MXPA05013915A - Novel lincomycin derivatives possessing antimicrobial activity. - Google Patents

Abstract

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

Description

NEW LINCOMYCIN DERIVATIVES THAT POSSESS ANTIMICROBIAL ACTIVITY CROSS REFERENCE WITH RELATED REQUESTS The present application is a continuation in part of U.S. patent application No. 10 / 777,455, filed on February 11, 2004, which is a continuation in part of U.S. patent application No. 10 / 642,807, filed on October 15, 2004. August 2003 and in turn claims the benefit under 35 USC §119 (e) of the provisional US application No. 60 / 479,296, filed on June 17, 2003 and of the provisional US application No. 60 / 479,502, filed on June 17, 2003, the descriptions of which are incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to lincomycin derivatives that exhibit antibacterial activity, as well as methods for using said derivatives.

STATE OF THE ART Lincomycin is a biosynthetic product that adversely affects the proliferation of several microorganisms, in particular gram-positive bacteria. The characteristics and preparation of lincomycin are described in U.S. Patent No. 3,086,912. A variety of lincomycin derivatives have been prepared, which also have antimicrobial activity. These derivatives include, for example, clindamycin, which is described in U.S. Patent No. 3,496,163. Lincomycin derivatives remain attractive targets for the discovery of antibacterial drugs. Accordingly, lincomycin derivatives possessing antimicrobial activity as potential antibacterial agents are desired.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides lincomycin derivatives that possess antibacterial activity. In some embodiments, said novel lincomycin derivatives exhibit antibacterial activity against anaerobic and gram positive pathogens. Surprisingly, the new selected lincomycin compounds described herein, exhibit atypical potency against Enterocci species such as Enterocci faecium and Enterocci faecalis, and / or against demanding gram-negative pathogens, such as Haemophilus influenzae, in comparison with known compounds such as clindamycin. . In one of its aspects of composition, the present invention is directed to a compound of Formula I m is 0, 1, 2 or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5; wherein when m is 3, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5, or between the positions of the nitrogen-containing ring 5 and 6; wherein the positions of the nitrogen containing ring are numbered consecutively in the counterclockwise direction, starting with "1" in the nitrogen; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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; R6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, methylmethyl, -C (O) O-alkyl, -C (0) 0-substituted alkyl, C (0) 0-aryl, -C (0) 0-substituted aryl, -C (0) 0-heteroaryl, -C (0) -O-substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, 5-alkyl- [1, 3] dioxol -2-one-4-yl-methyl, 5-alkyl- [1, 3] dioxol-2-one-4-yl-methoxy-carbonyl or the fragment -N (R6) - is part of the amidine structure, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, oxygen substituted, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, sulfanylalkyl heterocyclic, heteroarylsulfanyl and heterocyclic sulfanyl, propylidene (= CHCH2CH3), azido, - (CH2) n-OH, - (CH2) n-NR4R5 and its branched chain isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13, wherein q is an integer equal to zero, one or two, and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aikinii, aiq substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein not more than one group -S (0) qR13 is present in the nitrogen-containing ring; or its prodrug and / or pharmaceutically acceptable salt. In one of its composition aspects, the present invention is directed to a compound of Formula (II): W is a ring in which m is 0, 1, 2 or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5; wherein when m is 3, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5, or between the positions of the nitrogen-containing ring 5 and 6; wherein the positions of the ring containing nitrogen are numbered consecutively in a counter-clockwise direction, beginning with "1" in the nitrogen; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl and substituted alkylsulfanyl; R20 and R21 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo or one of R20 and R21 is = NOR7 and the other is absent, or one of R20 and R21 is = CH2 and the other is absent, or R20 and R21 taken together are cycloalkyl, aryl, substituted aryl, heterocycle or heteroaryl; R6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, -C (0) 0 -alkyl, -C (0) -substituted alkyl, -C (0) 0 -aryl, -C (0) 0-substituted aryl, -C (0) 0-heteroaryl, -C (0) -O-substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, 5-alkyl- [1, 3] dioxol -2-one-4-yl-methyl, 5-alkyl- [1, 3] dioxol-2-one-4-yl-methoxy-carbonyl or the fragment -N (R6) - is part of the amidine structure, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, sulfanylalkyl heterocyclic, heteroarylsulfanyl and heterocyclic sulfanyl, propylidene (= CHCH2CH3), azido, - (CH2) nOH, - (CH2) n -NR4R5 and its branched chain isomers, wherein n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13 in q is an integer equal to zero, one or two, and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and wherein not more than one group -S (0) qR13 is present in the nitrogen-containing ring; or its prodrug and / or pharmaceutically acceptable salt. In one of its composition aspects, the present invention is directed to a compound of Formula (IA): where: the represents a link that can be a double link or a single link; R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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; R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -substituted aryl, -C (0) -heteroaryl, -C (0) -substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, or the N (R) - fragment is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, nitrogen substituted, halo, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13 wherein q is an integer equal to zero, one or two and R 3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and where m1 = 0-2; and where t = 0-3; or their pharmaceutically acceptable salts and / or prodrugs; with the following provisos: A. that in the compounds of formula (I) when it is a single bond, m1 is zero or one, R2 and R3 are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkyl or one of R2 and R3 is = NOR7 and the other is absent, or one of R2 and R3 is = CI-12 and the other is absent, R6 is hydrogen, alkyl, hydroxyalkyl, -C (0) 0-alkylene cycloalkyl, -C (0) 0- alkylene-substituted alkyl, -C (0) 0-alkyl, -C (0) 0-substituted alkyl, -C (0) 0-aryl, -C (0) -or substituted aryl, -C (0) 0- heteroaryl, -C (0) -substituted heteroaryl, -C (0) 0-heterocycle, -C (0) 0 -substituted heterocycle, - [C (0) 0] p alkylene-heterocycle, - [C ( 0) 0] p-heterocycle substituted with alkylene, wherein p is zero or one, and R7 is selected from the group consisting of hydrogen and alkyl; R9 is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) nOH, - (CH2) nNR4R5, -alkylene-Ra wherein Ra is selects between monofluorophenyl or monochlorophenyl, and their branched isomers wherein n is an integer between 1 and 8 inclusive and R 4 and R 5 are hydrogen or alkyl; and then R1 is not -S-alkyl B. in the compounds of formula (I), when:? z is a single bond, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the another is absent, or one of R2 and R3 is = CH2 and the other is absent, with the provisos that both R2 and R3 are not hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -substituted aryl, -C (0) -heteroaryl, C (0) -substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, or the N (R) - fragment is part of the amidine structure, N -cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; and R1 is selected from the group consisting of -S-alkyl, substituted S-alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; then at least one of R9 is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) nOH, - (CH2) nNR4R5, -alkylene -R1 wherein Ra is selected from monofluorophenyl 0 monochlorophenyl, and its branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl, C. In the compounds of formula (I), when it is a single bond, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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 provisos that both R2 as R3 are not hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R7 is selected from the group consisting of hydrogen and alkyl; and R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; R9 is independently selected from another that is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR R5 , -alkylene-Ra in which Ra is selected from monofluorophenyl or monochlorophenyl, and its branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl, then R6 is selected from the group consists of substituted alkyl (which are not monosubstituted heterocycle or substituted heterocycle), (carboxamido) alkyl, and a fragment -N (R6) - which is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure; wherein, as used in these provisos only, the following specific terms and expressions have the following specific meanings: substituted alkyl refers to alkyl groups in which one or more of the hydrogen atoms have been replaced with a halogen , oxygen, hydroxy, amine (primary), amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl), substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, wherein alkyl is as defined above or a group in which one or more of the hydrogen atoms have been replaced with a halogen, oxygen, hydroxy, amine (primary), amine (secondary alkyl) substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl, substituted oxygen refers to the group -ORd wherein Rd is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, cycloalkyl and substituted cycloalkyl, substituted nitrogen or amino refers to the group NRaRb in which Ra and R are each one independently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, substituted aryl refers to an aryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl in which alkylthio refers to the group -S-alkyl and thioalkyl refers to an alkyl group having one or more -SH groups, and substituted heteroaryl refers to a heteroaryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl, in which alkylthio refers to the group -S-alkyl and thioalkyl refers to an alkyl group having one or more -SH groups. In one of its composition aspects, the present invention is directed to a compound of Formula (IB): . { IB) wherein: R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is H, alkyl or hydroxyalkyl; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR R5 and their branched chain isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl; and m is 1 or 2 or their prodrugs and / or pharmaceutically acceptable salts; In some embodiments, when the nitrogen-containing ring is saturated, R2 and R3 are independently hydrogen, hydroxyl, halo, alkoxy, alkylsulfanyl, substituted alkylsulfanyl, alkyl, substituted alkyl, hydroxyalkyl, R6 is hydrogen, alkyl, hydroxyalkyl; R9 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR4R5 and their branched isomers in which n is a whole between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl; and then R1 is not -S-alkyl. In some embodiments, when the nitrogen-containing ring is saturated, m is 0, 1, 2 or 3, R2 and R3 are independently hydrogen, alkyl, hydroxy, fluoro, 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, R6 is hydrogen, alkyl, hydroxyalkyl, -C (0) 0-alkylene-cycloalkyl, -C (0) -alkylene-substituted alkyl, -C (0) 0-alkyl, -C (0) 0-substituted alkyl, -C (0) 0-aryl, -C (0) 0 -substituted aryl, -C (0) 0-heteroaryl, -C (0) 0-substituted heteroaryl, -C (0) 0-heterocycle, -C (0) 0-substituted heterocycle, - [C (0) 0] p alkylene-heterocycle, - [C (0) 0] p alkylene- substituted heterocycle, wherein p is zero or one, and R7 is selected from the group consisting of hydrogen and alkyl; R9 is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, (CH2) n-OH, - (CH2) -NR4R5, -alkylene-Ra in which Ra is selected from monofluorophenyl or monochlorophenyl, and their branched isomers wherein n is an integer between 1 and 8 inclusive, and R 4 and R 5 are hydrogen or alkyl; and then R1 is not -S-alkyl. In some embodiments, when the nitrogen-containing ring is saturated, m is one or two, R2 and R3 are independently hydrogen, alkyl, hydroxy, fluoro, 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, R6 is hydrogen, alkyl, hydroxyalkyl, -C (0) 0-alkylene-cycloalkyl, -C (0) -alkylene-substituted alkyl, -C (0) 0 -alkyl, -C (0) 0-substituted alkyl, -C (O) O-aryl, C (0) -or substituted aryl, -C (0) -heteroaryl, -C (0) -O-substituted heteroaryl, -C (0) 0-heterocycle, -C (0) 0 -substituted heterocycle, - [C (0) 0] p-alkylene-heterocycle, - [C (0) 0] p-alkylene-substituted heterocycle, wherein p is zero or one, and R7 is selected from the group consisting of hydrogen and alkyl; R9 is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) nOH, - (CH2) nNR4R5, -alkylene-Ra wherein Ra is selects between monofluorophenyl or monochlorophenyl, and their branched isomers in which n is an integer between 1 and 8 inclusive, and R 4 and R 5 are hydrogen or alkyl; and then R1 is not -S-alkyl.

In some embodiments, when the nitrogen-containing ring is saturated, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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 caveats that both R2 and R3 are not hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -are substituted, -C (0) 0-heteroaryl, C (0) 0 -substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, or the fragment N (R6) - is part of the amidine structure , N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; and R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; then at least one of R9 is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR4R5, alkylene-Ra in which Ra is selected from monofluorophenyl or monochlorophenyl, and their branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl. In some embodiments, when the nitrogen-containing ring is saturated, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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 caveats that both R2 and R3 are not hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R7 is selected from the group consisting of hydrogen and alkyl; and R is selected from the group consisting of -S-alkyl, -S-substituted alkyl, (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, -alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; R9 is independently selected from another that is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR4R5, -alkylene-R1 in which Ra is selected from monofluorophenyl or monochlorophenyl, and their branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl, then R is selected from the group consisting of in substituted alkyl (which are not monosubstituted heterocycle or substituted heterocycle), (carboxamido) alkyl, and a fragment -N (R6) - which is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure. When used in these provisos only, the following terms and expressions have the following specific meanings: substituted alkyl refers to alkyl groups in which one or more of the hydrogen atoms have been replaced with a halogen, oxygen, hydroxy, amine ( primary), amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl), substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, those which alkyl is as defined above or a group in which one or more of the hydrogen atoms have been replaced with a halogen, oxygen, hydroxy, amine (primary), amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl, substituted oxygen refers to the group -ORd in which Rd is alkyl, haloalkyl , aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, cycloalkyl and substituted cycloalkyl, substituted nitrogen or amino refers to the group NRaR wherein Ra and Rb are each independently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, substituted aryl refers to an aryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano , nitro, alkylthio and thioalkyl in which alkylthio refers to the group -S-alkyl and thioalkyl refers to an alkyl group having one or more g -SH, and substituted heteroaryl refers to a heteroaryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl, in which alkylthio refers to the group -S-alkyl and thioalkyl refers to an alkyl group having one or more -SH groups. In some embodiments, both R2 and R3 are not hydrogen.

In some embodiments, when one of R2 and R3 is halo, the other is not hydrogen or hydroxy. In some embodiments, when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy.

In a r). In other embodiment, m is 1 (W ion, m is 2. In another embodiment, m is 2 and the ring containing nitrogen is saturated (W is ). In another embodiment, m is 2, and the ring containing nitrogen contains a double bond between the ring positions containing nitrogen 4 and 5 (W is in one embodiment, m is 3. In another embodiment, m is 3 and the ring containing nitrogen is saturated (W is ). In another embodiment, m is 3, and the nitrogen-containing ring contains a double bond between the ring positions containing nitrogen 4 and 5 (W is). In another embodiment, m is 3, and the nitrogen-containing ring contains a double bond between the positions of the ring containing nitrogen 5 and 6 (W is). In one embodiment, the nitrogen-containing ring is saturated. In a preferred embodiment, the present invention provides compounds wherein the nitrogen-containing ring in the above-described Formulas is selected from In one embodiment, R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, halo, alkylsulfanyl and substituted alkylsulfanyl. In one embodiment, R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl. In one embodiment, R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkoxy, cycloalkylalkyl, alkylsulfanyl and substituted alkylsulfanyl. In one embodiment, R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkoxy, cycloalkylalkyl and substituted alkylsulfanyl. In a preferred embodiment, R1 is selected from the group consisting of hydrogen, -S-methyl, -S-isopropyl, -S-tert-butyl, propyl, 2,2,2-trifluoroethylsulfanyl, ethoxy-et-1-yl, butoxy, 2-hydroxy-ethyl, 3-hydroxy-propyl, hydroxy-methyl, 2- (methyl-sulfanyl) -ethyl and cyclopropy-methyl. In a preferred embodiment, R is selected from the group consisting of hydrogen, -S-iso-propyl, -S-tert-butyl, propyl, 2,2,2-trifluoroethyl-sulfanyl, 2-ethoxy-et-1- I, butoxy, 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, 2- (methyl-sulfanyl) -ethyl and cyclopropyl-methyl. In another preferred embodiment, R1 is -S-methyl. Preferred R1 groups can be found in Tables I, II and III. In some embodiments, R1 is not -S-aikyl. In some embodiments, R1 is not -S-methyl. In other embodiments, R1 is not -S-substituted alkyl. In other embodiments, R 1 is preferably -SR ° wherein R ° is preferably C 1 -4 alkyl and more preferably methyl, 2-hydroxyethyl or 2-ethyl salicylate. In another embodiment, R1 is preferably hydrogen, alkyl, substituted alkyl or 2,2,2-trifluoroethylsulfanyl. More preferably, R 1 is hydrogen, propyl, 2-ethoxyeti or 2,2,2-trifluoroethylsulfanyl. In one embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, hydroxy and halo. In a preferred embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, methyl, hydroxy and chloro. In another preferred embodiment, R2 and R3 are hydrogen and hydroxy. In another preferred embodiment, R2 and R3 are hydrogen and chlorine. In another preferred embodiment, R2 and R3 are hydrogen and methyl. The preferred R2 and R3 groups can be found in the Tables I, II and III.

In one embodiment, R and R are independently alkyl or alkenyl, or R20 and R21 taken together are cycloalkyl, aryl, substituted aryl, heterocycle or heteroaryl. In one embodiment, one of R20 and R21 is H and the other is alkyl or alkenyl. In a preferred embodiment, one of R20 and R2 is H and the other is ethyl or ethenyl. In a preferred embodiment, R20 and R21 taken together are cycloalkyl or aryl. In a preferred embodiment, R20 and R21 taken together are cyclopropyl, cyclopentyl, phenyl or 4-chloro-phenyl. Preferred groups R20 and R21 can be found in Tables I, II and III. In one embodiment, when one of R20 and R21 is hydrogen, then the other is not hydrogen, alkyl, hydroxy, cyano, alkylsulfanyl or substituted alkylsulfanyl. In one embodiment, R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxyalkyl, substituted alkyl, methylmethyl, -C (0) -substituted alkyl, 5-alkyl- [1, 3] dioxol-2- ona-4-yl-methyl and 5-akyl- [1, 3] dioxol-2-one-4-yl-methoxy-carbonyl. In another embodiment, R6 is selected from hydrogen and alkyl. In one embodiment, R6 is selected from the group consisting of 1H-imidazol-2-ylmethyl; 2- [HC (0)] - et-1-yl; 2-amino-et-1-yl; 2-hydroxyethyl; 2-methoxy-et-1-yl; 5-methyl-2-oxo- [1, 3] dioxol-4-yl-methoxy-carbonyl; 5-methyl-2-oxo- [1, 3] d -oxol-4-yl-methyl; aminocarbonylmethyl; aminocarbonyleryl; cyanomethyl; cyclopropyl; hydrogen; Minomethyl; methyl; and methoxycarbonylmethyl. In one embodiment, R6 is selected from the group consisting of 1 H-imidazol-2-yl-methyl; 2-hydroxyethyl; 5-methyl-2-oxo- [1, 3] dioxol-4-yl-methoxy-carbonyl; 5-methyl-2-oxo- [1, 3] dioxol-4-yl-methyl; aminocarbonylmethyl; cyanomethyl; cyclopropyl; hydrogen; iminomethyl; and methyl. In a preferred embodiment, R6 is selected from the group consisting of 1 H-imidazol-2-yl-methyl; 2- [HC (0)] - et-1-yl; 2-amino-et-1-yl; 2-hydroxyethyl; 2-methoxy-et-1-yl; aminocarbonylmethyl; aminocarbonylethyl; cyanomethyl; cyclopropyl; hydrogen; iminomethyl; methyl; and methoxycarbonylmethyl. In a preferred embodiment, R6 is hydrogen or methyl. In another preferred embodiment, R6 is selected from the group consisting of: 5-methyl- [1, 3] dioxol-2-one-4-yl-methyl and 5-methyl- [1, 3] dioxol-2-one -4-methoxy-carbonyl. Preferred R6 groups can be found in Tables I, II and III. In another embodiment, R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, substituted alkenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroaryl-sulfanylalkyl, heterocyclic sulfanylalkyl, halogen, propylidene (= CHCH2CH3), azido, substituted oxygen, heteroarylsulfanyl and heterocyclic sulfanyl. In another embodiment, R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, substituted alkenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, sulfanylalkyl heterocyclic, halogen, propylidene (= CHCH2CH3), azido, substituted oxygen , heteroarylsulfanyl and azido. In a preferred embodiment, R9 is alkyl. In another preferred embodiment, R9 is halogen. In another embodiment, R9 is selected from the group consisting of (2-fluorocyclopropyl) methoxy; (3-fluoropropoxy) methyl; H-pyrrolylmethyl; 2- (4-ethylthiazol-2-yl) -et-1-yl; 2- (4-methylthiazol-2-yl) -et-1-yl; 2- (5-ethyl-isoxazol-3-yl) -et-1-yl; 2,2,2-trifluoroethyl sulfamide; 2,2-difluoroethoxymethyl; 2- [1, 3] dithiolan-2-yl-et-1-yl; 2-chlorophenyl-methylsulfanyl; 2-cyclobutylethyl; 2-cyclobutylidene-ethyl; 2-cyclopropylethyl; 2-mercaptoethoxy-ethyl-sulfanyl; 2-fluoroethoxy; 2-propoxyethyl; 3- (1 H- [1,2,3] triazole) -prop-1-yl; 3- (3-fluoropropoxy) propyl; 3- (cyclohexyloxy) propyl; 3- (difluoromethylsulfanyl) propyl; 3- (ethylthio) propyl; 3- (furan-2-ylmethylsulfanyl) -prop-1-yl; 3,3,3-uro-trifluoroprop-1-yl-sulfanyl; 3,3,3-nifluoropropoxy; 3,3-difluoroalyl; 3,3-difluorobutyl; 3,3-difluoropropyl; 3 - [(cyclopropyl) methoxy] propyl! 3-cyanoprop-1-yl; 3-cyclohexyloxypropyl; 3-cyclopropyl propyl; 3-ethoxyminoprop-1-yl; 3-ethylsulfanylprop-1-yl; 3-fluoropropoxy; 3-fluoropropoxymethyl; 3-fluoropropyl; 3-imidazol-1-yl-prop-1-yl; 3-mercaptopropylsulfanyl; 3-methoxy-amino-prop-1-yl; 3-methylbut-1-l-sulfanyl; 3-methylbutyl; 3-pyridin-4-yl-allyl; 3- pyridin-4-yl-propyl; 3-pyrrolidin-2-on-1-prop-1-yl; 3-thiophen-2-yl-sulfanylprop-1-yl; 4- (methoxy) butyl; 4,4-difluorobutyl; 4,4-difluoropentyl; 4-fluorobutoxy; 5,5-difluoropentiio; azido; butoxy; butyl; Butylsulfanyl; chlorine; cyclobutylmethyl; cyclohexylmethyl; cyclopropyl; cyclopropylmethyl; ethyl; ethylsulfanyl; fluoro; isobutyl; methyl; m-methylbenzylsulfanyl; ? -butylsulfanyl; or, p-dichlorobenzylsulfanyl; pentoxy; pentyl; p-fluorobenzylsulfanyl; p-fluorophenylsulfanyl; p-methylbenzylsulfanyl; propoxy; propyl; propylidene (= CHCH2CH3); p-trifluoromethoxybenzyl-sulfanyl; pyrazin-2-yl-methyl-sulfanyl; pyridin-2-yl-methylsulfanyl; pyridin-4-yl-sulfanyl; and thiophen-2-yl-methylsulfanyl. In another embodiment, R9 is selected from the group consisting of 2- (4-methylthiazol-2-yl) -et-1-yl; 2- (5-ethyl-isoxazol-3-yl) -et-1-yl; 2- [1,3] dithioan-2-yl-et-1-yl; 2-cyclobutylethyl; 2-cyclobutylidene-ethyl; 2-cyclopropyl-ethyl; 3- (difluoromethylsulfanyl) -prop-1-yl; 3- (furan-2-ylmethylsulfanyl) -prop-1-yl; 3,3,3-trifluoroprop-1-yl-sulfanyl; 3,3-difluoroalyl; 3,3-difluoro-propyl; 3-cyanoprop-1-yl; 3-cyclopropyl-propyl; 3-ethoxyiminoprop-1-yl; 3-ethylsulfanylprop-1-yl; 3-imidazol-1-yl-prop-1-yl; 3-methoxyimino-prop-1-No; 3-methylbut-1-yl-sulfanyl; 3-methylbutyl; 3-pyridin-4-ü-allyl; 3-pyridin-4-yl-propyl; 3-thiophen-2-ylsulfanylprop-1-yl; 4-propyl; azido; butyl; Butylsulfanyl; cyclobutylmethyl; cyclopropyl; cyclopropylmethyl; ethyl; ethylsulfanyl; fluoro; methyl; n-butylsulfanyl; ?,? - dichlorobenzylsulfanyl; pentyl; p-fluorophenylsulfanyl; p-methylbenzylsulfanyl; propyl; propylidene (= CHCH2CH3); pyrazin-2-yl-methyl-sulfanyl; and thiophen-2-yl-methylsufanyl. In one embodiment, at least one of the group R9 is other than hydrogen. In a preferred embodiment, R 9 is propyl. Preferred R9 groups can be found in Tables I, II and III. In one embodiment, Z is selected from the group consisting of hydrogen, phosphate and palmitate. In one embodiment, Z is hydrogen. In another embodiment, Z is phosphate. In another embodiment, Z is palmitate. The compounds of the present invention also include prodrugs of Formulas (I), (II), (IA) and (IB). Said prodrugs include the compounds of Formulas (I), (II), (IA) and (IB) wherein R6 or one of the hydroxy groups in the sugar are modified to include a substituent selected from phosphate, palmitate or Preferred prodrugs include the compounds of Formulas (I), (II), (IA) and (IB) wherein R6 or one of the hydroxy groups in the sugar are modified to include a substituent selected from Preferred compounds of formulas (I), (II), (IA) and (IB) have a minimum inhibition concentration of 32 pg / ml or less against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae , Staphylococcus aureus, Staphylococcus epidermldis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron and Clostridium difficile.

In one embodiment, the compounds of formulas (I), (II), (IA) and (IB) have a minimum inhibition concentration of 4 μ9 ??? or less against at least one of the organisms selected from the group consisting of Haemophilus influenzas and Moraxella catarrhalis. In one embodiment, the compounds of formulas (I), (II), (IA) and (IB) have a minimum inhibition concentration of 4 pg / ml or less against at least one of the organisms selected from the group consisting of in Enterococcus faecali and Enterococcus faecium. In one embodiment, the compounds of formulas (I), (II), (IA) and (IB) have a minimum inhibition concentration of 4 pg / ml or less against at least one of the organisms selected from the group consisting of in the gram-negative organisms Haemophilus influenzae VHIN1003 and Haemophilus influenzae VHIN1004. In another aspect of the invention there are provided pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an amount of a therapeutically effective compound described herein. In another aspect of the invention methods are provided for the treatment of a microbial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound described herein. In one embodiment, the microbial infection being treated is caused by one or more of the following pathogens: H. influenzae, M catarrhalis, E. faecalis and E. faecium. The administered compound can be formulated in a pharmaceutical composition as described herein. The compound can be administered at mammal in oral, parenteral, transdermal, topical, rectal or intranasal form in a pharmaceutical composition. In one embodiment, the compound can be administered in an amount between about 0.1 and about 100 mg / kg body weight / day. Lincomycin derivatives within the scope of the present invention include those of Formula I set forth in Table I below, in which the positions of the nitrogen-containing ring are numbered consecutively in the counterclockwise direction, beginning with "1" in nitrogen, that is, TABLE 1 1 H-imidazole 4-pentyl 1 S SMe -2-yl-methyl H / Me HN = CH 4 -pentyl 1 S SMe H / Me e 4-propyl H / Me H 4-propyl 2 S S-iPr H / Me e 4-propyl S-tBu H / Me H 4-propyl 2 S S-tBu H / CI 5-methyl-5-propyl 3 S SMe [1, 3] dioxol-2-one-4-ylmethyl H / CI 5-methyl-5-propyl 3 S S e [1, 3] dioxol-2-one-4-yl-methoxycarbonyl H / CI H 5-methyl 3 S SMe H / C! H 5 -ethyl 3 S SMe H / CI H 5 -cyclopropylmethyl 3 S SMe H / CI H 5-cyclopropyl 3 S SMe H / CI H 4-methyl / 5-ethyl 3 S SMe H / CI H 4 -ethyl / 5-methyl 3 S SMe H / CI H 5 -ethyl / 6-methyl 3 S SMe H / CI H 4-propyl 3 S SMe H / CI H 5-propyl / 5-fluoro 3 S SMe H / CI H 4-propyl 2 D SMe H / Me H 4-butyl 2 D SMe H / CI 2-hydroxyethyl 4-propyl / 4-fluoro 2 S SMe H / CI H 4 -butyl / 4-fluoro 2 S SMe H / CI H 4- (2-cyclobutylethyl) 2 S SMe H / CI H 4- (cyclopropylmethyl) 1 S SMe H / CI H 4- (cyclopropylmethyl) 2 S SMe H / Me H 4- (2-cyclobutylidene- 1 S SMe ethyl) H / CI H 4- (2-cyclobutylidene- 1 S SMe ethyl) H / CI H 4- (2-cyclobutyl-ethyl) 1 S SMe H / CI H 4- (cyclobutylmethyl) 2 S SMe H / CI H 5-propyl 3 D 4,5 S e H / CI H 4- (2-cyclopropyl-ethyl) 1 S SMeH / CI H 4-cyclopropylmethyl / 4- 2 S SM fluoro H / CI H 5 -propyl 3 S SMe H / CI H 5-propyl 3 S SMe H / Me Cyclopropyl 5-propyl 2 S SMe H / CI H 4-butyl 2 D SMe H / Me H 5-propyl 3 S S-iPr H / Me H 5-propyl 3 S S-tBu 80 H / CI H 3 -cyclopropylmethyl 0 S SMe 81 H / CI H 3- (2-cyclobutylethyl) 0 S SMe 82 H / CI H 3- (2-cyclopropylethyl) 0 S SMe 83 H / CI H 3- (3-cyclopropyl- 0 S SMe propyl) 84 H / CI H 3-propy! 0 S SMe 85 H / CI H 3 -butyl 0 S SMe 86 H / CI 2-hydroxy-ethyl 3-butyl 0 S SMe 87 H / CI H 3-pentyl 0 S SMe 88 H / CI H 3- (3-methylbutyl) 0 S SMe 89 H / CI H 3- (3,3-difluoro- 0 S SMe propyl) 90 H / CI Me 3-butyl 0 S SMe - H / Me H (2-fluorocyclopropyl) - 2 S SMe methoxy - H / OH H 4- (p-trifluoromethoxy-1 S SMe benzyl-sulfanyl) - H / CI H 2- (3-fluoropropoxy) - 2 S SMe methyl / fluoro - BICI H 2- (propoxy) - 2 SS and ethyl / fluoro - H / CI H 2,2-difluoro- 2 S SMe ethoxymethyl - H / CI H 2,2-difluoro- 2 S SMe ethoxymethyl / fluoro - H / CI H 2 -fluoroethoxy 2 D SMe - H / CI H 2 -fluoroethoxy / fluoro 2 S SMe - H / CI H 3- (3-fluoropropoxy) - 2 S SM propyl / fluoro - H / CI H 3- (cyclohexyloxy) - 2 DJ "SM propyl - H / CI H 3- (cyclohexyloxy) - 2 S SM propyl / fluoro - H / CI H 3- (difluoromethyl- 2 D SMe its! fanyl) -propyl - H / CI H 3- (ethylthio) - 2 S SMe propyl / fluoro - H / Me H 3,3,3-trifluoropropoxy 2 S SMe - H / CI H 3,3,3-trifluoro- 2 S SMpropoxy / fiuoro - H / CI H 3,3-difluoro- 2 D SMe butyl / fluoro - H / CI H 3,3-difluoropropyl 2 S SMe - H / Me H 3,3-difluoro-2 S SMe propyl / fluoro-H / CI H 3 - [(cyclopropyl) -2 S methoxy] propyl H / Me 2-amino-et-1- 4- pentyl 1 SS and ilo H / Me ethoxy 4-pentyl 1 SS and carbonyl methyl - H / CI H 5,5-difluoropentyl 2 D SMe - H / CI H 5,5-difluoro- 2 S SMe pentyl / fluoro - H / CI H Butoxy 2 D SMe - H / CI H butoxy / fluoro 2 S SMe - H / CI H Butyl 2 D SMe - H / CI H butyl / fluoro 2 S SMe - H / CI H Cyclohexylmethyl 2 D SMe - H / CI H cyclohexyl- 2 D SMe methyl / fluoro - H / CI H ethyl 2 S SMe H / CI H Isobutyl 2 D SMe - H / CI H isobutyl / fluoro 2 S SMe H / CI H pentoxy / fluoro 2 S SMe H / CI H Pentilo 2 D SMe - H / CI HN = CH pentyl / fluoro 1 S SMe - H / CI H Propoxy 2 D SMe - H / CI H Propoxy / fluoro 2 S SMe - H / CI HN = CH Propyl 2 S SMe - H / CI HN = CH Propyl 2 D SMe - H / CI H propyl / chlorine 2 S SMe - H / CI H propyl / chlorine 2 S SMe - H / CI Me propilo / fluoro 2 S SMe H / CI Me Propyl / fluoro 2 S SMe - H / Me HN = CH- 2- (3-fluoropropoxy) -2-s SMe methyl - H / Me H 2- (propoxy) ethyl 2 s SMe - H / Me H 2,2-difluoroethoxy-2 s SMe methyl / fluoro-H / Me H 2 -fluoroethoxy 2 s SMe - H / Me H 3- (3-fluoropropoxy) - 2 s SM propyl - H / Me H 3,3,3-trifluoropropoxy 2 s SMe - H / Me H 3,3-difluoro- 2 s SM propyl / fluoro - H / Me H 3 - [(cyclopropyl) - 2 s Methoxy] propyl - H / Me H 3 - fluoropropoxy 2 s SMe H / Me H 3-fluoropropyl / fluoro 2 s SMe - H / Me H 4- (methoxy) butyl 2 s SMe - H / Me H 4,4-difluoropentyl 2 s SMe - H / Me H 4-fluorobutoxy 2 s SMe H / Me 9H-4-propyl 2 S SMe fluoren-9-yl-methoxy carbonyl - H / Me Ethoxy 4-propyl 2 S SMe carbonyl - H / Me phenyloxy- 4- propium 2 S SMe carbonyl H / Me 5-methyl-2-oxo-4-propyl 2 SS e [1, 3] dioxol-4-ylmethyl H / Me 5-methyl-2- 4-propyl 2 S SMe oxo- [ 1, 3] dioxol-4-H-methoxy carbonyl-H / Me H 4-propyl / 4-fluoro 2 S SMe - H / Me H 4-propiio / 4-fluoro 1 S SMe - H / e H butyl / fluoro 2 S SMe - H / Me H ethyl / fluoro 2 S SMe 107 H / Me H 4-Pentyl 1 S propyl 108 H / Me H 4-Propyl 2 S propyl 109 H / Me H 4-Propyl 2 S 2,2,2-Trifluoroethylsulfanyl 110 H / Me H 4-Pentyl 1 S 2 -ethoxy-et-1-yl 111 H / Me 2-Hydroxy-4-phenyl 1 s propyl ethyl 112 H / Me H 4-Pentyl 1 • - s H 113 H / Me H 4-pentyl 1 s Butoxi 114 H / Me Me 4-butyl 1 s propyl 119 H / Me 5-methyl-2- 4-pentyl 1 s propyl oxo- [1,3] -dloxol-4-ylmethyl 120 H / Me 5-methyl-2- 4-pentyl 1 s propyl oxo- [ 1,3] dioxol-4-yl-methoxycarbonyl 121 H / Me 5-methyl-2- 4-propyl 1 s propyl oxo- [1,3] dioxol-4-ylmethyl 122 H / Me 5 -methyl-2-oxo-4-propyl 1 s propyl [1,3] dioxol-4-yl-methoxycarbonyl 123 H / Me H 4-propyl 1 S 2 -hydroxy-ethyl 124 H / Me H. 4-propyl s 3-hydroxy-1-propyl 125 H / Me H 4-propyl s Hydroxyl-1 methyl 126 H / Me H 4-propyl s 2- (Methyl-1-sulfanyl) -ethyl 127 H / e H 4-propyl s Cyclopropyl-1 methyl In Table I, unless otherwise indicated, substituents of R9 are substituted at position 4, when m is 0 or 1. Additional lincomycin derivatives within the scope of the present invention include those of Formula II, such as set forth in Table II below, in which the positions of the nitrogen-containing ring are numbered as in Formula (I).

