% DCM to obtain the title compound (20 mg, 66%) as a white powder. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 6.0, 1), 4.26 (dd, J = 3.6, 9.6, 1), 3.79 (d, J = 3.0, 1), 3.55 (dd, J = 3.3, 10.2, 1) 2.85 (m, 2), 2.13 (m, 4), 1.37 (m, 12), 0.94 (m, 9); MS (ESPOS): 420 [M + H] +.

EXAMPLE 52 Preparation of 4- (3-fluoro-propoxp-piperidine-2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (3-fluoro-propoxp-piperidine-2- carboxylic The title compound was prepared using the synthetic sequence found in Method S, starting from 4-hydroxypyridine-2-carboxylic acid substituting 3-fluoropropyl bromide as alkylating agent Compound 15a (R9 = 3-fluoropropoxy) : 1 H NMR (300 MHz, CD3OD) d 8.41 (d, J = 5.1, 1), 7.65 (d, J = 2.1, 1), 7.14 (dd, J = 2.1, 5.7, 1), 4.59 (m, 2), 4.24 (t, J = 6.0, 2), 1.91 (m, 2). MS (ESNEG): 212 [M-H] "Compound 15b (R1 = Me, R2 = Me, R9 = 3-fluoropropoxy): NMR 1H (300 MHz, CD3OD) d 8.44 (d, J = 5.7, 1), 7.65 (d, J = 2.4, 1), 7.12 (dd, J = 2.4, 5.7, 1), 5.48 (d, J = 5.7 , 1), 4.87 (m, 2), 4.30 (m, 2), 4.12 (dd, J = 3.0, 10.2, 1), 3. 85 (d, J = 3.3, 1), 3.56 (dd, J = 9.9, 3.3, 1), 2.26 (m, 1), 2.11 (s, 3), 1.37 (m, 4), 1. 00 (t, J = 5.11, 6). MS (ESPOS): 443 [M + H] +.

Title compound (60 mg, 31%): 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.50 (m, 2), 4.21 (dd, J = 3.3, 9.9, 1) , 4.06 (m, 2), 3.80 (d, J = 2.7, 1), 3.66 (m, 3), 3.59 (m, 1), 3.33 (m, 1), 2.87 (m, 1), 2.41 (m, 1), 2.18 (m, 1), 2.10 (s, 3) 1.91 (m, 4), 1.51 (m, 2), 0.92 (m, 6); MS (ESPOS): 439 [M + H] +.

EXAMPLE 53 Preparation of the 4- (3,3,3-trifluoro-propoxp-piperidine-2-r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-y-propyl-2-yl) -amide of the acid - carboxylic The title compound was prepared using the synthetic sequence found in General Method S from 4-hydroxypyridine-2-carboxylic acid substituting 2-trifluoroethyl bromide as the alkylating agent. Compound 15a (R 9 = 3,3,3-trifluoropropoxy): 1 H NMR (300 MHz, CD 3 OD) d 8.67 (m, 1), 7.92 (s, 1), 7.43 (m, 1), 4.65 (m, 2) , 3.01 (m, 2). MS (ESNEG): 234 [M-H] ".

Compound 15b (R1 = Me, R2 = Me, R9 = 3,3,3-trifluoropropoxy): 1 H NMR (300 MHz, CD3OD) d 8.46 (d, J = 6.0, 1), 7.65 (d, J = 2.7, 1), 7.13 (dd, J = 2.7, 6.0, 1), 5.27 (d, J = 5.7, 1), 4.39 (t, J = 6.0, 2), 4.30 (m, 2), 4.11 (m, 1), 3. 85 (d, J = 3.0, 1), 3.57 (dd, J = 3.0, 10.2, 1), 2.88 (m, 2), 2.25 (m, 1), 2.11 (s, 3), 1.00 (t, J = 6.9, 6). MS (ESPOS METHOD): 469 [M + H] +. Title compound (10 mg, 10%): 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 5.7, 1), 4.18 (dd, J = 3.0, 9.9, 1), 4.15 (m, 2) , 3.80 (d, J = 3.6, 1), 3. 74 (m, 2), 3.52 (dd, J = 3.3, 10.2, 2), 3.38 (m, 2), 3.18 (m, 1), 2.66 (m, 1), 2.66 (m, 1), 2.44 (m, 2), 2.22 (m, 1), 2.10 (s, 3) 1.34 (m, 2), 0.91 (d, J = 7.2, 6); MS (ESPOS): 475 [M + H] +.

EXAMPLE 54 Preparation of 4-isobutyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide The 4-isobutyl-2-cyanopyridine was prepared as follows. To isobutyltriphenylphosphonium iodide (Aldrich) (8 g, 18.5 mmol) in THF (20 ml) at 0 ° C, potassium tert-butoxide (1.8 g, 16 mmol) was added, stirred at room temperature for 1 h, added pyridine-4-carboxaldehyde (1 g, 9.3 mmol), and stirred at room temperature overnight. The reaction mixture was then poured into water (100 ml) and extracted with EtOAc (100 ml). The product obtained by removing the solvent was purified by column chromatography using 40% EtOAc in hexane as eluent (1.05 g, 84%). To the resulting product (4.2 g, 31.5 mmol) was added 10% Pd / C (0.4 g) and hydrogenated at 1 atm pressure overnight. Removal of the solvent and purification by column chromatography using 30% EtOAc in hexanes resulted in 4-isobutylpyridine (3.8 g, 90%). The intermediate product, 4-isobutylpyridine-2-carboxylic acid, compound 10b, (R9 = isobutyl) was prepared using Method P. To 4-isobutylpyridine (2 g, 14.8 mmol) in acetic acid (20 ml), He added hydrogen peroxide (3.35 g, 30%, 30 mmol) and heated to reflux overnight. After removing the solvent, the residue was dissolved in DCM, dried over magnesium sulfate and collected as it was during the next step. To the compost in DCM (10 ml) trimethylsilyl cyanide (1.73 g) was added, 17.4 mmol) and dimethylcarbonyl chloride (1.89 g, 17.4 mmol) and stirred at room temperature for 24 hours. Aqueous potassium bicarbonate (100 mL, 10%) was added and extracted twice with DCM (50 mL each time). The crude product obtained by removing the solvent was taken up in HCl (6 N, 100 ml) and heated to reflux for 24 hours. Separation of the acid and purification of the crude product by column chromatography using MeOH in 30% DCM resulted in the acid 10b (R 9 = sobutyl) (1.5 g, 100%). 1 H NMR (300 MHz, CD3OD) d 8.78 (d, J = 5.7, 1), 8.44 (s, 1), 8.13 (d, J = 5.7, 1), 2.92 (d, J = 7.5, 1), 2.15 (m, 1), 0.98 (d, J = 6.6, 6). MS (ESNEG): 178 [MH]. "To amine 2b (R = Me, R2 = Me) (200 mg, 0.79 mmol) in DMF (2 ml), TEA (161 mg, 1.6 mmol), BSTFA ( 614 mg, 2.4 mmol) at 0 ° C and stirred at room temperature for 1.5 h, Acid 10b (R9 = isobutyl) (214 mg, 1.2 mmol) and HATU (368 mg, 1.2 mmol) were added and allowed to stir at room temperature for 4 hours The DMF was separated and the residue was extracted with EtOAc (50 ml), washed with sodium bicarbonate (10%, 50 ml), brine (50 ml) and dried over magnesium sulfate. obtained by removing the solvent, it was dissolved in methanol (10 ml) and treated with NR-50 resin (300 mg) for 3 h After filtering the resin, the methanol was removed to obtain the crude product. silica gel column chromatography using MeOH in 3% DCM to obtain compound 11 b (R 1 = Me, R 2 = Me, R 3 = H, R 9 = isobutyl) (200 mg, 60%) 1 H NMR (300 MHz , CD3OD) d 8.41 (d, J = 4.8, 1), 8.28 (d, J = 9.6, 1), 7.95 (s, 1), 5.35 (d, J = 5.4, 1), 4.25 (m, 2), 3.99 (d, J = 10.8, 1), 3.78 (d, J = 3.6, 1), 3.55 (dd, J = 3.6, 10.8, 1), 2.52 (m, 3), 2.15 (s, 3), 1.93 (m, 1), 1.02 (m, 12). MS (ESPOS): 413 [M + H] +.

To compound 11b (R1 = Me, R2 = Me, R3 = H, R9 = isobutyl) (200 mg, 0.48 mmol) in water (10 ml), AcOH (2 ml) and MeOH (2 ml), Pt02 ( 200 mg), was hydrogenated at 3.85 kg / cm2 for 16 hours. After filtering the catalyst, the solvent was removed to obtain the crude material which was purified on a silica gel column using MeOH in 20% DCM as eluent. The fraction of lower Rf provided the title compound (70 mg, 34%). 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.20 (dd, J = 9.9, 3.3, 1), 4.07 (m, 2), 3.80 (d, J = 3.0, 1) , 3.60 (m, 2), 3.34 (m, 2), 2.84 (m, 1), 2.17 (m, 1), 2.10 (s, 3) 2.01 (m, 1), 1.77 (m, 3), 1.40 (m, 4), 0.91 (m, 12); MS (ESPOS): 419 [M + H] +.

EXAMPLE 55 Preparation of 4-propyl-piperidine-2-carboxylic acid [2,2-difluoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propip-amide] To the acid 10b (R9 = propyl) prepared by the method P (53 mg, 0. 32 mmole) in DMF (3 ml), intermediate lincosamide, compound 5b (R1 = Me), prepared by method I (63 mg, 0.16 mmol) and HATU (121 mg, 0.32 mmol), triethylamine (70 mg, 0.48 mmoles) at 0 ° C and stirred at room temperature 16 hours. The DMF was removed and the residue was taken up in ethyl acetate and washed with saturated bicarbonate solution (30 ml). The product obtained by removing the solvent was purified on a silica gel column using 30% ethyl acetate in hexanes (40 mg, 45%). To the pure product in methanol (5 ml), water (5 ml), acetic acid (5 ml) and platinum dioxide (50 mg, mmol) were added and 4.2 kg / cm2 was hydrogenated for 16 hours. After filtering the catalyst, the solvent was removed to obtain the crude product which was taken up in methanol (3 ml). Potassium carbonate (125 mg, 0.83 mmol) in water (1 ml) was added and stirred 16 hours. The solvents were then removed and the crude product was purified by column chromatography using methanol in 20% dichloromethane. The fraction of lower Rf yielded the title compound (10 mg, 33%). 1 H NMR (300 MHz, CD30D) d 5.28 (d, J = 5.4, 1), 4.73 (s, 1), 4. 57-4.65 (m, 1), 4.33-4.42 (m, 1), 4.05 (m, 1), 3.89 (s, 1), 3.53-3.57 (m, 2), 2.83 (t, J = 12.3, 1 ), 2.09 (s, 3), 1.63-1.84 (m, 5), 1.16-1.37 (m, 6), 0.93 (m, 3). MS (ESPOS): 427 [M + H] +.

EXAMPLE 56 Preparation of 4-fluoro-4-propyl-pyrrolidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl-amide To a stirred solution of (2S, 4R) -4-hydroxyproline (Aldrich) (25 g, 108 mmol) in methanol (50 ml) at 0 ° C was added trimethylsilyldiazomethane (24.6 g, 216 mmol). The mixture was stirred at 0 ° C for 1 hour. The residue obtained after removing the solvent and purifying by column chromatography using 50% ethyl acetate in hexanes (27 g, 100%) was used in the next step. Oxalyl chloride (15 g, 118 mmol) in DCM (15 ml) was added slowly at -78 ° C, DMSO (18.6 ml, 236 mmol) in 15 minutes. After the addition was complete, the above product, the methyl ester of (2S, 4R) -N-Boc-4-hydroxyproline (26.5 g, 108 mmol) in DCM (100 ml) was added at -78 ° C during 20 minutes Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. Then, the reaction mixture was washed with aq. to 10% (200 ml) and the organic layer was separated and dried over sodium sulfate. The crude product obtained by removing the solvent was purified by silica gel column chromatography using EtoAc in 50% hexanes to obtain the methyl ester of the (2S, 4R) -N-Boc-4-ketoproline (20 g, 78%). 1 H NMR (300 MHz, CDCl 3) d 4.80 (m, 1), 3.88 (d, J = 8.7, 2), 3.77 (s, 3), 2.98 (m, 1), 2.58 (m, 1), 1.45 ( s, g); MS (ESPOS): 244 [M + H] +. To a stirred solution of the methyl ester of (2S, 4R) -N-Boc-4-ketoproline (1 g, 4.11 mmol) in THF (10 mL), tetraalyltin (1.08 mL, 4.52 mmol) in dry THF was added. , and then cooled to 0 ° C before boron trifluoride etherate (0.520 ml) was added dropwise., 4.11 mmoles). The mixture was stirred at 0 ° C for 1 h and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in 5 ml of water) and celite (1 g) were added and the reaction mixture was stirred for one hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 ml), washed with water (100 ml) and brine (100 ml), dried over MgSO 4 and evaporated to dryness. The residue obtained after removing the solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain the methyl ester of 4-Hydroxy-4-allylproline (0.94 g, 80%). 1 H NMR (300 MHz, CDCl 3) d 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 (d, J = 4.8, 3), 3.50 (m, 3), 2.37 ( m, 1), 2.21 (m, 1), 1.39 (d, J = 12.9, 9); MS (ESPOS): 308 [M + Na] +. To a stirred solution of DAST (1.06 g, 6.58 mmol) in DCM (10 mL) at -78 ° C, the methyl ester of 4-hydroxy-4-allyl proline (940 mg, 3.3 mmol) was added slowly Dry DCM (10 ml). The mixture was then stirred at -78 ° C for 1 h, and then at -10 ° C for an additional 2 h. DCM (50 ml) was added, quenched with NH 4 Cl (10%, 150 ml) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained after removing the solvent was purified by silica gel column chromatography using 5% EtOAc in hexanes as eluent to obtain the methyl ester of 4-fluoro-4-allylproline (330 mg, 34%). 1 H NMR (300 MHz, CDCl 3) d 5.82 (m, 1), 5.12 (m, 2) .4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1) , 2.43 (m, 4), 1.37 (dd, J = 4.5, 13.8, 9); MS (ESPOS): 310 [M + Na] +. To a solution of the methyl ester of 4-fluoro-4-allylproline (0.33 g, 1.15 mmol) in MeOH (15 mL) was added 10% Pd / C (40 mg) and hydrogenated at 1 atm. The catalyst was filtered through celite and washed with methanol. To the product obtained by removing the solvent (330 mg, 1.15 mmol) in THF (12 ml) was added aqueous lithium hydroxide monohydrate (60 mg, 1.38 mmol). The reaction mixture was stirred at room temperature overnight. The THF was separated and the residue was taken up in ethyl acetate (50 ml), washed with 10% citric acid (100 ml) and brine (20 ml). Removal of the solvent resulted in 4-fluoro-4-propylproline (310 mg, 100%). H NMR (300 MHz, CD3OD) d 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96 (m, 3); MS (ESNEG): 274 [MH]. "To a solution of 4-fluoro-4-propylproline (310 mg, 1.15 mmol) in DMF (3 mL) at 0 ° C, 7-methyl-MTL 2b (R1) was added. = Me, R2 = Me) (272 mg, 1.15 mmol), HBTU (469 mg, 1.3 mmol) and DIEA (290 mg, 2.3 mmol), and allowed to stir at room temperature for 16 hours. The obtained residue was purified with MeOH in 3% DCM (40 mg, 93%) The product of the purification by column was taken up in DCE (6 ml), to which was added triethylsilane (0.16 ml), TFA (2 ml) and water (0.16 ml) and stirred at room temperature for 1.5 hours.Solvent removal followed by silica gel column chromatography using MeOH in 10% DCM resulted in the title compound as isomeric mixtures, with the fraction of lowest RF (160 mg, 50%): 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.46 (m, 1), 4. 24 (dd, J = 5.7, 10.2, 1), 4.08 (m, 2), 3.81 (d, J = 2.4, 1), 3.52 (m, 3), 2.73 (m, 1), 2.10 (m, 4 ), 1.88 (m, 2), 1.50 (m, 2), 0.99 (t, J = 7.5, 3), 0.91 (dd, J = 3.0, 6.9, 6); MS (ESPOS): 409 [M + H] +; and the fraction of highest Rf (40 mg, 12%). 1 H NMR (300 MHz, CD3OD) d 5.38 (d, J = 5.4, 1), 4.46 (m, 1), 4.24 (dd, J = 2.7, 7.2, 1), 4.08 (m, 2), 3.81 (d , J = 2.4, 1), 3.64 (m, 3), 2.73 (m, 1), 2.11 (m, 4), 1.84 (m, 2), 1.47 (m, 2), 0.98 (t, J = 7.5 , 3), 0.91 (dd, J = 3.0, 6.9, 6); MS (ESPOS METHOD): 409 [M + H] +.

EXAMPLE 57 Preparation of 4-butyl-4-fluoro-pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4-butyl-4-fluoro-pyrrolidine-2-acid carboxylic To ethyl acetylene (140 mg, 2.6 mmol) in THF (5 ml) at -78%, n-butyllithium (1.1 ml, 2.6 mmol) was added with stirring and stirred at -78 ° C for 1 hour. Then, n- (tert-butoxycarbonyl) -L-proline-4-ketone (described in example 56) (570 mg, 2.3 mmol) in THF (5 ml) was added at -78 ° C with stirring for 2 hours and then it was allowed to warm to -40 ° C in 1 hour. The reaction mixture was extracted with EtOAc (20 mL), washed with saturated NH 4 Cl solution (5 mL) and dried over sodium sulfate. Purification of the crude product was carried out by chromatography on silica gel using 50% EtOAc in hexane to obtain the methyl ester of N-boc-4-butyl-4-hydroxy-proline (520 mg, 73%). To DAST (556 mg, 3.4 mmol), in DCM (5 mL) at -78 ° C, a solution of the above ester (520 mg, 1.7 mmol) in DCM (5 mL) was added at -78 ° C and stirred for 1 hour. The reaction mixture was extracted with DCM (50 ml) and washed with NaHCO 3 (30 ml, 10%). The product obtained after removing the solvent was purified by chromatography on silica gel using 5% EtOAc in hexanes to obtain N- (tert-butoxycarbonyl) -L-proline-4-fluoro-4-butane (276 mg, 52 %). 1 H NMR (300 MHz, CD3OD) d 4.41 (m, 1), 3.83 (m, 1), 3.71 (s, 3), 3.45 (m, 1), 2.55-1.54 (m, 8), 1.39 (m, 9), 0.89 (m, 3); MS (ESPOS): 326 [M + Na] +. To a solution of N- (tert-butoxycarbonyl) -L-proline-4-fluoro-4-butane (270 mg, 0.89 mmol) in THF (12 ml) and water (4 ml), lithium hydroxide monohydrate was added. (45 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 16 hours. THF was removed in vacuo and the residue was taken up in ethyl acetate (150 ml), washed with 10% citric acid (100 ml) and brine (20 ml). Removal of the solvent resulted in N- (tert-butoxy) -1-proline-4-fluoro-4-butyl-2-carboxylic acid (260 mg, 100%). 1 H NMR (300 MHz, CD3OD) d 4.32 (m, 1), 3.72 (m, 2), 2.58 (m, 2), 2.10-1.63 (m, 6), 1.42 (m, 9), 0.93 (t, J = 6.6, 3); MS (ESNEG): 288 [MH] ". To a solution of N- (tert-butoxy) -L-proline-4-fluoro-4-butyl-2-carboxylic acid (135 mg, 0.46 mmole) in DMF (3 ml) at 0 ° C, 7-Methyl-MTL 2b (R 1 = Me, R 2 = Me) (135 mg, 0.46 mmol), HBTU (194 mg, 0.51 mmol), DIEA (120 mg, 0.93 mmol) were added, and left at room temperature for 16 hours The product obtained after removing the DMF and purifying by column chromatography using MeOH in 5% DCM (189 mg, 77%) was taken up in DCE (6 ml) Triethylsilane was added. (0.16 ml), TFA (2 ml) and water (0.16 ml), was stirred at room temperature for 1.5 hours.The residue obtained by removing the solvent was purified by column chromatography using MeOH in 10% DCM to obtain the compound Titre (156 mg, 96%). 1 H NMR (300 MHz, CD3OD) d 5.26 (d, J = 5.7, 1), 4.55 (m, 1), 4.27 (dd, J = 3.3, 10.2, 1), 4.08 (m, 2), 3.82 (d, J = 3.0, 1), 3.58 (m, 3), 2.79 (m, 1), 2.22 (m, 1), 2.10 (s, 3), 1.89 (m, 3), 1.40 (m, 4), 0.91 (m, 9), MS (SPOS): 423 [M + H] +.

EXAMPLE 58 Preparation of 4-Fluoro-4-Propyl-pyrrolidine-2-carboxylic acid ~ 2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-P- propinamide The N- (tert-butoxycarbonyl) -4-fluoro-4-propyl-L-proline prepared as described in the previous example (except that n-propyl-lithium was used in place of n-butyllithium) (164 mg 0.57 mmole) was suspended in dry acetonitrile (4 ml). Triethylamine (332 μL, 3.02 mmol) was added and the reaction mixture was cooled to 0 ° C. Isobutyl chloroformate (78 μl, 0.57 mmol) was added and after 10 min the reaction was allowed to warm to 4 ° C. After 1.5 h a solution of MTL (151 mg, 0.57 mmol) in acetone: water 1: 1 (4 mL) was added and the reaction mixture was stirred for 10 h at rt The reaction mixture was evaporated to dryness and chromatographed on silica with dichloromethane / MeOH 95: 5 to dichloromethane / MeOH 95: 8 to give the product as a colorless oil (137 mg, 45%): TLC Rf 0.32 (dichloromethane / MeOH 9: 1). To a solution of the previous boc-protected lincosamide (125 mg) in DCM (2.0 ml) was added a solution of DCE (10.0 ml), trifluoroacetic acid (5 ml) methyl sulfide (0.3 ml) and water (0.3 ml). ). The reaction mixture was stirred at t.a. for 40 min and then diluted with DCE (25.0 ml). The solvent was removed in vacuo and coevaporated with DCE twice. The residue was purified by chromatography on fluorosil with MeOH (0.25 M NH3) in 20% DCM to provide the product as a colorless solid (30.0 mg, 30%).

EXAMPLE 59 Preparation of 4- (2-methoxyethoxp-piperidine-2-r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yD-propylamide of 4- (2-methoxyethoxp-piperidine-2- The title compound was prepared using the synthetic sequence found in Method S, from 4-hydroxypyridine-2-carboxylic acid, substituting 2-methoxyethyl bromide as the alkylating agent. Compound 15a (R9 = 2-methoxyethoxy): 1 H NMR (300 MHz, CD3OD) d 8.40 (d, J = 6.0, 1), 7.69 (d, J = 2.4, 1), 7.20 (d, J = 2.7, 6.3, 1), 4.35 2), 3.80 (m, 2), 3.40 (s, 3). MS (ESNEG): 196 [M-H] ". Compound 15b (R 1 = Me, R 2 = Me, R 9 = 2-methoxyethoxy): 1 H NMR (300 MHz, CD3OD) d 8.43 (d, J = 5.7, 1), 7.65 (d, J = 2.4, 1), 7.12 (d, J = 2.4, 5.7, 1), 5.27 (d, J = 5.4, 1), 4.10-4.87 (m, 4), 3.85 (d, J = 3.3, 1), 3.77 (m, 2), 3.55 (m, 1), 3.41 (s, 3), 2.26 (m, 1), 2.11 (s, 1), 0.998 (m, 6). EM (SPOS): 431 [M + H] +. Title compound (10 mg, 10%). 1 H NMR (300 MHz, D20) d . 18 (d, J = 6.0, 1), 4.00 (m, 3), 3.70 (m, 1), 3.56 (m, 1), 3.45 (m, 3), 3.26 (m, 1), 3.16 (m, 3), 3.10 (m, 1), 2.80 (m, 1), 2.48 (m, 1), 2.22 (m, 1), 1.96 (m, 4), 1. 17-1.72 (m, 4), 0.70 (m, 6); MS (ESPOS): 437 [M + H] +.

EXAMPLES 60-62 EXAMPLE 60 Preparation of 4-butyl-pyrrolidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-fetrah-pyroran-2-yl) -propyl-1-amide EXAMPLE 61 Preparation of 4- (4,4-difluoro-pentiP-piperidine-2 [2-methyll-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propip-amide of 4 (4,4-difluoro-pentiP-piperidine - carboxylic EXAMPLE 62 Preparation of 4- (3-fluoro-propyl) -piperidine-2-[2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyrran-2-yl) -prop-p-amide of 4- (3-fluoro-propyl) -piperidine-2 - carboxylic Examples 60 to 62 were prepared using methods and techniques described herein using commercially available starting materials as appropriate.

EXAMPLE 63 Preparation of the 4-fluoro-4-propyl-piperidine-2-carboxylic acid 2-methiM- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yD-propylamide) Lincosamine 2b (R1 = Me, R2 = Me) was coupled with carbamate 21 d (P2 = Boc, m = 2, R9 = n-propyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = propyl / fluoro, P1 = H, P2 = tere-butyl ester of carboxylic acid, m = 2) which was deprotected under acidic conditions to provide the title compound. HPLC: Column C18 3.5 μm 4.6 x 30 mm; eluent with gradient MeCN at 2% -98% in 10 min; 1.5 mi / min): Rt = 3.696 min); 1 H NMR (300 MHz, CD3OD) d 5.36 (d, J = 5.8, 1), 4.24 (dd, J = 3.3, 12.9, 1), 4.20 (s, 2), 4.12 (dd, J = 6.0, 10.4, 1), 3.88 (d, J = 3.3, 1), 3.65 (dd, J = 3.0, 10.4, 1), 3.48 (dd, J = 4.1, 13.1, 1), 3.33 (ddd, J = 3.6, 3.6, 13.5, 1), 2.43-2.45 (m, 1), 2.22-1.58 (m, 6), 2.16 (s, 3), 1.48 (m, 2), 0.94 (t, J = 7.1, 3), 0.88 ( d, J = 6.9, 6); NMR 19F (CD3OD) d-158.8-d159.0 (sextuplet), MS (SPOS): 423.2.

EXAMPLE 64 Preparation of 4- (2-fluoroethoxy-piperidine-2-carboxylic acid f2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide The title compound was prepared using the synthetic sequence found in the General Method S starting from 4-hydroxypyridine-2-carboxylic acid 10b (R9 = hydroxy) substituting 2-fluoro-ylbromide as the alkylating agent. 15a (R9, = 2-fluoroethoxy): 1 H NMR (300 MHz, CD3OD) d 8.40 (d, J = 6.0, 1), 7.73 (d, J = 2.7, 1), 7.24 (dd, J = 2.4, 6.0, 1), 4.87 (m, 2), 4.50 (m, 2). MS (ESNEG): 184 [M-H] ". 15b (R 1 = R 2 = Me, R 3 = H, R 9, = 2-fluoroethoxy): 1 H NMR (300 MHz, CD3OD) d 8.45 (d, J = 5.7, 1), 7.67 (d, J = 2.4, 1), 7.14 (dd, J = 2.7, 5.7, 1), 5.27 (d, J = 5.7, 1) , 4.68 (m, 1), 4.43 (m, 1), 4.12-4.33 (m, 3), 4.10 (dd, J = 6.0, . 2, 1), 3.18-3.84 (m, 3), 2.26 (m, 1), 2.11 (s, 3), 1.00 (t, J = 5.1, 6). EM (SPOS): 419 [M + H] +. Title compound (20 mg, 14%): 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 5.7, 1), 4.59 (t, J = 4.2, 1), 4.43 (t, J = 4.2, 1), 4.18 (dd, J = 3.3, 6.6, 1), 4.07 (m, 2), 3.80 (m, 2), 3.73 (m, 1), 3.55 (m, 2), 3.48 (m, 1) , 3.21 (m, 1), 2. 74 (m, 1), 2.32 (m, 1), 2.18 (m, 1), 2.10 (s, 3) 1.38 (m, 3), 0.93 (m, 6); EM (SPOS): 425 [M + H] +.

EXAMPLE 65 There is no Example 65.

EXAMPLE 66 Preparation of 4- (2-cyclopropyl-ethyl) -piperidine-2-r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (2-cyclopropyl-ethyl) -piperidine-2-acid - carboxylic Compound 14c (R9 = 2-cyclopropylethyl) was prepared using the methods described in General Method R. To a stirred suspension of product 14a (0.5 g, 1.9 mmol, 1 equiv), triphenylphosphine (39.9 mg, 0.15 mmol, 0.08 equiv. ), copper iodide (I) (28.9 mg, 0.15 mmol, 0.08 equiv), palladium acetate (17 mg, 0.076 mmol, 0.04 equiv) in triethiamine (7 ml) in dry nitrogen atmosphere, cyclopropyl-acetylene ( Aldrich) (0.25 g, 3.8 mmol, 2 equiv). The mixture was stirred at t.a. all night. The solvent was removed in vacuo to give a dark residue. The residue was purified by column chromatography to give product 14b (R9 = 2-cyclopropyl-et-1-innyl) (0.39 g, 100%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3) d 8.65-8.56 (m, 1), 8.06-7.99 (m, 1), 7.40-7.32 (m, 1), 3.98 (s, 3), 1.50-1.40 (m, 1 ), 0.96-0.81 (m, 4). MS (Spores): 202.0 [M + H] +.

To a solution of product 14b (R9, = 2-cyclopropyl-et-1-innyl) (0.39 g, 1.9 mmol) in methanol (15 ml) was added 10% palladium on charcoal (0.2 g). The mixture was purged and charged with hydrogen (1 atm) and stirred at r.t. all night. The palladium was removed by filtration and the filtrate was concentrated to give the product 14c (R9 = 2-cyclopropylethyl) (0.38 g, 97%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3) d 8.60 (d, J = 4.5, 1), 8.00-7.96 (m, 1), 7.34-7.29 (m, 1), 3.99 (s, 3), 2.78 (t, J = 7.6, 2), 1.58-1.49 (m, 2), 0.71-0.59 (m, 1), 0.47-0.38 (m, 2), 0.06-0.02 (m, 2); MS (ESPOS): 228.2 [M + Na] +. To a mixture of the product 14c (R 9 = 2-cyclopropyethyl) (0.38 g) in MeOH (8 ml) and water (8 ml) were added concentrated HCl (158 μl) and platinum oxide (0.2 g). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give a yellow solid. To the previous residue were added 2N NaOH (3.8 ml) and t-butyl alcohol (2 ml). The reaction mixture was stirred at t.a. for 2 h, then di-t-butyl dicarbonate (0.62 g, 2.85 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo and then the resulting residue was diluted with water, and then washed with ether. The aqueous layer was acidified with 2 N HCl to pH = 2.0, and extracted with ethyl acetate (2x). The combined organic layers were dried and concentrated to give the 4- (2-cyclopropylethyl) -piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.42 g, 77%) as a clear syrup.

MS (ESPOS): 320.3 [M + Na] +. MS (ESNEG): 296.2 [M-H] '. To a solution of 4- (2-cyclopropylethyl) -piperidine-1-tert-butyl ester, 2-dicarboxylic (115 mg, 0.387 mmol, 1 equiv) and HCl of product 2b HCl (R1 = Me, R2 = Me) (111.4 mg, 0.387 mmol, 1 equiv) in DMF (2.4 ml) at t.a. DIEA (100 μl, 0.774 mmol, 2 equiv) was added, followed by HBTU (162 mg, 0.426 mmol, 1.1 equiv). The reaction mixture was stirred at t.a. for 3 h and then evaporated under high vacuum to dryness. The residue was diluted with ethyl acetate, washed with 10% citric acid / brine 1: 1 (1x), saturated aqueous sodium bicarbonate solution (1x), and brine (1x), dried and concentrated. The residue was purified by chromatography to give the product of lincosamide protected with Boc 11a (R1 = R2 = Me, R3 = H, R9 = 2-cyclopropylethyl, P1 = H, P2 = tere-butyl ester of carboxylic acid) (126 mg, 61%) in the form of a clear syrup. MS (ESPOS): 531.3 [M + H] +. To a solution of the previous product 11a (R1 = R2 = Me, R3 = H, R9 = 2-cyclopropylethyl, P1 = H, P2 = tere-butyl ester of carboxylic acid, m = 2) in DCE (12 ml) at 0 ° C was added a solution of trifluoroacetic acid (3 ml) and water (0.375) ml). The reaction mixture was stirred at 0 ° C for 5 min and at t.a. for 35 min. The reaction solvent was removed in vacuo and coevaporated with toluene twice, and the resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 at 5-60% with AcOH at 0.1%, in 30 min, flow rate 20 ml / min) to afford the title compound of Example 66 (25 mg, 27%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 6.11), 4.19 (dd, J = 3.4, , 1), 4.10-4.04 (m, 2), 3.81-3.72 (m, 2), 3.51 (dd, J = 3.3, 10.2, 1), 3.42-3.33 (m, 1), 3.02-2.90 (m , 1), 2.20-2.12 (m, 1), 2.11 (s, 3), 1.94-1.86 (m, 1), 1.76- 1.64 (m, 1), 1.48-1.20 (m, 7), 0.94-0.85 (m, 6), 0.73-0.62 (m, 1), 0.47-0.38 (m, 2), 0.05-0.02 (m, 2). MS (ESPOS): 431.3 [M + H] +.