TABLE II Additional lincomycin derivatives within the scope of the present invention include those of Formula III set forth in Table III below: (ID) in which the positions of the nitrogen-containing ring number in Formula (I).

TABLE III In Tables I, II and III above, the following abbreviations are used: S = single bond D = double bond D 4,5 = double bond between positions 4 and 5 of the ring containing nitrogen Me = methyl Pr · = propyl Bu = butyl / = β-tert-te-As used below, these compounds are named on the basis of amine derivatives but, alternatively, these compounds could have been named on the basis of 1-thio-L- derivatives. threo- -D-galacto-octopyranoside. Preferred compounds within the scope of the present invention include the following compounds: [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of the acid 4- (3,3-difluoro-allyl) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4- (3-pyridin-4-) il-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-tr'hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 4- (3-pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid; 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid; [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid; 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2- [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] carboxylic; [4- (4-Fluoro-phenylsulfanyl) -pyrrolidine-2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (3,3,3-Trifluoro-propylsulfanyl) -pyrrolidine- [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 2-carboxylic; [4- (3-Methyl-butylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4-dicyoro-benzylsulfanyl) -pyrrolidine-2-acid -carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-4-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (thiophen-2-yl-methylsulfanyl) -pyrrolidin-2 -amide. -carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ^^ -propyl] -amide of 4- (pyrazin-2-yl-methylsulfanyl) - pyrrolidine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4- -dichloro-benzylsulfan) -pyrrolidine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-butylsulfanil -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-azido-pyrrolidone dina-2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (furan-2-ylmethylsulfanyl) - prop-1-yl] -piperidine-2-carboxylic acid; [4- (3-imidazol-1-yl) -2- methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -prop-1-yl) -piperidine-2-carboxylic acid; [4- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (thiophen-2-ylsulfanyl)] -prop-1-yl] -piperidine-2-carboxylic acid; [4- (3-Ethylsulfanyl-prop-1-yl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-6-rnethylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic acid; [4- (3-Cyano-prop-1-yl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic acid; 4- (3-difluoromethylsulfanyl-prop-1-yl) -piperidine-2-carboxylic acid ^ -chloro-l-S ^. S-tri- hydroxy-e-methylsulfaniMetrahydro-pyran ^ -yl) -propyl] -amide; [4- (3-difluoromethylsulfanyl-propyl) -piperidine-2- [2-methyl-1- (3I4,5-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 of 4- (2- [1,3] dithiolan-2-yl-ethyl] ) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (4-methyl-thiazol-2-yl)] ) -ethyl] -piperidine-2-carboxylic acid; [4- (3-methoxyimino-prop-1-yl) - [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] - piperidine-2-carboxylic acid; <RTI ID = 0.0> 4- (3-ethoxyimino-prop-1-yl) -piperidine </ RTI> -methyl-1-γ-S-tri- hydroxy-e-methylsulfanyl-tetrahydro-pyran-4-yl) -propyl] -amide -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (5-ethyl-isoxazol-3-yl)] ethyl) -piperidine-2-carboxylic acid; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-piperidine-2-dubo-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide -carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl-p, rrolidine-2-carboxylic acid; 4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-ethyl-piperidine-2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide -carboxylic; 4-Propylidene-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide co; [2-Methyl-1- (3,4,5-trihydroxy-6-rnet-lsu-propyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6- -tetrahydro-pyridine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsufanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6- tetrahydro-pyridine-2-carboxylic acid; 1-Carbamoylmethyl-4-pentiol-pyrrolidin-2-methyl-1-γ-S-trihydroxy-e-methylsulfanyl-tetrahydro-pyran ^ -yl) -propyl] -amide -carboxylic acid [2-methyl-1- (3,4,5-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-cyanomethyl-4-pentyl -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (1 H -imidazole-2- ilmetiI) -4-pentyl-pyrrolidine-2-carboxylic acid; 1-iminomethyl-4-pentyl-pyrrolidine [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -2-carboxylic; 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyll-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-piperidine-2-carboxylic acid; [1- (6-tert-Butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyrn-2-yl) -2-methyl-propyl] -amide of 1-methyl-4-propyl-pyrrolidine-2 acid -carboxylic; [1- (6-tert-buylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl-4-propyl-2-methyl-4-propyl-2-methyl-4-propyl-2-methyl-4-propyl-piperidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (5-methyl-2-oxo- [1, 3] ] dioxol-4-ylmethyl) -5-propyl-azepane-2-carboxylic acid; 2- [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrah-5-methyl-2-oxo- [1, 3] d-oxo-4-ylmethyl-2-yl ester) Dro-pyran-2-yl) -propylcarbamoyl] -5-propyl-azepane-1-carboxylic acid; 5-Methyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-ethyl-azepane-2-carboxylic acid; 5-Cyclopropylmethyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-chloro-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-5-cyclopropyl-azepane-2-carboxylic acid amide; 5-Ethyl-4-methyl-azepane-2-carboxylic acid-5-ethyl-4-methyl-azepane-2-carboxylic acid-5-ethyl-4-methyl-azepane-2-carboxylic acid-5-ethyl-4-methyl-azepane-2-hydrochloride; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethyl-5-methyl-azepane-2-carboxylic acid; 5-Ethyl-6-methyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-azepane-2-carboxylic acid; 5-Fluoro-5-propyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6-tetrahydro-pyridine -2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-butyl-1,2 acid, 3,6-tetrahydro-pyridine-2-carboxylic acid; [2-Chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-fluoro-1- (2- hydroxy-ethyl) -4-propyl-pyrrolidine-2-carboxylic acid; 4-Butyl-4-fluoro-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-cyclobutyl-ethyl) -piperidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid; 4-Cyclopropylmethyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (2-Cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahiclro-pyran-2-yl) -propyl] -amide of 4- (2-cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (2-cyclobutyl-ethyl) -pyridinidine -2-carboxylic; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-cyclobutylmethyl-piperidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-propyl-2,3,6,7-tetrahydro-1 -amide H-azepine-2-carboxylic acid; [2-Chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (2- cyclopropyl-ethyl) -pyrrolidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-cyclopropylmethyl-4- fluoro-piperidine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-cyclopropyl-5-propyl-azepane-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-butyl-1, 2,3,6- tetrahydro-pyridine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid; [1- (6-tert-Butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide of 5-propyl-azepane-2-carboxylic acid; 3-Chloropropylmethyl-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide.; 3- (2-cyclobutyl-ethyl) -azetidine-2-cyclo-1- (3,4,5-ylhydroxy-6-methylsulfanyl-ylehiradro-pyran-2-yl) -propyl] -amide -carboxylic; 3- (2-Cyclopropyl-ethyl) -zetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3- (3-Chloropropyl-propyl) -zetidine-2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [3-propyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsu-phenyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3-Butyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 3-butyl-1- (2-hydroxy) ethyl) -azetidine-2-carboxylic acid; 3-Pentyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 3- (3-Methyl-butyl) -zetidine-2-carboxylic acid P-chloro-l-IS-3-trihydroxy-e-methylsulfanyl-tetrahydro-pyran ^ -yl) -propyl] -amide; 3- (3,3-difluoro-propyl) -zetidine-2- [3-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide carboxylic; 3-Butyl-1-methyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; [Cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; [4-propyl-p-pperidine-2-carboxylic acid cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanii-tetrahydro-pyran-2-yl) -methyl-amide; [5-propyl-azepane-2-carboxylic acid cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide; [4-propyl-piperidine-2-carboxylic acid phenyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide; [Phenyl- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; [4-propyl-piperidine-2-carboxylic acid cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide; [1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid] cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide; [5-propyl-azepane-2-carboxylic acid cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl-amide; 5-propyl-azepane-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide; [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -but-3-enyl] -amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; co; 4-propyl-piperidine-2-carboxylic acid [1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -but-3-enyl] -amide; 4-propyl-piperidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide; 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [(4-chloro-phenyl) - (3-4,5-tri- hydroxy-6-methylsulfanyl-terahydro-pyran-2-yl) -methyl] -amide]; 4-Propyl-piperidine-2-carboxylic acid (4-chloro-phenyl) - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -methyl] -amide; [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid; 5-Propyl-azepano- [(4-chloro-phenyl) - (3,4,5-triv] -hydroxy-6-methylsulfanyl-terahydro-pyran-2-yl) -methyl] -amide 2-carboxylic; 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyI-tetrahydro-pyran-2-II) -propyl] -amide; [2-methyl-1- (3,4,5-tri- hydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylpiperidine -2-carboxylic; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-piperidine-2-carboxylic acid amide; 4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-ethoxy-ethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide; [1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine [2-meityl-1- (3,4,5-trihydroxy-6-propyI-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic acid; 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propyl] -amide; [1- (6-Butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide of 4-penti-pyrrolidine-2-carboxylic acid; 4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; mono- (4,5-dihydroxy-6-. {2-methyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl.} 2-propyl-tetrahydro-pyridine- 3-yl) ester of phosphoric acid; 4,5-d¡h¡droxi-6-. { 2-methyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; mono- (4,5-D-hydroxy-6-. {2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl.} 2- propyl-tetrahydro-pyran-3-yl) ester of phosphoric acid; 4,5-dihydroxy-6-. { 2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -arnino] -propyl} -2-propyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; [2-methyI-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propi!] -amide of 1- (5-methyl-2-) oxo- [1,3] dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid; 5-methyl-2-oxo- [1,3] dioxol-4-ylmethylic acid 2- [2-methyl-1] ester (3 | 5-trihydroxy-6-prop ?? -tetrahydro-p? Yan-2-yl) -prop ?? carbamo ??] -4-pent ?? -pyrrolidine-1-carboxylic acid; [2-Rethyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 1- (5-methyl-2-oxo- [1, 3] dioxol-4-yltrnenyl) -4-propyl-pyrrolidine-2-carboxylic acid; 5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester of 2- [2-methyl-1 (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran 2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-pyrrolidine-2-carboxylic acid amide; . { 2-methyl-1- [3,4,5-trihydroxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-pyrrolidine-2-carboxylic acid amide; [2-Methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-pyrrolidine-2-carboxylic acid; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2-methylsulfanyl-eyl) -tetrahydro-pyrn-2-yl] -propyl} -amide of 4-propyl-pyrrolidine-2-carboxylic acid; [1- (6-Cyclopropylmethyl-3,4,5-tr, hi-d, x-tetrahydro-pyrn-2-yl) -2-methyl-propyl] -amide of 4- propyl-pyrrolidine-2-carboxylic acid; or its pharmaceutically acceptable prodrug and / or sai. Additional compounds within the scope of the present invention include: [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of the acid 4- (thiophen-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid; [4- (4-Fluoro-benzylsulfanyl) -3- (4,5,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -pyrrolidine-2-carboxylic acid; [4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [2-Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (pyridyl) -amide ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -. 4- (pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid propyl] -amide; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl- pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4-dicyoro-benzylsulfanyl) -pyrrolidine-2- carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-butylsulfanyl-pyrrolidine-2-carboxylic acid; [4- (3,3-difluoro-allyl) -pyrrolidine-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-pyrn-2-yl) -propyl] -amide of 1-carbamoylmethyl-4-pentyl-pyrrole dina-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methyl] -fanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-cyanomethyl acid -4-pentyl-pyrrolidine-2-carboxylic acid; N- (3-pyridin-4-yl-) -2- methyl- 1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- ( 3-pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-methoxy-ethyl) -4-pentyl- pyrrolidine-2-carboxylic acid; [1- (1 H -methazol-2-ylmethyl) 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide) -4-pentyl-pyrrolidine-2-carboxylic acid; 1- (2-formylamino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid-methyl- -IS-4,6-pentyl-pyrrolidine-2-carboxylic acid-methyl-β-S-trihydroxy-S-methylsulfanyl-tetrahydro-pyran ^ -yl) -propyl] -amide; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-amino-ethyl) -4-pentyl -pyrrolidine-2-carboxylic acid; [4- (3-Cyclohexyloxy-propyl) -piperidine-2-methyl-2-methyl-1- (3,4,5-ylhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; acid methyl ester. { 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidin-1-yl} -acetic; acid [2-methyl I- 1 - (3, 4, 5-tri h id roxi-6-meti Isu If an i l-tetrah id ro-pyran-2-yl) -propyl] -amide 1-methylcarbamoylmethyl -4-pentyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-yl-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi!] -amide of 4- (2- [1,3] dithic acid) olan-2-yl-ethyl) -piperidine-2-carboxylic acid; 1-iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (3- (furan-2-ylmethylsulfanyl) -propyl] 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -piperidine-2-carboxylic acid; [4- (3-imidazole-1-yl-) -2- methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide propyl) -piperidine-2-carboxylic acid; [4- (3- (thiophen-2-ylsulfanyl) -propyl] -2- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -peridine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-imidazol-1-yl-propyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (2- oxo-pyrrolidin-1-yl) -propyl] -piperidine-2-carboxylic acid; [4- (2- (4-methyl-thiazole-2-methoxy) -3- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -yl) -ethyl] -piperidine-2-carboxylic acid; [4- (3-methoxyimino-propyl) -3- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide 1) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (4-ethyl-thiazole-2 -amide] -yl) -ethyl] -piperidine-2-carboxylic acid; [4- (3-Ethylsulfanyl-propyl) -2- methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide piperidine-2-carboxylic acid; [4- (3-Ethoxyimino-propyl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-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 4-pyrrol-1-ylmethyl-piperidine-2-carboxylic acid; 9-Fluoren-9-ylmethyl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine- 1 -carboxylic; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid ethyl ester; [4- (3-Cyano-propyl) -piperidine-2-methyl-4- (3-cyano-propyl) -piperidine-2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsufanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid phenyl ester; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid phenyl ester; [2-Methyl-1- (3,4,5-tr, hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2- [1,2,3] triazol-1-yl-ethyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylidene-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsuifanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (5-methyl-2-oxo- [1 , 3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; 4-Fluoro-4-propyl-piperidine-2-methyl-3- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide carboxylic; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi] -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-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide; 2- (3-difluoromethylsulfanyl) -3- (3-difluoromethylsulfanyl) -3- (3, 4-difluoromethylsulfanyl- propyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-rnethylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6-tetra idro- pyridine-2-carboxylic acid; [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1,2,3,6-tetra-idro-pyridine -2-carboxylic acid; [4- (3-difluoromethyl-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; 4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-ethoxymethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide; or its prodrug and / or pharmaceutically acceptable salt. Additional compounds of the invention include: mono- (6-. {2-chloro-1 - [(5-propyl-azepane-2-carbonyl) -amino] -propyl.) -4,5-d-hydroxy -2-methylsuifanyl-tetrahydro-pyran-3-yl) ester of phosphoric acid; mono- (6-. {2-chloro-1 - [(5-fluoro-5-propyl-azepane-2-carbonyl) -amino] -propiV.} -4,5-dihydroxy-2-methylsulfanyl -tetrahydro-pyran-3-yl) ester of phosphoric acid; mono- (6- { 2-chloro-1 - [(5-cyclopropylmethyl-azepane-2-carbonyl) -amino] -propyl.} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-p, ran-3-yl) ester of phosphoric acid; mono- (6-. {2-chloro-1 - [(4-fluoro-4-propyl-piperidine-2-carbonyl) -am! no] -propyl.) -4,5-dihydroxy-2 -methylsulfan (l-tetrahydro-pyran-3-yl) ester of phosphoric acid; 6- { 2-Chloro-1 - [(5-propyl-azepane-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; 6- { 2-Chloro-1 - [(5-fluoro-5-propyl-azepane-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsufanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; 6- { 2-Chloro-1 - [(5-cyclopropylmethyl-azepane-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; and 6-. { 2-Chloro-1 - [(4-fluoro-4-propyl-piperidine-2-carbonyl) -amino] -propyl} -4,5-Dihydroxy-2-methylsulfanyl-teirahydro-pyran-3-yl ester of hexadecanoic acid. Additional compounds of the invention include: 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (S ^ .S-trihydroxy-e-methylsulfaniketrahydro- Piran ^ -i-propylcarbamoyl-S-propyl-azepane-1-carboxylic acid, 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl 2- [2-chloro-1- (3, 4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propylcarbamoyl] -5-fluoro-5-propylazene-1-carboxylic acid; [2-chloro-1- (3,4, 5-Fluoro-1- (5-methyl-2-oxo- [1,3] dioxol-4- 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. i-methyl) -5-propyl-azepane-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-cyclopropylmethyl-1- (5-methyl-2-) oxo- [1,3] dioxol-4-ylmethyl) -zepane-2-carboxylic acid; 5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2) -yl) -propylcarbamoyl] -5-cyclopropylmethi-azepane-1-carboxylic acid; 5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-te'-propylpiperidine-1) -carboxylic acid; and [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-1- (5-methyl- 2-oxo- [1, 3] dioxoI-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid The compounds, their prodrugs and pharmaceutically acceptable salts, as defined herein, may have activity against bacteria, protozoa, fungi and / or parasites In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compounds defined herein.The pharmaceutical compositions of the present invention may also comprise one or more additional antibacterial agents In one embodiment, one or more additional antibacterial agents may be active against gram-negative bacteria. In addition, one or more of the additional antibacterial agents may be active against gram-positive bacteria. In another embodiment, at least one of the antibacterial agents can be active against both gram-negative bacteria and gram-positive bacteria. In one of its aspects of method, the present invention relates 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 the present invention. The compound of the present invention can be administered to the mammal in oral, parenteral, transdermal, topical, rectal or intranasal form in a pharmaceutical composition. In another of its aspects of method, the present invention relates to a method for the treatment of a microbial infection in a mammal, which comprises administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. The pharmaceutical compositions of the present invention may also comprise one or more additional antibacterial agents. In one embodiment, one or more additional antibacterial agents can be active against gram-negative bacteria. In one embodiment, one or more of the antibacterial agents can be active against gram-positive bacteria. The pharmaceutical composition can be administered to the mammal in oral, parenteral, transdermal, topical, rectal or intranasal form.

In a preferred embodiment, the microbial infection being treated is a Gram-positive infection. In another embodiment, the infection can be a Gram-negative infection. In another 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 described herein.

DETAILED DESCRIPTION OF THE INVENTION As previously described, the present invention relates to lincomycin derivatives that exhibit antibacterial activity, in particular, gram-positive antibacterial activity. In some embodiments, said novel lincomycin derivatives exhibit antibacterial activity against anaerobic and gram-positive pathogens. Surprisingly, the new selected lincomycin compounds described herein exhibit atypical potency against Enterocci species such as Enterocci faecium and Enterocci faecalis, and / or against demanding gram-negative pathogens, such as Haemophilus influenzae, in comparison with known compounds such as clindamycin. However, before describing the present invention in more detail, the following terms and expressions will be defined first.

It should be noted that as used herein and in the appended claims, the singular forms "a / a" and "the" include plural references, unless the context clearly dictates otherwise. Thus, for example, a reference to "a pharmaceutically acceptable excipient" includes a plurality of said excipients; a reference to "an additional antibacterial agent" is a reference to one or more agents and their equivalents known to those skilled in the art, etc.

Definitions Unless otherwise specified, the following terms and expressions used in the specification and claims have the meanings set forth below: "Acyl" means the group -C (0) R14 wherein R14 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle. "Acylamino" refers to NRaC (0) R14 wherein Ra and R14 are as previously defined. "Alkenyl" means an 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-) and preferably 1-2 double links. Examples of alkenyl groups include, but are not limited to, ally, 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-pentox; , n-hexoxy, 1,2-dimethylbutoxy and the like. "Alkyl" means a saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, and the like. "Alkylene" means a linear divalent hydrocarbon group of one to eight carbon atoms or a branched divalent hydrocarbon group of three to eight carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, 2-methylpropylene, and the like. "Alkylsulfanyl" refers to the group "alkyl-S" in which alkyl is as defined herein, which includes, by way of example, methylsulfanyl, butylsulfanyl 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-) and preferably a single triple bond. 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 hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocycle, substituted heterocycle or wherein Ra and Rb are linked together with the nitrogen atom to which they are attached to form a heterocyclic ring. "Aminoacyl" refers to -C (0) NRaRb. "Aminocarbonylalkyl" means a group "-R0C (O) NRaR" in which Rc is an alkylene, and Ra and Rb are as previously defined. "Aryl" means a monovalent monocyclic or bicyclic aromatic carbocyclic group of 6 to 14 ring atoms. Examples include, but are not limited to, phenyl naphthyl and anthryl. The aryl ring may optionally be fused to a 5-, 6- or 7-membered non-aromatic monocyclic ring which optionally contains 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, with the remainder of the ring atoms being C, in which or two C atoms are optionally replaced with a carbonyl. Representative aryl groups with fused rings include, but are not limited to, 2,5-dihydro-benzo [b] oxepin, 2,3-dihydrobenzo [1,4] dioxane, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo [1,3] dioxol, 1, 2,3,4-tetrahydroisoquinoline, 2,3,4-tetrahydroquinoline, 2,3-dihydro-1 H-indole, 2,3-dihydro-I H-isoindol, benzimidazol-2-one, 2-H-benzoxazol-2-one and the like. "Carboxi" means the group "C (0) OH". "Cyanoalkyl" refers to an alkyl substituted with one or more cyano (-CN) groups, provided that no more than one simple cyano group is present on the same carbon atom. Examples of cyanoalkyl groups include, for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl and the like. "Cycloalkyl" means a cyclic saturated hydrocarbon group of 3 to 8 ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Cycloalkylalkyl" means a group -RcRd in which Rc is an alkylene group and Rd is a cycloalkyl group, as previously defined. Examples include, but are not limited to, cyclopropylmethylene, cyclohexylethylene, and the like. "Halo" or "halogen" means fluoro, chloro, bromo or iodo. "Haloalkyl" means an alkyl substituted with one or more, preferably one to 6, same or different halo 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 remaining ring atoms being C. "Heterocycle" or "heterocyclic" "refers to a saturated or unsaturated group having a single ring or multiple condensed rings, between 1 and 10 carbon atoms and between 1 and 4 heteroatoms selected from the group consisting of nitrogen, oxygen or S (0) q (in which is zero, one or two) within the ring in which, in fused ring systems, one or more of the rings may be aryl or heteroaryl. 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, siathiazole, phenazine, soxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3, 4-tetrahydro-isoquinoline, 4,5,6,7-tetrahydrobenzofbjthiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl and the like. "Hydroxy" means the -OH group. "Hydroxyalkyl" refers to an alkyl substituted with one or more -OH groups, provided that no more than one simple hydroxy group (-OH) is present on the same carbon atom. Examples of hydroxyalkyl groups include, for example, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and the like. "Mammal" refers to all animals, including humans, livestock and pets. "Optional" or "optionally" means that the event or the circumstance subsequently described may, but need not, occur and that the description includes cases in which the event or circumstance occurs and cases in which it does not. For example, "aryl group optionally mono or disubstituted with an alkyl group" means that alkyl may, but need not, be present, 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 excipient" means an excipient that is useful for preparing a pharmaceutical composition that is generally safe, non-toxic and not undesirable from a biological point of view or from any other point of view, and includes an excipient that is acceptable for veterinary use, as well as for human pharmaceutical use. "A pharmaceutically acceptable carrier", as used in the specification and claims, includes one or more of said vehicles. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses desired pharmacological activity of the parent compound. Said salts include: (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, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-Toluenesulfonic acid, camphorsulfonic acid, 4-methyl-glycol [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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, conical and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, for example, an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. "Prodrugs" means any compound that releases an active parent drug according to a compound of the present invention in vivo when said prodrug is administered to a mammal. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in a compound of the invention, in such a way that the modifications can be cleaved in vivo to release the parent compound. Prodrugs include compounds of the present invention in which a hydroxy, sulfhydryl or amino group in the compound is linked to any group that can be cleaved in vivo to regenerate the hydroxy, sulfhydryl or free amino group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate derivatives, palmitate and benzoate form), carbamates (e.g.,?,? -dimethylaminocarbonyl) of hydroxy functional groups in the compounds of the present invention, and similar. Preferred substituents of prodrugs include the following substituents attached to the N-position of the five to six membered nitrogen containing heterocycle: "phosphate, palmitate or "Substituted alkyl" means an alkyl group, as previously defined, having 1-3 substituents independently selected from the group consisting of cyano, a halogen (ie, Cl, Br, F or I), acyl, substituted oxygen , hydroxy, alkylsulfanyl, substituted alkylsulfanyl, cycloalkyl, substituted cycloalkyl, aminocarbonylalkyl, carboxy, -C (0) H, -C (0) OR15 (wherein R15 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , aryl, substituted aryl, heteroanyl, substituted heteroaryl, and the like), -C (0) NRaRb, substituted nitrogen, = N-OR7 wherein R7 is hydrogen or alkyl, -SH, -S (0) qR16 [wherein q is zero, one or two, and R16 is alkyl, haloalkyl, aryl, heteroaryl, heterocycle, and alkyl substituted with aryl, heteroaryl, cycloalkyl, and heterocycle], aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle. Examples of substituted alkyl groups include, but are not limited to, 1-fluoroethyl, 1-chloroethyl, 2-fluoroetyl, 2-chloroethyl, 1-bromopropyl, 2-iodopropyl, 1-chlorobutyl, 4-fluorobutyl, 4-chlorobutyl, 2-ethoxy-1-yl, -CH2-S (0) 2CH3 and the like. "Substituted alkenyl" means an alkenyl group, as previously defined, wherein one or more of the hydrogen atoms, and preferably 1 to 3 hydrogen atoms, have been replaced with substituents such as those defined for substituted alkyl. "Substituted alkynyl" means an alkynyl group, as previously defined, in which one or more of the hydrogen atoms, and preferably 1 to 3 hydrogen atoms, have been replaced with substituents such as those defined for substituted alkyl. "Substituted alkylsulfanyl" refers to the group -S-substituted alkyl, wherein substituted alkyl is as previously defined, including, by way of example, 2-hydroxyethyl sulfanyl and the like.

"Substituted alkoxy" refers to the -O-substituted alkyl group in which substituted alkyl is as defined above. "Substituted aryl" means an aryl ring substituted with one or more substituents, preferably one to three substituents selected from the group consisting of alkyl, substituted alkyl, alkylsulfanyl, substituted alkylsulfanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, alkoxy , substituted alkoxy, acyl, amino, acylamino, acylamino, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxy, carboxy, -C (0) OR15, -C (0) NRaRb, cyano, nitro and sulfanylalkyl. The aryl ring may optionally be fused to a 5-, 6- or 7-membered non-aromatic monocyclic ring which optionally contains 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, with the remainder of the ring atoms being C, in which or two C atoms are optionally replaced with a carbonyl. "Substituted cycloalkyl" means a cycloalkyl substituted with an alkyl group or a group as previously defined for substituted alkyl. Representative examples include, but are not limited to, 2-cyclopropylethyl, 3-cyclobutylpropyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, and the like. "Substituted heteroaryl" means a heteroaryl ring substituted with one or more substituents, preferably one to three substituents selected from the group defined above for substituted aryl.

"Substituted heterocycle" refers to heterocycle groups that are independently substituted with 1 to 3 of the same substituents, as defined for substituted cycloalkyl. "Substituted oxygen" refers to the group "-0-Rd" wherein Rd is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle. "Phenyl "substituted" refers to phenyl groups having between 1 and 3 substituents selected from the group defined for substituted aryl. "Sulfanylalkyl" refers to an alkyl substituted with one or more -SH groups, provided that if two thiol groups are present, no they are both on the same carbon atom Examples of sulfanylalkyl groups include, for example, sulfanylmethyl, 2-sulfanylethyl, 2-sulfanylpropyl and the like. "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal to treat a disease, it is sufficient to effect such treatment of the disease.The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated. "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 suffers or exhibits symptoms of it, (2) inhibit the disease, that is, prevent or reduce the development of the disease or its clinical symptoms, or (3) alleviate the disease, that is, cause the regression of the disease or its clinical symptoms The compounds of the present invention are named generally according to the IUPAC or CAS nomenclature system. Abbreviations that are known to one of ordinary skill in the art can be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours and "TA" for room temperature). Unless otherwise defined, all technical and scientific terms used herein have the meaning normally understood by one skilled in the art to which this invention pertains. Before describing the present compositions and methods, it is to be understood that the invention is not limited to the particular methodologies, protocols, assays and reagents described, since these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the present invention and is not intended to limit the scope of the present invention, as set forth in the appended claims.

While any method and material similar or equivalent to those described herein can be used in the practice or tests of the present invention, preferred methods, devices and materials are now described. All publications cited herein are incorporated by reference in their entirety in order to describe the methodologies, reagents and tools indicated in the publications that could be used in relation to the invention. Nothing will be construed as an admission that the invention is not authorized to anticipate said description by virtue of a prior invention. The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology and pharmacology, within the skill in the art. These techniques are fully explained in the literature.

General Synthetic Schemes The compounds of the present invention can be made by the methods depicted in the reaction schemes shown below. The starting materials and reagents used to prepare these compounds are marketed by commercial suppliers such as Toronto Research Chemicals (North York, ON Canada), Aldrich Chemical Ca (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, EE. UU.), Emka-Chemie or Sigma (St. Louis, Missouri, USA) or. are prepared by methods known to persons skilled in the art, following the procedures set forth in references such as Fieser and FieseR1s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (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 Organic Transformations (VCH Publishers Inc., 1989). These schemes are purely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications can be made to these schemes, which will be suggested to the person skilled in the art to refer to this description. As will be obvious to the person skilled in the art, conventional protective groups may be necessary to prevent certain functional groups from suffering unwanted reactions. Suitable protecting groups for the various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and in the references cited therein. The starting materials and intermediates of the reaction can be isolated and purified, if desired, using techniques. conventional ones including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means that include physical constants and spectral data. The compounds of the present invention will typically contain one or more chiral centers. Accordingly, if desired, said compounds can be prepared or isolated as pure stereoisomers. All of the aforementioned stereoisomers (and enriched mixtures) are included within the scope of the present 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 separation agents and the like.

Preparation of the Compounds of the Invention In general, to prepare the compounds of formula (I) of the present invention, an appropriately 7-substituted lincosamine intermediate and an appropriately substituted pyrrolidinyl, piperidyl, azetindinyl or azepane carboxylic acid are condensed 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 number of known coupling reagents, such as 0- (7-azabenzotriazol-1-yl) -N,,? ', N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT) with carbodiimides, isobutyl chloroform and the like. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methyl morpholine, and the like. Inert organic solvents that can 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 to lincosamine at temperatures in the range of about 0 ° C to about 50 ° C. The reaction continues until complete, which typically occurs in about 2 to 12 hours. Appropriately 7-substituted lincosamine intermediates, as defined in the present invention (ie, R2 / R3), are synthesized by methods known to those skilled in the art from methyl 6-amino-6, 8-deoxy-1-thio-erythro-aD-galacto-octopyranoside, which can be prepared as described by Hoeksema, H. et. to the. Journal of the American Chemical Society, 1967, 89 2448-2452. Illustrative syntheses of 7-substituted lincosamine intermediates are shown below in Schemes 1-6. Suitable additional 7-substituted lincosamine intermediates, as defined in the present invention (ie, R2 / R3), are synthesized by methods known to those skilled in the art from methyl 6-amino-6,8- d-deoxy-1-thio-erythro-aD-galacto-octopyranoside, as described in U.S. Patent No. 3,086,912 (R2 = OH, R3 = H), U.S. Patent No. 3,496,136, U.S. Patent No. 3,502,646 or preferably in European Patent No. 0161794 (R2 = Halogen, R3 = H), U.S. Patent No. 3,179,565 (R2 = SR, R3 = H), U.S. Patent No. 3,544,551 (R2 = SH, R3 = H). Intermediates of appropriately substituted pyrrolidinol or piperidyl carboxylic acid, 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 carboxylic acid intermediates of the present invention include, for example, 4-oxoproline and 4-substituted pyridines. The prolines and pyridines used in the syntheses are marketed by suppliers such as Aldrich and Sigma. Alternatively, these prolines and pyridines can be prepared by methods known in the art. Illustrative syntheses for appropriately substituted pyrrolidinyl or piperidyl carboxylic acid intermediates are shown below in Schemes 7-12. Scheme 1 below illustrates a general synthesis of an intermediate of lincosamine 1c wherein P is a protecting group of N, preferably Cbz or Boc, and R1 is as defined for formula (I). 1B (HTO0 ib Scheme 1. General synthesis of the intermediate of lincosamine 1c (a) Protection of N (Boc, Cbz), (b) Protection of O-silyl (TMS), (c) Swern oxidation, as shown in In Scheme 1, methyl 6-amino-6,8-dideoxy-1-thio-erythro-aD-galacto-octopyranoside 1a is prepared as described by Hoeksema, H. et al, Journal of the American Chemical Society, 1967 , 89, 2448-2452 The amino functional group and the hydroxy functional groups of product 1a are then protected with suitable protecting groups Suitable protective groups of N (P) can be formed by the addition of di-t-butyldicarbonate, N - (benzyloxycarbonyloxy) succinimide and the like The hydroxy groups can be protected as silyl ethers The hydroxy group can be converted to trimethylsilyl ethers (TMS) by reaction with N, 0-bis- (trimethylsilyl) -trifluoroacetamide in the presence of a appropriate organic base such as triethylamine or trimethylsilyl chloride in the presence of an organic base such as triethylamine. The protection of N is typically achieved before the protection of O. Chromatography of the crude product on silica after evaporation of the solvent provides the protected product 1b. The 7-O-trimethylsilyo group of 1 b is chemoselectively deprotected and oxidized to provide the 7-keto-lincosamine 1e derivative. This selective transformation is effected by the addition of the protected product 1b to dimethylsulfoxide and oxalyl chloride in an inert organic solvent such as dichloromethane, followed by an appropriate organic base such as triethylamine. Alternatively, the transformation can be carried out by the addition of 1b to dimethyl sulfoxide and an appropriate 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. The resulting reaction mixture is stirred at low temperature and then allowed to warm to about -50 ° C. The reaction is maintained at this second 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 prepared to provide the product 1e. The general class of conditions used in the transformation of 1b to 1e is known in the art as Swern oxidation conditions. Scheme 2 below illustrates a general synthesis of an lincosamine 2b intermediate wherein P is a protecting group of N, preferably Cbz or Boc, R3 is hydrogen, R2 'is consistent with R2 as defined for the formula (I ), and R1 is as defined for the formula (i) - 2a Scheme 2. General synthesis of the lincosamine 2b intermediate. (a) Wittiq Olefin (R2'CH? Ph X- or R2'CH? PO (OEt) 9. base, solvent); (b) Hg / Pd, (c) Overall deprotection As shown in Scheme 2, a keto-lincosamine 1 c intermediate is reacted to form an alkene, using the reaction of Wittig or Homer-Wadsworth-Emmons. In this reaction, a suitable phosphonium or phosphonate salt is deprotonated, using a strong base to form a phosphorus ylide. Suitable phosphonium salts that can be used are alkyltriphenylphosphonium halides, which can be prepared by the reaction of 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 organolithium reagents, potassium tert-butoxide and the like. The formation of the phosphorus ylide is typically carried out under an inert atmosphere, such as 2, in an inert organic solvent such as toluene, THF or the like, at low temperatures. After the formation of the phosphorus ylide, the product is added to the reaction. The reaction can conveniently be carried out at temperatures between -40 ° C and room temperature, and is stirred until complete, typically 1 to 4 hours. The resulting organic solution is developed and chromatography of the crude product on silica provides the product of alkene 2a.