EXAMPLE 67 Preparation of 4-cyclopropylmethyl-piperidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl-amide 4-Cyclopropylmethylpyridine-2-carboxylic acid, compound 10b (R9 = cyclopropylmethyl), was prepared using Method P using 4-cyclopropylmethylpyridine prepared as described in Osuch et al., Journal of the American Chemical Society, 1955, 78.1723. To a -78 ° C solution of 4-picoline (1.1 g, 11.8 mmol) in THF (5 mL) was added a solution of 2 M LDA in THF / heptane / ethylbenzene (Aldrich) (5.9 mL, 11.8 mmol). The resulting reaction mixture was stirred at -78 ° C for 3 h and then at -0 ° C for 1 h. Cyclopropyl bromide (1.43 g, 11.8 mmol) was added at -78 ° C, the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 1 h. Saturated NH CI solution (10 ml) was added to the reaction mixture, the aqueous phase was extracted with EtOAc (10x2 ml), and the combined organic extracts were dried over Na2SO4. 4-Cyclopropylmethylpyridine-2-carboxylic acid (0.5 g, 31%) was obtained after removing the solvent and used without further purification. To a solution at 0 ° C of the salt of 4-cyclopropylmethylpyridine-2-carboxylic acid (10b) (R 9 = cyclopropylmethyl) (147 mg, 0.83 mmole), 2b (R 1 = Me, R 2 = Me) (238 mg, 0.83 mmoles) and TEA (231 μl, 1.66 mmol) in DMF (2 ml) was added solid HBTU (346 mg, 0.91 mmol), and the resulting reaction mixture was stirred overnight. The reaction solvents were separated and the residue was purified by silica gel column chromatography with 50-100% EtOAc / Hexane to provide the desired lincosamide, product 11 b (R1 = R2 = Me, R3 = H, R9 = cyclopropylmethyl, P1 = H) (260 mg, 76%). To a solution of product 11b (R1 = R2 = Me, R3 = H, R9 = cyclopropylmethyl, P1 = H) (250 mg, 0.6 mmol) in water (10 ml), AcOH (2 ml), and MeOH (3 ml) Pt02 (200 mg) was added, and the reaction mixture was hydrogenated at 3.5 kg / cm2 for 5 h. The solvent was removed to obtain the crude lincosamide product. Purification was carried out by silica gel column chromatography (MeOH / DCM ai 20%), and then by HPLC (Waters Nova-Pak® HR C18, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 at 5-60% with AcOH at 0.1%, in 30 min, flow rate 20 ml / min) to give the title compound (13 mg, 5%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.23 (d, J = 6.1), 4.26-4.10 (m, 3), 3.83-3.78 (m, 2), 3.55-3.33 (m, 2), 3.07-2.95 (m , 1), 2.34-2.17 (m, 2), 2.12 (s, 3), 2.00-1.80 (m, 4), 1.42-1.15 (m, 4), 1.00-0.90 (m, 6), 0.79-0.66 (m, 1), 0.53-0.45 (m, 2), 0.12-0.04 (m, 2); MS (ESPOS): 417.3 [M + H] +.

EXAMPLE 68 Preparation of 4- (2-cyclobutyl-etiP-piperidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yD-propylamide) 4- (2-Cicybutyl-ethyl) -pyridine-2-carboxylic acid, compound 10b (R9 = 2-cyclobutyl-ethyl), was prepared using Method P using 4- (2-cyclobutyl-ethyl) -pyridine as prepared material as described by Osuch et al, Journal of the American Chemical Society, 1955 , 78, 1723. Lincosamine 2b (R1 = Me, R2 = Me) was coupled with 4- (2-cyclobutyl-ethyl) -pyridine-2-carboxylic acid 10b (R9 = cyclobutyl-ethyl) as described in general coupling scheme 11 to provide intermediate 11b (R1 = R2 = Me, R3 = H, R9 = 2-cyclobutyl-ethyl, P1 = H) which was reduced by catalytic hydrogenation to the title compound. MS (ESPOS): 445.2 [M + H] +.

EXAMPLE 69 Preparation of 4-cyclobutylmethyl-piperidine-2-carboxylic acid f2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-ip-propylamide 4-Cyclobutylmethylpyridine-2-carboxylic acid, compound (10b) (R9 = 4-cyclobutylmethyl) was prepared using Method P using 4: cyclobutylmethylpyridine as the starting material prepared as described by Osuch et al, Journal of the American Chemical Society, 1955, 78.1723.

Lincosamine 2b (R1 = Me, R2 = Me) was coupled with 4-cyclobutylmethylpyridine-2-carboxylic acid, compound 10b (R9 = 4-cyclobutylmethyl), as described in general coupling scheme 11 to provide the intermediate 11 b (R = R2 = Me, R3 = H, R9 = cyclobutyl-5 methyl, P1 = H), which was reduced by catalytic hydrogenation to the title compound. MS (ESPOS): 431.3 [M + H] +.

EXAMPLE 70 0 Preparation of 3-butyl-azetidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl-amide To a solution of azetedine acid 16f (R9 = butyl) (52 mg, 0.20 mmol, 1 equiv), aminosugar (58 mg, 0.20 mmol, 1 equiv) and HBTU (84 mg, 0.22 mmol, 1.1 equiv) in DMF ( 2.0 ml) at 23 ° C, DIPEA 0 (88 μl, 0.51 mmol, 2.5 equiv) was added. After stirring for 12 h at 23 ° C, the DMF was removed in vacuo, and then the residue was partitioned between EtOAc (100 ml) and brine: 10% aqueous citric acid 1: 1 (100 ml). The organic layer was separated and washed with brine / saturated aqueous solution of NaHCO 3 1: 1 (100 mL), brine (50 mL), dried (MgSO 4), filtered and concentrated to provide 82 mg (0.17 mmol, 84 mL). %) of the product 11a (R1 = R2 = Me, R3 = H, R9 = butyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) in the form of a glassy solid. MS (SPOS): [M + H] +. To a solution of carbamate 11a (R1 = R2 = Me, R3 = H, R9 = butyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) (82 mg, 0.17 mmol, 1 equiv) in 1,2-dichloroethane (10 ml) at 23 ° C was added H20 (0.40 ml) followed by TFA (4.0 ml). After stirring for 20 min at 23 ° C, toluene (50 ml) was added and the resulfanie solution was concentrated to dryness. The residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 5-60% with AcOH 0.1%, 30 min, flow rate 20 ml / min) to give 41 mg of the title compound as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.60 (d, J = 7.2, 1), 4.25 (dd, J = 3.3, 9.9, 1), 4.16-4.05 (m, 2), 3.99 (t, J = 9.0, 1), 3.81 (d, J = 3.0, 1), 3.74 (dd) , J = 8.4, 9.9, 1), 3.50 (dd, J = 3.3, 10.2, 1), 2.90-2.74 (m, 1), 2.23-2.10 (m, 1), 2.10 (s, 3), 1.90- 1.67 (m, 2), 1.44-1.24 (m, 4), 1.00-0.86 (m, 9 H). MS (SPOS): 391.4 [M + Hf.

EXAMPLE 71 Preparation of 3-cyclopropylmethyl-azetidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propin-amide Lincosamine 2b (R1 = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = cyclopropylmethyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = cyclopropylmethyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0), which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.65 (d, J = 7.5, 1), 4.25 (dd, J = 3.9, 9.6, 1), 4.13-3.99 (m, 3), 3.86-3.79 (m, 2), 3.51 (dd, J = 3.3, 10.2, 1), 3.00-2.87 (m, 1), 2.21-2.09 (m, 1), 2.11 (s, 3), 1.83-1.72 (m, 1), 1.62-1.51 (m, 1), 0.94 (d, J = 6.9, 3), 0.89 (d, J = 6.9, 3), 0.82-0.70 (m, 1), 0.58 -0.47 (m, 2), 0.18-0.08 (m, 2 H). MS (ESPOS): 389.2 [M + H] +.

EXAMPLE 72 Preparation of 3-Propyl-Azetidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyn-amide Lincosamine 2b (R = Me, R = Me) was coupled with azetedine acid 16f (R9 = propyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = propyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0), which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.26 (d, J = 5.4, 1), 4.60 (d, J = 7.5, 1), 4.26 (dd, J = 3.3, 9.6, 1), 4.13-3.99 (m, 3), 3.81 (d, J = 3.3, 1), 3.76 (dd, J = 5.11, 110.2, 1), 3.51 (dd, J = 3.3, 9.9, 1), 2.93-2.76 (m, 1), 2.24-2.09 (m, 1), 2.11 (s, 3), 1.84-1.67 (m, 2), 1.48-1.30 ( m, 2), 1.01-0.87 (m, 9H). MS (ESPOS): 377.0 [M + H] +.

EXAMPLE 73 Preparation of f-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl] -amide of 3-butyl-1- (2-hydroxy-etiP) -azetidine-2-carboxylic acid A sample of 3-butyl-azetidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide prepared in Example 70 was alkylated with ethylene oxide as described in scheme 12 (R6 = 2-hydroxyethyl) to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.4, 1), 4.13-4.05 (m, 3), 3.83-3.77 (m, 2), 3.64 (t, J = 9.9, 1), 3.58-3.48 (m, 2), 3.37-3.30 (m, 1), 2.78-2.55 (m, 2), 2.44-2.34 (m, 1), 2.25-2.10 (m, 2), 2.11 (s, 3), 1.80-1.40 (m, 2), 1.39-1.20 (m, 4), 0.95-0.84 (m, 9 H). MS (ESPOS): 435.1 [M + H] +.

EXAMPLE 74 Preparation of the 3-pentyl-azetidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyn-amide Lincosamine 2b (R1 = Me, R2 = Me) was coupled with the azetedine acid 16f (R9 = pentyl) as described in the general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = pentyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.55 (d, J = 6.9, 1), 4.25 (dd, J = 3.3, 9.9, 1), 4.13-4.04 (m, 2), 4.00 (t, J = 9.3, 1), 3.80 (d, J = 3.0, 1), 3.73 (dd, J = 7.8, 9.9, 1), 3.51 (dd, J = 3.3, 10.5, 1) , 2.88-2.75 (m, 1), 2.23-2.10 (m, 1), 2.11 (s, 3), 1.84-1.60 (m, 2), 1.44-1.26 (m, 6), 0.97-0.86 (m, 9H). MS (ESPOS): 405.4 [M + H] +.

EXAMPLE 75 Preparation of f 3 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iD-propylamide of 3-, 3-methyl-buty-p-azetidine-2- carboxylic Lincosamine 2b (R = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = 3-methyl-builel) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = 3-methyl-butyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 6.0, 1), 4.55 (d, J = 7.5, 1), 4.26 (dd, J = 3.6, 10.2, 1), 4.13-4.04 (m, 2), 4.00 (t, J = 9.3, 1), 3.80 (d, J = 3.3, 1), 3.73 (dd, J = 8.1, 10.2, 1), 3.51 (dd, J = 3.3, 10.2, 1) , 2.87-2.72 (m, 1), 2.24-2.10 (m, 1), 2.11 (s, 3), 1.84-1.70 (m, 2), 1.66-1.50 (m, 1), 1.26-1.10 (m, 2), 0.97-0.86 (m, 12 H). MS (ESPOS): 405.0 [M + H] +.

EXAMPLE 76 Preparation of 3- (3-cyclobutyl-propyl) -zetidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) Lincosamine 2b (R1 = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = 3-cyclobutyl-propyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = (3-cyclobutyl-propyl), P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.24-4.14 (m, 2), 4.11-4.04 (m, 2), 3.78 (d, J = 3.3, 1), 3.71. (í, J = 9.0, 1), 3.54-3.43 (m, 1), 2.76-2.60 (m, 1), 2.34-2.10 (m, 2), 2.10 (s, 3), 2.09-1.97 (m, 2), 1.90-1.51 (m, 7), 1.44-1.11 (m, 3), 0.90 (d, J = 2.1, 3), 0.88 (d, J = 2.1, 3H). MS (ESPOS): 431.3 [M + H] +.

EXAMPLE 77 Preparation of 3- (2-cyclobutyl-ethyl) -zetidine-2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsuifanii-tetrahydropyran-2-iP-propylamide of 3- (2-cyclobutyl-ethyl) -zetidine-2 - carboxylic Lincosamine 2b (R1 = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = 2-cyclobutyl-ethyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = 2-cyclobutyl-etyl, P = H, P2 = carboxylic acid f-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound RMN 1H (300 MHz, CD3OD) d 5.24 (d, J = 6.0, 1), 4.51 (d, J = 10.2, 1), 4.25 (dd, J = 3.3, 9.9, 1), 4.12-4.03 (m, 2), 3.96 (t, J = 9.3, 1), 3.79 (d, J = 3.0, 1), 3.69 (dd, J = 8.1, 10.2, 1), 3.50 (dd, J = 3.3, 10.2, 1), 2.85-2.69 (m, 1), 2.36-2.10 (m, 2), 2.10 (s, 3), 2.09-2.00 (m, 2), 1.95-1.33 (m, 10), 0.92 (d, J = 6.9, 3) , 0.89 (d, J = 6.9, 3H). MS (ESPOS): 417.3 [M + H] +.

EXAMPLE 78 Preparation of f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl-amide of 3- (2-cyclopropyl-etiP-azetidine-2-) carboxylic Lincosamine 2b (R1 = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = 2-cyclopropyl-ethyl) as described in general coupling scheme 11 to provide intermediate 11a (R = R2 = Me, R3 = H, R9 = 2-cyclopropyl-ethyl, P = H, P2 = carboxylic acid f-buyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.53 (d, J = 7.2, 1), 4.24 (dd, J = 3.3, 9.9, 1), 4.11-4.03 (m, 2), 3.98 (t, J = 9.6, 1), 3.79 (d, J = 3.0, 1), 3.73 (dd, J = 8.1, 9.9, 1), 3.50 (dd, J = 3.3, 10.2, 1) , 2.92-2.77 (m, 1), 2.22-2.09 (m, 1), 2.10 (s, 3), 1.95-1.77 (m, 2), 1.33-1.18 (m, 2), 0.91 (d, J = 6.9, 3), 0.88 (d, J = 6.9, 3), 0.73-0.60 (m, 1), 0.48-0.40 (m, 2), 0.08-0.01 (m, 2 H). MS (ESPOS): 403.3 [M + H] +.

EXAMPLE 79 Preparation of 3- (3-cyclopropyl-propyl) -zetidine r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yD-propylamide of 3- (3-cyclopropyl-propyl) -acetyl -2- carboxylic Lincosamine 2b (R1 = Me, R2 = Me) was coupled with azetedine acid 16f (R9 = 3-cyclopropylpropyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = 3-cyclopropyl-propyl, P1 = H, P2 = carboxylic acid f-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.54 (d, J = 7.5, 1), 4.24 (dd, J = 3.3, 9.9, 1), 4.11-4.03 (m, 2), 3.97 (t, J = 9.6, 1), 3.79 (d, J = 3.0, 1), 3.71 (dd, J = 7.8, 9.9.1), 3.50 (dd, J = 3.0, 10.2, 1) , 2.88-2.74 (m, 1), 2.23-2.09 (m, 1), 2.10 (s, 3), 1.90-1.68 (m, 2), 1.57-1.33 (m, 2), 1.23 (q, J = 6.9, 2), 0.91 (d, J = 6.9, 3), 0.89 (d, J = 6.9, 3), 0.75-0.60 (m, 1), 0.45-0.38 (m, 2), 0.04-0.02 (m , 2 H). MS (ESPOS): 417.3 [M + H] +.

EXAMPLE 80 Preparation of r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-P-propynamide of 3-butyl-1-methyl-azetidine- 2 -carboxylic The azetedine acid 16f (R9 = butyl) was deprotected and N-methylated by treatment with formic acid and formaldehyde under conditions known to those skilled in the art to provide 3-butyl-1-methyl-azetidine-2-carboxylic acid. Lincosamine 2b (R1 = Me, R2 = Me) was coupled with 3-butyl-1-methyl-azetidine-2-carboxylic acid as described in general coupling scheme 11 to provide the title compound. 1 H NMR (300 MHz, D 2 O) d 5.36 (d, J = 6.0, 1), 4.67 (d, J = 8.7, 1), 4. 31 (t, J = 9.3, 1), 4.22 (s, 2), 4.10 (dd, J = 6.0, 10.5, 1), 3.86 (d, J = 3.3, 1), 3.79 (t, J = 9.6, 1), 3.64 (dd, J = 3.3, 10.2, 1), 3.04-2.84 (m, 1), 2.93 (s, 3), 2.25-2.05 (m, 1), 2.14 (s, 3), 1.87- 1.68 (m, 2), 1.40-1.20 (m, 4), 0.87 (t, J = 7.5, 9H). MS (ESPOS): 405.4 [M + H] +.