The product 2a is then hydrogenated to provide 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 flask. The bottle is purged and loaded with z to approximately 3.51 to 4.92 kgf / cm2 (50 to 70 psi) and stirred until complete, typically around 12 to 24 h. The resulting reaction mixture is filtered, for example, through celite, and rinsed with a polar organic solvent such as methanol. The organic solution is developed by transferring to a resin funnel containing dried and washed Dowex 50w-400x H + form, and stirring. After washing the resin with methanol and water, the product 2b is eluted from the resin, washing with 5% TEA in McOH. The product can also be purified by column chromatography on silica gel. Scheme 3 illustrates a general synthesis of an intermediate of lincosamine 3b wherein P is a protecting group of N, preferably Cbz or Boc, one of R2 or R3 is alkyl and the other is -OH, and R1 is as defined for the formula (I). 1 C Scheme 3. General synthesis of the lincosamine 3b intermediate. (a) R2M (carbon nucleophile); (b) (i) Deprotection TMS (? - or R and (¡i) Deprotection of N As shown in Scheme 3, suitable carbon nucleophiles are added to the intermediate of 7-cetolincosamine 1c in inert organic solvents suitable for provide the intermediate of 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 employed 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.The reaction is then cooled with a saturated aqueous acid solution, such as saturated aqueous NH4Cl / H20.The rapidly cooled mixture develops then and it can be purified by chromatography to provide the product 3b. Scheme 4 below illustrates a general synthesis of an intermediate of lincosamine 4b wherein P e s a protecting group of N, preferably Boc, R1 is as defined for formula (I) and R2 / R3 is an oxime (= NOR), wherein R7 is as defined for formula (I). 1c Scheme 4. General synthesis of 7-oxime-lincosamines 4b (a) H? NOR7.HCI. Pyridine EtOH (b) TFA As shown in Scheme 4, the lincosamine 1c intermediate is converted to the oxime by stirring in the presence of a suitable reagent such as O-trimethylsilylhydroxylamine, O-alkylhydroxylamine hydrochloride (e.g., O-hydrochloride). methylhydroxylamine) and the like. The reaction is typically carried out in a polar organic solvent such as methanol. The reaction can conveniently be carried out at RT in about 8 to 24 h. The solvent is removed to provide the protected product of N 4a. The 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, dichloroethane, dioxane, THF and the like. The removal is typically carried out at low temperatures, for example, 0 ° C, and then allowed to gradually warm to room temperature to provide the product 4b. Scheme 5 below illustrates a general synthesis of an intermediate of 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 5. General synthesis of 7-deoxy-7.7-difluorolincosamines 5b (a) F: (b) Ac20. pyridine. DMAP: fe) DAST: (d) TFA As shown in Scheme 5, the intermediate of lincosamine 1c is contacted with a suitable fluoride in an inert organic solvent. Suitable fluorides that can be used include tetrabutylammonium fluoride, resin form Amberlite A-26 F, HF'pyridine and the like. Suitable inert organic solvents include THF, acetonitrile, dichloromethane, dioxane, and the like. The reaction is conveniently carried out at RT in about 1 to 2 h. The product (not shown) can be purified in a column on silica gel. The protecting groups of O in the product obtained from the column are converted by contact with acetic anhydride 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 conveniently be carried out at RT in about 6 to 12 hours. The product can be purified in column on silica gel to provide the product 5a.

The product 5a is contacted with a suitable fluorinating reagent and then the protective group is removed. N to provide the product 5b. Suitable fluorinating reagents that may be employed include, for example, dimethylaminoazufretrifluoride, [bis (2-methoxyethyl) -amino-sulfur-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. The 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, dichloroethane, dioxane, THF and the like. The removal is typically carried out at low temperatures, for example, 0 ° C, and then allowed to gradually warm to room temperature to provide the product 5b. Scheme 6 below illustrates a general synthesis of an intermediate of lincosamine 6b wherein P is a protecting group of N, preferably trifluoroacyl, one of R2 and R3 is hydrogen and the other is Cl, Br or 1, and R1 is such as defined for formula (I). 6 »8b Scheme 6. General synthesis of 7-deoxy-7-halolincosamines 6b. (a) Methyltrifluoroacetate. triethylamine; (b) Halogenation reagent (ie, PPhgX? in which X = Cl, Br, I or preferably a salt of l-N- (halomethylene) piperidine); fe) aqueous base (ie, KOH, ammonia). As shown in Scheme 6, the lincosamine intermediate is protected with N with a suitable trifluoroacylating reagent in the presence of base in a suitable organic solvent. Suitable trifluoroacylating reagents include methyltrifluoroacetate, ethyltrifluorothioacetate, trifluoroacetic anhydride and the like. Suitable organic solvents include methanol, THF, acetonitrile, dichloromethane, dioxane, and the like. The reaction is conveniently carried out at room temperature in about 2 to 4 h. The protected lincosamide intermediate 6a can be purified by crystallization or can be used crude in the subsequent reactions. The halogenation of the 7-position of the protected intermediate 6a is achieved by contact with a suitable Rydon reagent, as described by Magerlein, B. J .; Kagen, F. Journal of Medicinal Chemistry, 1969, 12, 780-784 or an amidahalide salt, as described in European patent 0161794. Suitable Rydon reagents include triphenylphosphene dichloride, triphenylphosphene dibromide and the like in a solvent Inert organic such as acetonitrile, dichloromethane, dichloroethane or toluene. Suitable haloamide salt reagents include 1-N- (Chloromethylene) -piperidine chloride, 1-N- (Chloromethylene) -N-methylmethane, and the like in inert organic solvents such as acetonitrile, dichloromethane, dichloroethane or toluene. The reaction is typically carried out at temperatures in the range of about 24 ° C to 70 ° C, for 16 to 24 hours with an excess of halogenation reagent. Hydrolysis of the halogenated product adducts (not shown) and removal of the aqueous base protecting group provides the intermediate 7-deoxy-7-halolincosamide 6b. Suitable bases are NaOH, KOH and concentrated ammonia in water or mixtures of water with miscible organic solvent such as methanol, acetonitrile, tetrahydrofuran, dioxane and the like. The reaction is typically carried out under conditions which precipitate the crude 7-deoxy-7-halolincosamide intermediate 6b. The intermediate 7-deoxy-7-halolincosamide 6b can be purified by crystallization from an appropriate solvent or a solvent system. Alternatively, 1c can be halogenated directly as described in U.S. Patent No. 3,496,136 or U.S. Patent No. 3,502,646 by contact with a suitable Rydon reagent or an amidahalide salt, such as described in European Patent No. 0161794 The hydrolysis of the halogenated product adduct (not shown) in aqueous base provides. the intermediate 7-deoxy-7-halolincosamide 6b. Scheme 7 below illustrates a general synthesis of R9"-proline 7d intermediates, wherein R9" is alkyl or substituted alkyl. 7? 7b 7c Scheme 7. General synthesis of trans-alkylprolines 7d (a) (i) LIHMDS, THF -78 ° C, (i) bromoalkene; (b) (i) LiBHEk THF -78 ° C. (¡) BFs OEt ?. EkSiH; (c) H? Pd / C As shown in Scheme 7, a protected 5-oxoproline 7a is enolysed with a suitable base and then alkylated with a suitable alkylating agent in an inert organic solvent to provide a lactam 7b (wherein R9 'is alkenyl), such as described in the literature procedure of Zhang, R .; et. to the. Journal of the American Chemical Society, 1998, 120, 3894-3902. The compound 7a is marketed by suppliers such as Bachem. Alternatively, 7a can be prepared by methods known in the art. Suitable enolizing agents include LIHMDS, LiN (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, allylbromide and the like. . Lactam 7b is reduced by using a suitable reducing agent to provide a pyrrolidine 7c, wherein R9 'is alkenyl. The reduction is carried out by means of a two-step sequence involving the reduction with Superhydride® of the lactam to the hemiaminal and the subsequent reduction of the hemiaminal. Suitable reducing agents that can be employed include Et 3 SiH / BF 3 * OEt 2, Et 3 SiH / TiCl 4 and the like. The pyrrolidine 7c is then hydrogenated to simultaneously remove the unsaturation in the R 9 'substituent and remove the benzyl protecting group from the carboxylic acid to provide 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 flask. The bottle is purged and charged with H2 to approximately 3.51 to 4.92 kgf / cm2 (50 to 70 psi) and stirred until complete, typically around 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 filtrate provides the product 7d, wherein R9"is an alkyl or substituted alkyl." Scheme 8 below illustrates a general synthesis of intermediate trans-R9-proline 8b and 8c, wherein R9 'is alkenyl or substituted alkenyl, and R9"is alkyl or substituted alkyl.

Scheme 8. General synthesis of prolines substituted with trans-R9 8b, wherein R9 'is alkenyl and R9"is the saturated form of R9', and 8c, where R9 'is alkenyl or substituted alkenyl, (a) i.Os, PCM -78 ° C, ii.DMS, (b) Salt of R9 'CH? P * Pr, Base: fe) H ?, Pd / C: (d) LiOH ac. THF. Scheme 8, the product 7c is ozonized to provide the aldehyde which is then treated under Wittig conditions to provide 8a.The ozonolysis reaction is typically carried out in an anhydrous inert organic solvent, such as dichloromethane, dioxane, THF and the like, at low temperatures, for example, -78 ° C, followed by rapid cooling of the reaction with a reductive agent such as DMS, Ph3P The aldehyde is reacted with a suitable phosphonium salt in the presence of a strong base in an organic solvent Suitable phosphonium salts that can be used include, for example, fluorobenzyl phosphonium chloride, 4-chlorobenzyl phosphonium chloride, bromofluoromethane and triphenylphosphine, and the like. Suitable bases that can be used include potassium t-butoxide, organolithium reagents and activated zinc. Suitable organic solvents that can be used include toluene, THF, dimethylacetamide and the like. . The reaction is typically carried out in an inert atmosphere, such as nitrogen, with vigorous stirring. The reaction is typically carried out at RT up to about 110 ° C for 1 to 2 h. The resulting reaction mixture is developed appropriately and can be purified by chromatography to provide 8b. Intermediate 8b is then hydrogenated to provide product 8c.

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 flask. The bottle is purged and charged with H2 to approximately 2.81 to 4.92 kgf / cm2 (40 to 70 psi) and stirred until complete, typically around 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 filtrate gives the product 8c, wherein R9"is an alkyl or a substituted alkyl and corresponds to the saturated form of the product 8b. Alternatively, the intermediate 8b can be saponified by methods known to those with experience in the art by contact with a miscible organic co-solvent and an aqueous alkaline co-solvent to provide the unsaturated amino acid intermediate of R9 '8c Scheme 9 below illustrates a general synthesis of a proline intermediate 9d wherein R9 is as define for formula (I).

Scheme 9. General synthesis of cyclic amino acids substituted with c / s-R9 or trans-Rs 9d (a) Activation reagent, ie ((Ts)? Q, pyridine or PPhgBR2) (b) Nucleophilic reagent. Base (RSH, TBU), DMF (c) LiOH, THF, H? Q. Scheme 10 below illustrates a general synthesis, as described in Shuman, R. T .; Journal of Organic Chemistry. 990, 55, 741-750, of substituted intermediates of carboxylic acid and pyridine 10b, wherein R9 is as defined for formula (I). 10 * 10b 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 organic solvent. Appropriately substituted pyridine starting materials are marketed by suppliers such as Aldrich and Sigma. Alternatively, these pyridines can be prepared by methods known in the art. Suitable oxidation 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. The reaction mixture is then contacted with a suitable cyanide reagent to provide the pyridine substituted with cyano 10a. Suitable cyanide reagents that can be used include trimethylsilyl cyanide, HCN and the like. Inert organic solvents include dichloromethane, dioxane, THF and the like. The reaction can conveniently be carried out at RT in about 6 to 12 h. The reaction mixture is developed to provide the pyridine substituted with cyano 10a. The pyridine substituted with cyano 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 include hydrochloric acid, aqueous sulfuric acid and the like. The reaction is typically carried out at reflux in 6 to 12 h. Scheme 11 below illustrates a general synthesis of pyridine and piperidine intermediates, wherein R9 is as defined for formula (I).

Scheme 11. General synthesis of 4-substituted intermediates 11c, 11d and Hepha) SOCI ?. eOH (not shown) (b) Hl. H? POa, (c) MeOH. HgSOj (cat.). (d) Pd (OAc. Cul. PPha R9 'alauino (e) PtO? H ?. H * (f) protection reagent of N (ie, (Boc)? Q. CbzCI etc.) base (g) AcOH, Dioxane Scheme 12 below illustrates a general synthesis of a proline intermediate 12d wherein R9 is as defined for the formula (D) Scheme 12. General synthesis of the proline intermediate 12d from 4-ketopyrrolidine (m = 1) and 4-cetopiperidines (m = 2) 12a. (a) Tetraalyltin, BFg'EbO or R9M (carbon nucleophile R9 (b) DAST (c) H? / Pd (d) LiOH a. or appropriate conditions of carboxylate deprotection.

As shown in Scheme 12, ketoproline 12a is allylated to form a hydroxylllproline, whose hydroxy functionality is subsequently replaced fluorine. Hydrogenation of the allyl double bond provides the fluoroalkyl proline 12c, which is deprotected to form 12d. Scheme 13 below illustrates the coupling reaction of an lincosamine intermediate, prepared as described in Schemes 1-6, and a pyrrolidinyl or piperidyl carboxylic acid, prepared as described in Schemes 7-12, in the that R1, R2, R3, R6 and R9 are as defined for formula (I) and P is a suitable protecting group of O and P2 is a suitable protecting group of N.

Scheme 13. General methods of coupling and deprotection. As shown in Scheme 13, an intermediate of lincosamine appropriately substituted with 7 (prepared, for example, according to any of Schemes 1-6) and an appropriately substituted pyrrolidinyl or piperidyl carboxylic acid (prepared, for example, are condensed). according to any of Schemes 7-9 or 11-12), 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 number of coupling reagents, such as 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT) with carbodiimides, isobutylchloroformate and the like. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methyl morpholine, and the like. Inert organic solvents that can be used include, for example, α, β-dimethylformamide, acetonitrile, dichloromethane and the like. This reaction is typically carried out using an excess of carboxylic acid to lincosamine at temperatures in the range of about 0 ° C to about 50 ° C. The reaction continues until complete, which typically occurs in about 2 to 12 hours. The removal of the protecting group can be carried out with acids such as acid, 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, for example, 0 ° C, and then allowed to gradually warm to room temperature to provide the product. Also as shown in Scheme 13, an appropriately 7-substituted lincosamine intermediate (prepared, for example, according to any of Schemes 1-6) and an appropriately substituted pyridin-2-yl 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 previously described. The pyridine 13b 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 oxide. { IV) in the presence of an acid such as HCl, acetic acid and the like, in a Parr bottle. The bottle is purged and loaded with H2 to approximately 2.81 to 4.92 kgf / cm2 (40 to 70 psi), and stirred until complete, typically around 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 filtrate yields the piperidyl product.

The coupling of pyridine carboxylic acids and lincosamines to provide pyridine 13b, with subsequent reduction to the piperidyl product can also be performed as described in Birkenmeyer, R. D; et al; Journal of Medicinal Chemistry 1984, 27, 216-223. Scheme 14 below illustrates the coupling reaction of an lincosamine intermediate, prepared as described above in Schemes 1-6, and a pyrrolidinyl or piperidyl carboxylic acid, prepared as described above in Schemes 7-12, in R, R2, R3 and R9 are as defined for formula (I) and P is a suitable protecting group of N. The coupling reactions described herein can also be used to couple the azetidinyl and azepane carboxylic acids.

Scheme 14. General synthesis of 4-thioetherlincosamides 14c. (a) (TEA, CFgCOOEt) (b) MTL, BSTFA, TEA, HATU (c) Dowex H * MeOH resin. (d) (Ac) 20. pyridine. DMAP (e) TFA, DMS. DCE, H? 0 (f) (Ts)? Q, Pyridine, PCM (g) R9H MTBU wherein R9 is selected such that an alkylsulfanyl or substituted alkylsulfanyl substituent is introduced: a sulfoxide or sulfone substituent is also within the scope of the invention and can be obtained by conventional oxidation methods known in the art (h) MeONat.

, MeOH. Scheme 15 illustrates the general synthetic methods for building protected 1-allylic intermediates 15b, 15c, 15e, 15f, wherein R2, R3, R9 are as defined for formula (I), and Pi and P2 indicate protecting groups of N and O suitable, respectively.

Scheme 15. General construction synthesis of 1-allylic intermediates protected 15b, 15c, 5e, 5f. (a) DAST. NBS (b) BFg.E O, CH3CN, TMS, CH? CH = CH ?. In Scheme 15, P and P2 are preferentially removable by protecting groups. Displacement of the methylsulfanyl group (methylsulfanyl) by a fluoro substituent is achieved by contacting DAST in the presence of N-bromosuccinimide (NBS) and a suitable solvent such as dichloromethane (DCM), which provides compounds 15b and 15e. In turn, the fluoro group is displaced to form the allyl substituent by contact with trimethylallylsilane in the presence of the trifluoroborate and diethyl ether complex. Subsequent removal of the protective group Boc (t-butoxycarbonyl) with trifluoroacetic acid (TFA) provides the deprotected product. Alternatively, defluorination of l-des (methylsulfanyl) -1-fluoro-2,3,4-tri-0-benzyl-7-deoxy-7-methyl-lincosamine leads to 1-de (methylsulfanyl) -2, 3,4-tri-0-benzyl-7-deoxy-7-methyl-lincosamine (i.e., R 1 is hydrogen). The conventional amide coupling of the carboxyl group of N-Boc-4-pentyl-proline with 1-de (methylsulfanyl) -1-allyl-2,3,4-tri-0-benzyl-7-deoxy-7 methyl-lincosamine, in the presence of a coupling promoter such as 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in dimethylformamide (DF) and triethylamine (TEA) , leads to compounds 15c and 15f. The allyl group of compounds 15c and 5f provides an easy source for numerous modifications at position 1 of the lincosamine group. Scheme 16 illustrates general synthetic methods for construction, wherein R1 is alkylsulfanyl, substituted alkylsulfanyl, R2, R3, R9 are as defined for formula (I), and Pi and P2 indicate suitable N and O protecting groups, respectively.

Scheme 16. Displacement of fluoro effected by the sulfanyl moiety Scheme 16 illustrates that the nucleophilic displacement of the 1-fluoro group by a suitable sulfanyl moiety can be achieved either in the lincosamine moiety to form the compound 16a or in the derivative of lincosamine coupled to form compound 16b. Nucleophilic displacement occurs using conventional techniques known in the art.

Scheme 17 illustrates the general synthetic methods for constructing ether and alcohol substituents at position 1, wherein R2, R3, R9 are as defined for formula (I), Pi and P2 indicate protective groups of N and Or suitable, respectively, and R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Scheme 17. General synthesis of lincosamine derivatives in position 1 of alcohol and ether (a) i. Og -78 ° C to 0 ° C, ii. NaBH4 (b) RX, Base in which R can be selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Scheme 17 illustrates that the 1- (des-sulfanylmethyl) -1-allyl-lincosamine derivative can be oxidized to the corresponding aldehyde which is reduced to the primary alcohol by conventional methods such as ozone, followed by reduction with sodium borohydride, preferably in a protic solvent such as methanol. Subsequently, the primary alcohol is contacted with an appropriate base such as sodium hydride and a suitable alkyl halide to form the ether derivative either as the lincosamine entity or as the coupled lincosamine derivative to produce the compounds 17c and 17f respectively . Scheme 18 illustrates the deprotection schemes for 15f, 16b and 17f, wherein R2, R3, R9 are as defined for formula (I), P is a suitable protecting group of N and R is consistent with schemes 15, 16 and 17, respectively.

Scheme 18 Scheme 18 illustrates that conventional deprotection leads to the compounds of formula (I). Scheme 19 below illustrates the nitrogen alkylation of the pyrrolidinyl or piperidyl ring, wherein R6 is alkyl or hydroxyalkyl and R, R2, R3 and R9 are as defined for formula (I). 18s. 18b, Scheme 19. General synthesis of lincosamides substituted with 1'-N. (a) Alkylating agents As shown in Scheme 19, lincosamine 18a can be replaced with N by contact with an alkylating agent in the presence of a suitable base to provide the product 18b. Suitable alkylating agents that can be used include epoxides, alkyl bromides and the like. Suitable bases that may be employed 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. In Scheme 20, R2, R3, R6 and R9 are as defined for formula (I), P2 is a suitable protecting group of O. 19a. 19b.

Scheme 20. a. Rainev Ni, EtOH, reflux Scheme 21 below illustrates the versatile synthetic sequence that allows synthesis of the 21 K ring of protected amino acids with unsaturated N, wherein m and R 9 are as defined for formula (I). 21E 2K < (a) NaH, R Br, DMF (b) KOH, H2Q EtOH (c) CH2Q (ac), Piperidine, EtOR (d) DIBALH, CH? CI ?, (e) PBR3, EtzO (f) bromoacetate ethyl (q) HCI / dioxane (h) LiOt-Bu, THF (i) 21 d, LiHMDS, ÜCI, THF 0 ° C (í) Boc? Q. EtjN, CH2CI? ik) olefin metathesis catalyst CHZCI? (I) 1 M NaOH (aq), eOH. As shown in Scheme 2, suitable N-allyl aminoesters 21f can be linked with pseudoephedrine, which acts as a chiral auxiliary, allowing stereospecific alkylation of the carbon with a suitable allylic bromide 21d. Protection of the secondary amine followed by olefin metathesis and cleavage of the chiral auxiliary leads to the cyclic amino acids protected with N-unsaturated N-21 k.

Scheme 22. a. H +, MeOH b. 2-nitrobenzenesulfonyl chloride, 2,4,6-collidine, dichloroethane c. CspCOg. TBABr, DMF, 22c (Y = Br. Or OTs) or c. by alkylation of Mitsunobu PPhs, Diisopropylazidodicarboxylate, 22c (Y = OH) d. Benzylidene, 3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidenedichloro- (tricyclohexylphosphine) ruthenium e. organic base (7-methyl, 1, 5,7-triazabicyclo [4.4.0ldec-5-ene), thiophenol f. (Boc) 20, TEA g. LiOH ac, Dioxane. 23d 23e Scheme 23. General synthesis of lincosamine C6 derivatives. (a) R20 + R21Metal, Et? AICI, Et? Q; (b) (i) MsCI, EfaN, CH? Cl, (i¡) Girard T reagent, MeOH, (iii) Trifluoroacetic anhydride, 2,6-lutidine, CH2Cl2; (c) (i) TFA, H; Q. (ii) Ac2Q, Et2N, DMAP CH2Cl, (ii) HBr, AcOH, CH2Cl ?; (d) (i) AcOAc, AcOH, (ii) PCb, BFj.OEt ?, CH? C; (e) (i) MeSNa. HMPA, DMF, (ii) Ac20, EtaN, DMAP, CH? CIZ; (f) NaOH, H2Q, MeOH.

Scheme 24. General synthesis of 2-substituted esters, a. (Boc) Q, KHCOg ac. THF b. dimethylacetal of p-anisaldehyde PPTS, c. acetylation agent R11, base d. TFA, DCE, water. 25a 25d 25e Scheme 25. General synthesis of trans-alkylazetidine carboxylic acids. (a) (i) LDA, THF, 0 ° C, (i) bromoalkane or bromoalkene; (b) TMSCHN ?, MeOH. 23 ° C: (c) (i) TMSCHN ?, MeOH. 23 ° C. (ii) H ?. Pd / C EtOAc, 23 ° C; (d) Et.cjN.3HF, THF, 23 ° C; (e) L¡AlH4, THF, 68 ° C; (f) Boc2O, CH? CI ?, 23 ° C; (q) RuC.xH? O, NalO4, acetone, HzO, 23 ° C. i 25f | 1 OTSS ^ OT S Boc Boc 25a 26b 26c 26d 293 26f Scheme 26. General synthesis of trans-alkylazetidine carboxylic acids via aldehyde. (a) TBSCI, midazole, D F, 23 ° C; (b) (i) ozone. CH2Cl2, -78 ° C, (i) PPh3; (c) olefination, base, solvent; (d) H2, Pd / C, EtOAc, 23 ° C or K02CN = NC02K, AcOH, dioxane, 23 ° C; (e) TBAF, THF, 23DC; (f) RuCI3.xH20, NalQ4 acetone, H20, 23 ° C.

Scheme 27. General synthesis of 4-substituted cis racemic intermediates 27a and resolution to provide intermediates 2S, 4R R9 27b (a) PtO ?, H ?, H + (b) (Boc)? Q. ?? (c) i. Chiral amine, recrystallization ii. H +.

Scheme 28. General synthesis of 2-substituted esters. to. (Boc) 2Q, KHCOj ac THF b. dimethylacetal of p anisaldehyde. PPTS, c. R 1 acylating agent, base d. TFA, DCE, water. (Method V) Pharmaceutical Formulations When used as pharmaceutical compounds, the compounds of the present invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered in a variety of routes including oral or parenteral, rectal, transdermal, topical, subcutaneous, intravenous and intranasal routes. 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. The present invention further includes pharmaceutical compositions containing, as the active ingredient, one or more of the compounds of the present invention associated with pharmaceutically acceptable carriers. In the preparation of the compounds of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient or enclosed within a vehicle which may be in the form of a capsule, sachet, paper or other container. The excipient employed is typically a suitable excipient for administration to human subjects or other mammals. When the excipient serves as a diluent, it can be solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. To prepare a formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it is commonly milled to a particle size of less 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 the formulation, for example, about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, 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 methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated to provide rapid, slow or prolonged release of the active ingredient after administration to the patient, employing procedures known in the art. The amount of the active component, ie the compound according to the present invention, in the pharmaceutical composition and its unit dosage form may be varied or adjusted widely, depending on the particular application, the potency of the particular compound and the desired concentration. The compositions can be formulated in a unit dosage form, wherein each dose contains between about 5 and about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of the present invention is employed in no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about one weight percent, the balance being in pharmaceutically inert carriers.

The active compound is effective over a broad dosage range and is generally administered in a pharmaceutically or therapeutically effective amount. It is to be understood, however, that the amount of the compound actually administered will be determined by the physician, depending on the relevant circumstances, including the condition to be treated, the severity of the bacterial infection to be treated, the selected route of administration, the real compound administered, age, weight and response of the individual patient, the intensity 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 their pharmaceutical compositions will be administered orally, topically, transdermally and / or parenterally in a dose to obtain and maintain a concentration, i.e., an amount or level in blood of the active component in the animal that is subjected to the treatment, which will be effective from the antibacterial point of view. In general, said antibacterial or therapeutically effective amount of the dose of the active component (i.e., an effective dose) will be in the range of about 0.1 to about 100, more preferably about 1.0 to about 50 mg / kg of body weight per day. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is to be understood that the active ingredient is uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equivalently effective 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, between about 0.1 and about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise combined to provide a dosage form that produces the advantage of prolonged action. For example, the tablet or pill may comprise an internal dose component and an external dosage component, the latter being in the form of an envelope that coats the first. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or delay its release. A variety of materials can be used for said enteric coatings or coatings, including an amount of polymeric acids and mixtures thereof such as shellac, cetyl alcohol and cellulose acetate. Liquid forms in which new compositions of the present invention can be incorporated for oral or injection administration include aqueous solutions; suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable organic or aqueous 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 by oral or nasal respiratory route to obtain a local or systemic effect. The compositions in preferably pharmaceutically acceptable solvents can be nebulized through the use of inert gases. The nebulized solutions can be inhaled directly from a nebulizer device or the nebulizer device can be attached to a face mask or an intermittent positive pressure respirator. The compositions in solution, suspension or powder can be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. The following formulation examples illustrate the representative pharmaceutical compositions of the present invention.

Formulation Example 1 Hard gelatine capsules containing the following ingredients are prepared: Quantity Ingredient (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and poured into hard gelatin capsules in amounts of 340 mg .

Formulation Example 2 A formula is prepared in tablets, using the following ingredients: Amount Ingredient (mg / tablet) 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 weighing 240 mg each.

Formulation Example 3 A formulation of a dry powder inhaler containing the following components is prepared: Ingredient Weight Active ingredient 5 Lactose 95 The active ingredient is mixed with the lactose, and the mixture is added to a dry powder inhaler.

Formulation Example 4 Tablets are prepared containing 30 mg of the active ingredient each, as follows: Quantity Ingredient (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 0% solution in sterile water) ) 4.0 mg Sodium carboxymethion starch 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, Imidon and cellulose are passed through a No. 20 US mesh screen and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 16 US mesh screen. The granules thus produced are dried at 50 ° -60 ° C and passed through a No. 16 US mesh screen. The carboxymethyl starch of sodium, magnesium stearate and talc, previously passed through a No. 30 US mesh screen, are then added to the granules which, after mixing, are compressed in a tabletting machine to produce the tablets that They weigh 120 mg each.

Formulation example 5 Capsules are prepared, containing 40 mg of medicine each, as follows: Quantity Ingredient (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient is mixed, Magnesium starch and stearate are passed through a No. 20 US mesh screen and poured into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories, containing 25 mg of active ingredient each, are prepared as follows: Ingredient Amount Active ingredient 25 mg Saturated fatty acid glycerides up to 2,000 mg The active ingredient is passed through a No. 60 US mesh screen and suspended in the previously melted saturated fatty acid glycerides using the minimum heat required. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions are prepared each containing 50 mg of drug per 5.0 ml dose as follows: Ingredient Quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 0.0 mg Flavoring and coloring qv Purified water to 5.0 ml The active ingredient, sucrose and xanthan gum are mixed, passed through a No. 10 US mesh screen and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavoring and coloring are diluted with some water and added while stirring. Then enough water is added to produce the required volume.

Formulation example 8 Amount Ingredient (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, starch and magnesium stearate are mixed, passed through a No. 20 mesh screen US and are poured into hard gelatin capsules in amounts of 425.0 mg.

Formulation Example 9 A subcutaneous formulation is prepared as follows: Ingredient Amount active ingredient 5.0 mg Corn oil 1.0 ml Formulation Example 10 A topical formulation is 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 to melt. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solidified.

Formulation Example 11 An intravenous formulation is prepared in the following manner: Ingredient Amount Active ingredient 250 mg Isotonic saline solution 1000 ml Another preferred formulation used in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide the continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the administration of pharmaceutical agents are known in the art. See, for example, U.S. Patent 5,023,252, issued June 1, 1991, which is incorporated herein by reference. Said patches can be constructed for continuous, pulsating or on demand administration of pharmaceutical agents. Frequently, it will be convenient or necessary to introduce the pharmaceutical composition into the brain, either directly or indirectly. Direct techniques generally involve the provision of a catheter for delivery of drugs into the host ventricular system to cross the blood-brain barrier. Such an implantable delivery system employed for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472, which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve the formulation of the compositions to provide the latency of the drug by the conversion of hydrophilic drugs to lipid-soluble drugs. Latency in general is achieved by blocking the hydroxy, carbonyl, sulfate and primary amine groups in the drug to make it more soluble in lipid and responsible for transport through the blood-brain barrier.

Alternatively, the administration of hydrophilic drugs can be improved by intraarterial infusion of hypertonic solutions that temporarily open the blood-brain barrier. Other formulations suitable for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). As noted above, the compounds described herein are suitable for use in a variety of previously described drug delivery systems. Additionally, in order to improve the serum half-life in vivo of the administered compound, the compounds can be encapsulated, introduced into the lumen of liposomes, prepared as colloidal or other conventional techniques that provide an extended serum half-life of the compounds can be employed. . There are a variety of methods for preparing liposomes, as described, for example, in Szoka, et al., In U.S. Patent Nos. 4,235,871, 4,501, 728 and 4,837,028, each of which is incorporated herein by reference. As previously mentioned, the compounds administered to a patient have the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solutions can be packaged for use as they come, or lyophilized, by combining the lyophilized preparation with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be between 3 and 1, more preferably between 5 and 9 and more preferably between 7 and 8. It is to be understood that the use of certain excipients, vehicles or stabilizers mentioned above will produce 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 offering similar utilities. The toxicity and therapeutic efficacy of said compounds can be determined through standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (lethal dose up to 50% of the population) the ED50 (therapeutically effective dose at 50%). % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD5o / ED50 ratio. Compounds that exhibit high therapeutic indices are preferred. The data obtained from cell culture analyzes and animal studies can be used to formulate a range of doses for use in humans. The dosage of said compounds is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity at all. The dose may vary within this range, depending on the dosage form employed and the route of administration used. For any compound used in the method of the invention, the therapeutically effective dose can be estimated approximately initially from assays in cell cultures. A dose can be formulated in animal models to achieve a concentration range in circulating plasma that includes the IC50 (ie, the concentration of the test compound that achieves maximum mean inhibition of symptoms) as determined in the cell culture. Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

Utility The compounds, their prodrugs and pharmaceutically acceptable salts, as defined herein, may have activity against at least a variety of bacteria, protozoa, fungi and / or parasites. By way of example, the compounds, their prodrugs and pharmaceutically acceptable salts can be active against Gram-positive and Gram-negative bacteria. The compounds, their prodrugs and pharmaceutically acceptable salts can be active against a variety of fungi, including fungi of the genus Mucor and Candida, for example, Mucor racemosus or Candida albicans. The compounds, their prodrugs and pharmaceutically acceptable salts can be active against a variety of parasites, including the malaria parasite and cyptosporidium.