EXAMPLE 81 Preparation of the monoester of (4,5-dihydroxy-6-f2-methyl-1-r (4-propyl-piperidine-2-carboniP-amino-1-propyl-2-methylsulfanyl-tetrahydro-pyran-3-yl) phosphoric acid The synthesis of the title compound, 5 (in which R 1 - = D R 2 = M, R 3 = H, R 9 = 4-c / sn-propyl, R 11 = PO (OH) 2) is detailed in Method V. 1 H NMR (300 MHz, CD3OD) d 5.41 (d, J = 5.1, 1), 4.53-4.43 (m, 1), 4.10-3.88 (m, 4), 3.73 (dd, J = 3.0, 9.6 , 1), 3.44-3.30 (m, 2), 2.25-2.10 (m, 2), 2.11 (s, 3), 2.00-1.88 (m, 1), 1.86-1.70 (m, 1), 1.44-1.25 (m, 6), 0.98-0.88 (m, 9). MS (ESPOS): 485.1 [M + H] +. MS (ESNEG): 483.0 [M-H] ".

EXAMPLE 82 Preparation of monoester of (4,5-dihydroxy-6-f2-methyl-1-r (4-propyl-piperidine-2-carboniP-amino-1-propyl > -2-methylsulfanyl-tetrahydro-pyran-3-yl ) of succinic acid To a suspension of the alcohol 18b (in which R1 = R2 = Me, R3 = H, R9 = 4-c / sn-propyl, m = 2) (721 mg, 1.16 mmol, 1 equiv), succinic anhydride (174 mg , 1.74 mmol, 1.5 equiv) and DMAP (71 mg, 0.58 mmol, 0.5 equiv) in 1,2-dichloroethane (3.0 ml) at 23 ° C was added Et3N (0.34 ml, 2.43 mmole, 2.1 equiv). After stirring for 2 h at 23 ° C, the reaction mixture was partitioned between EtOAc (100 mL) and 10% aqueous citric acid (100 mL). The organic layer was separated, washed with brine (50 ml), dried (MgSO4), filtered and concentrated to provide 840 mg of the desired product 18c (wherein R1 = R2 = Me, R3 = H, R9 = 4-c / sn-propyl, R11 = mono-ester of succinic acid) (1.16 mmol, 100%) in the form of a white foam. The product was used without further purification. EM (SPOS): 745.2 [M + Naj +. MS (ESNEG): 721.2 [MH] \ A solution of the protected succinate 18c (wherein R1 = R2 = Me, R3 = H, R9 = 4-c / sn-propyl, R11 = succinic acid monoester) (251 mg, 0.35 mmol, 1 equiv) in 1,2-dichloroethane (20 ml) at 23 ° C was added H20 (1.0 ml) followed by TFA (8.0 ml). After stirring for 25 min at 23 ° C, toluene (30 ml) was added and the resulting solution was concentrated to a volume of 20 ml. This solution was further diluted with toluene (30 ml) and then concentrated to dryness. The product was purified by semipreparative HPLC (Waters Nova-Pak® HR C18, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 at 5-60% with AcOH at 0.1%, 30 min, flow rate 20 ml / min) to give 94 mg of the title compound as a white solid. 1 H NMR (300 MHz, D20) d 5.55 (d, J = 6.0, 1), 5.15 (dd, J = 6.0, 10.5, 1), 4.26-4.16 (, 2), 3.98-3.87 (m, 3), 3.51 (broad d, J = 13.5, 1), 3.07 (broad t, J = 9.9, 1), 2.69 (t, J = 7.2, 2), 2.56 (t, J = 7.2, 2), 2.28-2.21 ( m, 1), 2.16-2.06 (m, 1), 2.13 (s, 3), 2.04-1.96 (m, 1), 1.84-1.70 (m, 1), 1.54-1.28 (m, 6), 0.94- 0.84 (m, 9 H). MS (ESPOS): 505.1 [M + H] +. MS (ESNEG): 503.2 [M-H] \ EXAMPLE 83 Preparation of the ester of 4,5-dihydroxy-6-f2-methyl-1-r (4-propyl-piperidine-2-carboniP-amino-1-propyl > -2-methylsulfanyl-tetrahydro-pyran-3-yl of N-acid - (2-morpholinA-il-etiP-succinámico To a solution of the protected succinate 18c (in which R1 = R2 = Me, R3 = H, R9 = 4-c / sn-propyl, R11 = succinic acid monoester) (222 mg, 0.31 mmol, 1 equiv) in DMF (3.0 ml) at 0 ° C was added 4- (2-aminoethyl) morpholine (60 μl, 0.46 mmol, 1.5 equiv) followed by EDC HCl (89 mg, 0.46 mmol, 1.5 equiv) followed by HOB H20 (56 mg, 0.37 mmoles, 1.2 equiv). After stirring for 20 min at 0 ° C the reaction was heated to 23 ° C. After stirring for a further 16 h, the volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 ml) and brine / 10% aqueous citric acid 1: 1 (100 ml). The organic layer was separated, washed with brine (80 ml), dried (MgSO), filtered and concentrated to provide 242 mg (0.29 mmol, 94%) of product 18c (in which R1 = R2 = Me, R3 = H, R9 = 4-c / s-n-propyl, R11 = N- (2-morpholin-4-yl-ethyl) -succinic acid monoester) in the form of a clear oil. The product was used without further purification. MS (ESPOS): 835.5 [M + H] +. To a solution of the protected succinate 18c (in which R1 = R2 = Me, R3 = H, R9 = 4-c sn-propyl, R11 = N- (2-morpholin-4-yl-eyl) -succinic acid monoester ) (242 mg, 0.29 mmol, 1 equiv) in 1,2-dichloroethane (20 ml) at 23 ° C was added H20 (1.0 ml) followed by TFA (8.0 ml). After stirring for 25 min at 23 ° C, toluene (70 ml) was added and the resulting solution was concentrated to dryness. The product was purified by semipreparative HPLC (Waters Nova-Pak® HR C-.8, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 at 5-60% with AcOH at 0.1 %, in 30 min, flow rate 20 ml / min) to give 47 mg of the title compound as a white solid. 1 H NMR (300 MHz, D20) d 5.52 (d, J = 6.0, 1), 5.12 (dd, J = 6.0, 10.5, 1), 4.24-4.16 (m, 2), 3.95-3.85 (m, 3) , 3.63 (t, J = 6.0, 2), 3.50 (broad d, J = 13.5, 1), 3.34 (t, J = 6.0, 2), 3.05 (dt, J = 3.0, 13.5, 1), 2.76 (t, J = 6.0, 2), 2.61 (t, J = 6.0, 2), 2.28-2.21 (m, 1), 2.16-2.06 (m, 1), 2.11 (s, 3), 2.04-1.96 (m, 1), 1.84-1.70 (m, 1), 1.54-1.28 (m, 6), 0.94-0.84 (m, 9H); the protons of the morpholine are visible but very wide, producing humps in the baseline between d 4.15-3.14 (8 H). MS (ESPOS): 617.5 [M + H] +. MS (ESNEG): 651.2 [M + CI] ".

EXAMPLE 84 Preparation of the ester of 4,5-dihydroxy-6- (2-methyl-1-r (4-propyl-piperidine-2-carboniP-amino, -propyl.) -2-methylsulfanyl-tetrahydro-pyran-3 -dimethylaminoacetic acid To a solution of the alcohol 18b (in which R1 = R2 = Me, R3 = H, R .9a - = 4-c / sn-propyl, m = 2) (393 mg, 0.63 mmol, 1 equiv) in CH2CI2 ( 5.0 ml) at 23 ° C was added? /, / V-dimethylglycine (72 mg, 0.70 mmol, 1.1 equiv) followed by DCC (390 mg, 1.90 mmol, 3 equiv) followed by DMAP (54 mg, 0.44 mmol, 0.7 equiv). After stirring for 12 h at 23 ° C, the reaction mixture was filtered through a PTFE membrane (0.45 μm) with the aid of CH2Cl2 (20 ml). The filtrate was partitioned between EOAc (100 ml) and aqueous saturated solution of NaHCO3 (80 ml). The organic layer was separated, washed with brine: 10% aqueous citric acid 1: 1 (60 ml), and brine (50 ml), dried (MgSO 4) filtered and concentrated to provide 600 mg of brown solid which was determined that it contained the desired product. The crude product was used without further purification. MS (ESPOS): 708.5 [M + H] +. To a solution of the protected glycinate (600 mg, crude) in 1,2-dichloroethane (20 ml) at 23 ° C was added H20 (1.0 ml) followed by TFA (8.0 ml). After stirring for 20 min at 23 ° C, toluene (100 mL) was added and the resulting solution was concentrated to dryness. The residue was dissolved / suspended in H20 (10 ml) and filtered through a PTFE membrane (0.45 μm) with the help of H20 (10 ml). The resulting solution was purified by semipreparative HPLC (Waters Nova-Pak® HR C18, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H60 at 5-60% with 0.1% AcOH, in 30 min, flow rate 20 ml / min) to give 189 mg of the title compound as a white solid. 1 H NMR (300 MHz, D20) d 5.62 (d, J = 6.3, 1), 5.30-5.23 (m, 1), 4.27-4.16 (m, 4), 3.95-3.89 (m, 3), 3.50 (d width, J = 12.3, 1), 3.04 (wide t, J = 13.2, 1), 3.00 (s, 6), 2.28-2.19 (m, 1), 2.16-2.06 (m, 1), 2.13 (s, 3), 2.04-1.96 (m, 1), 1.84-1.70 (m, 1), 1.54-1.28 (m, 6), 0.93-0.83 (m, 9H). EM (SPOS): 490. 4 [M + H] +. MS (ESNEG): 524.2 [M + CI] -.

EXAMPLE 85 Preparation of 4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide The intermediate amino acid, the ester of 1-fer-butyl acid ^ S ^ RJ ^ -cyclopropylmethyl-pyrrolidine-l-dicarboxylic acid was prepared by the synthetic sequence described by Goodman et al., Journal of Organic Chemistry, 2003, 68, 3923. Lincosamine 2b (R1 = Me, R2 = Me) was coupled with the (2S, 4R) -4-cyclopropylmethyl-pyrrolidine-1, 2-dicarboxylic acid 1-f-butyl ester as described in general coupling scheme 11 to provide intermediate 11a (R1 = R2 = Me, R3 = H, R9 = cyclopropylmethyl, P1 = H, P2 = carboxylic acid ferric butyl ester, m = 1) which was deprotected under acidic conditions to provide the title compound. MS (ESPOS): 403.3 [M + H] +.

EXAMPLE 86 Preparation of 4- (2-cyclobutyl-etiP-pyrrolidine-2-r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl] -amide of 4- (2-cyclobutyl-etiP-pyrrolidine carboxylic acid The intermediate amino acid, the ester of 1 -ferc-butyl of carboxylic acid (, 2S, 4f?) -4- (2-cyclobutyl-eyl) -pyrrolidine-1,2-dicarboxylic acid was prepared by the general method K by alkylation of pyroglutamic acid ester, 7a with (2-bromo-ethylidene) -cyclobutane The starting material, the allylic halide (2-bromo-ethylidene) -cyclobutane, was prepared from cyclobutane in two steps as described in U.S. Patent 3,711, 555. Lincosamine 2b (R1 = Me, R2 = Me) was coupled with the protected amino acid 7d (R9 = 2-cyclobutyl-etyl) to provide the intermediate carbamate 11a (R1 = R2 = Me, R3 = H, R9 = 2-cyclobutyl-ethyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 1) which was deprotected under acidic conditions to provide the title compound. ): 432 .3 [M + H] +.

EXAMPLE 87 Preparation of 4- (2-cyclopropyl-etiP-pyrrolidine-2-carboxylic acid [2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propyl-amide of 4- (2-cyclopropyl-etiP-pyrrolidine-2-carboxylic acid Lincosamine 2b (R1 = Me, R2 = Me) was coupled with the protected amino acid 8c (R9 = 2-cyclopropyl-ethyl) prepared by the M method to provide the intermediate carbamate 11a (R1 = R2 = Me, R3 = H, R9 = 2-cyclopropyl-ethyl, P1 = H, P2 = t-butyl ester of carboxylic acid, m = 1) which was deprotonated under acidic conditions to provide the title compound. MS (ESPOS): 417.3 [M + H] +.

EXAMPLE 88 Preparation of 5-propyl-azepane-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yD-propylamide To a solution of the protected cyclic amino acid 19f (R12 = H, R13 = propyl), (81.4 mg, 0.29 mmol) prepared by General Method W, DIEA (100 μl, 0.57 mmol) and HCl salt of product 2b were added ( R1 = Me, R2 = Me) (83 mg, 0.29 mmol) in anhydrous DMF (2 mL) and HBTU (120 mg, 0.32 mmol). The resulting reaction mixture was stirred for 6 hours at room temperature under N2 atmosphere and then concentrated to a residue. The residue was taken up in ethyl acetate and washed with 10% citric acid, saturated sodium bicarbonate solution, and brine. The organic layer was dried and evaporated to dryness to give the 1'-N-protected lincosamide 11a (R1 = Me, R2 = Me, R3 = H, R9 = propyl, P1 = H, P2 = acid t-buyl ester) carboxylic acid) (148 mg, 100%). To a solution of the 1'-N-protected lincosamide 11a (R1 = Me, R2 = Me, R3 = H, R9 = propyl, P1 = H, P2 = t-butyl ester of carboxylic acid) (147 mg, 0.285 mmoles) in anhydrous DCE (2.0 ml) was added a solution of TES (10 μl, 0.13 mmol) in TFA (at 7.5% by weight in water) (0.44 ml). The resulting reaction mixture was stirred for one hour at room temperature under N2 atmosphere. The reaction mixture was concentrated and coevaporated with toluene to provide the desired product, [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. 5-propyl-2,3,6,7-tetrahydro-1 H-azepine-2-carboxylic acid (151 mg, 100%) as a white solid which was used in the next reaction without further purification. MS (ESPOS): 517 [M + H] +.

To a solution of [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-propyl-2,3,6 acid, 7-tetrahydro-1 / - / - azepine-2-carboxylic acid (112.4 mg, 0.212 mmol) in methanol (8.0 ml) was added 10% Pd / C Degussa in wet form (100 mg). The resulting suspension was hydrogenated at 3.5 kg / cm2 for two days. The reaction mixture was filtered through celite, then through a PTFE membrane of 0.45 μm and evaporated to dryness to give the crude product (96 mg, 88%).

The crude product was purified by semi-preparative HPLC (Waters Nova-Pak® HR C-is, particle size 6 μm, pore size 60 A, 20 mm ID x 100 mm, acetonitrile in H20 at 5-60% with AcOH at 0.1%, in 30 min, flow rate 20 ml / min) to provide the title compound (23.5 mg, 21.5%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, 1), 4.20-4.27 (m, 1), 4.04-4.15 (m, 2), 3.84 (d, 1), 3.41-3.55 (m, 2), 3.10-3.18 (t, 1), 1.88-2.20 (m, 6), 1.50-1.61 (m, 2), 1.25-1.39 (m, 3), 0.88-0.89 (m, 6); EM (SPOS): 419.4 [M + H] +.

EXAMPLE 89 Preparation of F2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4-butyl-piperidine-2-carboxylic acid Lincosamine 2b (R1 = Me, R2 = Me) was coupled with the 20o intermediate amino acid, (where R13 = H, R12 = 4-frar / sn-butyl, n = 1) prepared by method X, as describes in the general coupling scheme 11 to provide the intermediate carbamate 11a (R1 = R2 = Me, R3 = H, R9 = 4-frans-n-butyl, P1 = H, P2 = t-butyl ester of carboxylic acid, m = 2) which was deprotected under acidic conditions to provide the title compound. MS (ESPOS): 420 [M + H] +.

EXAMPLE 90 Preparation of 4- (3-cyclopentyl-propiP-piperidine-2-carboxylic acid [2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide To a mixture of the product 13c (R1 = R2 = Me, R3 = H, R9 = 3-Cyclopentyl-prop-1-inyl) prepared by the method Q (100 mg, 0.22 mmol) in MeOH (6 ml) and water ( 4 ml) were added platinum oxide (200 mg) and concentrated HCl (25 μl). The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (26.8 mg, 26%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.4, 1), 4.17 (dd, J = 3.3, 10.2, 1), 4.10-4.03 (m, 2), 3.81 (d, J = 3.3, 1), 3.57-3.48 (m, 2), 3.27-3.20 (m, 1), 2.84-2.74 (m, 1), 2.19-2.13 (m, 1), 2.10 (s, 3), 2.07-2.00 ( m, 1), 1.82-1.70 (m, 4), 1.64-1.50 (m, 5), 1.38-1.25 (m, 6), 1.23- (m, 4), 0.94-0.88 (m, 6). MS (ESPOS): 473.7 [M + Hf.

EXAMPLE 91 Preparation of 4- (3-methoxy-propyP-piperidine-2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (3-methoxy-propyP-piperidine-2- carboxylic The product 13b was added to a dry flask (R1 = R2 = Me, R3 = H) (130 mg, 0.27 mmol, 1 equiv), triphenylphosphine (45.3 mg, 0.17 mmol, 0.64 equiv), copper iodide (I) (32.9 mg, 0.17 mmol, 0.64 equiv), palladium acetate (19.4 mg, 0.086 mmole, 0.32 equiv) and triethylamine (1.5 ml). The mixture was degassed with nitrogen, followed by the addition of methylpropargyl ether (Aldrich) (114 μl, 1.35 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by column chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9 = 3-methoxy-prop-1-inyl) in the form of a yellow syrup (1 05 mg, 92%) . 1 H NMR (300 MHz, CDCl 3) d 8.52-8.49 (m, 1), 8.20 (broad s, 1), 8. 16 (s, 1), 7.46 (dd, J = 1.7, 5.0.1), 5.36 (d, J = 5.4, 1), 5.03 (d, J = 3, 1), 4.33 (s, 2), 4.27 -4.10 (m, 2), 3.98 (d, J = 10.2, 1), 3.75 (t, J = 3.6, 1), 3.55-3.45 (m, 1), 3.44 (s, 3), 2.67 (d, J = 9.9, 1), 2.47-2.40 (m, 1), 2.38 (d, J = 5.1, 1), 2.17 (s, 3), 1.04 (d, J = 7.2, 3), 0.96 (d, J = 6.9, 3); MS (ESPOS): 425.6 [M + H] +; MS (ESNEG): 423.5 [MH] ". To a mixture of the product 13c (R1 = Me, R9, = 3-methoxy-prop-1-ynyl) (95 mg, 0.22 mmol) in MeOH (6 ml) and water (4 ml) Platinum oxide (200 mg) and concentrated HCl (26 μl) were added.The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight.The plafino oxide was separated by filtration and the filtrate was evaporated The residue was purified by chromatography to give the title compound (8 mg, 8%) as a white solid.1H NMR (300 MHz, CD3OD) d 5.23 (d, J = 5.7, 1 ), 4.17 (dd, J = 3. 2, 10.1, 1), 4.10-4.02 (m, 2), 3.80 (d, J = 3.3, 1), 3.53-3.43 (m, 2), 3.39 (t, J = 6.5, 2), 3.31 (s) , 3), 3.27-3.18 (m, 1), 2.80-2.70 (m, 1), 2.21-2.11 (m, 1), 2.10 (s, 3), 2.06-1.98 (m, 1), 1.82-1.74 (m, 1), 1.65-1.54 (m, 3), 1.38-1.28 (m, 2), 1.23-1.08 (m, 2), 0.93-0.88 (m, 6); MS (ESPOS): 435.7 [M + H] +; MS (ESNEG): 433.6 [M-H] ".

EXAMPLE 92 Preparation of 4- (3-ethoxy-propyP-piperidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide In a dry flask, the product 13b was added (R1 = R2 = Me, R3 = H) prepared using Method Q (130 mg, 0.27 mmol, 1 equiv), triphenylphosphine (45.3 mg, 0.17 mmol, 0.64 equiv), copper iodide (I) (32.9 mg, 0.17 mmol, 0.64 equiv), acetate of palladium (19.4 mg, 0.086 mmol, 0.32 equiv) and triethylamine (1.5 ml). The mixture was degassed with nitrogen, followed by the addition of methylpropargyl ether (113 mg, 1.35 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9, = 3-Ethoxy-prop-1-ynyl) (78.1 mg, 66%). MS (ESPOS): 439.6 [M + H] +; MS (ESNEG): 437.5 [MH]. "To a mixture of the above syrup in MeOH (6 ml) and water (4 ml) were added platinum oxide (150 mg) and concentrated HCl (14 μl). and charged with hydrogen (4.55 kg / cm2) and stirred overnight.The platinum oxide was separated by filtration and the filtrate was evaporated.The residue was purified by chromatography to give the title compound (20 mg, 25%) in the form of a white solid, 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.21 (dd, J = 3, 9. 9, 1), 4.11-4.04 (m, 2), 3.89-3.80 (m, 2), 3.54-3.38 (m, 6), 3.10-2.98 (m, 1), 2.25-2.12 (m, 2), 2.11 (s, 3), 2.00-1.90 (m, 1), 1.78-1.56 (m, 2), 1.44-1.27 (m, ), 1.17 (t, J = 6.9, 3), 0.94-0.88 (m, 6). MS (ESPOS): 449.6 [M + H] +; EM (ESNEG): 447.7 [M-H] ".

EXAMPLE 93 Preparation of 4- (3-propoxy-propyP-piperidine-2-carboxylic acid r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide In a dry flask, the product 13b (R1 = R2 = Me, R3 = H) prepared using Method Q (150 mg, 0.31 mmol, 1 equiv), triphenylphosphine (52.4 mg, 0.2 mmol, 0.64 equiv), iodide copper (I) (38.1 mg, 0. 2 mmol, 0.64 equiv), palladium acetate (22.4 mg, 0.1 mmol, 0.32 equiv) and triethylamine (1.7 ml). The mixture was degassed with nitrogen, followed by the addition of methyl-propargue ether (117 mg, 1.24 mmol, 4 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3-prop-1-ynyl-oxy-prop-1-inyl) (40.9 mg, 29%). MS (ESPOS): 449.2 [M + H] +. To a mixture of the above syrup in MeOH (6 ml) and water (4 ml) were added platinum oxide (100 mg) and 0.1037 N HCl (0.86 ml, 0.089 mmol, 0.98 equiv) The mixture was purged and charged with hydrogen ( 4.55 kg / cm2) and stirred overnight The platinum oxide was removed by filtration and the filtrate was evaporated The residue was purified by chromatography to give a white solid, the title compound (11 mg, 26%). 1 H NMR (300MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.17 (dd, J = 3.2, 10.1, 1), 4.10-4.02 (m, 2), 3.79 (d, J = 3, 1 ), 3.53-3.32- (m, 6), 3.25-3.18 (m, 1), 2.80-2.68 (m, 1), 2.22-2.12 (m, 1), 2.10 (s, 3), 2.06-1.98 ( m, 1), 1.83-1.74 (m, 1), 1.66-1.08 (m, 9), 0.97-0.86 (m, 9), MS (SPOS): 463.4 [M + H] +.

EXAMPLE 94 Preparation of the 4- (3-cyclopropylmethoxy-propyP-piperidine-2 - r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4- (3-cyclopropylmethoxy-propyP-piperidine-2 carboxylic In a dry flask, the product 13b (R1 = R2 = Me, R3 = H) prepared using Method Q (200 mg, 0.42 mmol, 1 equiv), triphenylphosphine (69.7 mg, 0.27 mmol, 0.64 equiv), sodium iodide, was added. copper (I) (50.6 mg, 0.27 mmol, 0.64 equiv), palladium acetate (29.8 mg, 0.13 mmol, 0.32 equiv) and triethylamine (2.4 ml). The mixture was degassed with nitrogen, followed by the addition of prop-2-ynyloxymethyl-cyclopropane (229 mg, 2.08 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3-prop-2-ynyloxymethyl-cyclopropane) (113 mg, 59%). MS (ESPOS): 465.1 [M + H] +. To a mixture of the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3-prop-2-ynyloxymethyl-cyclopropane) in MeOH (6 ml) and water (4 ml) were added platinum oxide (230 mg ) and concentrated HCl (19.3 μl, 0.232 mmol, 0.95 equiv). The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (20 mg, 17%). [1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7, 1), 4.21 (dd, J = 3. 6, 9.9, 1), 4.11-4.04 (m, 2), 3.87-3.78 (m, 2), 3.54-3.38 (m, 4), 3.08-2.98 (m, 1), 2.27-2.07 (m, 2 ), 2.11 (s, 3), 2.01-1.91 (m, 1), 1.80-1.25 (m, 9), 1.01-0.85 (m, 7), 0.56-0.47 (m, 2), 0.22-0.15 (m , 2); MS (ESPOS): 475.2 [M + H] +.

EXAMPLE 95 Preparation of 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 4-r3- (2-fluoro-ethoxy-propyl) n-piperidine-2-carboxylic In a dry flask, the product 13b was added (R1 = R2 = Me, R3 = H) prepared using Method Q (230 mg, 0.48 mmol, 1 equiv), rifepylphosphine (80.1 mg, 0.31 mmol, 0.64 equiv), copper iodide (I) (58.2 mg, 0.31 mmol, 0.64 equiv), acetate of palladium (34.2 mg, 0.15 mmol, 0.32 equiv) and triethylamine (2.7 ml). The mixture was degassed with nitrogen, followed by the addition of 3- (2-fluoro-ethoxy) -propino (244 mg, 2.39 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9- = 3- (2-fluoro-ethoxy) -propino) (159 mg.73%). To a mixture of the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3- (2-fluoro-ethoxy) -propino) (159 mg, 73%) in MeOH (6 ml) and water (4 ml) ) Platinum oxide (320 mg) and concentrated HCl (27.7 μl, 0.33 mmol, 0.95 equiv) were added. The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated. The residue was purified by chromatography to give the title compound (25 mg, 15%). 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.60-4.56 (m, 1), 4.44-4.39 (m, 1), 4.20 (dd, J = 3.3, 9.9, 1) , 4.10-4.04 (m, 2), 3.81-3.75 (m, 2), 3.73-3.68 (m, 1), 3.63-3.58 (m, 1), 3.54-3.48 (m, 3), 3.43-3.34 (m, 1), 3.04- 2.93 (m, 1), 2.23- 2.12 (m, 2), 2.11 (s, 3), 1.98-1.88 (m, 1), 1.78-1.25 (m, 7), 0.95-0.87 (m, 6). EM (SPOS): 467.2 [M + H.

EXAMPLE 96 Preparation of 4- [3- (3-fluoro-propoxy) r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propiP-amide of 4- [3- (3-fluoro-propoxy) - propin-piperidine-2-carboxylic acid In a dry flask, the product 13b (R1 = R2 = Me, R3 = H) prepared using Method Q (230 mg, 0.48 mmol, 1 equiv), triphenylphosphine (80.1 mg, 0.31 mmol, 0.64 equiv), sodium iodide, was added. copper (I) (58.2 mg, 0.31 mmol, 0.64 equiv), palladium acetate (34.2 mg, 0.15 mmol, 0.32 equiv) and triethylamine (2.7 ml). The mixture was degassed with nitrogen, followed by the addition of 3- (3-fluoro-propoxy) propion (277 mg, 2.39 mmol, 5 equiv). The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo to give a dark residue. The residue was purified by chromatography to give the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3- (3-Fluoropropoxy) -propin) (137 mg, 61%). To a mixture of the product 13c (R1 = R2 = Me, R3 = H, R9 '= 3- (3-Fluoro-propoxy) -propin) in MeOH (6 ml) and water (4 ml) were added platinum oxide ( 280 mg) and concentrated HCl (23.1 μl, 0.28 mmol, 0.95 equiv). The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (23 mg, 16%). 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 5.7, 1), 4.57 (t, J = 5.9, 1), 4.41 (t, J = 6, 1), 4.20 (dd, J = 3.2, 10.1, 1), 4.10-4.04 (m, 2), 3.81 (d, J = 3, 1), 3.74-3.67 (m, 1), 3.55-3.42 (m, 5), 3.38-3.32 (m, 1 ), 2.98-2.87 (m, 1), 2.23-2.08 (m, 2), 2.11 (s, 3), 2.00-1.83 (m, 3), 1.72-1.57 (m, 2), 1.42-1.20 (m , 5), 0.97-0.87 (m, 6). MS (ESPOS): 481.2 [M + H] +.

EXAMPLE 97 Preparation of 4- (4-methoxy-butiP-piperidine-2-carboxylic acid f2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) To a mixture of NaH (60%, 37.6 mg, 0.94 mmol, 1 equiv) in dry DMF (2 ml) at 0 ° C was added dropwise a solution of the product 14c (R9 = 4-methoxybutyl) prepared by the Method R (197 mg, 0.94 mmol, 1 equiv) in DMF (0.5 ml). The mixture was stirred at 0 ° C for 20 min, and then cooled to -78 ° C. Iodomethane (134 mg, 0.94 mmol, 1 equiv) was added to the mixture. The mixture was stirred at 0 ° C for 2 h, and then at t.a. all night. The reaction mixture was then diluted with DCM, washed with brine, dried and concentrated. The residue was purified by preparative TLC to give 4- (4-methoxy-butyl) -pyridine-2-carboxylic acid methyl ester (43 mg, 21%). 1 H NMR (300 MHz, CDCl 3) d 8.61-8.58 (m, 1), 7.97-7.95 (m, 1), 7.29-7.26 (m, 1), 3.98 (s, 3), 3.37 (t, J = 6 , 2), 3.30 (s, 3), 2.70 (t, J = 7.7, 2), 1.78-1.54 (m, 4). To a mixture of 4- (4-methoxy-butyl) -pyridine-2-carboxylic acid methyl ester (107 mg, 0.48 mmol, 1 equiv) in THF (1.5 ml) and water (0.5 ml) was added monohydrate Lithium hydroxide (30.2 mg, 0.72 mmol, 1.5 equiv). The reaction mixture was stirred at t.a. for 4 h and then diluted with methanol (20 ml). Then, H + resin (0.4 g) was added and the mixture was stirred for 10 minutes. The resin was washed with methanol (1x), acetonitrile / water 1: 1 (1x), and acetonitrile (1x). The product was eluted with TEA in 5% methanol (4x) and acetonitrile (1x). The combined organic solvents were evaporated and coevaporated with toluene to give 4- (4-methoxy-butyl) -pyridine-2-carboxylic acid (63.4 mg, 63%): 1 H NMR (300 MHz, CD3OD) d 8.47-8.43 ( m, 1), 7.98-7.94 (m, 1), 7.43-7.37 (m, 1), 3.41 (t, J = 6.3, 2), 3.30 (s, 3), 2.75 (t, J = 7.5, 2 ), 1.80-1.55 (m, 4). To a solution of 4- (4-methoxy-buyl) -pyridine-2-carboxylic acid - (63.4 mg) in dry DMF (0.75 ml) at 0 ° C was added a mixture of the HCl salt of 7-Me 2b (R1 = Me, R2 = Me) (87.3 mg, 0.30 mmol, 1 equiv) and DIEA (78 mg, 0.61 mmol, 2 equiv) in DMF (0.75 ml), followed by the addition of HBTU (100 mg, 0.73 mmol) , 1 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated to dryness under high vacuum. The residue was purified by chromatography to give a syrup (88 mg, 65%). MS (ESPOS): 443.0 [M + H] +; MS (ESNEG): 441.2 [M-H]. "To a mixture of the above syrup (88 mg, 0.20 mmol, 1 equiv) in MeOH (6 ml) and water (4 ml) were added concentrated HCl (15.7 μl, 0.19). mmoles, 0.95 equiv) and platinum oxide (180 mg). The mixture was purged and charged with hydrogen (4.55 kg / cm2) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to a residue, which was purified by chromatography to give the title compound (lower isomer, 20 mg, 22%) as a white solid. 1 H NMR (300MHz, CD3OD) d 5.22 (d, J = 5.7, 1), 4.15 (dd, J = 3.2, 10.1, 1) .4.09-4.00 (m, 2), 3.78 (d, J = 2.7, 1 ), 3.49 (dd, J = 3.3, 10.5, 1), 3.38 (t, J = 6.3, 2), 3.30 (s, 3), 3.26-.3.22 (m, 1), 3.16-3.08 (m, 1 ), 2.66-2.55 (m, 1), 2.20-2.11 (m, 1), 2.09 (s, 3), 1.96-1.87 (m, 1), 1.73-1.64 (m, 1), 1.58-1.22 (m) , 7), 1.11-0.97 (m, 2), 0.93-0.86 (m, 6); MS (ESPOS): 449.4 [M + H] +; MS (ESNEG): 447.2 [M-H] ".