The compounds of the present invention may exhibit activity against at least a variety of bacterial infections including, for example, gram-positive infections, gram-negative infections, mycobacterial infections, mycoplasma infections and chlamydia infections. Since the compounds of the present invention can exhibit potent activities against a variety of bacteria, such as gram-positive bacteria, the compounds of the present invention can be useful antimicrobial agents and can be effective against at least a number of human and veterinary pathogens. , including gram-positive bacteria. Gram-positive organisms against the compounds of the present invention that may be effective include, for example; Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides-fragilis, Bacteroides thetaiotaomicron and Clostridium difficile and the like. The compounds of the present invention may be combined with one or more additional antibacterial agents: One or more additional antibacterial agents may be active against gram-negative bacteria. 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 a gram-negative infection. The combination of the compounds of the present invention and one or more of the additional antibacterial agents can be used to treat Gram-positive infection. The combination of the compounds of the present invention and one or more of the additional antibacterial agents can be used to treat a mycobacterial infection, mycoplasma or chlamydia. The in vitro activity of the compounds of the present invention can be determined by standard test methods, such as the determination of minimum inhibitory concentration (MIC) by dilution in agar, as described in "Approved Standard, Ethods for Dilution Antimicrobial Susceptibility. Tests for Bacteria that Grow Aerobically ", 3rd ed., Published in 1993 by the National Committee for Clinical Laboratory standards, Villanova, Pennsylvania, USA. UU The amount administered to the mammalian patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the mode of administration and the like. In one example, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An adequate amount to achieve this is defined as "therapeutically effective dose". The effective amounts for this use will depend on the condition being treated, as well as on the doctor's criteria based on factors such as the intensity of inflammation, age, weight and general condition of the patient, and the like. The compositions administered to a patient take the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solutions can be packaged for use as they are, or lyophilized, by combining the lyophilized preparation with a sterile aqueous vehicle before administration. The pH of the compound preparations will typically be between about 3 and about 11, more preferably between about 5 and about 9, and more preferably between about 7 and about 8. It is to be understood that the use of certain excipients, carriers or stabilizers above mentioned will produce the formation of pharmaceutical salts. The therapeutic dose of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the attending physician. prescribe For example, for intravenous administration, the dose will typically be in the range of about 20 pg to about 500 pg per kilogram of body weight, preferably about 100 pg to about 300 pg per kilogram of body weight. The dose ranges suitable for intranasal administration are generally about 0.1 mg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from dose and response curves derived from test systems of animal or in vitro models. The following synthetic and biological examples are offered to illustrate the present invention and should not be construed as limiting the scope thereof in any way.EXAMPLES In the antenor analysis and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. 7-methylMTL = 1-methyl-sulfanyl-7-deoxy-7-methyl-lincosamine Ac = acetyl apt: = apparent triplet Ac = aqueous Atm = atmospheres Bn = benzyl Boc = tert-butoxycarbonyl protecting group br s = = enlarged singlet BSTFA = N, 0-bs (trimethylsilyl) trifluoroacetamide 13C NMR = nuclear magnetic resonance of carbon Cbz = carboniloxybenzyloxy protecting group CDCI3 = deuterated chloroform CD3OD = deuterated methanol CD3SOCD3 = deuterated dimethylsulfoxide ufe = colony forming units D20 = deuterated water d = doublet DAST = dimetilamlnoazufretrifluoride dd = doublet of doublets dddd = doublet of doublets of doublet of doublets DIBALH = Düsobutylaluminum hydride dt = triplet double DCE = dichloroethane DCM = dichloromethane DIEA = diisopropyethylamine DMAP = dimethylaminopyridine DMF = dimethylformamide DMS = dimethyl sulfide DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide ED50 = therapeutically effective dose in 50% of the equiv = ESMS equivalents electrospray mass spectrometry Et ethyl EtOAc ethyl acetate Et20 ethyl ether g grams h hours HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl hexafluorophosphate luronium HOBT 1-hydroxybenzotriazole hydrate 1H NMR Hydrogen magnetic resonance NMR spectroscopy HPLC high pressure liquid chromatography Hz hertz IC50 concentration of test compound achieving maximum mean inhibition of symptoms J constant coupling in hertz L liters LD50 lethal dose up to 50% of the population LiHMDS lithium hexamethyldisilazide m multiplote M molar CPBA = 3-chloroperoxybenzoic acid Me = methyl MeCN = acetonitrile MeOH = methanol mg = milligrams MHB = broth Mueller Hinton MHz = megahertz MIC = minimum inhibitory concentration min = minute / s ml = milliliters mm = millimeter mmHg = millimeters of mercury mmol = millimol MS (ESPOS) = mass spectrometry by ionization with electrospray in positive mode MS (ESNEG) = ionization mass spectrometry with electrospray in negative mode MTBU = 7-methyl-1, 5,7-triazabicyclo- [4.4.0] dec-5-ene MTL = 1-methylsulfanyl-lincosamine (methyl 6-amino-6,8-dideoxy-1-thio-erythro-a-D-galacto-octopyranoside) N = normal NBS = N-bromosuccinimide NMR = nuclear magnetic resonance OBz = benzyloxy protecting group OtBu = tert-butoxy Pd / C = palladium on carbon pg = picograms Ph = phenyl Pro = L-proline psi = pounds per square inch q = quartet q.v. = quantitative Rf = Holding factor TA = room temperature s = singlet sat. = saturated t = triplet TCI = TCI America TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl Ts = tosyl = micrograms μ? _ = Micro liters μ? = micromolar v / v = volume in volume Additionally, the term "Aldrich" indicates that the compound or reagent used in the following procedures is marketed by Aldrich Chemical Company, Inc., 1001 West St. Paul Avenue, ILW., WL 53233 USA; the term "Fluka" indicates that the compound or reagent is marketed by Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 1 1779 USA; the term "Lancaster" indicates that the compound or reagent is marketed by Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA; the term "Sigma" indicates that the compound or reagent is marketed by Sigma, P.O. Box 14508, St. Louis MO 63178 USA; the term "Chemservice" indicates that the compound or reagent is marketed by Chemservice Inc., Westchester, PA, USA; the term "Sachem" indicates that the compound or reagent is marketed by Sachem Bioscience Inc., 3700 Horizon Drive, Renaissance by Gulph Mills, King of Prussia, PA 19406 USA; the term "Maybridge" indicates that the compound or reagent is marketed by Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom; the term "RSP" indicates that the compound or reagent is marketed by RSP Amino Acid Analogs, Inc., 106 South St., Hopkinton, MA 01748, USA, and the term "TCI" indicates that the compound or reagent is marketed by TCI America, 9211 North Harborgate St., Portland, Oregon, 97203, OR, USA; the term "Toronto" indicates that the compound or reagent is marketed by Toronto Reasearch Chemicals, Inc., 2 Brisbane Rd., New York, ON, Canada M3J2J8; the term "Alpha" indicates that the compound or reagent is marketed by Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 01835-0747; and the term "Nova Biochem" indicates that the compound or reagent is marketed by NovaBiochem USA, 10933 North Torrey Pines Road, P.O. Box 12087, La Jolla CA 92039-2087. In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated) and the following general procedures are used to prepare the compounds, as indicated.

General Methods Method A Methyl 6-amino-6,8-dideoxy-1-thio-erythro-a-D-galacto-octopyranoside 1 a (MTL) was prepared as described by Hoeksema, H. et. to the. Journal of the American Chemical Society, 1967, 89, 2448-2452. N- (Benzyloxycarbonyloxy) succinimide (5.8 g, 23.1 mmol) and 1a (5.0 g, 19.7 mmol) were suspended in pyridine (40 mL) and stirred under N2 atmosphere for 36 h. The reaction mixture was cooled to 0 ° C and then o / s-N, 0-trifluoroacetamide (15.7 ml, 59.0 mmol) was added by syringe for 2 min. The reaction mixture was allowed to warm to RT and was 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 (100 ml) and brine (2 x 100 ml) and dried over Na2SO4 and evaporated to dryness. Chromatography of the crude product on silica 10% EtOAc / hexanes containing 0.2% TEA after co-evaporation of toluene (100 mL) and cyclohexane (2 x 100 mL) gave the protected product 1 b (P = Cbz, R1 = SMe ) (7.2 g, 54%) as 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 (apt 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 dimethyl sulfoxide (413 pL, 5.82 mmol) in DCM (1.5 mL), cooled to -72 ° C, 2 M oxalyl chloride in DCM (1.49 mL, 2.98 mmol) was added over 1 min. After 25 min, protected product 1b (1.92 g, 2.84 mmol) in DCM (4.0 ml) was added by cannula. The resulting reaction mixture was stirred for 25 min and then allowed to warm to -50 ° C. (acetonitrile on dry ice) 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 (100 mL), brine (100 mL), dried over Na2SO4 and evaporated to dryness with toluene aid (100 ml) to provide the product 1e. Product 1e (P = Cbz, R1 = SMe) was obtained as a colorless crystalline solid after coevaporation with n-pentane and removal of the residual solvent at high vacuum (1.60 g, 94%): 1 H NMR (300 MHz, CDCI3) 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 (br s, 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 = SMe) can be prepared in general as detailed below. (MTL) (dried at 50 ° C under high vacuum) (21.8 g, 86 mmol) suspended in methanol (200 ml) and TEA (26 ml) cooled to 0 ° C on ice, was added di-t -butyldicarbonate (57.0 g, 0.26 mol), the reaction mixture was then stirred at room temperature overnight. To the reaction mixture was added toluene (100 ml), the solvents were removed to a total volume of 100 ml, leaving a thick suspension wing added with cyclohexane (300 ml). The resulting solid precipitate was evaluated and then filtered and washed with cyclohexane, ether and pentane, and dried to constant weight. The Boc-protected crude product was used without further purification (87%). TLC Rf = 0.75 (10% MeOH / DCM); MS (ESPOS): 354 [M + H] +; 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 it was allowed to stir at room temperature overnight. The DMF was removed and the crude product was rapidly passed through a column of silica gel (pretreated with 2% triethylamine in ethyl acetate) eluting with 10% ethyl acetate in hexanes 1b (P = Boc)., R1 = SMe) (350 mg, 95%). To oxalyl chloride (0.16 ml, 0.78 mmol) in dichloromethane (5 ml), at -60 ° C, dimethylsulfide (0.22 ml, 0.78 mmol) was added slowly and then allowed to stir for 15 min. After said period, 1 b (370 mg, 0.65 mmol) in dichloromethane (5 ml) was slowly added. The reaction mixture was allowed to stir for 45 min, during which the reaction temperature was increased to -40 ° C. Then triethylamine (0.70 ml, 3.25 mmol) was added and stirring continued for another 15 min at -40 ° C. It was then extracted with dichloromethane (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 10% ethyl acetate in hexanes as the eluent 1 c (P = Boc, Rl = SMe) as a colorless oil (289 mg, 78% ): TLC: Rf = 0.60 (10% EtOAc / 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, 9.20 mmol) and potassium tert-butoxide (7 mg, 6.4 mmol) were suspended under an N 2 atmosphere in toluene (31 mL) with vigorous stirring. After 4.0 h, the protected product 1 c (P = Cbz, R1 = SMe) (1.40 g, 2.36 mmol) in toluene (20 ml) was added with cannula. The resulting reaction mixture was stirred for 2 h and then diluted with EtOAc (250 mL). The resulting organic solution was washed rapidly with H20 (2 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4 and evaporated to dryness. Chromatography of the crude product on silica 6% EtOAc / hexanes containing 0.2% TEA gave the product of alkene 2a (P = Cbz, R1 = SMe, R2 '= H) as a colorless oil which crystallized after co-evaporation at from 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 = SMe, R2 '= H) (490 mg, 0.82 mmol) in ethanol (50 ml) was added to 10% palladium on carbon (wet form of deguse 50% w / w water ) (700 mg) in a jar parr. The bottle was purged and charged with H2 to 4.57 kgf / cm2 (65 psi), and stirred for 24 h. The reaction mixture was filtered through celite and rinsed with methanol. The organic solution was transferred to a resin funnel containing dried Dowex® 50w-400x H + form (0.8 g) and stirred for 10 min. After washing the resin three times with methanol and twice with water, the saturated product 2b was eluted from the resin by washing with 5% TEA in MeOH (35 ml x 10 min x 5). The combined filtrate was evaporated to dryness, coeyaporated from EtOH twice and lyophilized from 1: 1 MeCN / H20 to obtain product 2b (R2 '= H) as a colorless powder (198 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 + H] +, (ESNEG): 250.4 [M-H] \ Method D Alternatively, when a Boc protecting group is used in Scheme 1 (P = Boc), methyltriphenyl-phosphonium bromide (12 g, 33.6 mmol) and potassium t-butoxide (3 g, 26.7 mmol) are taken in THF (70 mL), at 0 ° C, and stirred at RT for 4 h. Then the product protected with Boc 1 c (P = Boc, R1 = SMe) (4.7 g, 8.2 mmol) in THF (30 ml) is added and stirred at RT for 2 h, after which it is extracted with EtOAc (300 g. mi), washed with brine (100 ml) and dried over sodium sulfate. The crude alkene product 2a (P = Boc, R1 = SMe, R2, = H) is purified by column chromatography on silica gel using 10% EtOAc in hexane as the eluent (4.1 g, 87.6%): TLC: Rf = 0.5 (0% EtOAc in Hexane): 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, 93.1), 1.99 (s, 3), 1.76 (s, 3), 1.43 (s, 9); MS (ESPOS): 444 [M-2TMS + Na] +. To product 2a (P = Boc, R1 = SMe, R2 '= H) in methanol (30 ml), Dowex® H + resin (1 g) was added and stirred at RT for 1 h. The resin was filtered and the product obtained after removal of the solvent (2.4 g, 6.8 mmol) was taken up in MeOH (30 ml); Pd / C (2.5 g) was added and hydrogenated at 3.86 kgf / cm2 (55 psi) overnight. The crude product obtained by filtering and removing the solvent was purified by gel column chromatography. silica, using 10% MeOH in DCM to provide Boc protected 7-Methyl MTL as a white solid (2.06 g, 86%): TLC Rf = 0.5 (10% MeOH in DCM); 1 H NMR (300 MHz, CD 3 OD) 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 + H] +. To 7-methyl MTL protected with Boc (150 mg, 0.43 mmol) in dichloroethane (6 ml), was added dimethisulfide (0.16 ml, 2.5 mmol), followed by TFA (2 ml) and water (0.16 ml), and stirred at RT for 1 h. The solvent was removed to obtain the crude product 2b (R1 = SMe, P = Boc, R2 '= H). After purification by column chromatography on silica gel, using 30% MeOH in DCM as the eluent, product 2b (R2, = H) identical in every sense to the material obtained from Method C was obtained.

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 1e (P = Cbz, R1 = SMe) (1.0 g, 1.7 mmol) in THF (3 mL) was added with cannula. The resulting reaction mixture was stirred for 4 h and then diluted with EtOAc (250 mL). The resulting organic solution was washed rapidly with saturated aqueous NaHCO3 (1 x 100 mL) and brine (1 x 50 mL), dried over Na2SO4 and evaporated to dryness. Chromatography of the crude product on silica 6% EtOAc / hexanes to 10% EtOAc / hexanes containing 0.2% TEA yielded the protected alkene product 2a (P = Cbz, R1 = SMe, R2 '= CN) as a colorless oil (0.38). g, 37%): MS (ESPOS): 625.5 [M + H] +, MS (ESNEG): 659.5 [M + CI]. "Product 2a was added (P = Cbz, R1 = SMe, R2 '= CN ) (180 mg, 0.29 mmol) in ethanol (15 ml) to 10% palladium on carbon (wet form of 50% w / w water) (300 mg) in a Parr flask and concentrated HCl (29 L) was added The flask was purged and charged with H2 to 4.57 kgf / cm2 (65 psi) and stirred for 24 h.The reaction mixture was filtered through celite and rinsed with methanol.The organic solution was transferred to a funnel. of resin containing the dried and washed form Dowex® 50w-400x H + (1 g) and stirred for 10 min After washing the resin twice with methanol and water, the saturated product 2b (R1 = SMe, R2 '= CN) was eluted from the resin by washing with 5% TEA in MeOH (20 ml x 20 min x 3) and MeCN (20 mi x 20 min). The combined organic filtrate was evaporated to dry lyophilized from 1: 1 MeCN / hbO to provide product 2b (R1 = SMe, R2 = CH2CN) as a colorless solid (70 mg, 91%): MS (ESNEG): 275.3 [MH] ".

Method F To the protected product 1e (P = Cbz, R = SMe) (0.75 g, 1.3 mmol) in THF (7.3 ml) was added 3 M MeMgCl (Aldrich) in THF (7.0 ml, 2.1 mmol) at 0 ° C. . For 30 min, the reaction mixture was heated to 4 ° C and after 4 h the reaction mixture was quenched with 1: 3 saturated aqueous NH 4 Cl / H 2 O (10 mL). The cooled mixture was rapidly diluted to 100 ml with water and extracted with DC (4 x 50 ml). The combined organic phase was dried and evaporated. The residue was dissolved in 1: 2: 4 H20 / HOAc THF (100 mL) and stirred for 20 h, and then evaporated with the aid of toluene (2 x 100 mL). Chromatography (10: 1 to 10: 2 DCM / MeOH) yielded product 3a (P = Cbz, R1 = SMe, R2 '= Me) (153 mg, 31%): MS (ESNEG): 399.5 [MH] " Add 3a (P-Cbz, R1 = SMe, R2"= Me) (79 mg, 0.2 mmol) in ethanol (10 ml) to 10% palladium on carbon (wet form of 50% w / w water) (400 mg) in a Parr bottle. The bottle was purged and charged with H2 to 4.57 kgf / cm2 (65 psi), and stirred for 6 h. The reaction mixture was filtered through celite and rinsed with methanol. The combined filtrate was evaporated to dryness and lyophilized from 1: 1 MeCN / H20 to give the product 3b (R1 = SMe, R2"= Me) as a colorless powder (42 mg, 80%): 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 (ESTH): 268.4 [M + H], MS (ESNEG): 266.2 [M - H] ".

Method G To the product protected with Boc 1c (P = Boc, R1 = SMe) (100 mg, 0. 18 mmol) in methanol (3 mL), O-trimethylsilylhydroxylamine (0.10 mL, 0. 88 mmol) and stirred at RT overnight. The solvent was removed to obtain the crude product protected with Boc 4a (R = SMe, R7 = H). To the crude product 4a (95 mg, 0.15 mmol), trifluoroacetic acid was added to the 30% in dichloroethane (10 ml) and dimethyl sulfide (0.5 ml) and stirred for 1 h.

The solvent was removed and the product 4b (R1 = SMe, R7 = H) was taken as such for the next step. TLC: Rf = 0.35 (10% MeOH / DCM); MS (ESPOS): 267 (M + H); 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), 4.1 1 (dd, J = 5.7, 10.20, 1), 4.19 (d, J = 5.4, 1), 4.30 (d, J = 5.1, 1), 5.36 (d, J = 5.7, 1).

Method H To the product protected with Boc 1e (P = Boc, R1 = SMe) (100 mg, 0. 176 mmol) in methanol (4 ml) and water (1 ml), O-alkylhydroxyamine hydrochloride (for example, O-methylhydroxylamine hydrochloride) (60 mg, 0.70 mmol) and sodium acetate (57 mg, 0.70 g. mmol), was heated at 80 ° C for 3 h and then stirred at RT overnight. The solvent was removed under high vacuum to obtain the crude product protected with Boc 4e (R1 = SMe, R7 = Me). The crude product 4a was taken in 30% trifluoroacetic acid in dichloroethane (10 ml), dimethylsulfide (0.5 ml) and stirred for 1 h at RT. The solvent was removed, the residue was kept under high vacuum for 1 h and the product 4b (R1 = SMe, R7 = Me) was taken as such for the next step: TLC Rf = 0.63 (10% MeOH / DCM); MS (SPOS): 281 [M + Hf; H NMR (300 MHz, CD3OD) d 1.95 (s, 3), 2.08 (s, 3), 3.60 (dd, J = 3.3, 10.2, 1), 3.92 (s, 3), 4.13 (dd, J = 4.8 , 10.2, 1), 4.49 (d, J = 1.2, 1), 5.38 (d, J = 5.4, 1).

Method I To the product protected with Boc 1e (P = Boc, R '= SMe) (500 mg, 0.88 mmol) in THF (10 ml), tetrabutylammonium fluoride (2.5 mmol, 1 M in THF) was added and the mixture of reaction was stirred at RT for 1 h. The solvent was removed and the residue was purified by column on silica gel, using 5% methanol in dichloromethane as the eluent. The product (11 mg, 0.31 mmol) obtained from the column was then taken in a mixture of dichloromethane (3 mL) and pyridine (3 mL) to which was added acetic anhydride (0.5 mL, 10.6 mmol) and dimethylaminopyridine (80 mg, 1.7 mmol) and stirred at RT overnight. The solvent was removed and the crude product was purified by column on silica gel, using 30% ethyl acetate in hexanes as the eluent to produce 5a (P = Boc, R1 = SMe) (58 mg, 38%): TLC Rf = 0.73 (50% EtOAc / hexanes); 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); MS (ESPOS): 500 [M + Na] +. To product 5a (P = Boc, R1 = SMe) (158 mg, 0.331 mmol) in DCM (5 mL), dimethylamino-sulfur trifluoride (732 μl, 3.31 mmol) was added and stirred overnight. More DCM was added and the organic portion was washed with sodium bicarbonate. The residue obtained after removal of the solvent was purified by column chromatography on silica gel, using 20% ethyl acetate in hexanes as the eluent (100 mg, 60%) to provide the protected product (P = Boc, R = SMe). The Boc-protected product was absorbed in 30% trifluoroacetic acid in dichloroethane and dimethylsulfide, and stirred for 1 h at RT. The solvent was removed to provide the product 5b (R1 = SMe): TLC Rf = 0.63 (40% MeOH / hexanes); 1 H NMR (300 MHz, CDC 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); MS (ESPOS): 522 [M + Na] +.

Method J Preparation of compound 6a (P = TFA). To a 1 l round bottom flask was added dry MTL 1a (R = SMe) (dried at 50 ° C under vacuum overnight) (20 g, 0.079 mol), anhydrous methanol (200 ml), triethylamine ( 8.77 g, 0.087 mol) and methyl trifluoroacetate (127.3 g, 0.99 mol). The reaction mixture was stirred at RT for 4 h, after which the solvent was evaporated to dryness to obtain protected MTL 6a (R1 = SMe, P = TFA) (26.2 g, 95%), which was taken as such to the next stage.

Chloromethylene piperidinium HCl (Scheme 6, Reagent b) To a 3-necked 3-necked round bottom flask equipped with a mechanical stirrer, a glass stirring rod (large Teflon vane), under a nitrogen atmosphere, was added diethyl ether (anhydrous, 1.8 I) and N-formylpiperidine (35.6 g, 0.3 mol). The reaction mixture was cooled to 0 ° C and triphosgene (31.2 g, 0.105 mol) was added in at least 5 portions over the course of 2 hours, maintaining at 0 ° C and stirring vigorously. The reaction mixture was then allowed to warm to RT (1 h) to ensure complete reaction of the triphosgene, and cooled again to 0 ° C. The reaction mixture was then filtered to a stream of nitrogen or argon (very hygroscopic, stink) and washed with cold diethyl ether (2 x 100 mL). The obtained white crystals were then dried under vacuum to produce chloromethylenepiperidium HCl (46.4 g, 95%). 7-CI MTL protected with TFA To a 3-necked round bottom flask, 3 I, under a nitrogen atmosphere, fitted with a mechanical stirrer, glass stirring rod, Teflon vane, and a reflux condenser, it is added chloromethylene piperidinium HCl (44.4 g, 0.286 mol) and dichloroethane (anhydrous, 1 I). The resulting suspension was stirred vigorously and the temperature was brought to 0 ° C. To the stirred reaction mixture was added crude 6a (R = SMe, P = TFA) (20 g, 0.057 mol) in a period of 1 minute. The reaction mixture was stirred for 1 h and then the temperature was raised to 65 ° C, during this procedure it was observed that the reaction turned into a clear solution. The reaction mixture was then stirred at 65 ° C for a period of 18 h. The reaction mixture was then cooled to 0 ° C and then poured rapidly into a 4 l Erlenmeyer flask equipped with a mechanical stirrer, to which water (1 L) and NaOH (22.9 g, 0.57 mol) had been added. cooled to 0 ° C. The reaction mixture was then allowed to stir for a period of 30 min and then the pH was adjusted to 10.5 (pH paper) with concentrated HCl (added over a period of 5 min while checking the pH after each addition of HCl, if the pH was reduced below 10.5, it was acceptable to simply add NaOH to adjust to 10.5.This adjusted pH mixture was then stirred for a period of 2 hours while the reaction was allowed to come to RT.The pH was then adjusted to pH 7 with more concentrated HCl and allowed to stir overnight, or until it was observed that the product was free of the adduct formed by the chlorinating agent and the OH functionality of the sugar.The reaction mixture was then evaporated to dryness with the high vacuum aid attached to a rotary evaporator (can be co-evaporated with solvents such as toluene to facilitate this procedure.) To the resulting solid was then added a mixture of 10% methanol / DC and stirred during a period of 1 hour to release the product from the salts. The mixture was then filtered and the filtrate was evaporated to dry to provide a syrup containing the product and N-formylpiperidine. Most of the N-formylpiperidine can be removed by triturating the mixture with hexanes and decanting the hexane from the product oil several times. The crude reaction product was chromatographed using 10% methanol / DCM to produce purified 7-CI MTL protected with TFA (21: 1 g, 75%). 6b (R '= SMe, R2 = Cl, R3 = H). To a 500 ml round bottom flask with 3 necks, equipped with a mechanical stirrer, the purified 7-CI MTL protected with TFA (20 g, 0.054 mol) in a minimum amount of methanol (10 ml) was added, followed by NaOH 1 M, (250 ml) at 0 ° C. The reaction mixture was then stirred at 0 ° C (it was observed that the mixture first formed a sticky hard-to-work solid which eventually became a solution and shortly after it was observed that crystals of crude product were formed) for 12 h with collection Periodic analysis of the crude product crystals to prevent the hydrolysis of the 7-chloro functionality, and washing with a minimum amount of cold water, followed by cold methanol to provide 7-CI MTL 6b (R1 = SMe, R2 = Cl, R3 = H) as a colorless solid (10 g, 50%).

Method K Enolization (LiHMDS) and alkylation of 7a with 4-bromo-2-methyl-2-butene produced a mixture of diastereomers of lactam 7b (R9 '= 2-methyl-2-butene) (61%) according to the literature procedure of Zhang, R .; et. al., Journal of the American Chemical Society. 1998, 120, 3894-3902. The compound 7a is marketed by suppliers such as Bachem. Alternatively, 7a can be prepared by methods known in the art, for example, see Baldwin J. E .; et al .; Tetrahedron, 1989, 45, 7449-7468. Lactam 7b was reduced to pyrrolidine 7c (R9 '= 2-methyl-2-butene) (70%) by the two-step sequence involving reduction with superhydride® from lactam to hemiaminal and subsequent reduction of hemiaminal with Et3SiH / BF3 »OEt2. Pyrrolidine 7c (778 mg2.08 mmol), 10% palladium on carbon (230 mg), in anhydrous methanol (25 ml), was subjected to hydrogenolysis in Parr at 3.51 kgf / cm2 (50 psi) for 5 h. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washings and filtrate were evaporated to dryness, yielding, without further purification, a colorless oil 7d (R9"= 2-methyl-2-butane): TLC Rf = 0.3 [Solvent system: DCM / hexanes / MeOH (6: 5: 1)]; MS (ESNEG): 284.5 [MH] \ Method LA a stirred solution of 7a (9.47 g, 29.7 mmol, 1 equiv) in anhydrous THF, at -78 ° C under N2, was added 1 M solution of LiHMDS in THF (33 mmol, 33 mL, 1.1 equiv) followed by cis-1-bromo-2-pentene (4.21 mL, 35.6 mmol, 1.2 equiv), which produced a mixture of diastereomers of lactam 7b (R9f = 2-pentene ) (43.2%) after purification on silica gel. Lactam 7b (3.96 g, 10.22 mmol) was reduced to pyrrolidine 7c (R9 '= 2-pentene) by the two-step sequence involving reduction with superhydride® from lactam to hemiaminal, at -78 ° C in THF anhydrous, and the subsequent reduction of the hemiaminal with Et3 SiH / BF30Et2 in anhydrous DCM at -78 ° C, yielding 7c (R9 '= 2-pentene) (71%) after purification on silica gel. Pyrrolidine 7c (2.1 g, 7.26 mmol) and 10% palladium on carbon (560 mg) in anhydrous methanol (30 mL) were subjected to hydrogenolysis in Parr at 3.51 kgf / cm2 (50 psi) for 5 h. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washings and filtrate were evaporated to dryness yielding, without further purification, a colorless oil 7d (R9 = pentyl) (1.68 g, 80%); TLC: Rf = 0.3 [Solvent system: DCM: hexanes: MeOH (6: 5: 1)]. MS (ESNEG): 284.5 [M-H] \ Method M 8a (R9 '= 3.3-difluoroprop-2-ene). The ozonolysis treatment of 7c (R9 '= 2-methyl-2-butene) in anhydrous dichloromethane, followed by treatment with DS at -78 ° C and then by slow heating to RT produced a terminal aldehyde 8a (77%), which was used in the next step without further purification. To a solution of aldehyde 8a from the previous reaction (407 mg, 1.17 mmol, 1 equiv) in dimethylacetamide (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. The reaction mixture was warmed to RT and stirred for 30 minutes, then an activated zinc (0.25 g, 3.82 mmol, 3.3 equiv) was added with the help of dimethylacetamide (0.3 ml). The resulting reaction mixture was stirred at 110 ° C for 1 h and cooled to RT 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 8a (R9 '= 3,3-difluoroprop-2-ene) (182 mg, 41%): MS (HORM): 282.4 [M Boc + H] +. 8c (R 9 = 3,3-difluoroprop-2-ene). To a solution of 8a (84.1 mg, 0.22 mmol, 1 equiv) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (46.3 mg, 1.10 mmol, 5 equiv). The reaction mixture was stirred at RT overnight. The THF was removed under vacuum. The residue was taken up in ethyl acetate (50 ml) and partitioned with 10% citric acid (20 ml). The organic layer was washed with water (1x), brine (1x), dried and concentrated to provide 8c (R9 '= 3,3-difluorooprop-2-ene) as a clear glass (56 mg, 87% ): MS (SPOS): 192.3 [M - Boc + H] +; MS (ESNEG): 290.3 [M - H] -. 8b (R9"= 3,3-difluoropropane) The saturated product of Scheme 8 can be obtained by the hydrogenation methods described, for example, in the K method for 7d.

Method N 9b (P = Boc. M = 1. LG = Ts). To a solution of methyl ester of N-Boc- (2S, 4R) -4-hydroxyproline (Bachem) 9a (P = Boc, m = 1) (5 g, 20.4 mmol, 1 equiv) and DMAP (0.25 g, 2.04 mmol) , 0.1 equiv) in DCM (80 ml) was added toluene sulfonic anhydride (8.65 g, 26.5 mmol, 1.3 equiv). The reaction mixture was cooled to 0 ° C and pyridine (6.59 mL, 81.5 mmol, 4 equiv) was added. The mixture was stirred at 0 ° C for 30 minutes and then at RT overnight. The solution was concentrated to dryness. The residue was taken up in ethyl acetate (400 ml), washed with 10% ac citric acid (2 x 400 ml), sat. NaHCO 3. ac. (400 ml) and brine, and dried over Na 2 SO 4 and concentrated to yield a yellow syrup 9b (P = Boc, m = 1, LG = Ts) (8.44 g, 100%): HPLC (Method RV-1), C18 3.5 pm, 4.6 30 mm Column; gradient eluent 2% -98% MeCN for 5 min; 1.5 ml / min): Rt (retention time) = 3.096. 9c (P = Boc, m = 1, R9 = 2,4-d1 chlorobenzylsulfide). To a solution of tosylate 9b (P Boc, m = 1, LG = Ts) (1.02 g, 2. 55 mmoles, 1 equiv) in dry DMF (7.6 ml), under N2, was added 2,4-dichlorobenzylthiol (1.48 g, 7.66 mmoles, 3 equiv), followed by the addition of MTBU (0.55 ml, 3.83 mmol, 1.5 equiv). The reaction mixture was stirred at RT overnight and concentrated to dryness. The residue was taken up in ethyl acetate (100 ml), washed with 10% citric acid (50 ml) and brine, and concentrated. The residue was purified by chromatography to provide a clear syrup, 9c (P = Boc, m = 1, R9 = 4- (2,4-dichlorobenzyl sulfide) (1.0 g) MS (ESPOS): 320.2 [M-Boc + H] +; MS (ESNEG): 418.4 [M-H]. "To a solution of methyl ester 9c (P = Boc, m = 1, R9 = 2,4-dichlorobenzylsulfide) (1.0 g, 2.38 mmol, 1 equiv. ) in THF (9 ml) and water (3 ml) was added lithium hydroxide (0.5 g, 11.9 mmol, 5 equiv.) The reaction mixture was stirred at RT overnight, the THF was removed in vacuo. The residue was partitioned between ethyl acetate (150 ml) and 10% citric acid (100 ml) The organic layer was washed with water (1 x) and brine (1 x), dried over Na 2 SO 4 and evaporated to produce a clear syrup, 9d (P = Boc, m = 1, R9 = 2,4-dichlorobenzyl sulfide) (1.0 g): MS (ESPOS): 306.3 [M-Boc + H] +; MS (ESNEG): 404.2 [M - Hj. " Method O 4-propylpyridine-2-carboxylic acid 10b (R9 = n-propyl). To 4-propylpyridine (TCI) (2.5 g, 20 mmol), 30% hydrogen peroxide (2.4 g) was added and refluxed 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 dimethyl carbamyl chloride (2.8 g, 26 mmol) and allowed to stir at room temperature overnight. 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 refluxed in hydrochloric acid (6N, 60 ml) overnight. The 4-propylpyridinecarboxylic acid 10b (R9 = nPr) was obtained after crystallization from acetonitrile (2.0 g, 71%): MS (ESPOS): 166 [M + H]; 1 H NMR (300 MHz, CD 3 OD) 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). 4-Propyl- (3-phenyl) pyridine-2-carboxylic acid 10b (R9 = 4-propyl- (3-phenyl)). To 4-propyl- (3-phenyl) pyridine-N-Oxide (1 g, 4.69 mmol) in dichloromethane (10 mL) was added trimethylsilyl cyanide (1.3 mL, 10 mmol) and dimethylcarbamyl chloride (10 mL). mmol) and stirred at room temperature for 24 hours. Aqueous potassium carbonate (10%, 10 mL) was added and extracted with dichloromethane (100 mL). The crude product obtained after removal of the solvent was taken up in hydrochloric acid (6N, 30 ml) and refluxed for 24 hours. Removal of acid followed by crystallization of the crude product from acetonitrile yielded 10b acid (1 g, 86%): MS (ESPOS): 240 [M-1]; 1 H NMR (300 MHz, CD 3 OD) d 2.03-2.17 (m, 2), 2.74 (t, J = 7.2, 2), 3.04 (t, J = 7.8, 2), 7.16-7.38 (m, 5), 8.07 (d, J = 4.2, 1), 8.40 (s, 1), 8.71 (d, J = 5.7, 1 ).

Method P 4-Chloropicolinic acid methyl ester A mixture of picolinic acid (20 g, 162 mmol, 1 equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 ml) was refluxed. for 5 h. The solvent was removed in vacuo. Absolute methanol (160 mL) was added and the mixture was stirred at RT for 30 minutes. The solvent was evaporated and the residue was taken up in 5% sodium bicarbonate and extracted with ethyl acetate (3 x). The organic layers were combined and dried over MgSO4 and evaporated. The residue was purified by chromatography to yield 4-chloropicolinic acid methyl ester (19.9 g, 72%) as a white solid: 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). 4-iodopicolinic acid 1 1 a. A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydroiodic acid (13.3 mL) and 50% aqueous hypophosphoric acid (0.66 mL) was stirred at 85 ° C for 2 h and then stirred at 107 ° C throughout the night. The mixture was cooled to 95 ° C. At this temperature, in 10 minutes, aqueous solution of 10 M sodium hydroxide (4.2 ml) was added, followed by the addition of water (15.2 ml). The mixture was cooled to RT and stirred for 1 h. The precipitate was filtered, washed with water and dried under high vacuum overnight to yield a yellow solid 1 1a, 4-iodopicolinic acid (3.5 g, 66%): H NMR (300 MHz, DIVISO 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 (SPOS): 250.2 [M + H] +.

Methyl ester of 4-iodopicolinic acid 11 b. To a solution of 4-iodopicolinic acid 11 a (7.0 g, 18.6 mmol) in MeOH (70 ml), at 23 ° C, concentrated sulfuric acid (350 pL) was added, and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and concentrated to provide the desired product 4-iodopicolinic acid methyl ester 11b (4.4 g, 90%) as a yellow oil; 1 H NMR (300 MHz, CDCl 3) d 8.52 (t, J = 0.6, 1.5, 1), 8.40 (d, J = 5.1, 1), 7.86-7.88 (dd, J = 0.6, 5.1, 1), 4.02 ( s, 3); MS (ESPOS): 263.9 [M + H]; 285.9 [M + Na]. 4-f3- (tert-Butyl-dimethyl-s-lanyloxy) -prop-1-inin-pyridine-2-carboxylic acid methyl ester c (R9 '= tert-butyl-dimethyl-silanyloxy). To a dry flask were added 1 1 b (5.41 g, 20.6 mmol, 1 equiv), triphenylphosphine (431.5 mg, 1.65 mmol, 0.08 equiv), copper iodide (I) (313.4 mg, 1.65 mmol, 0.08 equiv), palladium acetate (184.5 mg, 0.82 mmol, 0.04 equiv) and triethylamine (74 ml). The mixture was degassed with nitrogen, followed by the addition of t-butyldimethyl (2-propynyloxy) silan (Aldrich) (8.34 ml, 41.14 mmol, 2 equiv). The mixture was stirred at RT for 3 h. The solvent was removed under vacuum to produce a dark residue. The residue was purified by chromatography to yield the ester 11e (R9, = 3- (tert-butyl-dimethylsilanyloxy) -prop-1-ynyl) (6.07 g, 97%) as a brown oil: 1 H NMR (300 MHz , CDCI3) d 8.67 (dd, J = 0.8, 5.0, 1), 8.09 (m, 1), 7.43 (dd, J = 1.7, 5.0, 1), 4.54 (s, 2), 3.99 (s, 3) , 0.92 (s, 9), 0.14 (s, 6). MS (ESPOS): 306.5 [M + H] +. 4-f3- (tert-Butyl-dimethyl-silanyloxy) -propyl-piperidine-2-carboxylic acid methyl ester 1 (d) R (3- (tert-butyl-dimethyl-silanyloxy-propyl).) To a mixture of 1 1c (R 9, = 3- (tert-butyl-dimethyl-silanyloxy) -prop-1-ynyl) (6.05 g, 19.8 mmol, 1 equiv) in MeOH (60 mL), water (60 mL) and acetic acid (1.14) mi, 19.8 mmol, 1 equiv) was added with platinum oxide (2.0 g) The mixture was purged and charged with hydrogen 3.51 kgf / cm2 (50 psi) and stirred at RT overnight. it was removed by filtration and the filtrate was concentrated to obtain the product 1 d (R9 '= 3- (tert-butyl-dimethyl-silanyloxy) -propyl) (5.0 g, 80%): MS (ESPOS): 316.6 [M + Hf. 1-tert-butyl ester 2-methyl ester of 4-f3- (tert-butyl-dimethyl-silanyloxy) -propin-piperidine-1,2-dicarboxylic acid e (R9 '= 3- (tert-butyl-dimethyl- silanyloxy-propyl, P = Boc). A 1 1 d (R 9, = 3- (tert-butyl-dimethyl-silanyloxy) -propyl) (4.99 g, 15.8 mmol, 1 equiv) in methanol (60 ml) was added. triethylamine (4.42 ml, 31.7 mmol, 2 equiv) and di-t-butyldicarbonate (4.7 ml, 20.6 mmol, 1.3 equiv) The mixture was stirred at RT overnight The solvent was removed in vacuo The residue was purified by chromatography to produce carbamate 11e (R9 '= 3- (tert-butyldimethyl-silanyloxy) -propyl, P = Boc) (2.75 g, 42%) as a clear syrup: 1 H NMR (300 MHz, CDCl 3) d 4.28 ( t, J = 6.6, 1), 3.70 (s, 3), 3.55 (t, J = 6.3, 2), 3.55-3.48 (m, 1), 3.40-3.30 (m, 1), 2.00-1.92 (m , 1), 1.82-1.69 (m, 2), 1.64-1.20 (m, 6), 1.41 (s, 9), 0.86 (s, 9), 0.01 (s, 6), MS (SPOS): 316.6 [ M + H - Boc] + 4- [3- (tert-Butyl-dimethyl-silanyloxy) -propyl] -piperidine-1-tert-butyl ester 1,2-dicarboxylic acid 1 1 f (R 9 '= 3- (tert-butyl-dimethyl-silanyloxy) -propyl, P = Boc). To a mixture of 11e (R9, = 3- (tert-butyl-dimethyl-silanyloxy) -propyl, P Boc) (2.75 g, 6.63 mmol, 1 equiv) in THF (12 ml) and water (4 ml) were added. added lithium hydroxide monohydrate (306 mg, 7.29 mmol, 1.1 equiv). The mixture was stirred at RT overnight. Additional lithium hydroxide monohydrate (834 mg, 19.89 mmol, 3 equiv) was added and the mixture was stirred at RT for 5 h. The THF was removed under vacuum. The aqueous layer was taken up in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1x) and brine (1x), dried and concentrated to yield a yellow syrup which was purified by chromatography to provide the desired acid 1 1f (R 9 '= 3- (tert -butyl -dimethylsilanyloxy) -propyl, P = Boc) (1.83 g, 69%) as a colorless syrup: H NMR (300 MHz, CDCl 3) d 4.26 (t, J = 6.9, 1), 3.57 (t, J = 6.5, 2), 3.53-3.44 (m, 1), 3.43-3.33 (m, 1), 2.05-1.96 (m, 1), 1.82-1.68 (m, 2), 1.64-1.45 (m, 3 ), 1.42 (s, 9), 1.37-1.27 (m, 3), 0.86 (s, 9), 0.02 (s, 6). MS (SPOS): 424.7 [M + Naf.

Method Q Methyl ester of (2S, 4R) -N-Boc-4-hydroxyproline. To a stirred solution of (2S, 4R) -4-hydroxyproline (Bechem) (25 g, 108 mmol) in methanol (50 ml), at 0 ° C, was added trimethylsilyldiazomethene (24.6 g, 216 mmol). The mixture was stirred at 0 ° for 1 h. The residue obtained after removal of the solvent was purified by chromatography using 50% ethyl acetate in hexanes to obtain (2S, 4R) -N-Boc-4-hydroxyproline methyl ester (27 g, 100%) as a colorless oil: 1 H NMR (300 MHz, CDCl 3) d 4.47 (m, 1), 4.39 (m, 1), 3.70 (s, 3), 3.60 (m, 2), 2.27 (m, 1), 2.05 (m, 1) , 1.38 (s, 9); MS (SPOS): 268 (M + Na).

Methyl ester of (2S, 4R) -N-Boc-4-ketoproline 12a (P = Boc, P? = Me m = 1). To oxalyl chloride (15 g, 118 mmol) in DCM (ml), at -78 ° C, DMSO (18.6 mL, 236 mmol) was added slowly over minutes. After the addition was complete, methyl (2S, 4R) -N-Boc-4-hydroxyproline (26.5 g, 108 mmol) in DCM (100 mL) was added dropwise and stirred at -78 ° C for 20 minutes. min, then triethylamine (54.6 g, 540 mmol) was added and allowed to stir for 2 h. The reaction mixture was then washed with aq. to 10% (200 mi). The organic layer was separated and dried over sodium sulfate. The crude product obtained after removal of solvent was purified by column chromatography on silica gel, using 50% EtOAc in hexanes to obtain 12a (P = Boc, P2 = Me, m = 1) - (20 g, 78% ) as a brown solid: 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, 9); MS (SPOS): 244 (M + H).

Methyl ester of N-Boc-4-hydroxy-4-allylproline 12b (P = Boc, P? = Me, m = 1, R9 '= allyl). To a solution of 12a (P Boc, P2 = Me) (1 g, 4.11 mmol) in THF (10 mL), tetraalyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to 0 ° C before of slowly adding borotrifluoride etherate (0.520 ml, 4.11 mmol). The mixture was stirred at 0 ° C for 1 h and then at room temperature for 2 h. additional Potassium fluoride (360 mg in 5 ml 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. The residue was dissolved in DCM (200 ml) and washed with water (100 ml) and brine (100 ml), dried over MgSO 4 and evaporated to dryness. The obtained residue was purified by column chromatography on silica gel using 50% EtOAc in hexanes to obtain 12b (P = Boc, P2 = Me, m = 1, R9 = allyl) (0.94 g, 80%) as an oil colorless: 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] +.

Metherster of N-Boc-4-fluoro-4-allylproline 12c (P = Boc, P2 = Me, m = 1. R9 '= allyl). To a solution of DAST (1.06 g, 6.58 mmol) in DCM (10 mL), at -78 ° C, 12b was slowly added (P = Boc, P2 = Me, R9 = allyl) (940 mg, 3.3 mmol) in dry DCM (10 ml). The mixture was then stirred at -78 ° C for 1 h, then at -10 ° C for an additional 1 h. DCM (50 mL) was added, quenched with NH4CI (10%, 150 mL), the organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel, using 5% EtOAc in hexanes as the eluent to provide the desired product 12c (P = Boc, P2 = Me, m = 1, R9 = allyl) (330 mg, 34%) as a colorless oil: 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 (SPOS): 310 [M + Naf.

Methyl ester of N-Boc-4-fluoro-4-propylproline acid 12c (P = Boc, P2 = Me, m = 1. R9 = propyl). To a solution of 12c (P = Boc, P2 = Me, m = 1, R allyl) (0.33 g, 1.15 mmol) in MeOH (mi) was added 10% Pd / C (40 mg). The reaction mixture was stirred at room temperature under hydrogen (30 atm) for 3 h. The catalyst was filtered through celite and washed with methanol. The filtrate was concentrated to yield the desired protected amino acid ester 12c (P = Boc, P2 = Me, R9 = propyl) (0.33 g, 100%) as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 4.43 ( m, 1), 3.71 (m, 4), 3.47 (m, 1), 2. 51 (m, 1), 1.98 (m, 5), 1.40 (dd, J = 5.1, 13.8, 9), 0.93 (J = 7.8, 3); MS (SPOS) 190 [M-Boc] +.

N-Boc-4-fluoro-4-propylproline 12d (P = Boc, R9 = propyl, m = 1). To a solution of methyl ester 12d (330 mg, 1 mmol) in THF (12 mL) and water (4 mL) was added lithium hydroxide monohydrate (60 mg, 1.38 mmol). The reaction mixture was stirred at room temperature overnight. The THF was removed, the residue was taken up in ethyl acetate (50 ml), washed with 10% citric acid (100 ml) and brine (20 ml). The concentration of the organic portion produced the desired protected amino acid 12e (P = Boc, R9 = propyl, m = 1) (310 mg, 100%) as a white solid: 1H RN (300 Hz, 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 [M-1]Method R (2S, 4R) -N-Trifluoroacyl-4-tert-butyloxyproline. To a solution of 4-tert-butyloxyproline (Bachem) (5.0 g, 27 mmol, 1 equiv) and TEA (11.2 mL, 80 mmol, 3 equiv) in dry MeOH (30 mL) was added ethyl trifluoroacetate (4.8 mL). , 40 mmoles, 1.5 equiv). The mixture was stirred at 24 ° C overnight. The solution was concentrated to dryness, dissolved in DCM (200 ml) and the organic phase was washed with KHS04. 0. 2M aq (2 x 100 mL) and brine (1 x 100 mL), dried over MgSO4 and evaporated to dryness. The resulting residue was triturated with cyclohexane and pentane to provide the product (2S, 4R) -N-Trifluoroacyl-4-tert-butyloxyproline as a light yellow powder (5.5 g, 72%). 14a (P = CF.CO.m = 1, R2 = H. R3 = OH) To a solution of MTL (1.32 g, 5.3 mmol, 1 equiv) in dry DMF (16 ml), at 0 ° C, he added triethylamine (2.20 ml, 15.9 mmol, 3 equiv), followed by bis- (trimethylsilyl) trifluoroacetamide (2.81 ml, 10.6 mmol, 2.0 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. To the reaction mixture were added (2S, 4R) -N-Trifluoroacyl-4-tert-butyloxyproline (1.8g, 6.3mmol, 1.2 equiv) and HATU (3.02g, 8.0mmol, 1.5 equiv. ). The reaction mixture was stirred for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (500 ml), washed with 10% citric acid (100 ml), water (100 ml), partially saturated aqueous NaHCO 3 (200 ml) and brine. The organic layer was dried over Na 2 SO 4 and evaporated to yield a yellow syrup, which was dissolved in MeOH (100 ml). The dried Dowex® H + resin form (500 mg) was added and the resulting suspension was stirred for 50 min, filtered and evaporated to dry to yield a yellow solid (2.89 g). Purification of the product by chromatography on silica gel DCM / hexanes / MeOH 6: 5: 1 to 7: 2: 1 yielded product 14a (P = CF3CO, m = 1, R2 = H, R3 = OH) as a colorless solid (1.7 g, 51%). 14b (P = CF3CO, m = 1. R2 = H. R3OAc) To a solution of 14a (P = CF3CO, m = 1, R2 = H, R3 = OH) (1.63 g, 3.1 mmol), pyridine (3 ml) , 30 mmol) and DMAP (38 mg, 0.31 mmol) in dry DCM (10 mL), at 0 ° C, acetic anhydride (3 mL, 31 mmol) was added. The reaction temperature was allowed to rise to 24 ° C for 1 h and was stirred for 48 h. The reaction mixture was diluted with chloroform (200 ml) and the organic phase was washed with 10% aqueous acetic acid (3 x 200 ml), 10% citric acid (200 ml) aq. NaHCO 3. partially saturated (200 ml) and brine (1 x 100 ml), dried over Na 2 SO and evaporated to yield the peracylated intermediate 14b (P = CF 3 CO, m = 1, R 2 = H, R 3 = OAc) (2.14 g, 99 %) as colorless crystals.

To a solution of the aforementioned peracylated intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) (2.1 g, 3.1 mmol) in DCE (64 ml) with methylsulfide (1.4 ml) was added trifluoroacetic acid. (21 mi) and water (1.4 mi). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and coevaporated twice with DCE. The residue was purified by chromatography with 5% MeOH in DCM to provide the intermediate alcohol (1.6 g, 83%) as a colorless solid which was taken to the next step without characterization. 14b (P = CFjCO, m = 1, R2 = H. R3 = OAc) To a solution of the aforementioned 4-alcohol intermediate (1.5 g, 2.38 mmol, 1 equiv) and DMAP (29 mg) in DCE (9.5 ml) p-Toluenesulfonic anhydride (1.01 g, 3.09 mmol, 1.3 equiv) was added. The reaction mixture was cooled to 0 ° C and pyridine (0.77 mL, 9.52 mmol, 4 equiv) was added. The reaction mixture was stirred at 0 ° C for 30 minutes, then at RT overnight. The reaction mixture was concentrated to dryness. The residue was taken up in ethyl acetate (200 ml), washed with 10% citric acid (2 x 200 ml), sat. NaHCO 3. (200 mL) and brine, and dried over Na2SO4 and concentrated to yield a yellow syrup which was purified by chromatography 4: 1 hexanes / EtOAc to provide the product of p-toluenesulfonic ester 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) (1.7 g, 92%) as a colorless solid.

Method S Diethyl n-propylmalonate. To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 3 mmol, 1.05 equiv) in DMF (300 ml), at 23 ° C, a solution of diethyl malonate (45.5 ml, 300 mmol) was added. , 1 equiv) in DMF (100 ml) via a cannula during the course of 10 min. The addition caused a slight exotherm and an evolution of hfe gas was observed, it was not necessary to cool.

After the addition, the reaction was stirred for 45 min at 23 ° C, then treated with 1-bromopropane (27.3 ml, 300 mmol, 1 equiv). The reaction was stirred at 23 ° C for 25 min, then heated to 65 ° C for 3 h, then stirred at 23 ° C overnight. The reaction mixture was added to 1.0 N HCl (1 L), then extracted with diethyl ether (700 mL). The ether extracts were washed with H20 (400 mL) and brine (200 mL), dried (MgSO), filtered and concentrated to yield 65.1 g of product as a clear oil. The 3 C NMR revealed approximately 4: 1 of mono: b-alkylated product. The diethyl n-propylmalonate was used without further purification: 1 H NMR (300 MHz, CDCl 3) 4.18 (q, J = 6.9 Hz, 4 H), 3.32 (t, J = 7.8 Hz, 1 H), 1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J = 6.9 Hz, 6H), 0.92 (t, J = 7.5 Hz, 3H); 13 C NMR (300 MHz, CDCl 3) (* denotes the signal due to the minor product of bisacylation)? 169.6, 61.2, 60.9 *, 51.8, 34.4 *, 30.7, 20.5, 17.3 *, 14.4 *, 14.0, 13.7.

Ethyl n-propylmalonate 21 b (R 9 = n-propyl). To a solution of diethyl n-propylmalonate (contaminated with approximately 20% diethyl bis (n-propylmalonate, 55.0 g, 273 mmol, 1 equiv) in EtOH (500 ml), at 23 ° C, was added a solution of KOH 1.0 M (273 ml, 273 mmol, 1 equiv.) After the addition, the reaction was heated to 80 ° C (internal temperature) for 4 h After cooling to 23 ° C, the EtOH was removed in vacuo. The residue was partitioned between diethyl ether (400 ml) and H2O (200 ml) The layers were separated and the ether layer was extracted with saturated aqueous NaHCO3 (100 ml) The aqueous NaHCO3 layer was combined with the original aqueous layer and this solution was acidified to pH 1 with 1.0 N HCl, then extracted with EtOAc (2 x 600 mL). The EtOAc extracts were dried (gSO4), filtered and concentrated to yield 21b (R9 = n-propyl) 41.3 g ( 237 mmole, 79% over 2 steps) of pure product as a clear oil: H NMR (300 MHz, CDCl 3) 4.43 (q, J = 7.2 Hz, 2H), 3.60 (t, J = 7. 5 Hz, 1 H), 2.18-2.02 (m, 2), 1.66-1.50 (m, 2H), 1.49 (t, J = 7.2 Hz, 3H), 1, (t, J = 7.5 Hz, 3H).

Ethyl n-propylacrylate 21 c (R 9 = n-propyl). To a solution of ethyl n-propylmalonate (41.3 g, 237 mmol, 1 equiv) in EtOH (500 mL), at 23 ° C, piperidine (28.1 mL, 284 mmol, 1.2 equiv) was added followed by aqueous formaldehyde (37 %, 88 mi). After the addition, the reaction was refluxed for 29 h. After cooling to 23 ° C, the mixture was partitioned between diethyl ether (500 ml) and HCl 10 N (800 ml). The layers were separated and the aqueous layer was extracted with diethyl ether (500 ml). The combined organic layers were washed with H20 (500 mL) and brine (300 mL), dried (MgSO4), filtered and concentrated (rotovap). only, the product is potentially volatile). The product was vacuum distilled (boiling point 70 ° C to 15 mmHg) to yield 16.4 g 21c (R9 = n-propyl) (1 mmole, 49%) of the desired product: 1 H NMR shows contamination with unidentified material; the product was used in the subsequent step without further purification: H NMR (300 MHz, CDCl 3) 6.12 (s, 1 H), 5.50 (s, 1 H), 4.19 (q, J = 7. 2 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 1.55-1.42 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H) . 2-Propyl-prop-2-en-1-ol. To a solution of 21 c (R9 = n-propyl) (16.4 g, 1 mmol, 1 equiv) in CH2C! 2 (500 ml), at 78 ° C, DIBALH (1.0 M in hexanes, 403 ml, 403 mmoles, 3.5 equiv) via a cannula, during the course of 20 min. After the addition, the reaction was stirred at 78 ° C for 30 min, then allowed to warm to 55 ° C over the course of 60 min. Once the reaction bath had reached 55 ° C, EtOAc (15 mL) was added to rapidly cool the excess DIBALH. After stirring for 5 min, the cooled reaction mixture was slowly added via a cannula to a stirred mixture of 1: 1 saturated aqueous sodium potassium tartrate: saturated aqueous NaHCO 3 (1 L) at 23 ° C. The biphasic mixture was stirred for 1 h, then the layers were separated. The aqueous layer was extracted with diethyl ether (500 ml).

The combined organic layers were dried (MgSO ^, filtered and concentrated (rotovap only, the product is potentially volatile) .The product was vacuum distilled (boiling point 100-120 ° C at 15 mmHg) to yield 7.58 g (75.8 mmol) , 66%) of the desired product 2-propyl-prop-2-en-1-ol as a clear oil: 1 H NMR (300 MHz, CDCl 3) 5.22 (s, 1 H), 5.06 (s, 1 H), 4.27 (s, 2H), 2.24 (t, J = 7.5 Hz, 2H), 1.75-1.60 (m, 2H), 1.12 (t, J 6.9 Hz, 3H). 2-Bromomethyl-pent-1-ene 21 d (R9 = n-propyl). To a solution of n-propyl allyl alcohol (7.58 g, 75.8 mmol, 1 equiv) in Et20 (65 mL), at 0 ° C, pyridine (0.58 mL) was added. A solution of PBr3 (4.28 mL, 45.5 mmol, 0.6 equiv) in Et20 (20 mL) was then added via a cannula over the course of 15 min. After the addition, the reaction was stirred at 0 ° C for 75 min, then the cold reaction mixture was slowly added to saturated aqueous cooled ice-cooled NaHCO 3 (500 ml). The resulting biphasic mixture was extracted with diethyl ether (250 ml). The organic extracts were washed with saturated aqueous NaHCO3 (2 x 100 mL), brine (100 mL), 1.0 N HCl (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated (rotovap at 0 ° C). C, the product is volatile). The product was purified by flash column chromatography on silica gel using pentane as the eluent to yield 5.97 g (36.8 mmol, 49%) of the desired product 21d (R9 = n-propyl) as a clear oil: 1 H NMR (300 MHz , CDCI3) 5.16 (s, 1 H), 4.95 (s, H), 3.97 (s, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.56-1.43 (m, 2H), 0.93 (t, J = 7.8 Hz, 3H).

N-allylcholine ethyl ester. To a solution of allylamine 21e (R9b = H, m = 1) (50 ml, 666 mmol, 2 equiv) in Et20 (167 ml), at 0 ° C, was added ethyl bromoacetate (36.9 ml, 333 mmol, 1 equiv). A white precipitate and an exothermic reaction were observed immediately after the addition; the exotherm caused the solvent to boil for approximately 2 min. After the addition, the reaction was stirred for 2.5 h, then the ice-water bath was removed and the reaction was stirred at 23 ° C overnight. After 15 h at 23 ° C, the reaction mixture was filtered through a glass frit to remove the by-product hydrobrominated salt of allylamine. The collected solid was washed with Et20 (200 ml), then the combined filtrates were concentrated. The product was vacuum distilled (boiling point 48-55 ° C at 1.0 mm Hg) to yield 35.5 g (249 mmol, 75%) of the desired product N-allyl glycine ethyl ester as a yellow oil: H NMR (300 MHz , CDCI3) 5.93-5.79 (m, 1 H), 5.22-5.08 (m, 2H), 4. 18 (q, J = 7.2 Hz, 2H), 3.39 (s, 2H), 3.29-3.23 (m, 2H), 1.27 (t, J 7.2 Hz, 3H); MS (SPOS): 144.1 [M + H] +.

H id N-allylglycine ethyl ester ruride 21 f (R = H, m = 1). To a solution of N-allylglycine ethyl ester (10.0 g, 70.0 mmol, 1 equiv) in Et20 (260 mL) and hexane (1.3 L), at 23 ° C, 4.0 M HCI in dioxane (16.6 mL) was slowly added. , 66.5 mmole, 0.95 equiv) over the course of 35 min via an addition funnel. After the addition, the suspension was stirred for another 40 min, then the product was isolated via filtration through a glass frit, washing with hexane (200 ml). The collected white solid was transferred to a flask and vacuum (0.5 mm Hg) for 1 h to produce 1.5 g of the desired product as a white solid. The reaction was repeated on the same scale to yield a total of 22.73 g (127 mmol, 90%) of the desired amine hydrochloride 21f (R9b = H, m = 1) as a white solid: 1 H NMR (300 MHz, DMSO- d6) 9.50 (s, 2H), 5.95-5.81 (m, 1 H), 5.49-5.37 (m, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.92 (s, 2H), 3.59 (d , J = 6.6 Hz, 2H); 1.24 (t, J = 7.2 Hz, 3H); MS (SPOS): 144.1 [M + H] +.

Pseudoephedrine N-allyl-phenylamide 21 h (R9b = H, m = 1). To a flask containing 21f (R9 = H). (20.3 g, 13 mmol, 1.3 equiv) and (1 R, 2R) pseudoephedrine 21 g (14.4 g, 86.9 mmol, 1 equiv) was added THF (130 mL). The resulting mixture was stirred vigorously for 20 minutes at 20 ° C to produce a uniform suspension, then treated with solid lithium tert -butoxide (9.74 g, 122 mmol, 1.4 equiv) added in a single portion. The reaction was stirred at 20 ° C for 2 d, after which period the analysis revealed that both starting materials were still present. The incomplete reaction was treated with H2O (200 ml), then the THF was removed in vacuo. The resulting aqueous solution was extracted with CH 2 Cl 2 (2 150 mL), then saturated with NaCl, and extracted further with CH 2 Cl 2 (2 100 mL). The organic extracts were dried (K2CO3), filtered and concentrated. The crude product was purified via flash column chromatography on silica gel, using 2: 2: 96 MeOH / Et3 / CH2Cl2 as the eluent to yield 18 g of product. This material was still substantially contaminated with N-allylglycine ethyl ester, removed with moderate agitation (60 ° C) under vacuum (1.0 mmHg) for h to yield 14.88 g (56.8 mmol, 65%) of the desired glycinamide product 21h ( R9b = H, m = 1) as a viscous oil: 1 H NMR (300 MHz, CDCl 3) (the spectrum shows rotamers) 7.41-7.24 (m, 5H), 6.00-5.80 (m, 1 H), 5.29-5.07 ( m, 2H), 4.64-4.44 (m, 1 H), 3.96-3.84 (m, 0.5H), 3.63 (d, J = 13.8 Hz, 0.5H), 3.45-3.21 (m, 4H), 2.95 (s) , 1.5H), 2.78 (s, 1.5H), 1.11 (d, J = 6.9 Hz, 1.5H), 0.98 (d, J = 6.9 Hz, 1.5H); MS (SPOS): 263.2 [M + H] 4. HPLC (Symmetry C 18, 3.5 pm particle size, 100 A pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN in H20 0.1% TFA for 10 min, 2 ml / min flow): Rt = 3.10 min.

Alkylation of pseudoephedrine N-allyl pinamide. To a flask containing LiCI (flame dried in vacuo, 3.14 g, 74.1 mmol, 4 equiv), at 0 ° C, was added a solution of pseudoephedrine N-allyl succinamide 21 h (R9b = H, m = 1) (4.85 g, 18.5 mmol, 1 equiv) in THF (50 ml). The resulting mixture was stirred at 0 ° C for 25 min, then treated with a solution of LiHMDS (1.0 M in THF, 37.0 ml, 37 mmol, 2 equiv) added slowly via a cannula over the course of 40 min. After the addition of LiHMDS, the enoiato solution was stirred at 0 ° C for another 30 min, then allyl bromide (3.00 g, 18.5, mmol, 1 equiv) was added dropwise via syringe over the course of 30 sec. . The reaction was stirred at 0 ° C for another 90 min, then quenched with H20 (200 mL) and extracted with CH2Cl2 (3 x 150 mL). The organic extracts were dried (K2CO3), filtered and concentrated to yield 8.0 g of yellow oil. A small portion of the crude product was purified via flash column chromatography on silica gel, using (3: 2: 95 MeOH / Et 3 N / CH 2 Cl 2) as the eluent to provide an analytically pure sample of the product. The remaining material was used without any purification in the subsequent step: 1 H NMR (300 MHz, CDCl 3) (the trum shows rotamers) 7.40- 7.24 (m, 5H), 5.90-5.76 (m, 1 H), 5.20-5.02 ( m, 2H), 4.92-4.75 (m, 2H), 4.66-4.45 (m, 2H), 4.20-4.00 (m, 1 H), 3.62 (t, J 6.3 Hz, 1 H), 3.34-3.16 (m, 1 H), 3.05-2.94 (m, 2H), 2.84 (s, 3H), 2.55 (q, J 7.2 Hz, 1 H), 2.22-1.80 (m, 5H), 1.58-1.36 (m, 3H), 1.11 (d, J = 6.9 Hz, 2H), 1.04 (t, J = 7.2 Hz, 1 H), 0.96 (d, J 6.9 Hz, H), 0.89 (t, J = 7.2 Hz, 2H); MS (SPOS): 345.0 [M + H] +. HPLC (C18 symmetry, 3.5 gm particle size, 100 A pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN in H20 0.1% TFA for 10 min, 2 ml / min flow rate): Rt = 4.28 min.

Boc-protection of amino amide diene 21 i (R9 = n-propyl, R9b = H, m = 1). To a solution of amine diene (crude from the previous step, 8.0 g, approximately 18 mmol, 1 equiv) in CH 2 Cl 2 (100 ml), at 23 ° C, triethylamine (2.83 ml, 20 mmol, 1.1 equiv) was added. followed by (Boc) 20 (8.07 g, 37 mmol, 2 equiv). The resulting mixture was stirred at 23 ° C for 13.5 h, then concentrated. The crude product was purified via flash column chromatography on a silica gel gradient (5.5 cm diameter column, 17 cm height) eluting first with 25% EtOAc / hexanes (1 L), then 30% EtOAc / hexanes (600 ml) , then 40% EtOAc / hexanes (400 ml). This gave 21 i (R9 = n-propyl, R9b = H, m = 1). 5.20 g (.7 mmoles, 65% in 2 stages) of pure product. Some mixed fractions that also contained smaller amounts of product were discarded: 1 H NMR (300 MHz, CDCl 3) (the trum shows rotamers) 7.52-7.24 (m, 5H), 5.90-5.62 (m, H), 5.44 (t, J = 6.9 Hz, 0.5H), 5.20-4.96 (m, 2.5H), 4.77 (d, J = 13.2 Hz, 2H), 4.68-4.35 (m, 2H), 4.00-3.55 (m, 1 H), 3.79 (d, J = 5.7 Hz, 1 H), 2.91 (s, 1 H), 2.87 (s, 2H), 2.52-2.29 (m, 2H), 2.10-1.96 (m, 2H), I. 54-1.35 (m, 9H), 1.13-1.00 (m, 2H), 0.96-0.86 (m, 3H); MS (SPOS): 467.3 [M + Naf. HPLC (Symmetry C18, 3.5 pm particle size, 100 A pore size, 4.6 mm diameter, 30 mm length, 2% -98% MeCN in H20 0.1% TFA for 10 min, 2 ml / min flow): Rt = 6.85 min.

Diene metathesis with ring closure 21 i (R9 = n-propyl, R9b = H, m = 1). To a solution of diene 21 i (R 9 = n-propyl, R 9b = H) (5.20 g, 1.7 mmoles, 1 equiv) in CH 2 Cl 2 (700 ml), at 23 ° C, benzylidene was added [1, 3 bis (2,4,6-trimethylphenyl) -2-imidazolidin-1-ruthenium (2nd generation Grubbs catalyst, 320 mg, 0.38 mmole, 0.03 equiv). The reaction was refluxed for 2 h, then cooled to 23 ° C and concentrated. The resulting product was first purified via flash column chromatography on silica gel (40% EtOAc in hexanes as the eluent) to provide the desired product still slightly contaminated with unidentified material. The product was then dissolved in hot hexanes (100 ml), and allowed to crystallize during the course of 2 days. The crystallized product was isolated via filtration through a glass frit, washing with hexane cooled with ice (100 ml), to provide 3.425 g of the desired tetrahydropyridine (8.23 mmoies, 70%): The mother liquor was concentrated to yield 0.57. g of brown oil which was again subjected to flash column chromatography on silica gel (40-50% EtOAc in hexanes as eluent) to yield another 392 mg (0.94 mmoies, 8%) of the desired product 21 j (R9 = n- propyl, R9b H, m = 1): H NMR (300 MHz, CDCl 3) (the spectrum shows rotamers) 7.50- 7.25 (m, 5H), 5.52-5.26 (m, 1 H), 5.05-4.96 (m, 1 H), 4.63-4.35 (m, 2H), 4.30-3.58 (m, 3H), 2.91 (s, 3H), 2.50-2.34 (m, 1 H), 2.20-1.94 (m, 3H), 1.46 (s) , 7H), I .41 (s, 2H), 1.19-1.01 (m, 2H), 0.94-0.85 (m, 3H); MS (SPOS): 439.3 [+ Naf. HPLC (Symmetry C 18, 3.5 pm particle size, 100 A pore size, 4.6 mm diameter, 30 mm length, 2% -98% MeCN in H20 0.1% TFA for 10 min, 2 ml / min flow): Rt = 6.29 min.