EXAMPLE 98 Preparation of the 4-propoxymethyl-piperidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-prop-p-amide Al (1-oxy-pyridin-4-yl) -methanol (5 g, 0.04 mol) in a solution of dichloromean (10 ml) and pyridine (10 ml) was added acetic anhydride (12.2 ml, 0.12 mol) and the mixture of The reaction was stirred for 16 h at room temperature. Then, the reaction mixture was poured into water and extracted with dichloromethane (200 ml) and then washed with brine (100 ml). The obtained crude product (4.27 g, 64%) was taken without purification for the next reaction. To the crude product (4.27 g, 25.6 mmol) in DCM (25 ml) and trimethylsilyl cyanide (3.40 ml, 25.6 mmol), dimethylcarbamyl chloride (2.35 ml, 25.6 mmol) was slowly added, and then the reaction mixture was stirred at room temperature overnight. Aqueous potassium carbonate (100 mL, 10%) was added and stirred for 10 minutes. Extraction with ethyl acetate followed by removal of the solvent gave the crude product which was purified by silica gel column chromatography using 50% ethyl acetate in hexanes to obtain cyanopyridine 10a (R9 = acetoxymethylene) (2.37 g. , 48%). 1 H NMR (300 MHz, CDCl 3) d 8.68 (d, J = 5.7 Hz, 1), 7.65 (s, 1), 7.45 (d, J = 5.7 Hz, 1), 5.13 (s, 2), 2.16 (s) , 3). MS (ESPOS): 199 [M + Na] +.

To the 2-cyano-pyridin-4-ylmethyl ester of acetic acid 10a (R9 = acetoxymethylene) (2.37 g, 0.012 mole), aqueous hydrochloric acid (50 ml, 6 N) was added and heated to reflux for 16 h. Evaporation separation of the hydrochloric acid and water resulted in the acid 10b (R9 = acetoxymethylene) (2.47 g, 100%). 1 H NMR (300 MHz, CD3OD) d 8.83 (d, J = 5.7 Hz, 1), 8.56 (s, 1), 8. 24 (d, J = 5.7 Hz, 1), 4.92 (s, 2). MS (ESNEG): 152 [MH]. "To product 10b (R9 = acetoxymethylene) (2.40 g, 0.012 mol) in methanol (25 ml), water (15 ml) and acetic acid (15 ml), dioxide was added. platinum (1 g) and hydrogenated at 3.5 kg / cm2 for 16 h The catalyst was filtered and the solvent was removed to obtain the hydrogenated product (2.50 g, 100%) which was taken as it was for the next reaction. of the previous reaction in dioxane (30 ml) and water (30 ml), sodium hydroxide (2.2 g, 0.05 mole) and di-t-butyl dicarbonate (12 g, 0.05 mole) were added and stirred at room temperature for 16 h The reaction mixture was then extracted with ethyl acetate (100 ml) to remove any excess Boc anhydride, then the aqueous phase was carefully acidified with HCl (1 N) and extracted with ethyl acetate. The crude product obtained by removing the solvent was purified by silica gel column chromatography using ethyl acetate to obtain the ester of 1-tert-butyl of 4-hydroxymethyl-piperidine-1,2-dicarboxylic acid (0.62 g, 20%). 1 H NMR (300 MHz, CD3OD) d 4.27 (d, J = 6.3 Hz, 1), 3.37-3.65 (m, 4), 2.05 (m, 1), 1.70-1.84 (m, 4), 1.52 (s, 9). MS (ESNEG): 258 [MH]. "To the 1-dibutyl-4-hydroxymethyl-piperidine-1,2-dicarboxylic acid ester (100 mg, 0.39 mmol) in DMF (5 mL), sodium hydride was added. (30 mg, 0.67 mmol) and stirred at 0 ° C for 10 minutes, propyl bromide (0.5 ml) was added., 4.0 mmol) (0.5 ml, 0.35 mmol) and stirred at room temperature for 30 minutes and then at 50-60 ° C for 2 h. Dry DMF was removed, water (50 ml) was added and extracted with ethyl acetate (50 ml). The product obtained by removing the solvent purified by column chromatography using 50% ethyl acetate in hexanes to provide the ester of 1 -ferc-butyl and 2-butyl ester of 4-butoxymethyl-piperidine-1,2-dicarboxylic acid (100 mg, 75%). 1 H NMR (300 MHz, CDCl 3) d 4.10 (q, J = 6.6, 7.2 Hz, 4), 3.46- 3.53 (m, 2), 3.25-3.36 (m, 2), 2.05 (m, 2), 1.44- 1.75 (m, 6), 1.45 (s, 9), 0.88-0.98 (m, 6). MS (ESPOS): 366 [M + Na] +. To the ester of 1-fer-butyl and 2-butyl ester of 4-butoxymethyl-piperidine-1,2-dicarboxylic acid (100 mg, 0.29 mmol) in THF (5 ml), hydroxide was added. of lithium (122 mg, 2.90 mmol) in water (1 ml) and stirred at room temperature for 16 h. Water was then poured and extracted with ethyl acetate and discarded. The water layer was acidified and then extracted with ethyl acetate (50 ml). Removal of the solvent gave the acid which was then taken as it was for the next coupling reaction. To the 1-fer-butyl ester of 4-butoxymethyl-piperidine-1,2-dicarboxylic acid (88 mg, 0.29 mmol) in DMF (3 ml), amine 2b (R1 = Me, R2 = Me) was added ( 100 mg, 0.34 mmol), HBTU (132 mg, 0.34 mmol) and DIEA (0.1 mL, 0.58 mmol) and stirred at room temperature for 3 h. The DMF was separated and the product was purified by silica gel column chromatography using 50% ethyl acetate in hexanes to provide the Boc protected lincosamide (R9 = 4-Butoxymethyl) (77 mg, 49%). 1 H NMR (300 MHz, CD3OD) d 5.25 (m, 1), 4.47-4.64 (m, 2) .4.41 (t, J = 6.0 Hz, 1), 4.26 (s, 1), 3.99-4.12 (m, 4), 3.85 (d, J = 3.3 Hz, 1), 3.50-3.54 (m, 2), 3.31-3.36 (m, 2), 2.14-2.2, 19 (m, 2), 1.81 (m, 3) , 1.53 (m, 2), 1.45 (broad s, 12), 0.88-0.98 (m, 9). MS (ESPOS): 535 [M + H] +. To the above Boc-protected lincosamide (R9 = 4-Butoxymethyl) (77 mg, 0.14 mmol), TFA in 30% DCE (30 ml), triethylsilane (1 ml) and water (1 ml) was added and stirred at room temperature for 1 h. The residue obtained by removing the solvent was chromatographed using methanol in 20% DCM to obtain the title compound (10 mg, 16%) as a white solid. 1 H NMR (300 MHz, CD3OD) d 5.25 (d, J = 5.7 Hz, 1), 4.05-4.19 (m, 3), 3.74-3.86 (m, 2), 3.50-3.54 (m, 2), 3.40- 3.54 (m, 4), 2.14 (m, 2), 2.10 (s, 3), 2.00 (m, 1), 1, 71-1.75 (m, 2), 1.54-1.61 (m, 2), 1.31 ( m, 1), 0.89-0.94 (m, 9). MS (ESPOS): 435 [M + H] +.

EXAMPLE 99 Preparation of 4- (3-fluoro-propoxymethiD-piperidine- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propip-amide of 4- (3-fluoro-propoxymethiD-piperidine- 2- carboxylic The title compound was prepared by the same sequence of reactions of example 98 starting from the 1-methyl-butyl ester of 4-hydroxymethyl-piperidine-1,2-dicarboxylic acid protected with Boc, substituting 3-fluoropropyl bromide in the alkylation. 1 H NMR (300 MHz, CD3OD) d 5.22 (d, J = 5.4 Hz, 1), 4.58 (q, J = 3.9, 6.9 Hz, 1), 4.22 (q, J = 5.1, 5.7 Hz, 1), 3.90 -4.16 (m, 3), 3.82-3.86 (m, 1), 3.74 (d, J = 2.1 Hz, 1), 3.47-3.59 (m, 3), 3.35-3.39 (m, 1), 3.04 (m, 2), 2.07 (s, 3), 1.85-1.98 (m, 4), 1.47-1.56 (m, 2), 1.02-1.12 (m, 2), 0.90-0.96 (m, 6).

MS (ESPOS): 453 [M + H] +.

EXAMPLE 100 Preparation of f-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide 1- (5-methyl-2-oxo-ri, 31-dioxolA-ilmetiPA- propyl-piperidine-2-carboxylic To the title compound of Example 17 (50 mg, 0.123 mmol) in DMF (5 mL) at room temperature, sodium carbonate (25 mg, 0.246 mmol) and 4-bromomethyl-5-methyl- [1, 3] dioxol were added. -2-one, prepared as described by J. Alexander, et.al. J. Med. Chem, 1996, 39, 480-486; (47 mg, 0.246 mmol) and stirred overnight at room temperature. The DMF was removed and the crude material was loaded onto a column of silica gel and eluted with a mixture of methanol and dichloromethane (5%) to obtain the title compound as a white solid (30 mg, 48%) . TLC: Rf = 0.5 (EtOAc). MS (ESPOS): 517 [M + H] +; 1 H-NMR (CD3OD, 200 MHz): d 5.22 (d, J = 3.8 Hz, 1), 4.05-4.20 (m, 3), 3.86 (d, J = 2 Hz, 1), 3.51-3.60 (m, 2 ), 2.88-3.01 (m, 2), 2.17 (m, 2), 2.13 (s, 3), 2.10 (s, 3), 1.88 (d, J = 6.2 Hz, 1), 1.70 (d, J = 8.2 Hz, 1), 1.21-1.35 (m, 6), 0.90-0.96 (m, 9).

EXAMPLE 101 Preparation of the 5-methyl-2-oxo-ri. 31-dioxol-4-ylmethyl ester of 2- f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-acid) iP-propylcarbamop-4-propyl-piperidine-1-carboxylic acid To the title compound of Example 17 (50 mg, 0.123 mmol) in DMF (5 mL) at room temperature, bicarbonated poasic (20 mg, 0.30 mmol) and 5-methyl-2-oxo- ester were added [1, 3 ] dioxol-4-ylmethyl and 4-nitro-phenyl ester of carbonic acid, prepared as described by F. Sakamoto, et.al., Chem. Pharm. Bull. 1984, 32 (6), 2241-2348; (36 mg, 0.123 mmol) and stirred overnight at room temperature. The DMF was removed and the crude material was loaded onto a column of silica gel and eluted with a mixture of methanol and dichloromethane (5%) to obtain the title compound (30 mg, 44%) as a white solid . TLC: Rf = 0.5 (EtOAc). MS (ESPOS): 561 [M + H] +; 1 H NMR (CD3OD, 200 MHz): d 5.23 (d, J = 3.8 Hz, 1), 4.92 (m, 2), 4.21-4.24 (m, 1), 4.07-4.13 (m, 3), 3.98 (m, 1 ), 3.57 (d, J = 2.2 Hz, 1), 3.54 (d, J = 2.2 Hz, 1), 2.16 (s, 3), 2.08 (s, 3), 1.95-1.97 (m, 2), 1.76 -1.85 (m, 2), 1.60 (m, 1), 1.32 (m, 4), 0.88-0.98 (m, 9).

EXAMPLE 102 Preparation of 4,5-dihydroxy-6- ester. { 2-methyl-1-l74-propyl-piperidine-2-carboniP-aminol-propyl > -2-methylsulfanyl-tetrahydro-pyran-3-yl of hexadecanoic acid The title compound, 5 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, R11 = CO (CH2) 1 CH3, m = 2) was prepared using Method V by alcohol treatment 18b (wherein R1 = R2 = Me, R3 = H, R6 = Boc, R9 = 4-c / sn-Pr, and m = 2) with the acylation reagent palmitoyl chloride.

EXAMPLE 103 Preparation of the 1- (1-methyl-3-oxo-but-1-enyl) -4 r 2 -methyl-, 3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide -propyl-piperidine-2-carboxylic acid The title compound can be prepared using the method described, by Jensen et al, Journal of Medicinal Chemistry 1980, 23, by way of the product 1 (in which R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) with acetylacetone.

EXAMPLE 104 Preparation of the 1-acetoxy-ethyl ester of 2-r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylcarbamoinA-propyl-piperidine-1-carboxylic acid The title compound can be prepared using the method described by Alexander et al., Journal of Medicinal Chemistry 1988, 31, 318-322, by treatment of product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / s-n-propyl, and m = 2) with the acylating agent the 1- (4-nitro-phenoxycarbonyloxy) ethyl ester of acetic acid.

EXAMPLE 105 Preparation of the 2-amino-3-methyl-pentanoyloxymethyl ester of 2- f2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylcarbamoy-4-propyl) piperidin-1-carboxylic The compound of the tíulo can be prepared using the method described by Alexander et al., Journal of Medicinal Chemistry 1988, 31, 318-322, by treatment of the product 1 (in which R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) with the appropriate acylation reagent (2-tert-butoxycarbonylamino-3-methyl-pentanoic acid 4-nitro-phenoxycarbonyloxymethyl ester), followed by deprotection with TFA .

EXAMPLE 106 Preparation of the piperidine-4-carbonyloxymethyl ester of 2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoip-4-propyl ester -piperidine-1-carboxylic acid The compound of the title can be prepared using the method described by Alexander et al., Journal of Medicinal Chemistry 1988, 31, 318-322, by treatment of product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) with the appropriate acylating reagent (4-nitro-phenoxycarbonyloxymethyl ester and 1-tert-butyl ester of piperidine-1,4-dicarboxylic acid), followed of deprotection with TFA.

EXAMPLE 107 Preparation of 1- (propionylamino-meth.P-4-propyl-piperidine- r- methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propyl-amide) 2 -carboxylic The thioule compound can be prepared from product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / 'sn-propyl, and m = 2) using the method described by Bundgaard et al., Journal of Pharmaceutical Sciences, 1980, 69 (1), 44-46.

EXAMPLE 108 Preparation of N-, 2- [2-Methyl-1-Q ^^ - trihydroxy-e-methylsulfanyl-tetrahydropyran-2-iP-propylcarbamoinA-propyl-piperidin-1-ylmethyl > -nicotinamide The title compound can be prepared from product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) using the method described by Bundgaard et al., Journal of Pharmaceutical Sciences, 1980, 69 (1), 44-46.

EXAMPLE 109 Preparation of 1- (2-amino-proponyl) -4-propyl-piperidine f2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide) -2-carboxylic acid The title compound can be prepared using the method described by Weiss et al., Antimicrobial Agents and Chemotherapy, 1999, 43 (3), 460-464, by treatment of product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4- sn-propyl, and m = 2) with Boc-alanine and HATU in the presence of DIEA in a suitable solvent, followed by deprotection with TFA.

EXAMPLE 110 Preparation of 1- (2-amino-3-phenyl-propionyl [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 1- (2-amino-3-phenyl-propionyl) acid ) -4-propyl-piperidine-2-carboxylic acid The title compound can be prepared using the method described by Weiss et al., Antimicrobial Agents and Chemotherapy, 1999, 43 (3), 460-464, by treatment of product 1 (in which R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / s-n-propyl, and m = 2) with Boc-phenylalanine and HATU in the presence of DIEA in a suitable solvent, followed by deprotection with TFA.

EXAMPLE 111 Preparation of 1- (2-methyl-3-methyl-3-methyl-3-methyl-3-methyl-1- (3,4,5-trihydroxy-6-methylsulfani] -tetrahydropyran-2-iP-propylamide pentanoiP-4-propyl-piperidine-2-carboxylic acid The title compound can be prepared using the method described by Weiss et al., Antimicrobial Agents and Chemotherapy, 1999, 43 (3), 460-464, by treatment of product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) with Boc-isoleucine and HATU in the presence of DIEA in a suitable solvent, followed by deprotection with TFA.

EXAMPLE 112 Preparation of 1- (2-amino-3-methyl-butyryl) -4-propyl r2-methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 1- (2-amino-3-methyl-butyryl) -4-propyl acid - piperidine-2-carboxylic The title compound can be prepared using the method described by Weiss et al., Antimicrobial Agents and Chemotherapy, 1999, 43 (3), 460-464, by treatment of product 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) with Boc-valine and HATU in the presence of DIEA in a suitable solvent, followed by deprotection with TFA.

EXAMPLE 113 Preparation of r 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-iP-propylamide of 1- (1-methyl) Adihydro-pyridine-3-carboniPA -propyl-piperidine-2-carboxy The title compound can be prepared from the production 1 (wherein R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) using the method described by Shek et al., Journal of Medicinal Chemistry 1976, 19 ( 1), 108-112.