Excision of pseudoephedrine auxiliary 21 k (R9 = n-propyl, R9b = H. m = 1). To a solution of amide 21j (R 9 = n-propyl, R 9b = H, m = 1) (3.42 g, 8.22 mmol, 1 equiv) in MeOH (170 ml), at 23 ° C, 1.0 M aqueous NaOH was added. (41.1 ml, 41.1 mmol, 5 equiv). The reaction was refluxed for 24 h (oil bath temperature at 100 ° C), then cooled to 23 ° C and concentrated via rotary evaporation to remove most of the MeOH. The resulting aqueous solution was transferred to a separatory funnel, diluted with H20 (100 mL) and extracted with Et20 (100 mL). The ether extract was washed with aqueous NaOH 0.5 M NaOH (70 ml) and then discarded. The combined basic aqueous layers were acidified to pH 2 with 1.0 N HCl, then extracted with EtOAc (200 mL). The organic extracts were dried (MgSO4), filtered and concentrated to yield 2.46 g of the desired Boc protected amino acid 21 k (R9 n-propyl, R9b = H, m = 1): 1 H NMR (300 MHz, CDCl 3) (the spectrum shows rotamers) 5.36 (d, J = 22.8 Hz, 1 H), .5.09 (d, J = 4.8 Hz, 0.5 H), 4.90 (br s, 0.5 H), 4.14-3.97 (m, 1 H), 3.83 -3.67 (m, 1 H), 2.57-2.37 (m, 2H), 1.98 (t, J = 7.2 Hz, 2H), 1 .48 (s, 6H), 1.47-1.35 (m, 2H), 1.46 ( s, 3H), 0.86 (t, J = 7.2 Hz, 3H); MS (ESPOS): 292.1 [M + Na] +; MS (ESNEG): 268.2 [M - H] '.

Method T To anhydrous MeOH (20 mL) at 0 ° C was added dropwise SOCI2 (1.58 mL, 21.6 mmol). The solution was stirred at 0 ° C for 10 minutes, then L-2-amino-4-pentenoic acid 22a (R9b = H) (Aldrich) (1.0 g, 8.7 mmol) was added. The reaction mixture was stirred for 48 h at room temperature and the solvents were removed in vacuo. Purification by column chromatography on silica gel (10% MeOH / DCM) provided L-2-amino-4-pentenoic acid methyl ester 22b (R9b = H) (0.95 g, 85%). To a solution of methyl ester of L-2-amino-4-pentenoic acid in dichloroethane (32 ml) at 0 ° C was added 2,4,6-collidine (2.3 ml, 19.1 mmol, 2.2 equiv) and sodium chloride. Solid 2-nitrobenzenesulfonyl. The reaction was stirred for 3 h at RT. The solvent was removed in vacuo and the residue was partitioned between EtOAc (200mL) and saturated aqueous NH 4 Cl. The organic layer was washed with 1.0 M aqueous KHS04, sat aq NaHC03. and brine, dried (MgSO4) and concentrated to provide a residue which was purified by column chromatography on silica (gradient 10 to 20% EtOAc / h exan) to provide the desired product 22b (R9b = H) 0.70 g (26% ) as a yellow oil. H NMR (300 Hz, CDCl 3) S 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 22b (R9b H) (685 mg, 2.18 mmol), CS2CO3 (710 mg, 2.18 mmol) and tetrabutylammonium bromide (702 mg, 2.18 mmol), in DMF (5.0 mL), was added a solution of 3-methylenehex-1-yl-toluensuifonate 22c (R9 = propyl) (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 mi). The reaction mixture was heated to 60 ° C overnight. The reaction solvent was removed by evaporation, the resulting residue was taken up in EtOAc and washed with 10% aqueous citric acid and brine, the organic phase was dried over MgSO4 and concentrated to yield a residue which was purified by column chromatography. on silica gel (17% -20% EtOAc / hexanes) to provide the desired product 22d (R9 = propyl, R9b = H), (0.38 g, 42%) as an oil. MS (ESPOS): 433 [M + Na] +. To a solution of 22d (R9 = propyl, R9b = H) (0.38 g, 0.92 mmol) in anhydrous DCM (40 mL) was added benzylidene [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro- (tri- cyclohexylphosphine) ruthenium (23.3 mg, 0.0276 mmol). The resulting reaction mixture was refluxed 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 yield the desired compound 22e (R9 = propyl, R9b = H) (0.29 g, 81%).

MS (ESPOS): 383 [M + Na] +. To a stirred solution of thiophenol (183 μ? _, 1.79 mmol) and 7-methyl-1, 5,7-triazabicyclo- [4,4,0] dec-5-ene (214 μ ?,, 1.49 mmol) in anhydrous DMF (3 mL) was added a solution of alkene 22e (R9 = propyl, R9b = H) (228 mg, 0.596 mmol) in anhydrous DMF (3.0 mL) via a cannula. 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 aqueous 1 N HC1 (15.0 ml) for 5 min. The aqueous phase was washed with ether, then made basic with solid potassium carbonate. The resulting basic aqueous phase was extracted three times with ether. The combined organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated, cooled to 0 ° C and 2M HCl in ether (0.8 ml) was added and the resulting mixture was stirred for 5 min and then evaporated to dry to provide the desired product 22f (R9 = propyl, R9b = H) as the hydrochloride salt (144 mg, 103%). MS (ESPOS): 198 [M + H] +. To a solution of 22f (R 9 = propyl, R 9b = H) (143 mg, 0.61 mmol) in anhydrous dichloromethane (2.0 ml) was added triethylamine (170 μ ?, 1.22 mmol) and di-t-butyldicarbonate (350 mg, 1.6 mmol). The resulting reaction mixture was stirred overnight at room temperature under N2, then evaporated to dryness and purified by flash column chromatography on silica gel using ethyl acetate a! 20% in hexanes as the eluent to yield the desired compound 22g (R9 = propyl, R9b = H) (176 mg, 86%). MS (SPOS): 320 [M + Na] +. To a solution of ester 22g (R9 = propyl, R9b = H) (75 mg, 0.59 mmol) in dioxane / water (6: 1) (4 mL) was added aqueous lithium hydroxide 1 (0.65 mL, 0.648 mmol). . The resulting reaction 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 dry to yield the desired protected cyclic amino acid 22h (R9 propyl, R9b = H) (175 mg, 105%). MS (ESNEG): 292 [M - H] ".

General method UA a solution of nitrone 23a (prepared as described by Dondoni et al, Synthetic Communications, 1994, (5.96 g, 16.4 mmol, 1 equiv) in Et20 (200 ml), at 23 ° C, was added a solution of Et2AICI (1.0 M in heptane, 16.4 ml, 16.4 mmol, 1 equiv.) The reaction was stirred for 15 min at 23 ° C, then cooled to -78 ° C and treated with a solution of cyclopropylmagnesium bromide (0.5 M in THF, 99 ml, 49 mmol, 3 equiv) added with cannula over the course of 25 min After stirring for another 1.7 h at -78 ° C, the reaction was cooled rapidly to low temperature with aqueous NaOH 1.0 ( 80 mL) The resulting mixture was stirred at 23 ° C for 25 min, then transferred to a separatory funnel and the layers were separated.The organic layer was washed with brine (100 mL, using moderate agitation to avoid formation of a emulsion) The original aqueous layer was extracted with Et20 (3 x 150 ml), washing each extract once with brine (100 ml). i) The combined organic layers were dried (MgSO4), filtered and concentrated to yield 5.89 g (14.5 mmol, 89%) of the desired product 23b (R20 + R2 = cyclopropane) as a white solid. This material was used without further purification. MS (SPOS): 406.0 [M + H] To a solution of hydroxylamine 23b (R20 + R2 = cyclopropane) (5.89 g, 14.5 mmol, 1 equiv) and Et3N (12.2 ml, 87.3 mmol, 6 equiv) in CH2Cl2 (200 mi), at 0 ° C, methanesulfonyl chloride (2.25 ml, 29.1 mmol, 2 equiv) was added. The reaction was stirred for 20 min at 0 ° C, then at 23 ° C for another 25 min, then it was added to aqueous NaOH 1.0: brine (1: 1, 200 ml). The layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 50 mL), then the combined organics were dried (MgSO4), filtered and concentrated. The resulting residue was dissolved in 1: 1 EtOAc: hexane (200 ml) and washed with H20 (150 ml), saturated NaHCO3 (200 ml) and brine (150 ml), dried (MgSO), filtered and concentrated to yield 5.95 g of brown oil of which the main component is the desired one. MS (ESPOS): 388.2 [M + H] To a crude imine solution (5.95 g) in MeOH (150 ml), at 23 ° C, Girard T reagent (2.84 g, 16.9 mmol, 1.1 equiv) was added. . After stirring for 70 min, the solution was concentrated. The residue was partitioned between EtOAc (150 mL) and 1: 1: 1 H20: brine: saturated aqueous NaHCO3 (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organics were dried (MgSO 4), filtered and concentrated to yield 4.70 g of yellow oil of which the main component is the desired amine. MS (SPOS): 300.0 [+ Hf. To a solution of crude amine (4.70 g) and 2,6-lutidine (7.31 ml, 62. 9 mmol, 4 equiv) in CH 2 Cl 2 (200 mL), at 0 ° C, was added trifluoroacetic anhydride (3.28 mL, 23.6 mmol, 1.5 mmol). The reaction was stirred at 0 ° C for 1 h, then at 23 ° C for 3 h, then rapidly quenched with H20 (100 mL). The rapidly cooled reaction mixture was stirred for 10 min, then partitioned between 1: 1 EtOAc: hexanes (300 ml) and brine (200 ml). The layers were separated, the organic layer was washed with 1.0 N HCl (300 ml), Saturated aqueous NaHCO3 (300 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated. The product was purified using flash column chromatography on silica gel, using 25% EtOAc in hexanes as the eluent to provide 4.50 g of the desired trifluoroacetamide 23c (R20 + R21 = cyclopropane) (11.3 mmol, 78% from hydroxylamine) . MS (ESPOS): 418.0 [M + Na] + To a solution of diacetonemide 23c (R20 + R21 = cyclopropane) (4.50 g, 11.3 mmol, 1 equiv), at 23 ° C, was added aqueous TFA (80%, 100 ml, pre-cooled to 0 ° C). The reaction was stirred at 23 ° C for 35 min, then concentrated to provide 3.87 g of white solid of which the main component is the desired protected galactose. MS (RANGE): 338.1 [M + Na] + A solution of crude galactose (3.65 g, 1.6 mmol, 1 equiv) and Et3N (16.1 mL, 116 mmol, 10 equiv) in CH2Cl2 (130 mL), at 23 ° C, AC2O (7.65 mL, 81.1 mmol, 7 equiv) was added with subsequent addition of DMAP (141 mg, 1.2 mmol, 0.1 equiv). The reaction was stirred at 23 ° C for 2 h, then quenched with MeOH (5 mL). The reaction mixture quenched rapidly was stirred for 5 min and then diluted with Et20 (300 mL). The resulting solution was washed with H20 (2 x 300 mL), 1.0 N HCl (300 mL), saturated aqueous NaHCO3 (300 mL) and brine (300 mL), dried (MgSO4), filtered and concentrated to provide 5.07 g of acetylated product as a mixture of alpha / beta and pyranose / furanose isomers. MS (SPOS): 506.1 [M + Na] +. To a solution of isomers of peracetate (5.07 g) in CH 2 Cl 2 (150 ml), at 0 ° C, a solution of HBr in acetic acid (33%, 30 ml) was added. The reaction was stirred at 0 ° C for 30 min and then warmed to 23 ° C. After stirring another 3.5 h, the reaction mixture was diluted with CH2Cl2 (50 mL), washed with ice water (2 x 300 mL), 50% NaHCC > 3 saturated aqueous cooled with ice (2 x 300 ml) and 50% saturated brine cooled with ice (300 ml), dried (MgSO 4), filtered and concentrated to provide 4.33 g of a-bromide 23d (R20 + 21 = cyclopropane) (8.60 mmol, 76% from diacetone). This material was used without further purification. To a solution of bromide 23d (R20 + R21 = cyclopropane) (4.33 g, 8.60 mmol, 1 equiv) in AcOH (100 mL) at 23 ° C was added AgOAc (1.44 g, 8.60 mmol, 1 equiv). After stirring for 45 min at 23 ° C, the reaction mixture was diluted with CH 2 Cl 2 (350 mL) and washed with H 2 O (2 x 400 mL), 50% saturated aqueous ice-cooled NaHCO 3 (3 x 300 mL) and Brine (400 mL), dried (MgSO 4), filtered and concentrated to yield 3.76 g (7.78 mmol, 91%) of the desired 3-acetate as a white foam This material was used without additional MS purification (ESPOS): 506.1 [M + Na] To a solution of β-acetate (3.76 g, 7.78 mmol, 1 equiv) in CH2CI2 (50 mL) at 23 ° C was added PCI5 (1.70, 8.17 mmol, 1.05 equiv) followed by BF3 * OEt2 (50 μ? _). After stirring for 1 h, the reaction was diluted with CH2Cl2 (300 mL) and washed with ice-cooled brine (500 mL), 50% aqueous saturated ice-cold NaHC03 (2 x 500 mL) and ice-cooled brine ( 500 ml), dried (MgSO 4), filtered and concentrated to yield 3.72 g of the desired (3-chloride-23e (R 20 + R 21 = cyclopropane) The product was used without further purification MS (ESNEG): 458.2 [M-H ] To a solution of galactosyl chloride 23e (R20 + R21 = cyclopropane) (3.72 g, 8.10 mmol, 1 equiv) in DMF (30 ml) and HMPA (7.5 ml), at 23 ° C, McSNa (1.70 g) was added. g, 24.3 mmol, 3 equiv.) After stirring for 35 min at 23 ° C, the reaction mixture was partitioned between Et20 (150 mL) and 1: 1 hrO / brine (70 mL). The aqueous layer was re-extracted with Et2.sub.2 (150 mL) The combined organics were dried (MgSO.sub.4), filtered and concentrated, The residue was dissolved in CH.sub.2 Cl.sub.2 (130 mL) and treated with Et3N (1.3 mL, 81.0 mmol, 10 equiv), Ac20 (5.35 ml, 56.7 mmol, 7 equiv) and DMAP (99 mg, 0.81 mmol, 0.1 equiv). After stirring for 1 h at 23 ° C, the reaction was quenched with MeOH (3.0 mL). The reaction mixture quenched rapidly was stirred for 10 min, then it was partitioned between Et20 (200 ml) and H20 (200 ml). The layers were separated, the organic layer was washed with 1.0 M aqueous HCl (200 ml), NaHCC > 3 saturated aqueous (200 ml) and brine (100 ml), dried (MgSO 4), filtered and concentrated. The crude product was purified via flash column chromatography on silica gel using 30% EtOAc in hexane as the eluent to yield 2.03 g (4.30 mmol, 53%) of the desired product 23f (R20 + R21 = cyclopropane, R1 = SMe) as a white solid. 1 H NMR (300 MHz, CDCl 3) (3 6.52 (br d, J = 9.3 Hz, 1 H), 5.65 (d, J = 5.4 Hz, 1 H), 5.56 (dd, J = 0.9, 3.0 Hz, 1 H ), 5.27 (dd, J = 5.4, 11.1 Hz, 1 H), 5.20 (dd, J = 3.0, 10.5 Hz, 1 H), 4.43 (dd, J = 0.9, 7.5 Hz, 1H), 3.66 (q, J = 9.0 Hz, 1 H), 2.15 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 0.94-0.78 (m, 1 H), 0.70-0.61 (m, 1 H), 0.57-0.33 (m, 3H); MS (SPOS): 493.9 [M + Na]; MS (ESNEG): 470.2 [M - H] \ A solution of triacetyl trifluoroacetamide 23f (R20 + R21 =: cyclopropane, R = SMe) (2.03 g, 4.30 mmol, 1 equiv) in MeOH (35 mL), at 23 ° C, 1.0 M aqueous NaOH (43 mL, 43 mmol, 10 equiv) was added. The reaction was stirred for 100 min, then acidified to pH 2 with 1.0 M aqueous HCl (48 mL) The resulting solution was concentrated to dryness in vacuo, then the residue was dissolved / suspended in EtOH (40 mL) and filtered at room temperature. Through a glass frit of medium porosity to remove NaCl, the solid was washed with EtOH (2 x 20 mL). bound with Amberlite IRA400 resin (OH 'form) (60 ml resin bed in MeOH), transferring the resin with MeOH (2 x 20 ml). The resulting mixture was stirred at 23 ° C for 1 h and then filtered. The resin was washed with MeOH (3 x 100 mL) and CH 3 CN (100 mL). The combined filtrate was concentrated to yield 1.04 g of the desired galactoside 23g (R20 + R2 = cyclopropane, R1 = SMe) as a white solid (4.19 mmol, 97%). The product was used without further purification. H NMR (300 MHz, CD3OD) (3 5.28 (d, J = 5.7 Hz, 1 H), 4.13-4.06 (m, 2H), 3.97 (d, J = 6.6 Hz, 1 H), 3.59 (dd, J = 3.3, 9.9 Hz, 1 H), 2.33 (dd, J = 6.9, 9.0 Hz, 1 H), 2.05 (s, 3H), 0.91-0.77 (m, 1 H), 0.58-0.43 (m, 2H) , 0.39-0.31 (m, 1 H), 0.28-0.19 (m, 1 H); MS (SPOS): 272.0 [M + Na]; MS (ESNEG): 248.2 [M-H].

General Method V Following the general method in Scheme 24, to a solution of hydrochloride compound 1 (9.90 mmol, 1 equiv) in THF (70 ml) at 23 ° C was added H2O (70 ml) followed by KHCO3 (12.9). mmol, 1.3 equiv) and subsequent addition of (Boc) 20 (12.9 mmol, 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, washed with brine (150 ml) and dried (MgSO 4). The solvent was removed in vacuo and the crude product was purified using a Biotage® column chromatography system (40 + M cartridge)., 40 mm ID x 150 mm) using a linear gradient (75% EtOAc / hexanes- 00% EtOAc) over 1.2 I of total eluent at 50 ml / min to produce the carbamate 24a (8.91 mmol, 90%). To a solution of carbamate 24a (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 of p-anisaldehyde dimethyl acetal (2.0 ml, 1.7 mmol, 0.74 equiv) was added. After a further 17 h, a third portion of p-anisaldehyde dimethyl acetal (2.0 ml, 11.7 mmol, 0.74 equiv) was added. After the final addition, the reaction was refluxed for 3 h, then cooled to 23 ° C and partitioned between EtOAc (300 mL) and H20 (300 mL). The organic layer was washed with 50% aqueous saturated NaHCO 3 (300 mL) and brine (150 mL), dried (MgSO 4), filtered and concentrated. The crude product was purified via flash column chromatography on silica gel using 40% EtOAc in hexane as the eluent to produce acetal 24b (11.3 mmol, 71%). To a solution of alcohol 24b (4.82 mmol, 1 equiv) in trimethyl phosphate (60 ml), at 0 ° C, pyridine (3.90 ml, 48.2 mmol, 10 equiv) was added, followed by POCI 3 (0.88 ml, 9.65 mmol). , 2 equiv) during the course of 60 sec. In this step, other acylation reagents such as acid anhydrides (R11CO) or acid chlorides R1 COCI can be used in the presence of an appropriate base to provide different acyl substituents R11. After the addition, the reaction was maintained at 0 ° C for 2 h, then triethylammonium bicarbonate buffer (1.0 M, pH 8.5, 40 ml) was carefully added to rapidly quench the reaction. H2O (60 mL) was then added and the resulting mixture was stirred at 0 ° C for 30 min, then heated to 23 ° C. After stirring the cooled reaction mixture for 2 h at 23 ° C, the volatiles were removed in vacuo with the aid of moderate heating in a water tank (40-45 ° C). The resulting crude product was azeotropically dried by co-evaporation with DMF (3 x 100 mL), then with toluene (150 mL, vat temperature = 40-45 ° C) to provide a white solid. The crude product 24c (R11 = PO (OH) 2) was substantially contaminated with triethylammonium salts, but continued without purification. To a solution of the protected phosphate 24c (R11 = PO (OH) 2) prepared as described above (crude from the previous step, about 4.8 mmol) in 1,2-dichloroethane (600 ml), at 0 ° C, added H20 (25 ml) followed by TFA (200 ml). After the additions, the reaction was maintained at 0 ° C for 5 min and then warmed to 23 ° C. After stirring for 25 min at 23 ° C, the volatiles were removed in vacuo to yield 16.2 g of oil. The crude product was dissolved in 1: 1 H20 / MeOH (70 mL), filtered, and the resulting solution was purified by preparative HPLC (Waters Nova-Pak® HR Gis, particle size 6 μ ??, pore size 60 Á, 40 mm ID x 200 mm, 5-60% acetonitrile in H20 0.1% AcOH for 30 min, flow rate 75 ml / min) to produce the desired 2-phosphate 5 (R1 = PO (OH) 2) (3.10 mmol , 64% from free alcohol) as a white solid.

Method W To a solution of β-lactam 25a (2.92 g, 12.8 mmol) 1 equiv; prepared from benzyl (S) - (-) - 4-oxo-2-azetidine carboxylate (Aldrich) as described by Baldwin et al, Tetrahedron, 1990, 46, 4733, in THF (30 ml) at 0 ° C was added a solution of LDA (2.0 M, 14.0 ml, 28.1 mmol, 2.2 equiv) via a syringe pump for 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 over ca. 1.5 min, and the mixture was stirred for 2 h at 0 ° C, and then partitioned between aqueous KHSO41.0 M (100 mL) and EtOAc (100 mL). The organic layer was separated and washed with 1.0 M aqueous KHSO4 (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to yield 25b (R9 '= 2-butenyl) 3.65 g (00 %) of greenish-yellow solid. This material was used without further purification. MS (ESNEG): 282.2 [M-H]. "Trimethylsilyldiazomethane (2.0 M in Et ^ 0, 25. 0 mL, 50 mmol, 3.9 equiv) to a solution of 25b (R9-2-butenyl) acid (3.65 g, 12.9 mmol, 1 equiv) in methanol (70 mL) at 0 ° C. The solvent was removed under vacuum to yield 3.53 g (1 1 .9 mmol, 92%) of the desired ester product as a yellow oil. This material was used in the subsequent reaction without further purification. To a solution of alkene 25c (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 pad of Celite was washed with EtOAc (200 mL) and the filtrate was concentrated to provide 3.51 g (1.7 mmol, 99%) of 25c (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 ß-lactam 25c (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% saturated brine (150 ml) and EtOAc (200 ml). The organic layer was separated and washed with brine (150 ml), dried (MgSO 4), filtered and concentrated. The product was purified via flash column chromatography on silica gel, using 50% EtOAc in hexane as the eluent to yield 1.48 g (8.0 mmol, 68%) of 25d (R9 = butyl) as a clear oil. MS (SPOS): 578.3 [3M + H] +. To a solution of β-lactam 25d (R9 butyl) (2.06 g, 1.1 mmol, 1 equiv) in THF (150 mL), at 23 ° C, a solution of LiAlH4 (1.0 M in THF, 22.9 mL) was added. , 22.9 mmol, 2.06 equiv) via a syringe during 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 refluxed for 3 h. The mixture was then cooled to 0 ° C and cooled rapidly via 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 Et220 (250 mL) and filtered through Celite, washing with Et220 (250 mL). The filtrate was concentrated to provide 1.42 g of the desired product 25e (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 amino alcohol 25e (R9 = butyl) (1.41 g, 9.86 mmol, 1 equiv) in dichloromethane (50 ml), at 23 °, Boc20 (2.59 g, 1.9 mmol, 1.2 equiv) was added. ). After stirring for 2 h at 23 ° C, the reaction mixture was concentrated. The product was purified via flash column chromatography on silica gel using 33% EtOAc in hexane as the eluent to yield 1.53 g (6.31 mmol, 64%) of 25f (R9 = butii) 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 an alcohol solution 25f (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 layer. The aqueous residue was extracted with two additional portions of EtOAc (2 x 150 mL). The combined organic extracts 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 deliver 0.78 g of the desired product 25 g (R 9 = butyl) (3.04 mmol, 74%) as a dark oil. The product was used without further purification. MS (ESPOS): 280.0 [M + Na] +.

Method XA a solution of alcohol 25f (R9 '= 2-methyl-2-butenyl) (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) and brine (200 mL), dried (MgSO4), filtered and concentrated to yield 26a (R9 = 2-methyl-2-butenyl) 4.13 g (11.2 g). mmol, 86%) of the desired product as a clear oil. MS (SPOS): 392.4 [M + Na] +. A solution of intermediate 26a (R9 = 2-methyl-2-butenyl) (2.03 g, 5.50 mmol, 1 equiv) in dichloromethane (80 ml), at -78 ° C, was treated with ozone (1.2 L / min) introduced via a gas dispersion tube until a blue color was observed (20 min). An oxygen stream (1.2 L / min) was then passed through the reaction mixture to discharge the excess ozone. After min, the oxygen flow stopped and PPh3 (2.16 g, 8.25 mmol, 1.5 equiv) was added. The reaction mixture was stirred at -78 ° C for 30 min, then at 0 ° C for min, and then warmed to 23 ° C. After stirring for 10 min at 23 ° C, silica gel was added and the resulting mixture was concentrated to dry in vacuo to yield a free-flowing powder that was directly charged to a column of silica gel. Flash column chromatography, using 30-33% EtOAc in hexane as the eluent, afforded 1.52 g (4.42 mmol, 80%) of aldehyde 26b as a clear oil. MS (ESPOS): 398.0 [+ MeOH + Na] +. To a suspension of cyclopropylmethyltriphenylphosphonium bromide (1.22 g, 3.06 mmol, 1.5 equiv) in THF (10 mL), at 0 ° C, a solution of NaHMDS (1.0 M in THF, 3.06 mL, 3.06 mmol, 1.5 equiv. ) drop by drop via a syringe during the course of 1 min. The resulting solution was stirred for 20 min at 0 ° C, then treated with a solution of aldehyde 26b (700 mg, 2.04 mmol, 1 equiv) in THF (3.0 ml, 2 x 1.0 ml) transferred via a cannula. After min at 0 ° C, the reaction was warmed to 23 ° C, stirred for another 10 min and then quenched with saturated NH 4 Cl (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 hexane as the eluent, afforded 588 mg (1.54 mmol, 76%) of 26c (R9 '= 3-cyclopropyl-prop-3-enyl) as a clear oil. MS (SPOS): 404.3 [M + Na] +. To a solution of alkene 26c (R9 '= 3-cyclopropyl-prop-3-enyl) (191 mg, 0.50 mmol, 1 equiv) in dioxane (5.0 ml), at 23 ° C, potassium azodicarboxylate was added. (973 mg, 5.01 mmol, 10 equiv) followed by slow addition of an AcOH solution (573 μl, 10.0 mmol, 20 equiv) in dioxane (5.0 ml) over the course of 16 h via a syringe pump. After the addition was complete, the reaction was stirred an additional 6 h, then filtered through a glass frit with the aid of Et20 (150 ml) to remove the precipitate. The resulting solution was washed with saturated aqueous NaHCO3 (2 x 100 mL) and brine (80 mL), dried (MgSO4), filtered and concentrated. The above procedure was repeated three times in the raw material obtained to produce the complete conversion of the alkene, yielding 183 mg (0.48 mmol, 96%) of the saturated product 26d (R9 = 3-cyclopropyl-propyl) as a clear oil. MS (SPOS): 406.0 [M + Na. To a solution of ether TBS 26d (R9 '= 3-cyclopropyl-propyl) (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 mmol, 1.1 equiv). The resulting solution was stirred for 40 min at 23 ° C, then partitioned between Et20 (50 μm) and H20 (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO 4), filtered and concentrated to yield 133 mg (0.50 mmol, 100%) of 26e (R 9 = 3-cyclopropyl-propyl) as a clear oil.

MS (SPOS): 290.2 [M + Naf. Oxidation of catalytic ruthenium from 26e to the desired carboxylic acid product 26f (R9 = 3-cyclopropyl-propyl) was carried out as described in the previous examples. MS (NEG): 282 [M-H] ".

Method and Synthesis of racemic 27a (R9 = n-propyl). To a solution of 10b (R9 = n-propyl) (22 g, 0.13 mol) in methanol (30 mL), concentrated HCl (10 mL) was added platinum (IV) oxide (5 g). The reaction mixture was hydrogenated at 3.5153 kgf / cm2 (50 psi) for 16 h, the catalyst was removed by filtration through celite® and the filtrate was evaporated to dryness. The crude pipecolic acid was used without further purification. The crude pipecolic acid residue 19g was dissolved in acetonitrile (200 ml), tetramethiamonium hydroxide "5H20 (33 g) was added and the reaction mixture was stirred for 30 minutes, di-t-butyl pyrocarbonate (39 g) was added. , 0.46 mol) and the reaction mixture was stirred at room temperature for 72 h. Additional tetramethylammonium hydroxide • 5H20 (8 g) and di-t-butyl pyrocarbonate (9 g) were added, and the reaction mixture was stirred for 24 h. The reaction solvent was removed in vacuo and the resulting oil was diluted with water (200 ml) and washed with ether (200 ml). The aqueous portion was acidified to pH 3-4 with solid citric acid and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was removed to give Va (R9 = n-propyl) (19 g, 77%) as a yellow oil which crystallized on standing. 1 H NMR (300 MHz, CD 3 OD) d 4.31 (m, 1), 3.60 (m, 1), 3.33 (m, 1), 2.01 (m, 4), 1.24 (m, 14), 0.89 (t, J = 5.7, 3); MS (ESNEG): 270 [M-1]. "The racemic mixture 27a (R9 = n-propyl) is diluted with acetonitrile (5 volumes) and Sa-methylbenzylamine (0.5 eq), the mixture is heated to reflux and left The mixture is allowed to stand overnight The first crop of salt formed is then filtered and set aside until final recrystallization.The filtering liquors are concentrated in vacuo and then absorbed in DC (4 volumes) the DCM is then washed with 1 M citric acid (2/3 volumes of DCM), the DCM is then separated, dried over magnesium sulfate, filtered and concentrated in vacuo.The free acid enriched with 2R enantiomer, 4S It is then absorbed in 5 volumes of acetonitrile, 0.85 eq of R-methylbenzyl amine is added, the mixture is heated to reflux and allowed to cool with seeding, the mixture is allowed to stand overnight, the salt formed is then filtered and it moves away (the salt ee is in general 85-90%) .The procedure to obtain the second at 2S salt harvest, 4R is identical to that of the previous paragraph, except that the R- -methylbenzylamine is replaced with S-a-methylbenzylamine. The salt of the second crop is formed and then filtered (in general it has an ee of around 80-90%) and it moves away until the final crystallization.

The filtration liquors (2S, 4R, second crop salt formation liquors) are concentrated in vacuo. The salt is broken by the previously described method. In this stage, the impurities have been concentrated to a level such that salt formation is not possible. The free acid is subjected to column chromatography (30% EtOAc / Hexane) and this removes unwanted impurities. The column used a 10: 1 weight ratio of silica to compound. In addition, the compound was absorbed in 3 equivalents (p: p) of silica. The free acid in the column (which is enriched with the 2R, 4S enantiomer) is diluted with acetonitrile (5 volumes) and R-α-methylbenzylamine is added and recrystallization is repeated. The breaking of the salt and the formation of salt 2S, 4R is identical to that previously described. The third salt crop that is usually formed has an ee of 80-90%. The 3 crops of salt of 2S, 4R are combined and diluted with acetonitrile (7 volumes). The mixture is heated to reflux, at which point all the salt is dissolved. The mixture is then allowed to cool to RT and allowed to stand overnight with sowing. The salt that has precipitated from the solution is filtered. The salt shows an ee of about 97%. The procedure is repeated to produce a salt with an ee greater than 99%. The salt is taken up in DCM (4 volumes) and washed twice with 1 M citric acid (approximately 2/3 volume of DCM), dried over magnesium sulfate, filtered and concentrated in vacuo. This procedure produces 77% of the theoretical yield of the 2S, 4R enantiomer as an amber oil 98% ee.

Method Z The following conditions are representative of the general coupling and deprotection scheme represented in the method Z, wherein P1 = H and P2 = t-butyl ester of carboxylic acid (Boc). To a solution of azetidine acid 25f (R9 butyl) (52 mg, 0.20 mmol, 1 equiv), 7-CI MTL 6b (R2 H, R3 = Cl) (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 (88 μ ?, 0.51 mmol, 2.5 equiv) was added. After stirring for 12 h at 23 ° C, the DMF was removed in vacuo, then the residue was partitioned between EtOAc (100 mL) and brine 1: 1: 10% aqueous citric acid (100 mL). The organic layer was separated and washed with 1: 1 brine / saturated aqueous NaHCO 3 (100 mL) and brine (50 mL), dried (MgSO 4), filtered and concentrated to provide 82 mg (0.17 mmol, 84%) of 13a (R2 = H, R3 = Cl, R9 = butyl, P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 0) as a glassy solid which was used without purification in the next step. To a solution of carbamate 13a (R2 = H, R3 = Cl, R9 = butyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 0) (82 mg, 0.17 mmol, 1 equiv) in 1,2-dichloroethane (10 ml), at 23 ° C, H2O (0.40) was added. mi) followed by TFA (4.0 mi). After stirring for 20 min at 23 ° C, toluene (50 ml) was added and the resulting solution was concentrated to dryness. The residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR Co., 6 μpt? Particle size, 60 A pore size, 20 mm ID x 100 mm, 5-60% acetonitrile in H20 with 0.1% HCl over 30 min, 20 ml / min flow) to yield 41 mg of the title compound [2-chloro-1- (3,4,5-trihydroxy-6-rnetylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -arnide of 3-butyl azetidine-2-carboxylic acid as a white solid. 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J = 6.0 Hz, 1 H), 4.64 (d, J = 7.8 Hz, 1 H), 4.63-4.52 (m, 2 H), 4.29 (d, J = 10.2 Hz, 1 H), 4.07 (dd, J = 5.7, 10.2 Hz, 1 H), 4.00 (t, J = 6.6 Hz, 1 H), 3.82 (d, J = 3.3 Hz, H), 3.75 (dd) , J = 8.4, 9.9 Hz, 1 H), 3.56 (dd, J = 3.3, 10.2 Hz, 1 H), 2.92-2.76 (m, 1 H), 2.14 (s, 3H), 1.90-1.67 ( m, 2H), 1.45 (d, J = 6.6 Hz, 3H), 1.44-1.24 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H); S (SPOS): 4 1 .0 [M + H] +.

Method AA To pyridine-2-carboxylic acid 10b (0.5 mmol) in DMF (2 mL) was added lincosamine as defined in general coupling scheme 13 (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 column chromatography on silica gel to obtain the compound 13b.

To a solution of pyridine 13b (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 under 3.5153 kgf. / cm2 (55 psi) of hydrogen overnight, or for a prolonged period at a lower hydrogen pressure. The residual catalyst was removed by filtration through celite, and the solvent was removed to obtain the crude product. Purification was carried out by column chromatography on silica gel, using MeOH in DCM to obtain lincosamide analogs of type 1, as defined in scheme 13. In general, chromatography with silica easily separates the cis-diastereomer 2S of the unwanted isomer. In some cases, the separation of the isomers requires semi-preparative HPLC. A representative set of conditions is as follows: (Waters Nova-Pak® HR C18 column, 6 μ ?? particle size, 60 A pore size, 20 mm ID x 100 mm, 5-60% acetonitrile 0.1% AcOH / H20 0.1% AcOH for 30 min, 20 ml / min flow.

Method AB Synthesis of [2-methyl-1- (3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -carbamic acid tert-butyl ester, 15b step a ( P ^ Boc, P2 = Bn, R2 = Me, R3 = H), (the intermediate is not shown). To a rapidly stirred solution of 2a (P = Boc, R1 = Me, R2 = H) in benzene (40 ml) (2 g, 5.7 mmol) was added 50% aqueous KOH (12.8 ml), tetrabutylammonium bisulfate (0.67 g) and benzyl bromide (6.77 ml, 57.0 mmol), and suspended under a N2 atmosphere with vigorous stirring. After 3.5 h, benzylamine (6.0 ml) was added and the reaction mixture was stirred for an additional 20 ', then toluene (300 ml) was added and the organic layer was washed with H20 (2 x 100 ml), 2M KHS04 (3 ml). x 100 ml), NaHC03 sat. ac. (1 x 100 mL) and brine (1 x 100 mL), dried over MgSO4 and evaporated to dryness. Chromatography of the crude product on silica 10% EtOAc / Hexanes up to 15% EtOAc / Hexanes yielded 15b, step a, tert-butyl ester of tert-butyl ester of 2-methyl-1- (3,4,5-tr! s-Benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylj-carbamic acid as a colorless foam (2.6 g, 72%); S (SPOS): 522.8 [M + H-Boc] +.

Synthesis of tert-butyl ester of r2-methyl-1-y3,4,5-tris-benzyloxy-6-fluoro-tetrahydro-pyran-2-yl) -propyl-1-carbamic acid, 15b Pr = Boc Pg = Bn, R2 = Me, R3 = H), stage b. To a solution cooled to -16 ° C of the above-stated intermediate, tert-butyl ester of 2-methyl-1- (3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) - propyl] -carbamic acid, (1.54 g, 2.5 mmol) in DCM (25 mL) was added DAST (0.599 mL, 4.46 mmol) and suspended under a N2 atmosphere with vigorous shaking. After 5 minutes, solid NBS (0.599 mL, 4.46 mmol) was added over 5 minutes and the reaction mixture was stirred another 45 ', then DCM (300 mL) was added and the organic layer was washed with sat. NaHCO 3. ac. (1 x 100 mL), dried over MgSO4 and evaporated to dryness. Chromatography of the crude product with silica 15% to 30% Et20 / Hexanes, a mixture of tert-butyl ester of [2-methyl-1- (3,4,5-tns-benzyloxy-6-fluoro-tetrahydro- pyran-2-yl) -propyl] -carbamic 1-a and ß fluorinated 15b (P ^ Boc, P2 = Bn, R2 = Me, R3 = H), was isolated as a colorless oil (0.85 g, 58%); TLC (20% Et220 / Hexanes) isomer Rf 1 = 0.2, isomer Rf 1 = 0.05. 19 F NMR (CDCl 3) d isomer 1: -132.78, -132.96, isomer 2: -145.05, -145.13, -145.23, -145.31, HPLC C18 3.5 μ ?, 4.6 x 30 mm Column; gradient eluent 2% -98% McCN for 10 min; 1.5 ml / min): Retention time = 7.93 min, 7.98 min; MS (ESPOS): 494.7 [M + H-Boc] +; MS (ESNEG): 592.7 [MH] Synthesis of 2-Methyl-1- (6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyrn-2-yl) -propylamine, 15c (Pi = H, P2 = Bn, R1 = Allyl, R2 = e, R3 = H). To a solution stirred at -32 ° C of the above-mentioned intermediate 15b (831 g, 2.5 mmol) in DC (30 ml) was added, under N 2, allytrimethylsilane (1.12 ml, 7.0 mmol). After 10 minutes BF3"Et20 (0.36 ml, 2.8 mmol) was added over 2 minutes and the reaction mixture was stirred an additional 1.5 h, then warmed to 0 ° C for 30 minutes. Water (1 ml) and TFA (15 ml) were added to the reaction mixture, the reaction mixture was allowed to warm to RT, stirred 1 h and evaporated to dryness. The residue was dissolved in Et20 (200) mi), washed with K2C03 aq. 1 M (50 ml) and brine, dried over Na 2 SO 4 and evaporated to dryness. The product 15c (Pi = H, P2 = Bn, R1 = Allyl, R2 = Me, R3 = H) was isolated as a colorless oil (0.69 g, 96%); TLC (20% EtOAc / Hexanes) Rf = 0.05; MS (HOOKS): 516.4 [M + H-Boc] +. 2- (1-Amino-2-methyl-propyl) -6-propyl-tetrahydro-pyran-3,4,5-trol. 2-Methyl-1- (6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl) -propylamine, 15c 160 mg and 100 mg degussa 50% w / w palladium wet at 10 were suspended. % on carbon under N2 in THF (5 ml) and HCI ac 1 M (1 ml). The reaction mixture was stirred 24 h under H2 at 1 atm pressure. The reaction mixture was filtered through Celite and evaporated to dryness to provide the product 2- (1-amino-2-methyl-propyl) -6-propyl-tetrahydro-pyran-3,4,5-triol (60.8 g. 89% mg) as the HCI salt. TLC (CHCl3: MeOH: 32% AcOH aq.) Rf = 0.35. MS (SPOS): 248 [M + H] + Method AC In general, the purification and final separation of diastereoisomers of the compounds detailed in the following examples can be achieved by semi-preparative HPLC. The final products were purified in a Waters Prep LC 4000® system equipped with an absorbance detector set? dual Waters 2487® up to 214 nm and a light scattering detector S.E.D.E.R.E Sedex 55® evaporative in series. The general conditions used for the separation of diastereomers are as follows (Waters Nova-Pak® HR C-is column, 6 μ ?? particle size, 60 Á pore size, 20 mm ID x 100 mm, 5-60% acetonitrile 0.1% AcOH / H20 0.1% AcOH for 30 min, 20 ml / min flow The collected fractions are combined and lyophilized until dry.

EXAMPLES The following examples were prepared according to the aforementioned methods.

EXAMPLE 1 4- (3,3-difluoro-allyl) -pyrrolidine-2-f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide carboxylic f2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-α-propyl-amide of 4- (3, 3-difluoro-allyl) -pyrrolidine-2-carboxylic acid. To a solution of 2b (R2 '= H) (45 mq 0.18 mmol, 1 equiv) in dry DMF (0.5 ml), at 0 ° C, triethylamine (79.4 μ ?, 0.57 mmol, 3.2 equiv) was added. followed by bis- (trimethylsilyltrifluoroacetamide (71.2 uL, 0.27 mmol, 1.5 equiv.) The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes.The reaction mixture was added to the protected amino acid 8c (R -3,3-difluoroalyl) prepared with the general method M (56 mg, 0.19 mmol, 1.1 equiv) in a 25 ml round bottom flask, with subsequent addition of solid HATU (91.2 mg, 0.24 mmol, 1.3 equiv) The reaction mixture was stirred at RT for 3 h.The reaction mixture was evaporated to dryness, taken up in ethyl acetate (60 ml), washed with 10% citric acid (2 x 40 ml). water (40 ml) NaHCOa aq sat (40 ml brine) The organic layer was dried over NaSQ 4, evaporated to a yellow syrup, and a solution of the crude coupling product in DCM (9 ml) with methylsulfide (0.2 ml). mi) were added trifluoroacetic acid (3 mL) and water (0.2 mL) .The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by chromatography to provide the title compound [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-J-4-yl-amide. (3,3-difluoroalyl) -pyrrolidine-2-carboxylic acid (55.6 mg, 73%) as a white solid: HRN (300 MHz, CDCl 3) 8 7.93 (br s, 1), 5.30 (d, J = 4.8, 1 ), 4.20-4.05 (m, 2), 3.96-3.77 (m, 3), 3.71-3.52 (m, 2), 3.19-3.07 (m, 1), 2.78-2.63 (m, 1), 2.38-2.21 (m, 1), 2.13 (s, 3), 2.20-1.97 (m, 4), 1.94-1.80 (m, 1), 0.92-0.84 (m, 6); MS (SPOS): 425.5 [M + Hf; MS (ESNEG): 423.5 [M - G.

EXAMPLE 2 4- (3-Pyridin-4-yl-allyl) -pyrrolidine-2-carboxylic acid f2-methyl-1-OAS-trihydroxy-e-methylsulfanyl-tetrahydro-pyran ^ -iD-propyl] -amide The title compound of Example 2, [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4 - (3-pyridin-4-yl-ally) -pyrrolidine-2-carboxylic acid was prepared according to the procedures described in the Example and in General Method M, using the ylide derivative of triphenyl chloride ( 4-pyridylmethyl) phosphono in the step of olefination of wittig shown in Scheme 8. HPLC: column C-is 3.5 μ, 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 10 min; 1.5 ml / min): Rt = 2.99 min; MS (ESPOS): 466.4 [M + H] +, MS (ESNEG): 464.2 [M-H] ", 500.3 [M + HCl] \ EXAMPLE 3 4- (3-pyridin-4-yl-propyl) r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide of 4- (3-pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid The title compound of Example 3, 4- (3- (3-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide) pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid, was prepared according to the general method M, using the triphenyl (4-pyridylmethyl) phosphono chloride-derived ylide in the wittig olefination step depicted in Scheme 8, with subsequent reductive deprotection to the protected amino acid 8b (R9 = 3-pyridin-4-yl-propyl) , R2 = H). The deprotection and coupling procedures described in Example 1 provided the desired final product. HPLC: 3.5 μ C column, 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 10 min; 1.5 ml / min): Rt = 2.99 min; MS (ESPOS): 466.4 [M + H] +; MS (ESNEG): 468.3 [M- G, 502.4 [M + HCl] \ EXAMPLE 4 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide N-Cbz- (2S), (4S) - (n-butylsulfanyl) proline 9d (P = Cbz, m = 1, R9 = n-butylsulfanyl). The intermediate was prepared as described in the general method N. To a stirred solution of intermediate 9b (P = Cbz, m = 1, LG = Ts) (1.34 g, 3.08 mmol) in DMF (10 ml), under N2, 1-butantiol (0.7 ml, 6.16 mmol, 2 equiv) was added, followed by 7-methyl-1, 5,7-triazabicyclo [4.4.0] dec-5-ene (0.7 ml, 4.87 mmol, 1.6 equiv). After the addition, the resulting mixture was stirred at room temperature for 18 h and then partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over Na 2 SO 4, filtered and evaporated to dryness. The obtained crude residue was chromatographed on silica 3: 1 hexanes / EtOAc to yield the methyl ester 9c (P = Cbz, m = 1, R9 = n-butylthio) (470 mg, 44%). The methyl ester 9c was treated with lithium hydroxide (132.7 mg, 3.16 mmol, 2.4 equiv) in 4: 1 THF / H20, overnight. The pH of the reaction solution was adjusted to 3, with 1 M HCl aq. and extracted with EtOAc (3 x 100 ml). The combined organic phase was dried over Na 2 SO 4, filtered and evaporated to dry to give the product 9d N-Cbz- (2S), (4S) - (n-butylthio) proline (463 mg, quant). To a suspension of MTL 1 a (140 mg, 0.56 mmol, 1 equiv) in anhydrous DMF (2 ml), at 0 ° C under N2, triethylamine (0.3 ml, 2.2 mmol, 3.9 equiv) was added, followed by BSTFA (0.3 ml, 1.1 mmol, 2 equiv). The resulting mixture was stirred at 0 ° C for 10 min, then at room temperature for 30 min and cooled to 0 ° C. A solution of amino acid N-Cbz- (2S) protected, (4S) - (n-butylthio) proline (2 mg, 0.64 mmol, 1.2 equiv) in anhydrous DMF (1 ml), with subsequent addition of solid HATU (320 mg, 0.84 mmol , 1.5 equiv), the cold bath was removed and stirred at room temperature for 2 h. After evaporation of the reaction mixture under high vacuum, the obtained residue was diluted with ethyl acetate (150 ml), washed sequentially with 0% citric acid (2 x 50 ml), sat. NaHCO 3. ac. 0.5 M (2 x 50 mL) and brine (50 mL), dried over Na 2 SO 4, filtered and evaporated to dryness. The per-silílate intermediate obtained was treated with the resin in the form Dowex® 50w-400x H + (Aldrich) (200 mg) in MeOH (60 ml) for 45 min, filtered, evaporated to dryness and chromatographed on silica (92). 8 DCM / methanol) to provide the protected lincosamide with desired Cbz (185 mg, 61%). To a stirred suspension of 10% palladium on carbon (200 mg), in anhydrous EtOH (6 ml), under nitrogen, was added 1,4-cyclohexadiene (2 ml).; after 10 min, a solution of the aforementioned Cbz-protected lincosamide (178 mg, 0.33 mmol) in EtOH (6 mL) was added. The resulting mixture was stirred and heated to reflux overnight. After cooling, the reaction mixture was filtered through a pad of celite, washed with ethanol, and the filtrate and washings were evaporated to dryness. The obtained crude residue was chromatographed with silica (90: 9: 1 DCM / MeOH / conc. Ammonium hydroxide) to provide the title compound, which was absorbed in 1: 1 acetonitrile / water (4 ml), acidified (pH 4) with 1 M HCl and freeze-dried to provide the HCl salt (35 mg) as a colorless powder: MS (ESPOS): 439.3 [M + H] +, 461.2 [M + Naf.

EXAMPLE 5 f2-Hydroxy-1- (4-ethylsulfanyl-pyrrolidine-2-carboxylic acid (3-ethylsulfanyl) -3- (3-hydroxy-6-methylsulfanyl-tetrahydro-yran-2-yl) -propyl-2-yl-amide The title compound of Example 5 was prepared according to General Method N, using sodium ethantiolate, in the displacement step of Scheme 9. The coupling and deprotection procedures described in Example 4 produced the desired final product. MS (SPOS): 4 2.6 [M + H] +.

EXAMPLE 6 f2-Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-ethylsulfanyl-pyrrolidine-2-carboxylic acid The title compound of example 6 was prepared according to the general method N, using triphenylphosphonium bromide to install a leaving group 4- (S) bromide in 9b (P = Cbz, m = 1, LG = Br), then ethanothiolate was used of sodium in the displacement step depicted in Scheme 9. The stocking and deprotection procedures described in Example 4 provided the desired final product: MS (ESPOS): 411.6 [M] +.

EXAMPLE 7 r 2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid compound of the title of Example 7 was prepared according to the general method N, using triphenylphosphonium bromide to install a leaving group 4- (S) bromide in 9b (P = Cbz, m = 1, LG = Br), then ethanethiolate was used. sodium in the displacement step depicted in Scheme 9. The coupling and deprotection procedures described in Example 4 provided the desired final product: MS (ESPOS): 429.1 [M + H] +; MS (ESNEG): 427.6 [M-H] ", 463.6 [M + HCl] \ EXAMPLE 8 f2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-propyl-4-ethylsulfanyl-pyrrolidine-2-carboxylic acid) The title compound of Example 8 was prepared according to the general method N, then sodium ethanethiolate was used in the displacement step depicted in Scheme 9. The coupling and deprotection procedures described in Example 4 provided the desired final product . MS (SPOS): 429.1 [M + Hf.

EXAMPLE 9 4- 4-Methyl-benzylsulfanyl-pyrrolidine-2-carboxylic acid 2-4-hydroxy-1- (3,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-amide To a solution of the tosylate intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = 0Ac), prepared by the general method R, scheme 14 (73.2 mg, 92 μ ??) in dry DMF ( 300 μ?) Under N2 was added 4-methylbenzylthiol (Lancaster) (63.5 μ ?, 0.46 mmol), followed by MTBU (33.61 μ ?, 0.23 mmol). The reaction mixture was stirred at RT for 6 h. The reaction mixture was taken up in MeOH (1.5 ml), 0.5 M NaOMe in MeOH (920 μ ?, 9.2 mmol) was added and the reaction mixture was stirred at room temperature for 18 h, then Dowex resin bed was added. ® (3.3 ml in water). The resin was washed with methanol (5 x 10 mL), water (1 x 10 mL) and acetonitrile (2 x 10 mL), the product was eluted by washing with 5% NH OH conc. in MeOH (5 x 10 ml) and MeCN (1 x 10 ml). Evaporation of the combined washings and preparative TLC (95: 5 MeOH: 0.25M NH3 / DCM) provided the compound of! title (25.0 mg, 56%) as a colorless solid: MS (ESPOS): 487.3 [M + H] +; HPLC: 3.5 μ C18, column 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 5 min: Rt = 1.91 min.

EXAMPLE 10 4- (4-Fluoro-phenylsulfanyl) -pyridine-2-carboxylic acid f2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl tetrahydro-pyran-2-yl) -propyl amide The title compound of Example 10 was prepared by the procedure used in Example 9 from the tosylate intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) prepared in the general method R, scheme 14 4-Fluorothiophenol (Aldrich) was the nucleophile used in the displacement stage: MS (SPOS): 477.3 [M + H] +.

EXAMPLE 11 4- (3,3,3-Trifluoro-propylsulfanyl) 4- (3,3,3-trifluoro-propylsulfanyl) 4- (3,3,3-trifluoro-propylsulfanyl) - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide -pyrrolidine-2-carboxylic acid The title compound of Example 1 1 was prepared by the procedure used in Example 9 from the tosylate intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) prepared by the general method R, scheme 14. 1, 1, 1 -trifluoropropantiol (Aidrich) was the nucieophile used in the displacement stage. (300 MHz, CDCI3) d 5.32 (d, J = 5.8, 1), 4.43 (dd, J = 8.2, 8.2 1), 4.36-4.31 (m, 1), 4. 9-4.04 (m, 3), 3.90-3.88 (m, 1), 3.78-3.55 (m, 3), 3.37-3.31 (m, 1), 2.96-2.82 (m, 3), 2.61-2.49 (m, 2), 2.12 (s, 3 ), 2.07-2.01 (m, 2), 1 .14 (d, J = 6.6, 3); (19F CDCl3) d 68.8 t; MS (ESPOS): 479.2 [M + H] +, 963.3 [2M + H] +.

EXAMPLE 12 4- (3-Methyl-butyl-sulfanyl) -pyrrolidine-2-f-2-hydroxy-1-Q 4,6-trihydroxy-e-methylsulfanyl-tetrahydro-pyran ^ -iD-propylamide carboxylic The title compound of Example 12 was prepared by the procedure used in Example 9, from the tosylate intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) prepared by the general method R, scheme 14. 3-methylbutantiol (Aldrich) was the nucleophile used in the displacement stage. MS (ESPOS): 453.3 [M + H] +; HPLC: column C18 3.5 μG ?, 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 10 min: Rt = 3.90 min.

EXAMPLE 13 4- (2,4-Dichloro-benzylsulfanin-pyrrolidine-2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl) -tetrahydro-pyran-2-yl) -propyl-1-amide carboxylic The title compound of Example 13 was prepared by the procedure used in Example 9 from the tosylate intermediate 14b R3 = OAc) prepared in the general method R, scheme 14. 2,4-dichlorobenzyl, thiol (Maybridge) was the nucleophile used in the displacement stage: MS (SPOS): 541.2 [M] +; HPLC: column C183.5 μ, 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 10 min: Rt = 4.83 min.

EXAMPLE 14 4- (Thiophene-2-ylmethylisulfanyl) -pyrrolidine-2-carboxylic acid r2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2Hl) -propNamide The title compound of Example 14 was prepared by the procedure used in Example 9 from the tosylate intermediate 14b (P = CF3CO, m = 1,? ¾ = ?, R3 = OAc) prepared in the general method R, scheme 14. Tiofen-2-yl methyntiol (Aldrich) was the nucleophile used in the displacement step: MS (ESPOS): 479.2 [M + H] +; HPLC: column C 8 3.5 μ ??, 4.6 × 30 mm; gradient eluent 2% -98% MeCN for 10 min: Rt = 3.656 min.

EXAMPLE 15 4- (Pyrazin-2-methylmethylsulfanyl) -pyrrolidine-2-carboxylic acid (2-hydroxy-1- (314,5-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide) The title compound of the example was prepared by the procedure used in Example 9 from the tosylate intermediate 14b (P = CF3CO, m = 1, R2 = H, R3 = OAc) prepared in the general method R, scheme 14. 2-Mercaptomethyl pyrazine (Pyrazine Specialties Inc.) was the nucleophile used in the displacement stage. Purification of the title compound of the example was carried out by preparative TLC (16% methanolic ammonia / dichloromethane) which gave the product (9 mg, 15%) [2-hydroxy-1- (3,4,5-trihydroxy 4- (Pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. MS (ESPOS): 475.5 [M + H] +; 497.4 [M + Na] *.

EXAMPLE 18 4- (2,4-dichloro-benzylsulfanyl) -p 2- (2,4-dichloro-benzylsulfanyl) -p 2-methyl-1- (3,4,5- [1-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide } rroiidine-2-carboxanic To a solution of 2b (R2 '= H) (100 mg, 0.40 mmol, 1 equ in dry DMF (1 mL), at 0 ° C, triethylamine (0.18 mL, 1.27 mmol, 3.2 equiv) was added, with subsequent addition of Bis (trimethylsilyl) trifluoroacetamide (0.16 ml, 0.60 mmol, 1.5 equiv.) The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. amino acid protected with Boc 9d (P = Boc, m = 1, R9 = 2,4-dichlorobenzylsulfide) prepared in the general method N (263 mg, 0.65 mmol, .63 equiv), HATU (302 mg, 0.80 mmol, 2 equiv The reaction mixture was stirred at RT for 3 h.The reaction mixture was evaporated to dryness, taken up in ethyl acetate (150 ml), washed with 10% citric acid (2 x 80 ml), water (80 ml), partially saturated NaHCO 3 (80 ml) and brine The organic layer was dried over Na 2 SO 4 and evaporated to yield the desired Boc-protected lincosamide as a yellow syrup.

To a solution of the Boc-protected lincosamide in DCM (15 ml) with metiisulfide (0.33 ml) were added trifluoroacetic acid (5 ml) and water (0.33 ml). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by chromatography to provide a white solid (61 mg). The white solid was purified by preparative thin-layer chromatography to yield [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-acid. (2,4-dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid (47.5 mg, 22%) as a white solid: 1 H NMR (300 Hz, CDCl 3) d 7.84 (br s, 1), 7.39-7.19 (m, 3), 5.31 (d, J = 5.1, 1), 4.09 (dd, J = 5.4, 9.9, 1), 3.94-3.76 (m, 4), 3.81 (s, 2), 3.57-3.48 (m, 1), 3.40- 3.32 (m, 1), 3.22-3.14 (m, 1), 2.88-2.79 (m, 1), 2.64-2.54 (m, 1), 2.33-2.22 (m, 1), 2.14 (s, 3), 1.93-1.85 (m, 1), 0.92-0.85 (m, 6). MS (SPOS): 539.4 [M + H] +.

EXAMPLE 17 4-buylsulfanyl-pyrroiidine-2-carboxylic acid f2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide 9c (P = Boc, m = 1, R9 = n-butylsulfide). To a tosylate solution 9b (P = Boc, m = 1), prepared in general method N (1.61 g, 4.03 mmol, 1 equiv) in dry DMF (12 ml) under N2, n-butyl thiol (1.30 ml) was added. , 12.1 mmol, 3 equiv), with subsequent addition of 7-methyl-1, 5,7-triazabicyclo- [4.4.0] dec-5-ene (MTBU) (0.87 mL, 6.05 mmol, 1.5 equiv). The reaction mixture was stirred at RT overnight and concentrated to dryness. The residue was taken up in ethyl acetate (100 ml), washed with 10% citric acid (50 ml) and brine, and concentrated. The residue was purified by chromatography to provide a clear oil (1.24 g, 97%): 1 H NMR (300 MHz, CDCl 3) d 4.30 (t, J = 8.0, 0.36), 4.23 (t, J = 8.1, 0.64), 4.00-3.94 (m, 0.64), 3.87-3.82 (m, 0.36), 3.72 (s, 1.1), 3.71 (s, 1.9), 3. 29-3, (m, 2), 2.64-2.49 (m, 3), 1.97-1.84 (m, 1), 1 .60-1.32 (m, 4), 1.44 (s, 3.2), 1.38 (s, 5.8), 0.93-0.86 (m, 3). 9c (P = Boc, m = 1, R9 = n-butylsulfide). To a solution of methyl ester 9c (1.24 g, 3.91 mmol, 1 equiv) in THF (15 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.82 g, 19.55 mmol, 5 equiv). The reaction mixture was stirred at RT overnight. The THF was removed under vacuum. The residue was partitioned between ethyl acetate (200 ml) and 10% citric acid (100 ml). The organic layer was washed with water (1 x), brine (1 x), dried over Na 2 SO 4 and evaporated to yield a clear oil 9c (P = Boc, m = 1, R 9 = n-butyl) (1.21 g, 100%): MS (ESPOS): 204.4 [M-Boc + H] +, 326.4 [M + Naf; MS (ESNEG): 302.3 [M - H] +. 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -pro-p-1] -amide. . To a solution of 2b (R2 '= H) (75 mg, 0.30 mmol, 1 equiv) in dry DMF (0.8 ml), at 0 ° C, triethylamine (0.13 ml, 0.96 mmol, 3.2 equiv) was added, followed by by the addition of bis- (trimethylsilyl) trifluoroacetamide (0.12 ml, 0.45 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. To the reaction mixture was added amino acid protected with Boc 9c (P = Boc, m = 1, R9 = n-Butylsulfide) (147 mg, 0.49 mmol, 1.63 equiv) and HATU (227 mg, 0.60 mmol, 2 equiv) . The reaction mixture was stirred at RT 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), partially saturated NaHCO 3 (60 ml) and brine. . The organic layer was dried over Na 2 SO 4 and evaporated to a yellow syrup.

To a solution of the aforementioned syrup in DCM (15 mL) with methylsulfide (0.33 mL) was added trifluoroacetic acid (5 mL) and water (0.33 mL). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by chromatography to provide a white solid4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (95 mg, 73 %): 1 H NMR (300 MHz, CD30D) d 5.24 (d, J = 6.0, 1), 4.14-4.02 (m, 3), 3.94 (dd, J = 7.1, 8.9, 1), 3.82 (d, J = 3.3, 1), 3.51 (dd, J = 3.3, 10.2, 1), 3.45-3.32 (m, 2), 2.93 (dd, J = 6.4, 10.6, 1), 2.71-2.55 (m, 3), 2.23-2.13 (m, 1), 2.10 (s, 3), 1 .83-1.72 (m, 1), 1 .63-1 .52 (m, 2), 1 .48-1.38 (m, 2) , 0.97-0.88 (m, 9). MS (SPOS): 437.5 [M + Hf.

EXAMPLE 18 r 2 -hydroxy-1- (3,4,5-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -prop-amide of 4-azido-pyrrolidine-2-carboxylic acid Methyl ester of N-Boc- (2S, 4R) -4-methanesulfonylproline 9b (P = Boc m = 1, LG = Ms). To N-Boc- (2S, 4R) -4-hydroxyproline (Bachem) 9a methyl ester (P = Boc, m = 1), general method N (1 g, 4.0 mmol) in DCM (10 mL), was added pyridine (1.64 ml, 20.0 mmol) and methanesulfonyl chloride (0.631 ml, 5.52 mmol), was allowed to stir for 2 hours at 0 ° C and was further stirred at room temperature overnight. More DCM (100 mL) was added, washed with HCl (1 N, 50 mL) and the organic portion was dried over magnesium sulfate. The mesylate product was obtained after solvent removal (1 .30 g, 100%) and was used without further purification.

Methyl ester of N-Boc- (2S, 4S) -4-azidoproline 9c (P = Boc, m = 1.

R9 = azide). Methyl ester of N-Boc- (2S, 4R) -4-methanesulfonioline was absorbed in DMF (10 mL) to which was added sodium azide (1.30 g, 20.0 mmol) and was heated at 75-80 ° C overnight. . The DMF was removed and the product was extracted with ethyl acetate (100 ml) and washed with water (50 ml). The product of azide 9c (P = Boc, m = 1, R9 = azide) (0.98 g, 90%) was obtained after removal of the solvent. 9d (P Boc, m = 1, R9 = azide). A stirred solution of 9c (P = Boc, m = 1, R9 = azide) in THF (10 mL) was treated with lithium hydroxide (300 mg, 7.14 mmol) in water (0.5 mL) overnight. The excess solvent was removed by rotary evaporation and the residue was extracted with ethyl acetate and discarded. The aqueous portion was acidified, extracted with ethyl acetate and dried over magnesium sulfate. Removal of the solvent produced NBoc- (2S, 4S) -4-azidoproline of protected amino acid 9d (P = Boc, m = 1, R9 = azide) (0.8 g, 88%): 1 H NMR (300, MHz, CD3OD) d 4.34-4.24 (m, 2), 3.73-3.64 (m, 1), 3.39-3.34 (m, 1), 2.61-2.51 (m, 1), 2.16-2.09 (m, 1), 1.46 (s, 3), 1.42 (s, 6); MS (ESNEG): 255 (M-1). 1- (2- (S) -4- (S) - (Azide) -N-pyrrolidin-2-y1- (1 - (R) -r2- (S) .3- (S), 4 - (S, 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl1-2-hydroxy-prop-1-yl.} Acetamide A 2b (R9 '= H ) (200 mg, 0.788 mmol) in DMF (5 mL) at 0 ° C, triethylamine (0.164 mL, 1.18 mmol) and bis (trimethylsilyl) trifluoroacetamide (0.93 mL, 3.94 mmol) were added and then The mixture was allowed to stir at room temperature overnight, then N-Boc- (2S, 4S) -4-azidoproline (300 mg, 1.18 mmol) and HATU (444 mg, 1.18 mmol) were added at 0 ° C and allowed to stand still. After stirring for four hours, the DMF was removed and the residue was taken up in ethyl acetate (100 ml) and washed with citric acid (10%, 30 ml), saturated sodium bicarbonate (30 ml) and brine (30 ml). After drying the organic portion with sodium sulfate, the solvent was removed to obtain the crude product, which was brought as such to the next deprotection step, and trifluoroacetic acid was added to the crude product in dichloroethane. at 30% (10 mL) and dimethylsulfide (0.5 mL), and the reaction mixture was stirred for one hour. The solvent was removed and the obtained crude product was column chromatographed on silica gel, using 20% methanol in DCM to obtain the title compound as a white solid (278 mg, 90%) TLC: Rf = 0.3-8 (40 % methanol in DCM); 1 H NMR (300 MHz, CD 3 OD) d 4.24 (d, J = 5.4, 1), 4.16 (s, 1), 4.03-4.13 (m, 3), 3.95 (d, J = 3.6, 1), 3.80 (dd , J = 4.5, 9.9, 1), 3.31-3.56 (dd, J = 3.3, 10.2, 1), 3.13-3.22 (m, 1), 2.95-3.00 (m, 1), 2.35-2.45 (m, 1 ), 2.08 (s, 3), 1.93-2.04 (m, 1), 1.29 (t, J = 7.2.1), 0.97 (m, 3); MS (SPOS): 392 [+ H] +.