EXAMPLE 114 Preparation of the acid 1-methyl-1,2.3.6-tetrahydro-pyridin-4-yl ester 2-r2-methyl-1- (314,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylcarbamoy-4-propyl-piperidine-1-carboxylic acid The title compound can be prepared from the production 1 (in which R1 = R2 = Me, R3 = H, R6 = H, R9 = 4-c / sn-propyl, and m = 2) using the method described by Flaherty et al., Journal of Medicinal Chemistry 1996, 39, 4756-4761.

EXAMPLE 115 r 2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide of 4-cyclohexylmethyl-piperidine-2-carboxylic acid Intermediate 10b, (R9 = benzyl) was prepared using Method P using 4-benzylpyridine as the starting material. 1 H NMR (300 MHz, CD 3 OD) d 8.78 (m, 1), 8.40 (s, 1), 8.03 (m, 1), 7.26-7.40 (m, 5) .4.39 (s, 2); MS (ESNEG): 212 [M -1]. "Lincosamine 2b (R1 = Me, R2 = Me) was coupled with 4-benzylpyridine-2-carboxylic acid 10b (R9 = 4-benzyl) as described in general coupling scheme 11 to provide intermediate 11b (R 1 = Me, R 2 = Me, R 3 = H, R 9 = benz, P 1 = H), which was reduced by catalytic hydrogenation to the title compound. 1 H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.4, 1), 4.03-4.19 (m, 4), 3.78 (m, 1), 3.48-3.52 (m, 2), 3.21-3.24 (m , 2), 2.77 (t, J = 12.6, 1), 2.17 (m, 2), 2.15 (s, 3), 1.98-2.02 (m 1), 1.70-1.74 (m, 60), 1.12-1.37 ( m, 8), 0.91 (d, J = 6.9, 6); MS [ESPOSI: 459 [M + H] +.

EXAMPLE 116 4- (2-propyloxyethyl) -piperidine-2-carboxylic acid 2-4-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide) To a solution of 4- (2-hydroxyethyl) -pyridine (2.15 g, 17.48 mmol, 1 equiv) in glacial acetic acid (11.7 ml) was added 30% hydrogen peroxide (1.98 ml, 17.48 mmol, 1 equiv). The reaction mixture was heated to reflux overnight and concentrated. The residue was dissolved in DCM, and dried (MgSO). The solvent was evaporated in vacuo and co-evaporated with toluene to give the intermediate N-oxide in the form of a syrup. A solution of the above syrup in DCM (17 ml) was added to trimethylsilyl cyanide (2.95 ml, 22.14, 1.27 equiv) at t.a. and then cooled to 0 ° C. To the mixture was added dropwise a solution of dimethylcarbamyl chloride in DCM (4.4 ml) in 10 min. The reaction mixture was stirred at t.a. all night. A solution of 10% aqueous potassium carbonate (17.5 ml) was added dropwise and the mixture was stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried and concentrated. The residue was purified by chromatography to give the intermediate nitrile 10a (R9 = 2-hydroxyethyl) (0.82 g, %) in the form of a yellow oil. 1 H-NMR (300 MHz, CDCl 3) d 8.61 (d, J = 5.1, 1), 7.56 (d, J = 0.6, 1), 7.39-7.34 (m, 1), 4.31 (t, J = 6.5, 2) , 2.99 (f, J = 6.3, 2), 2.02 (s, 3). A solution of the above nitrile 10a (R9 = 2-hydroxyethyl) (0.82 g, 4. 32 mmole) in 6 N HCl (2 ml) was heated to reflux overnight. The reaction mixture was concentrated in vacuo. MeOH (18 ml) and water (18 ml) were added, followed by HCl aq. conc. (2.2 ml) and platinum oxide (450 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated in vacuo to give the intermediate pipecolic acid. The above intermediate pipecolic acid was taken up in 2 N NaOH (5 ml) and t-buanol (5 ml) and di-t-butyl dicarbonate (1.33 g, 6.1 mmol) were added with stirring. The mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water and the organic layer was washed with ether. The organic layer was acidified with 2 N HCl to pH = 2.0, and extracted with ethyl acetate (twice). The combined organic layers were dried (MgSO) and concentrated in vacuo. The crude intermediate N-Boc-pipecolinic acid was purified by chromatography to give the 1- (tert-butyl ester of 4- (2-hydroxyethyl) -piperidine-1,2-carboxylic acid (210 mg, 18%) in shape of a transparent syrup. 1 H NMR (300 MHz, CDCl 3) d 4.45-4.38 (m, 1 H), 3.64 (t, J = 7.1, 2), 3.63-3.56 (m, 1), 3.34-3.24 (m, 1), 1.99- 1.94 (m, 2), 1.85-1.65 (m, 2), 1.62-1.53 (m, 2), 1.48-1.43 (m, 1), 1.42 (s, 9). Sodium hydride (60% in oil, 28.9 mg, 0.72 mmol, 2 equiv) was washed with hexane (2x), and dried under high vacuum. A solution of the 4- (2-hydroxyethyl) -piperidine-1, 2-carboxylic acid 1 -ferc-butyl ester (98.6 mg, 0.36, 1 equiv) in DMF (0.8 ml) was added to a mixture of Sodium hydride in DMF (0.7 ml) at 0 ° C. The mixture was stirred at 0 ° C for 5 min, and then at t.a. for 20 min. 1-Bromopropane (0.33 ml, 3.6 mmol, 10 equiv) was added and the mixture was stirred at r.t. for 3 h and then inactivated with water. The mixture was then diluted with ethyl acetate, washed with water (1x), brine (1x), dried and concentrated to give a clear oil, which was purified by chromatography to give the intermediate ether, the ester of 1 - 4- (2-propyloxyethyl) -piperidine-1,2-carboxylic acid 2-propyl ester (35.8 mg, 28%). 1 H NMR (300 MHz, CDCl 3) d 4.36-4.29 (m, 1), 4.05 (t, J = 6.8, 2), 3.65-3.53 (m, 1), 3.39 (t, J = 6.5, 2), 3.32 (t, J = 6.8, 2), 3.33-3.25 (m, 1), 2.03-1.92 (m, 1), 1.87-1.70 (m, 3), 1.68-1.48 (m, 6), 1.41 (s, 9), 1.41-1.34 (m, 1), 0.97-0.84 (m, 6); MS (ESPOS): 258.2 [M-Boc + H] +.

To a solution of the intermediate ether, the ester of 1-fer-butyl ester and 2-propyl ester of 4- (2-propyloxyethi) -piperidine-1,2-carboxylic acid (73 mg, 0.20 mmol, 1 equiv) in dioxane (1 ml) and water (0.8 ml) was added lithium hydroxide monohydrate (84 mg, 2 mmol, 10 equiv). The reaction mixture was stirred at t.a. all night. The solvent was removed in vacuo. The residue was diluted with water, and washed with ether. The aqueous layer was taken up in ethyl acetate, and partitioned with 10% citric acid. The organic layer was washed with water (1x), brine (1x), and dried and concentrated to give the intermediate acid, the ester of 1- (2-propyloxyethyl) -piperidine-1, 2-butyl-butyl ester. -carboxylic (61.1 mg, 97%) in the form of a syrup. 1 H NMR (300 MHz, CDCl 3) d 4.37-4.30 (m, 1), 3.61-3.50 (m, 1), 3.42 (t, J = 6.5, 2), 3.34 (t, J = 6.8, 2), 3.42 -3.35 (m, 1), 2.06-1.95 (m, 1), 1.88-1.70 (m, 3), 1.65-1.50 (m, 4), 1.43 (s, 9), 1.42-1.34 (m, 1) , 0.88 (t, J = 7.5, 3). A mixture of lincosamine hydrochloride 2b (R1 = R 2 = Me; 55.8 mg, 0.19 mmol, 1 equiv) and DIEA (50 mg, 0.39 mmol, 2 equiv) in DMF (1 ml) was added to the previous intermediate acid ( 61.1 mg, 0.19 mmol, 1 equiv), followed by the addition of HBTU (80 mg, 0.21 mmol, 1.1 equiv). The reaction mixture was stirred at t.a. for 3 h. The reaction mixture was evaporated with high vacuum to dryness. The residue was then diluted with ethyl acetate, washed with 10% citric acid / brine 1: 1 (1x), saturated aqueous sodium bicarbonate solution (1x), brine (1x), dried and concentrated. The residue was purified by chromatography to give N-Boc. Intermediate lincosamide (60 mg, 56%).

MS (ESPOS): 549.5 [M + H] +. MS (ESNEG): 547.2 [M-H]. "To a solution of the intermediate product with above N-Boc in-DCM (9 ml) with methyl sulfide (0.2 ml), trifluoroacetic acid (3 ml) and water were added. (0.2 ml) The reaction mixture was stirred at rt for 1 h, the solvent was removed in vacuo and coevaporated with toluene twice, the residue was purified by chromatography to give the final product (lower Rf isomer, 12 mg 25%) in the form of a white solid.1H NMR (300 MHz, CD3OD) d 5.24 (d, J = 5.7, 1), 4.20 (dd, J = 3. 3, 9.9, 1), 4.11-4.04 (m, 2), 3.83-3.76 (m, 2), 3.55-3.48 (m, 3), 3.45-3.37 (m, 1), 3.38 (t, J = 6.6 , 2), 3.07-2.94 (m, 1), 2.29-2.12 (m, 2), 2.11 (s, 3), 1.98-1.83 (m, 2), 1.65-1.51 (m, 4), 1.45-1.33 (m, 2), 0.96-0.86 (m, 9); EM (SPOS): 449. 4 [M + H] +; MS (ESNEG): 447.2 [M - H] ".

EXAMPLE 117 4-Cyclopropylmethoxy-piperidine-2-carboxylic acid r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-p-propylamide The title compound was prepared using the synthetic sequence found in Method S starting from 4-hydroxypyridine-2-carboxylic acid, substituting cyclopropylmethyl bromide as the alkylating agent. Compound 15a (R9 '= cyclopropylmethyl): 1 H NMR (300 MHz, CD3OD) d 8.41 (d, J = 4.8, 1), 7.65 (d, J = 2.4, 1), 7.20 (m, 1), 4.09 (d , J = 6.9, 2), 1.32 (m, 1), 0.66 (m, 2), 0.43 (m, 2); MS (ESNEG): 192 [MH] \ Compound 15b (R1 = Me, R2 = Me, R3 = H, R9 '= cyclopropylmethyl): 1 H NMR (300 MHz, CD3OD) d 8.41 (d, J = 5.7, 1) , 7.61 (d, J = 2.7, 1), 7.07 (dd, J = 2.7, 5.7, 1), 5.27 (d, J = 5.4, 1), 4.87 (m, 2), 4.12 (dd, J = 3.0 , 10.2, 1), 3.98 (d, J = 6.9, 1), 3.84 (d, J = 3.0, 1), 3.56 (dd, J = 3.3, 9.6, 1), 3.33 (m, 1), 2.85 ( m, 1), 2.25 (m, 1), 2.11 (s, 3), 1.29 (m, 1), 0.98 (t, J = 5.7, 6), 0.66 (m, 2), 0.39 (m, 2); MS (ESPOS): 427 [M + H] +. Title compound (38 mg, 18%): 1 H NMR (300 MHz, CD 3 OD) d 5.24 (d, J = 5.4, 1), 4.88 (dd, J = 6.3, 9.6, 1), 4.04 (m, 2) , 4.21 (d, J = 2.7, 1), 3.50 (m, 3), 3.33 (m, 2), 2.78 (m, 1), 2.30 (m, 1), 2.16 (m, 1), 2.10 (s) , 3) 1.38 (m, 2) .1.02 (m, 9), 0.53 (m, 2), 0.22 (m, 2); MS (ESPOS): 433 [M + H] +.

EXAMPLE 118 r2-Methyl-1- (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide of 4-fluoro-4-butyl-piperidipa-2-carboxylic acid The title compound was prepared using the synthetic sequence found in Method Y (general scheme 21) starting from the ester of 1-fer-4-butoyl 4-oxo-piperidine-1, 2-dicarboxylic 2la (m = 2, P = H, P2 = Boc), susíiuuyendo by the butyllithium as the carbon nucleophile R9. Lincosamine 2b (R1 = Me, R2 = Me) was coupled with carbamate 21 d (P2 = Boc, m = 2, R9 = n-butyl) as described in general coupling scheme 11 to provide intermediate 11a (R1 = Me, R2 = Me, R3 = H, R9 = butyl / fluoro, P1 = H, P2 = 1-f-butyl carboxylic acid ester, m = 2) which was deprotected under acidic conditions to provide the composed of the title. MS (ESPOS): 437 [M + H] +.

EXAMPLE 119-122 Examples 119-124 were prepared in a manner analogous to Example 118 (Method Y, Scheme 21), substituting the appropriate R9 carbon nucleophile.

EXAMPLE 119 r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide of 4-fluoro-4-ethyl-piperidine-2-carboxylic acid EXAMPLE 120 f2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propynamide of 4-fluoro-4- (3-fluoropropyP-piperidine-2 -carboxylic EXAMPLE 121 r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-iP-propylamide of 4-fluoro-4- (3,3-difluoropropyD-pyridine Na-2-carboxylic EXAMPLE 122 r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -pro-pin-amide of 4-fluoro-4- (2,2-difluoroethoxymethiP-) piperidine-2-carboxylic acid The following Examples can be used to test the compounds of this invention.

EXAMPLE A Susceptibility test The compounds were tested following the microdilution method of NCCLS (National Committee of Clinical Laboratory Patterns) Methods for antimicrobial susceptibility testing by dilution for aerobic growing bacteria, approved standard - fifth edition NCCLS document M7-A5, NCCLS, Wayne, PA, 2000, National Committee of Clinical Laboratory Patterns, Methods to Test Antimicrobial Susceptibility of Anaerobic Bacteria, Approved Standard - Fifth Edition, NCCLS Document M11-A4, NCCLS, Wayne, PA, 2001). The tests were carried out in sterile plastic 96-well microtiter trays with round bottom wells (Greiner).

Preparation of the compound Stock solutions of the test compounds and the control antibiotics are prepared with 10 mg / ml in DMSO. Serial 2-fold dilutions of each drug are made in a microtiter plate in each row using DMSO as solvent, 100 times the final desired concentration. The wells in columns No. 1-11 contain drug and column No. 12 remained a growth witness for the drug-free organism. Each well in the mother plate is diluted with sterile deionized water, mixed, and 10 μl volumes are distributed in each well in the resulting assay plates.

Preparation of inoculation material The stock cultures were prepared using the method of Microbank® (Pro-Lab diagnostics) and stored at -80 ° C. To propagate the aerobic strains, a bead was separated from the frozen vial and aseptically tested on trypticase soy agar (Difco), chocolate agar (Remel) or blood agar (Remel), which were incubated at 35 ° C all the night. Anaerobic organisms were cultured on Brucella agar (Remel) supplemented with hemin and vitamin K and incubated in anaerobiosis using an anaerobic jar (Mitsubishi) at 35 ° C for 24 to 48 h. Standard inoculation material was prepared using the direct colony suspension method according to the NCCLS (National Clinical Laboratory Pairs Committee) Methods for antimicrobial susceptibility testing by dilution for bacteria growing aerobically; fifth edition NCCLS document M7-A5, NCCLS, Wayne, PA 2000, National Committee of Clinical Laboratory Patterns Methods for testing antimicrobial susceptibility of anaerobic bacteria, approved standard - fifth edition NCCI-S document M11-A4, NCCLS , Wayne, PA 2001). Isolated colonies were selected from an 18-24 h agar plate and resuspended in sterile 0.9% saline to correspond to a McFarland turbidity standard of 0.5. The suspension is used in the next 15 min from the preparation.

Streptococcus pneumoniae VSPN1001 Streptococcus pneumoniae ATCC 49619 Streptococcus pneumoniae VSPN3026 Streptococcus pneumoniae R6x Streptococcus pneumoniae VSPN4054 Streptococcus pneumoniae 488K Streptococcus pneumoniae VSPN4021 Streptococcus pneumoniae 9 Staphylococcus aureus VSAU1017 Staphylococcus aureus Smith Staphylococcus aureus VSAU1003 Staphylococcus aureus ATCC 25923 Staphylococcus aureus VSAU4020 Staphylococcus aureus 125 Staphylococcus aureus VSAU4048 Staphylococcus aureus 85-EPI Staphylococcus aureus VSAU4065 Staphylococcus aureus VSAU4065 Staphylococcus epidermidis VSEP1001 Síaphylococcus epidermidis ATCC 12228 Enterococcus faecalis VEFL1003 Enterococcus faecalis ATCC 51299 Enterococcus faecium VEFA1005 Enterococcus Haemophilus influenzae faecium BM4147.1 Haemophilus influenzae ATCC 49766 VHIN1003 Haemophilus influenzae Haemophilus influenzae ATCC31517 VHIN1004 Haemophilus influenzae Haemophilus influenzae VHIN1005 acr LS-2 Moraxella catarrhalis Moraxella catarrhalis ATCC 25238 VMCA1001 Escherichia coli Escherichia coli MG 1655 VECO2096 Escherichia coli tolC Escherichia coli MG1655 VECO2526 íolC Bacteroides fragilis VBFR1001 Bacíeroides fragilis ATCC 25285 Bacteroides thetaiotaomicron VBTH 1001 Bacteroides thetaiotaomicron ATCC no. 29741 Clostridium difficile VCDI1001 Clostridium difficile ATCC 9689 Preparation of test plates for CMl The medium was prepared with a 1.1 x concentration. Broth Mueller-Hinton MHB (Difco) supplemented with Ca ++ and Mg ++ as recommends the NCCLS, MHB supplemented with lysed horse blood at %, broth HTM Broth (Remel), or broth Brucella (Remel) supplemented with hemin and vitamin K. For each organism, the standard suspension is diluted in the appropriate growth medium in a sterile package. After mix, the wells in the test plates containing drug were inoculated with a volume of 90 μl. Therefore, for each MIC determination, each well contains a final volume of 100 μl with an inoculation material size of approximately 5 * 10 5 cfu / ml and no more than 1% DMSO.

Interpretation of the CMi Complete microtiter plates were incubated 16-20 h at 35 ° C in ambient air for aerobic organisms, and at 35 ° C for 46-48 h or in an anaerobic jar (Mistubishi) for anaerobic organisms. The optical density of each well was determined at 600 nm using a VersaMax microplate reader (Molecular Devices, Sunnyvale, CA). CMl was defined as the lowest drug concentration that produces the complete suppression of visible bacterial growth.

EXAMPLE B Efficacy in septicemia due to murine S. aureus Efficacy studies were carried out in a model of S. aureus septicemia according to models published elsewhere (Goldstein, BP, G. Candiani, TM Arain, G. Romano, I. Ciciliato, M. Berti, M. Abbondi, R. Scotti, M. Mainini, F. Ripamonti, et al., 1995. Antimicrobial activity of MDL 63, 246, a new semisynthetic glycopeptide antibiotic Antimicrob Agents Chemother 39: 11580-11588; Misiek, M., TA Pursiano, F. Leitner, and KE Price 1973. Microbiological properties of a new cephalosporin, BL-S 339: 7- (phenylacetimidoyl-aminoacetamido) -3- (2-methyl-1, 3,4-thiadiazol-5-ylhíhíomethyl) ceph-3-em-4-carboxylic acid Antimicrob Agents Chemother 3: 40-48).

Preparation of compounds The compounds were dissolved in 2% Tween 80 for oral dosing or in 0.9% NaCl solution for intravenous dosing. The compounds were administered 1 h after bacterial inoculation. Vancomycin or ampicillin were used as controls.

Efficacy model Male or female ICR mice weighing 22 ± 2 g of MDS Pharma Services were used for the evaluation. Food and water were administered ad libitum. Groups of 6 mice weighing 22 ± g were used for the experiment. The mice were inoculated intraperitoneally with Staphylococcus aureus Smiíh, 4,104 CFU in 0.5 ml of brain-heart infusion broth (Difco) containing 5% mucin (Sigma). Mortality was recorded once a day for 7 days after bacterial inoculation. Although the invention has been described and illustrated herein with reference to different specific materials, methods and examples, it is understood that the invention is not restricted by any particular combination of materials and methods selected for this purpose.

As will be appreciated by those skilled in the art, numerous variations of said details can be assumed.

EXAMPLE C Animal model in vivo The in vivo activity of different compounds of the present invention was evaluated in a standard model of Staphylococcus aureus sepficemia (MDS Pharma Services, Bothell, WA). Intraperioneal inoculation of male ICR derived rootstocks (ICR is a strain of exogenic breeding mice) provided by the MDS Pharma Services animal husbandry center, a DL90-? Oo of Staphylococcus aureus (Smith; ATCC19636) in 0.5 ml of BHI broth containing 5% mucin (Sigma). The compounds were formulated in 2% Tween 80 (Sigma) and single doses were orally administered one hour after bacterial inoculation. Mortality was monitored daily for seven days. In previous studies, the oral ED50 (ie, the concentration that protects 50% of the mice) was determined to be 19.9 mg / kg for clindamycin, a commercially available lincosamide (Sigma). To screen the compounds that were tested of this invention, the compounds were administered with 10 mg / kg to a group of eight ICR mice and the number of survivors at this concentration was compared with clindamycin. The results are presented in the following table.

Compound tested N ° of surviving mice (indicated by Example No.) with 10 mg / kg Clindamycin 6 17 1 34 2 35 2 36 0 100 7 101 7 It is assumed that when compound M example 36 is tested on a higher dose, the number of surviving mice will increase.

Claims (22)

NOVELTY OF THE INVENTION REVIVALS

1. - A compound of formula (1): wherein: R1 is alkyl; R2 and R3 are independently H, alkyl, hydroxy, fluoro, or cyanoalkyl, or one of R2 and R3 is = NOR7 and the other is absent, or one of R2 and R3 is = CH2 and the other is absent, under the conditions of that neither R2 nor R3 are H; when one of R2 and R3 is fluorine, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not fluorine, hydrogen or hydroxy; R6 is selected from the group consisting of H, alkyl, hydroxyalkyl, -C (0) -0-alkylene-cycloalkyl, -C (0) -0- (substituted alkylene) -cycloalkyl, -C (0) -0-alkyl , -C (0) -O- (substituted alkyl), -C (0) 0-aryl, -C (0) -0- (substituted aryl), -C (0) 0-heteroaryl, -C (0) -0- (substituted heteroaryl), - [C (0) 0] p-alkylene-heterocycle, - [C (0) 0] p-alkylene- (substituted heterocycle), wherein p is 0 or 1; R7 is H or alkyl; R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen , substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) n-NR4R5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the branched chain isomers of the same, wherein n is an integer from 1 to 8 included, and R4 and R5 are H or alkyl; and m is 0, 1, 2 or 3; and prodrugs, tautomers or pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula I has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Ciostridium difficile. 2. A compound of formula (II): wherein: R1 is alkyl; R2 and R3 are independently H, alkyl or cyanoaikyl, with the proviso that neither R2 nor R3 are H; R6 is H, alkyl, or hydroxyalkyl, R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, cycloalkyl substituted, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH 2) n-OH, - (CH 2) n-NR 4 R 5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the isomers of branched chain thereof, wherein n is an integer from 1 to 8 included, and R4 and R5 are H or alkyl; and m is 1 or 2; and prodrugs and pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula II has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile. 3. A compound of formula (III):

(HI) wherein: R1 is alkyl; R2 and R3 are fluorine; R6 is H, alkyl, or hydroxyalkyl, R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, cycloalkyl substituted, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH 2) n-OH, - (CH 2) n-NR 4 R 5, -alkylene-Ra wherein Ra is selected from monofluorophenyl and monochlorophenyl, and the isomers of branched chain thereof, wherein n is an integer from 1 to 8 included, and R4 and R5 are H or alkyl; and m is 1 or 2; and prodrugs and pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula III has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus nfluenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides theíaioíaomicron, and Clostridium difficile. 4. A compound of formula (IV):

(IV) wherein: R1 is alkyl; R2 and R3 are independently H, or alkyl, hydroxy, fluoro, or cyanoalkyl, or one of R2 and R3 is = NOR7 and the other is absent, or one of R2 and R3 is = CH2 and the other is absent, with the conditions that neither R2 nor R3 are H; when one of R2 and R3 is fluorine, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not fluorine, hydrogen or hydroxy; R6 is selected from the group consisting of -C (0) -0-alkylene-cycloalkyl, -C (O) -0- (substituted alkylene) -cycloalkyl, -C (0) -0-alkyl, -C ( 0) -0- (substituted alkyl), -C (0) 0-aryl, -C (0) -0- (substituted aryl), -C (0) 0-heteroaryl, -C (O) -0 - (substituted heteroaryl), - [C (0) 0] p-alkylene-heterocycle, - [C (0) 0] p-alkylene- (substituted heterocycle), wherein p is 0 or 1, with the proviso - C (O) O- (substituted alkyl) does not include the following

R7 is H or alkyl; R9, which may be substituted once or multiple times in the ring in the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen , phenyl, substituted phenyl, - (CH 2) n-OH, - (CH 2) n-NR 4 R 5, -alkylene-Ra wherein Ra is selected from monofluorophenium and monochlorophenyl, and the branched chain isomers thereof, wherein n is an integer from 1 to 8 included, and R 4 and R 5 are H or alkyl; and m is 1 or 2; and prodrugs, tautomers or pharmaceutically acceptable salts thereof; with the proviso that the compound of Formula I has a minimum inhibitory concentration of 32 μg / ml or less, against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium , Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium difficile.

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

6. The compound according to claim 1, further characterized in that R1 is methyl.

7. The compound according to claim 1, further characterized in that R6 is H, alkyl, or hydroxyalkyl.

8. The compound according to claim 1, further characterized in that each R9 is independently H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, or cycloalkyl.

9. A compound selected from the group consisting of: [4- (3-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] 2-methoxy-thioxy) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4-butyl-pyrrolidine-2-carboxylic acid; [4- (4,4-difluoro-pentyl) -piperidine [2-Met-l-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [4- (3-Fluoro-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi] -amide]; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-fluoroethoxy) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclopropyl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclobutyl-eyl) -piperidine-2 -amide -carboxylic; [2-Met.l-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclobutylmethyl-piperid. na-2-carboxylic acid; 3-Butyl-Azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3-Cyclopropylmethyl-azetidine-2-carboxylic acid [2-methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyra-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 3-propyl-azetidine-2-carboxylic acid; 3-Butyl-1- (2-hydroxy-ethyl) -azetidine [2-Methyl-1- (3,4,5-trihydroxy-6-methylisulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; 3-Pentyl-azetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-tr'hydroxy-6-methylsulfanyl-1-ehydro-pyran-2-yl) -propyl] -amide; 3- (3-Methyl-butyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; 3- (3-Cyclobutyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanii-tetrahydro-pyran-2-yl) -propyl] -amide.; 3- (2-Cyclobutyl-ethyl) -zetidine-2- [2-Metyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi!] -amide carboxylic; [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3- (2-cyclopropyl-ethyl) -azet Dina-2-carboxylic acid; 3- (3-Cyclopropyl-propyl) -zetidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; 3-Butyl-1-methyl-azeti-na-2-carboxylic acid [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid; 4- (2-Cyclobuyl-eyl) -pyrrolidine-4- (2-cyclobuyl-eyl) -pyrrolidine acid (3,4,5-tri- hydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propyl] -amide -2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclopropyl-ethyl) -amide) pyrrolidine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid 4-Butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (3-Cyclopentyl-propyl) -p-per-dine-2-carboxylic acid (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; [2-Metl-1- (3,4,5-trihydroxy) 4- (3-methoxy-propyl) -piperidine-2-carboxylic acid-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (3-Ethoxy-propyl) -piperidine- [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-terahydro-pyran-2-yl) -propyl] -amide of 4- (3-ethoxy-propyl) -piperidine- 2-carboxylic; [4- (3-propoxy-propyl) -piperidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (3-Cyclopropylmethoxy-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-terahydro-pyran-2-yl) -propyl] -amide]; [4- (3- (2-fluoro-ethoxy) -propyl] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -piperidine-2-carboxylic acid; [4- (3- (3-fluoro-propoxy) - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide] - propyl] -piperidine-2-carboxylic acid; 4- (4-methoxy-butyl) -piperidine [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; 4-Propoxymethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-fluoro-propoxymethyl) -piperidine-2 -amide -carboxylic; 4-Cyclohexylmethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (2-propyloxyethyl) -piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethoxy-piperidine-2-carboxylic acid; 4-Fluoro-4-butyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-ethyl-piperidine-2-carboxylic acid [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4- (3-fluoropropyl) -piperidine-2 -amide. -carboxylic; 4-Fluoro-4- (3,3-difluoropropyl) - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide piperidine-2-carboxylic acid; [4-fluoro-4- (2, 4-fluoro-4-fluoro-tetrahydro-pyrn-2-yl) -propyl] -amide (4,5,5-dihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. 2-difluoroethoxymethyl) -piperidine-2-carboxylic acid; and prodrugs, tautomers and pharmaceutically acceptable salts thereof.

10. A compound selected from the group consisting of: Monoester (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] - propyl.} -2-methylsulfanyl-tetrahydro-pyran-3-yl) of the phosphoric acid; Monoester of (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propyl.} -2-methylsulfanyl-tetrahydro-pyran-3 -yl) of succinic acid; 4,5-dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-p-peridine-2-carbonyl) -amino] -propyl} -2- Methylsulfanyl-tetrahydro-pyran-3-yl of N- (2-morpholin-4-yl-ethyl) -succinnamic acid; 4,5-Dihydroxy-6- ester. { 2-methyl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propl} -2-Methylsulfanyl-tetrahydro-pyran-3-yl of dimethylamino-acetic acid; [1- (5-methyl-2-oxo- [1, 3] - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] ] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester 2- [2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-teirahydro-pyran -2-il) -propylcarbamoii] -4-propyl-piperidine-1-carboxylic acid; 4,5-dihydroxy-6- ester. { 2-meityl-1 - [(4-propyl-piperidine-2-carbonyl) -amino] -propyl} -2-methylsulfanyl-tetrahydro-pyran-3-yl of hexadecanoic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (1-methyl-3-oxo-but-1-) enyl) -4-propyl-piperidine-2-carboxylic acid; 1-Acetoxy-ethyl ester of 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl ester -piperidine-1-carboxylic acid; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl 2-amino-3-methyl-pentanoyloxymethyl ester -piperidine-1-carboxylic acid; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-p-peridine piperidine-4-carbonyloxymethyl ester -1-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (propionylamino-methyl) .- 4-propyl-piperidine- 2-carboxylic; N-. { 2- [2-Methyl-1- (3,4,5-fr, 4-hydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidin-1-ylmethyl } -nicotinamide; 1- (2-Aminopropionyl) -4-propyl [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-amino-propionyl) -4-propyl -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-amino-3-phenyl-propionyl) -4 -amide -propyl-piperidine-2-carboxylic acid; [2-Amino-3-methyl-pentanoyl] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -propyl-piperidine-2-carboxylic acid; [2-Methyl-3-methyl-butyric acid] -2- Methyl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propyl] -amide -4-propyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 1- (1-methyl-1,4-d) Hydro-pyridine-3-carbonyl) -4-propyl-piperidine-2-carboxylic acid; 1-Methyl-1, 2,3,6-tetrahydro-pyridin-4-yl ester of 2- [2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid; and tautomers and pharmaceutically acceptable salts thereof.

11. The compound according to claim 9, further characterized in that the compound is: [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] 4-fluoro-4-propyl-piperidine-2-carboxylic acid amide.

12. The compound according to claim 9, further characterized in that the compound is: 4- (2-cyclopropyl) - [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. ethyl) -piperidine-2-carboxylic acid.

13. The compound according to claim 9, further characterized in that the compound is: [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethyl-piperidine-2-carboxylic acid.

14. The compound according to claim 10, further characterized in that the compound is: [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-eeryhydro-pyrn-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid.

15. The compound according to claim 10, further characterized in that the compound is: Monoester of (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-p-peridine -2-carbonyl) -amino] -propyl.} -2-mephilesulfanyl-tetrahydro-pyran-3-yl) of the phosphoric acid.

16. The compound according to claim 10, further characterized in that the compound is: [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] 1- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid amide.

17. The compound according to claim 10, further characterized in that the compound is: 5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-methyl-1- (3 , 4,5-trihydroxy-6-methylsulfanyl-pheirahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidin-1-carboxylic acid.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined in claim 1.

19. The use of a compound as defined in claim 1, to prepare a medicine for the treatment of a microbial infection in a mammal.

20. The use claimed in claim 19, wherein the medicament is administrable orally, parenterally, transdermally, topically, rectally, or intranasally.

21. The use claimed in claim 19, wherein the medicament is administrable in an amount of about 0.1 to about 100 mg of the compound / kg of body weight / day. 22.- The compound [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propy] -amide of 4-propyl-piperidine-2-carboxylic acid .