EXAMPLE 19 f2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -pro-pill-amide of 4-r3- (furan-2-ylmethylsulfanin-prop -1-in-piperidine-2 4- (3-Hydroxy-propyl) -2-r2-methyl-1- (S ^^ - trihydroxy-S-methylsulfanyl-tetrahydro-pyran ^ -in-propylcarbamoyl-piperidine-carboxylic acid tert -butyl ester. a mixture of 2b (R2-H) (532 mg, 1.85 mmol, 1 equiv) in dry DMF (4.5 ml)at 0 ° C, triethylamine (1.28 ml, 9.25 mmol, 5 equiv) was added, followed by the addition of Bis- (trimethylsilyl) trifluoroacetamide (0.74 ml, 2.78 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. To the reaction mixture was added amino acid protected with Boc 11f (R9, = 3-t-butyldimethyl-propyloxypropyl, P = Boc) prepared in the general method P (741 mg, 1.85 mmol, 1.0 equiv) and HATU (886 mg, 2.33 mmol, 1.26 equiv). The reaction mixture was stirred at RT for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 0% citric acid (1x), water (1x), NaHCC >3 sat (1 x) and brine. The organic layer was dried over Na 2 SO 4 and concentrated to yield a yellow syrup. The residue was taken up in methanol (20 ml) and then Dowex® resin (340 mg) was added. The mixture was stirred at RT for 1 h and the resin was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography to obtain the product 4- (3-hydroxy-propyl) -2- [2-methyl-1- (3,4,5-trihydroxy) tert -butyl ester. -6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid (694 mg, 72%) as a white solid: 1 H NMR (300 MHz, CDCl 3) d 5.33-5.28 (m, 1 ), 4.16-3.97 (m, 3), 3.89-3.69 (m, 3), 3.65-3.58 (m, 2), 3.56-3.47 (m, 1), 3.17-3.06 (m, 1), 2.33-2.23 (m, 1), 2.14 (s, 1.5), 2.13 (s, 1.5), 1.94-1.80 (m, 2), 1.67-1.50 (m, 5), 1.45 (s, 9), 1.42-1 .23 (m, 2), 0.93-0.82 (m, 6). MS (SPOS): 521.7 [M + Hf. 2-R 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoin-4- [3- (toluene-4-) tert-butyl ester sulphonyloxy) - propyn-piperidine-1-carboxylic acid To a solution of 4- (3-hydroxy-propyl) -2- [2-methyl-1- (3,4,5-trihydroxyl) tert-butyl ester ^ carbamoyl] -piperidine-1-carboxylic acid (196 mg, 0.38 mmol, 1 equiv) and p-toluenesulfonic anhydride (123 mg, 0.38 mmol, 1 equiv) in DCM (1.5 ml), at 0 ° C, was added drop dropwise triethylamine (63 μl, 0.45 mmol, 1.2 equiv) The reaction mixture was stirred at 0 ° C for 5 hours and then diluted with ethyl acetate.The organic layer was washed with sat'd sodium bicarbonate and brine. , dried and concentrated to provide a white solid which was purified by chromatography to yield 11 h (147.5 mg, 58%) as a white solid; 1 HN (300 Hz, CDCl 3) d 7.78-7.74 (m, 2) , 7.35-7.31 (m, 2), 5.30 (d, J = 5.7, 1), 4.13-4.06 (m, 1), 4.03-3.93 (m, 3), 3.91-3.60 (m, 4), 3.54- 3.45 (m, 1), 3.12-3 .02 (m, 1), 2.43 (s, 3), 2.32-2.21 (m, 1), 2.121 (s, 1.7), 2.117 (s, 1.3), 1.83-1.73 (m, 2), 1.65 -1 .59 (m, 4), 1.45 (s, 5), 1.44 (s, 4), 1.37-1.15 (m, 3), 0.93-0.81 (m, 6); MS (SPOS): 675.9 [M + H] +. 4- [3- (furan-2-ylmethylsulfani0-propyn-2-r2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-tert -butyl ester. -yl) -propylcarbamoyl-piperidine-1-carboxylic acid To a solution of tosylate protected with 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-) tert -butyl ester. tetrahydro-pyran-2-yl) -propylcarbamoyl] -4- [3- (toluene-4-sulfonyloxy) -propyl] -piperidine-1-carboxylic acid (91 mg, 0.13 mmol, 1 equiv) in dry DMF (0.42 ml) under N2 was added furfuryl mercaptan (68 μ! _, 0.67 mmol, 5 equiv), followed by the addition of 7-methyl-1, 5,7-triazabicyclo- [4.4.0] dec-5-ene (MTBU) (48 μ ?, 0.33 mmol, 2.5 equiv) The reaction mixture was stirred at RT overnight and was diluted with DCM, washed with brine (3 x), dried and concentrated. Preparative TLC (8% eOH / DC) to provide the protected thioether with 4- [3- (furan-2-ylmethylsulfanyl) -propyl] -2- [2-methyl-1 - ( 3,4,5-trihydroxy-6-methylsu L-phenyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -pperidine-1-carboxylic acid (63.3 mg, 76%) as a clear syrup: MS (ESPOS): 617.9 [M + H ] +. To a thioether solution protected with 4- [3- (furan-2-ylmethylsulfanyl) -propyl] -2- [2-methyl-1- (3,4,5-trihydroxy-6-tert -butyl ester. -methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid in DCM (9 ml) with methyl sulfide (0.2 ml) were added trifluoroacetic acid (3 ml) and water (0.2 ml). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by preparative TLC to provide the product of lincosamide of the title of Example 19 (13 mg, 25%) as a white solid; H NMR (300 Hz, CD3OD) d 7.39 (dd, J = 0.8, 2.0, 1), 6.32 (dd, J = 2.1, 3.3, 1), 6.18 (dd, J = 0.8, 3.2, 1), 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 = 3.3, 1), 3.71 (s, 2), 3.50 (dd, J = 3.3, 10. 2, 1), 3.43 (dd, J = 2.9, 1 1.9, 1), 3.24-3.17 (m, 1), 2.78-2.67 (m, 1), 2.49 (t, J = 7.1, 2), 2.20- 2.11 (m, 1), 2.10 (s, 3), 2.06-1.93 (m, 1), 1.78-1.70 (m, 1), 1.62- 1.52 (m, 3), 1.38-1.29, (m, 2) , 1.20-1.06 (m, 2), 0.91 (d, J = 7.2, 6); MS (SPOS): 517.8 [? +? EXAMPLE 20 4- (3-imidazol-1-yl-prop-1 - 4- (3-imidazol-1-yl-prop-1-) - (3,4,5-trihydroxy-6-rriethylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide il) -piperidine-2-carboxylic acid 4- (3-imidazol-1-yl-prop-1-yl) -2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-) tert-butyl ester 2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid. To a mixture of NaH (60%, 1.9 mg, 0.30 mmol, 2 equiv) in dry DMF (0.2 ml), at 0 ° C, was added a solution of imidazoi (40.4 mg, 0.60 mmol, 4 equiv) in DMF (0.25 ml) drop by drop. The mixture was stirred at 0 ° C for 10 min, then cooled to -78 ° C. To the mixture was added a solution of the Boc-protected tosylate prepared in Example 19 (100 mg, 0, mmol, 1 equiv) in dry DMF (0.4 ml) dropwise. The mixture was stirred at 0 ° C for 2 h, then at RT overnight. The reaction mixture was diluted with DCM, washed with brine (3 x), dried and concentrated. The residue was purified by chromatography to provide the Boc-protected imidazoi compound of the title (60 mg, 71%) as a white solid. MS (SPOS): 571.8 [M + Hf.

To a solution of the previously mentioned Boc imidazole in DCM (9 ml) with methyl sulfide (0.2 ml) were added trifluoroacetic acid (3 ml) and water (0.2 ml). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by chromatography to provide the title lincosamide compound of Example 20 (10 mg, 20%) as a white solid: 1 H NMR (300 MHz, CD30D) d 7.63 (s, 1), 7.11 (s, 1 ), 6.95 (s, 1), 5. 23 (d, J = 5.7, 1), 4.14 (dd, J 3.2, 10.1, 1), 4.10-3.99 (m, 4), 3.79 (d, J = 3.6, 1), 3.50 (dd, J = 3.3 , 10.2, 1), 3.27-3.21 (m, 1), 3.14-3.07 (m, 1), 2.64-2.54 (m, 1), 2.19-2.10 (m, 1), 2.10 (s, 3), 1.94 -1.76 (m, 3), 1.70-1.64 (m, 1), 1.55-1.43 (m, 1), 1.30-1.18 (m, 2), 1.1 1-0.94 (m, 2), 0.92-0.88 (m , 6); MS (SPOS): 471.7 [M + Hf.

EXAMPLE 21 r2-Methyl-1- (3,415-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-F3- (thiophen-2-yisulfan.). pyperidine-2-carboxylic 4-13- (Thiophene-2-ylsulfanyl) -propyl-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -pro-pill-amide 1-yl-1-piperidine-2-carboxylic acid. To a solution of the protected tosylate prepared in Example 19 (97 mg, 0.14 mmol, 1 equiv) in dry DMF (0.42 ml) under N 2 was added 2-thienyl mercaptan (Acras) (68 μl, 0.72 mmol, 5%). equiv), followed by the addition of 7-methyl-1, 5,7-triazabicyclo- [4.4.0] dec-5-ene (MTBU) (51.3 μ ?, 0.36 mmol, 2.5 equiv). The reaction mixture was stirred at RT overnight and was diluted with DCM, washed with brine (3 x), dried and concentrated. The residue was purified by preparative TLC (8% MeOH / DC) to give a clear syrup (65.5 mg, 74%): MS (ESPOS): 619.8 [M + H] +. To a solution of the above syrup in DCM (9 ml) with methylisulfide (0.2 ml) were added trifluoroacetic acid (3 ml) and water (0.2 ml). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and co-evaporated with toluene twice. The residue was purified by preparative TLC to provide the lincosamide compound of the title of Example 21 (16 mg, 29%) as a white solid; 1 H NMR (300 MHz, CD 3 OD) d 7.45-7.42 (m, 1), 7.12-7.09 (m, 1), 7. 01-6.96 (m, 1), 5.23 (d, J = 5.7, 1), 4.16 (dd, J = 3.3, 10.2, 1), 4.10-4.01 (m, 2), 3.79 (d, J = 3.3, 1), 3.50 (dd, J = 3.3, 10.5, 1), 3.34-3.28 (m, 1), 3.18-3.10 (m, 1), 2.76 (t, J = 7.1, 2), 2.68-2.58 (m , 1), 2.20-2.06 (m, 1), 2.10 (s, 3), 1.98-1.88 (m, 1), 1.71-1 .28 (m, 6), 1.13-1.00 (m, 2), 0.90 (d, J = 6.9, 6); MS (SPOS) 519.7 [M + H] +.

EXAMPLE 22 4- (3-Ethylsulfanyl-prop-1-yl) 2- (3-ethylsulfanyl-prop-1-yl) -2,5-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide -piperidine-2-carboxylic The title compound of Example 22 was prepared from the protected tosyl intermediate prepared in Example 19, according to the procedure used in Examples 19-21, using sodium ethenolate in the displacement step; MS (ESPOS): 465.3 [M + H] + EXAMPLE 23 r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propinármela 4- (3- cyano-prop-1-yl) -piperidine-2-carboxylic acid The title compound of Example 23 was prepared from the protected tosylate intermediate prepared in Example 19, 11h, according to the procedure used in Examples 19-21, using the nucleophile sodium cyanide in the displacement step; MS (SPOS): 430.3 [M + H] +.

EXAMPLE 24 4- (3-difluoromethylsulfanyl-prop-1) 4- [3-difluoromethylsulfanyl-prop-1] [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide -yl) -peridine-2-carboxylic acid 11 c (R9 '= 3-hydroxy-propine). To a mixture of methyl ester of 4-iodopicolinic acid 1 1 b (4.36 g, 16.5 mmol, 1 equiv), triphenylphosphine (346 mg, 1.32 mmol, 0.08 equiv), copper iodide (251 mg, 1.32 mmol, 0.08 equiv) , palladium acetate (148 mg, 0.66 mmoi, 0.04 equiv) in triethylamine (60 ml), at 23 ° C, was added propargyl alcohol (1.92 ml)., 33.0 mmol, 2 equiv), and the reaction mixture was stirred at 23 ° C overnight. The reaction mixture was concentrated in high vacuum and the black residue was purified by column chromatography (2% MeOH in methylene chloride) to yield a brown oil. The brown oil was purified again by column chromatography (100% EtOAc) to provide the desired product, 11c (R9, = 3-hydroxy-1-propyne) as a yellow oil (3.0 g, 95%): 1 H NMR (300 MHz, CDCI3) 8.70-8.74 (dd, J = 0.9, 5.1, 1), 8.14 (s, 1), 7.46-7.50 (dd, J = 1 .8, 5.1, 1), 4.54 (d, J = 6.3 , 2), 4.02 (s, 3); MS (SPOS): 192.1 [M + H]; 214.1 [M + Na]; HPLC: (Symmetry C18 3.5 μG ?, Column 4.6 30 mm, eluent gradient 2% -98% MeCN for 5 min, 1.5 ml / min): Rt = 1 .42 min. 11 c (R 9 - 3-hydroxy-propy) o). To a solution of 11 c (R9 '= 3-hydroxy-1-propin) (2.0 g, 10.5 mmol, 1.0 equiv) in MeOH (120 ml), at 23 ° C, was added 20 wt% Pd ( OH) 2 on carbon (1.0 g) and the reaction mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain the desired product, 4- (3-hydroxy-propyl) -pyridine-2-carboxylic acid methyl ester 1 1 c (R9-3-hydroxy). propyl) (2.03 g, 99%) as yellow oil: 1 H NMR (300 MHz, CDCl 3) 8.65 (d, J = 5.1, 1), 8.03 (s, 1), 7.34-7.36 (dd, J = 1.8, 5.1 , 1), 4.02 (s, 3), 3.71 (t, J = 6.0, 12.3, 2), 2.83 (t, J 7.8, 15.6, 2), 1.92-1.97 (m, 2); MS (ESPOS): 196.3 [M + H] MS (ESNEG): 194.2 [M H]; HPLC: (Symmetry C18 3.5 μ ??, Column 4.6 30 mm, eluent gradient 2% -98% MeCN for 5 min, 1.5 ml / min): Rt = 1.46 min. 11d (R9 '= 3-hydroxypropyl). To a solution of 4- (3-hydroxy-propyl) -pyridine-2-carboxylic acid methyl ester 1 1 c (R9 '= 1-hydroxypropyl) (1.81 g, 9.28 mmol, 1.0 equiv) in MeOH (30 mL) and H2O (20 ml), at 23 ° C, was added concentrated HCl (412 I, 1.1 mmol, 1.2 equiv), followed by platinum (IV) oxide (600 mg, 0.33 wt.%) and the reaction mixture. stirred vigorously under a hydrogen atmosphere at 1 atm for 48 h. The reaction mixture was filtered through celite, washing with methanol (200 ml). The combined filtrate was concentrated under reduced pressure to provide the desired product 1 1d, R9 '= (3-hydroxypropyl) as an HCI salt (2.02 g, 8.52 mmol, 91%): MS (HORMS): 202.2 [M + H] +. 11 e (R 9 - 3-hydroxy-propyl, P = Cbz). To a solution of 11 d, R9 - (3-hydroxy-propyl) (2.02 g, 8.52 mmol, 1 equiv) in dichloromethane (50 mL), at 5 ° C, was added triethylamine (1.54 mL, 1.07 mmol). , 1.3 equiv), and the reaction mixture was stirred for 10 min. To this solution was added benzylchloroformate (1.55 ml, 11.07 mmol, 1.3 equiv) and the reaction mixture was stirred at 5 ° C for 1 h, then warmed to room temperature. The reaction mixture was concentrated and the crude product was partitioned between dichloromethane (250 ml) and water (150 ml). The organic layer was collected, dried over Na 2 SO and concentrated. The residue was purified by column chromatography (gradient between 50% and 75% EtOAc / hexane) to provide the desired product, 1e (R 9 -3-hydroxy-propyl, P = Cbz) (2.28 g, 6.80 mmol, 80% ) as a yellow oil: 1 H NMR (300 MHz, CDCl 3) 7.34 (s, 5), 5.19 (s, 2), 4.48 (t, J = 6.3, 12.3, 1), 3.68 (bs, 3), 3.60- 3.64 (m, 2), 3.38-3.42 (m, 2), 1.94-1.98 (m, 3), 1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.20-1.24 (m, 2 ); MS (SPOS): 358.0 [+ Na]; HPLC: (Symmetry C18 3.5 μ ??, Column 4.6 30 mm; eluent gradient 2% -98% MeCN for 5 min; 1.5 ml / min): Rt = 2.50 min. 1 1 e (R = 3-methanesulfonylpropyl, P = Cbz) To a solution of the alcohol intermediate 11 e (R9 '= 3-hydroxypropyl, P = Cbz) prepared by the general method P (2.0 g, 5.97 mmol, 1 equiv) in dichloromethane (15 ml), at 0 ° C, triethylamine (1.0 ml 7.2 mmol, 1.2 equiv) was added, and the reaction mixture was stirred for 15 min. To this solution was added methanesulfonic anhydride (1.04 g, 5.97 mmol, 1 equiv), and the reaction mixture was stirred for another 30 min at 0 ° C. The reaction mixture was partitioned between dichloromethane (250 m!) And saturated aqueous aHC03 (100 ml). The organic layer was collected, dried over Na 2 SO 4 and concentrated to obtain the desired mesylate product 11e (R 9, = 3-methanesulfonylpropyl, P = Cbz) (2.25 g, 5.45 mmol, 91%) as a clear oil: 1 H NMR (300 MHz, CDCI3) d 7.34 (s, 5), 5.19 (s, 2), 4.48 (t, J = 6.3, 12.3, 1), 4.20 (t, J = 6.3, 14.1, 2), 3.70 (bs , 3), 3.38-3.42 (m, 2), 3.02 (s, 3), 1.94-1.98 (m, 3), 1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.20-1.24 (m, 2); MS (ESPOS): 436.3 [M + Na]; HPLC (Symmetry® C 8 3.5 μ ??, Column 4.6 x 30 mm, eluent gradient 2% -98% MeCN for 5 min, 1.5 ml / min): Rt = 2.86 min. 1 1 e (R9 '= 3-acetylsulfanyl-propyl, P = Cbz) To a solution of mesylate 1 1e (R9, = 3-methanesulfonylpropyl, P = Cbz) (2.25 g, 5.45 mmol, 1 equiv) in DF (30 mL), at 5 ° C, potassium thioacetate (3.11 g, 27.3 mmol, 5 equiv) was added and the reaction mixture was stirred at 5 ° C. ° C during the night. The reaction mixture was partitioned between EtOAc (250 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was collected, dried over Na2SO4 and concentrated. The crude product obtained was purified by column chromatography (25% EtOAc in hexane) to obtain the desired thioester product 1 1 e (R9 '= 3-acetylsulfanyl-propyl, P = Cbz) (1.90 g, 4.83 mmol, 89% ) as a yellow oil: 1 H NMR (300 MHz, CDCl 3) d 7.34 (s, 5), 5.12 (s, 2), 4.46 (t, J = 6.3, 12.3, 1), 3.69 (bs, 3), 3.38 -3.42 (m, 2), 2.81-2.85 (m, 3), 2.32 (s, 3), 1.89-2.05 (m, 3), 1 .65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.20-1 .24 (m, 2); S (ESPOS): 394.0 [M + H] 416.1 [M + Na]; HPLC (Symmetry® C 8 3.5 μ? T ?, Column 4.6 x 30 mm; Eluent gradient 2% -98% MeCN for 5 min; 1.5 ml / min): Retention time = 3.28 min. 11f (R9 '= 3-D-fluoromethylsulfanyl-propium, P = Cbz). To a solution of 11 (R9 '= (3-acetylsulfanyl-propyl), P = Cbz) (1.90 g, 4.83 mmol, 1 equiv) in ethanol (8 mL) was added 3 N NaOH (4.5 mL). The reaction mixture was stirred at room temperature for 45 min, then concentrated to produce a clear oil. The resulting oil was dissolved in ethanol (20 ml) and the reaction mixture was deoxygenated via evacuation of the reaction flask, then the reaction mixture was saturated with chlorodifluoromethane gas (Aldrich) under 1 atm pressure. The reaction mixture was stirred at 5 ° C for 16 h, then neutralized with 1 N HCl at 0 ° C, and concentrated under reduced pressure. The residue was converted to a base with 0.5 N aqueous NaOH and washed with ether. The aqueous layer was acidified to pH 2.0 with 1 N HCl and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine (2 x 100 mL), dried (MgSO4) and concentrated. The crude residue obtained was purified by column chromatography (50% EtOAc / 49% Hexane / 1% AcOH) to obtain the desired difluoromethylsulfide product 11f (R9 '= (3 difluoromethylsulfanyl-propyl), P = Cbz) (0.75 g, 1 .94 mmol, 40%) as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 7.36 (s, 5), 6.97 (s), 6.79 (s), 6.60 (s), 5.15 (s, 2 ), 4.51 (t, J = 6.3, 12.3, 1), 3.38-3.42 (m, 2), 2.75 (t, J = 7.2, 14.4, 1), 2.47-2.51 (m, 1), 1.89-2.05 ( m, 3), 1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.21-1 .23 (m, 2); MS (ESPOS): 388.1 [M + H] + 410.1 [M + Na] *; HPLC (Symmetry® Co. 3.5 μ ??, Column 4.6 x 30 mm, eluent gradient 2% -98% MeCN for 5 min, 1.5 ml / min): Rt = 2.85 min. 11f (R9 '= 3-difluoromethylsulfanyl-propyl, P = Boc). To a solution of (750 mg, 1.94 mmol, 1 equiv) in acetonitrile (100 ml), at 23 ° C, iodotrimethylsilane (0.8 ml, 5.81 mmol, 3 equiv) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated to yield the crude product deprotected (491 mg, 1.94 mmol, 100%). To this was added dichloromethane (100 ml), triethylamine (0.54 ml, 3.88 mmol, 2 equiv), and di-tert-butyl dicarbonate (0.67 ml, 2.91 mmol, 1.5 equiv). The reaction mixture was stirred at 5 ° C overnight. The reaction mixture was concentrated and the crude product was partitioned between dichloromethane (250 ml) and water (150 ml). The organic layer was collected, dried (Na2SO4) and concentrated. The obtained crude residue was purified by column chromatography (50: 49: 1 EtOAc / hexane / AcOH) to obtain the desired product 11f (R9 '= 3-difluoromethylsulfanyl-propyl, P = Boc) (671 mg, 98%) as a clear oil: 1H NMR (300 MHz, CD3OD) d 7.10 (s), 6.90 (s), 6.70 (s), 4.19-4.23 (m, 1), 3.48-3.53 (m, 1), 2.68 (t, J = 6.6, 13.8, 1), 2.56 (t, J = 7.2, 14.4, 1), 1.80-1.95 (m, 4), 1.50-1.80 (m, 5), 1.33 (s, 9), 1.13 -1.20 (m, 2); MS (ESPOS): 254.1 [M-Boc + H] MS (ESNEG): 352.2 [M - H] \ 4- (3-difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid r2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-in-pro-pill-amide A a stirred solution of 7-CI-MTL 6b (R2 = H, R3 = CI) (195 mg, 0.68 mmol, 1.2 equiv) in DMF (2.5 ml), at 23 ° C, was added diisopropylethylamine (0.3 ml, 1.71 mmol, 3 equiv), followed by an amino acid solution protected with boc 11f (R 9 '= 3-difluoromethylsulfanyl-propyl, P = Boc) (200 mg, 0.57 mmol, 1 equiv) in DMF (2.5 ml) and HBTU (324 mg, 0.85 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 3 h, then concentrated to dryness. The solid residue was partitioned between ethyl acetate (300 ml) and saturated aqueous NaHCO 3 (100 ml). The organic layer was collected, dried (Na2SO4) and concentrated. To a portion of this residue (60 mg, 0.12 mmol, 1 equiv) at 23 ° C was added 1,2-dichloroethane (5 mL), water (0.2 mL) followed by pure TFA (2.0 mL), and The reaction mixture was stirred for 15 min at room temperature, then concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound of Example 24 as a white powder: 1 H NMR (300 MHz, CD 3 OD) d 7.12 (s), 6.93 (s), 6.74 (s), 5.21 (d, J = 5.7, 1), 4.48 (d, J = 8.4, 2) 4.40 (d, J = 10.2, 1), 4.17 (d, J = 9.6, 1), 3.97- 4.02 (dd, J = 5.4, 9.9 , 1) 3.71 (d, J = 3.3), 3.46-3.52 (m, 2), 2.71-2.76 (t, J = 6.9, 13.8, 1), 2.05 (s, 3), 1.83 (s, 1), 1 .61-1.77 (m, 5), 1 .35 (d, J = 6.9, 4), 1.08-1.22 (m, 3); MS (SPOS): 507.1 [M + H} .

EXAMPLE 25 4- (3-difluoromethyisulfanyl-propyl) -piperidine-2-carboxylic acid 2- (3-difluoromethyisulphanyl-propyl) -piperidine-2-carboxylic acid r2-methyl-1 -O ^^ - trihydroxy-e-methylsulfanyl-tetrahydro-pyran-4-yl) -propyl-amide R 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-ii) -propyl amide of 4- (3-difluoromethylsulfanyl-propiD-piDeridine-2- carboxylic acid To a stirred solution of 2b (R2 * = H) in DMF (2.5 ml), at 23 ° C, diisopropylethylamine (0.3 ml, 1.7 mmol, 3 equiv) was added, followed by a solution of the amino acid protected with Boc. 11f (R 9 '= 3-difluoromethylsulfanyl-propyl, P = Boc) (200 mg, 0.57 mmol, 1 equiv) in DMF (2.5 ml) and HBTU The resulting solution was stirred at room temperature for 3 h and concentrated to dryness. The solid residue was partitioned between ethyl acetate (300 ml) and aqueous sat'd NaHCO 3, the organic layer was collected, dried (Na 2 SO 4) and concentrated to a portion of this residue (60 mg, 0.12 mmol, 1 equiv). , at 23 ° C, 1,2-dichloroethane (5 ml) and water (0.2 ml) were added followed by pure TFA (2.0 ml), and the reaction mixture was stirred for 15 min at room temperature, then concentrated The crude product was purified by HP LC preparative to provide the desired compound of the title of Example 25 as a white powder: 1 H NMR (300 MHz, CD 3 OD) d 7.13 (s), 6.94 (s), 6.75 (s), 5.16 (d, J = 5.7, 1 ), 4.12 (d, J = 9.9, 1), 3.97-4.02 (dd, J = 4.8, 10.2, 2), 3.71 (d, J = 3.3, 1), 3.42-3.46 (m, 2), 2.88-2.96 (m, 2), 2.75 (t, J = 7.8, 15.0, 2), 2.59-2.63 (m, 2), 2.03 (s, 3), 1.81-1.87 (m, 1), 1.61-1.70 (m, 5), 1.20-1.38 (m, 4), 0.82-0.84 (d, J = 6.9, 6); S (SPOS): 487.1 [M + Hf.

EXAMPLE 26 r2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propinármela 4- (2-f1, 31dithiolan-2-yl-ethyl) -piperidine-2-carboxylic Methyl ester of 4- (3,3-diethoxy-prop-1-ynyl) -pyridine-2-carboxylic acid. To a dry flask was added intermediary 1 b prepared in the general method P (2.98 g, 1.33 mmol, 1 equiv), triphenylphosphine (238 mg, 0.91 mmol, 0.08 equiv), copper iodide (I) (172.6 mg , 0.91 mmol, 0.08 equiv), palladium acetate (101.6 mg, 0.45 mmol, 0.04 equiv) and triethylamine (42 ml). The mixture was deaerated with nitrogen, and then 3,3-diethoxy-propine (Aldrich) (2.90 g, 22.7 mmol, 2 equiv) was added. The mixture was stirred at RT for 3 h. The solvent was removed under vacuum to produce a dark residue. The residue was purified by chromatography to produce a yellow oil 11 c (R9 '= 3,3-diethoxy-prop-1-ynyl) (3 g, 100%): 1 H NMR (300 MHz, CDCl 3) d 8.69 (dd, J = 0.8, 5.0, 1), 8, (d, 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 (HOOKS): 264.5 [M + H] +. 2-methyl ester of 4- (3,3-diethoxy-1-propyl) -piperidine-1,2-dicarboxylic acid 11 d (R9 '= 3,3-diethoxy-1-propyl) To a mixture of 11 c ( R 9 '= 3,3-diethoxy-prop-1-ynyl) (3 g) in MeOH (15 ml), acetic acid (15 ml) and water (15 ml) was added with platinum oxide (1.0 g). The mixture was purged and charged with hydrogen 3.5153 kgf / cm2 (50 psi) and stirred at RT for 5 h.The platinum oxide was removed by filtration and the filtrate was concentrated to give the desired product 1 d (R9-3, 3-diethoxy-1-propyl) (2.45 g, 79%) as an oil: MS (ESPOS): 296.5 [M + Na. 1-allyl ester 2-methyl ester of 4- (3,3-diethoxy-1-propiQ-piperidine-1,2-dicarboxylic acid 1 e (R9 '= 3,3-diethoxy-1-propyl, P = Alloc) To a solution of 11 d (R9 '= 3,3-diethoxy-1-propyl) (2.4 g, 8.79 mmol, 1 equiv) and pyridine (1.26 ml, 1.9 mmol, 1.35 equiv) in THF (29 ml) A solution of allyl chloroformate (0.96 ml, 1.9 mmol, 1.4 equiv) was added dropwise at 0 ° C. The mixture was slowly warmed to RT and stirred for 3 h. The solution was filtered and the solvent was removed The residue was purified by chromatography to give 1 1 e (R9 '= 3,3-diethoxy-1-propyl, P = Alloc) (2.1 g, 66%) as a clear oil: MS (ESPOS): 380.6 [M + Na] +. 1-allyl ester 2-methyl ester of 4- (3-oxo-propyl) -piperidine-1 acid, 2-dicarboxylic. A solution of 11e (R9 '= 3,3-diethoxy-1-propyl, P = Alloc) (2.03 g) in acetic acid (32 ml) and water (8 ml) was stirred at RT overnight. The solvent was removed in high vacuum. The residue was diluted with ethyl acetate and washed with sat. Sodium bicarbonate. (1 x) and brine (1 x). The organic layer was dried and concentrated. The residue was purified by chromatography to yield methyl ester 1 1 e (R9 '= 3-oxo-propyl, P = Alloc) (1.2 g, 75%) as a clear oil: H NMR (300 MHz, CDCl 3) d 9.75 (t, J = 1 .5,), 5.96-5.82 (m, 1), 5. 30-5.16 (m, 2), 4.57 (d, J = 5.4, 2), 4.46 (t, J = 6.0, 1), 3.74-3.65 (m, 1), 3.71 (s, 3), 3.42-3.32 (m, 1), 2.48-2.41 (m, 2), 2.02-1.35 (m, 7); MS (ESPOS): 306.5 [M + Na] +. 1-allyl ester 2-methyl ester of 4- (2-?. 31 Di-thiolan-2-yl-ethyl-piperidine-1,2-dicarboxylic acid.) To a mixture of 1 1 e (R9 '= 3-oxopropyl, P = Alloc) (248 mg, 0.87 mmol, 1 equiv) and 1,2-ethanediol (0.147 mL, 1.75 mmol, 2 equiv), under nitrogen, was added borotrifluoride-acetic acid complex (0.122 mL, 0.87 mmol, 1 equiv). The mixture was diluted with hexane and washed with saturated sodium bicarbonate (3 x) and brine (1 x), the organic layer was dried and concentrated, the residue was purified by chromatography to give 1 1 e (R9 '= 2- [1, 3] dithiolan-2-yl-etl, P = Alloc) (144 mg, 46%) as an oil: MS (SPOS): 382.5 [M + Naf. 1-allyl ester of 4- (2-G1, 31dithiolan-2-yl-ethyl) -piperidine-1,2-dicarboxylic acid 1 f (R9 '= (2-?, 31dithiolan-2-yl-ethyl), P = Alloc). To a mixture of 1 1 e (R9 * = 2- [1, 3] dithiolan-2-yl-ethyl, P = Alloc) (144 mg, 0.40 mmol, 1 equiv) in THF (3 mL) and water (1 mL) were added with lithium hydroxide monohydrate (67 mg, 1.6 mmol, 4 equiv). The mixture was stirred at RT overnight. The THF was removed under vacuum. The aqueous layer was taken up in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1x) and brine (1x), dried and concentrated to yield 1 1 f (R91 = (2- [1, 3] dithiolan-2-yl-ethyl), P = Alloc) (127 mg, 92%) as a syrup: 1 H NMR (300 MHz, CDCl 3) d 5.96-5.83 (m, 1), 5.30-5.17 (m, 2), 4.59 (d, J = 5.4, 2) , 4.48 (t, J = 6.4, 1), 4.41 (t, J = 6.9, 1), 3.75-3.64 (m, 1), 3.44-3.33 (m, 1), 3.25-3.12 (m, 4), 2.05-1.35 (m, 9). MS (ESPOS): 346.5 [M + H] + 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4- ( 2-i1, 31dithiolan-2-yl-ethyl) -piperidine-2-carboxylic acid. To a mixture of 2b (R2 '= H) (95 mg, 0.33 mmol, 1 equiv) in dry DMF (0.8 ml), at 0 ° C, triethylamine (0.23 ml, 1.65 mmol, 5 equiv) was added. , followed by addition of Bis (trimethylsilyl) trifluoroacetamide (0.13 ml, 0.49 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. To the reaction mixture were added 1 1f (R9 '= 2- [1, 3] dithiolan-2-yl-ethyl, P = Alloc) (1 mg, 0.33 mmol, 1.0 equiv) and HATU (158 mg, 0.42 mmol, 1.3 eq.). The reaction mixture was stirred at RT for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1 x), water (1 x), sat. NaHCO 3. (1 x) and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography to yield the lincosamide analogue protected with Alloc (133 mg, 70%) as a syrup: MS (ESPOS): 579.8 [M + Hi +. To a solution of the aforementioned Alloc-protected lincosamide (103 mg, 0. 8 mmol, 1 equiv) in THF (2.3 ml) were added dimedone (0.25 g, 1.78 mmol, 10 equiv) and tetrakis- (triphenylphosphine) palladium. (41 .1 mg, 0.036 mmol, 0.2 equiv). The mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was purified by chromatography to give the title compound of example 27 (34 mg, 49%) as a slightly yellow solid: H NMR (300 MHz, CD3OD) d 5.23 (d, J = 5.7, 1), 4.45 (t, J = 6.9, 1), 4.18-4.01 (m, 3), 3.81-3.77 (m, 1), 3.56-3.47 (m, 2), 3.25-3.07 (m, 5), 2.66-2.56 (m, 1), 2.18- 2.13 (m, 1), 2.10 (s, 3), 1.94-1.63 (m, 4), 1.55-1.35 (m, 3), 1.12-0.98 (m, 2), 0.95-0.88 (m, 6); MS (SPOS): 495.6 [M + H] +.

EXAMPLE 27 There is no Example 27.

EXAMPLE 28 442- (4-methyl-thiazol-2-yl) -etin r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-H) -propin-amide -piperidine-2-carboxanic Ester 1 -alí2- (4-methyl-thiazol-2-yl) -etl-piperidine-1,2-dicarboxylic acid ester 1 1f ÍR9 '= 4-Methyl-thiazol-2-yl, P-Alloc) . This intermediate was prepared using the reaction sequence described in general method P, Scheme 1 1, from intermediate 11 b, using 4-tert-butoxycarbonylethine (Aldrich) as the alkyne. The 4-methyl thiazole moiety was installed by preparing the protected dicarboxylic acid 1 1 e (R9 '= (tert-butyl ester of propionic acid, P = Alloc) from methods known to those skilled in the art. The ester, which was carried out as in the general method P, produced the desired carboxylate intermediate 1 1f (R 9 '= 4-Methyl-thiazol-2-yl, P = Alloc). 4- [2- (4-Methyl-thiazol-2-yl) - r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide etin-piperidine-2-carboxylic acid. The coupling of 2b (R2 '= H) to the protected amino acid 1 1f (R9' = 4-Methyl-thiazol-2-yl, P = Alloc) and deprotection were carried out by the procedure described in example 26 to provide the lincosamide of the title of example 28: (300 MHz, CD3OD) d 6.80 (s, 1) 5.07 (d, J = 5.5, 1), 4.43 (dd, J = 3.3, 9.9 1), 3.91-3.86 (m, 2), 3.60 (m, 1), 3.50-3.45 (m, 1), 3.30 (d, J = 3.3, 10.4, 1), 2.89-2.82 (m, 2), 2.76-2.67 (m, 1), 2.19 (s, 3), 1 .96 (s, 3), 1 .77-1.73 (m, 1), 1.61-1.57 (m, 3), 1 .22-1.09 (m, 2), 0.72 (d , J = 6.9, 6); MS (SPOS): 488.4 [M + H] +.

EXAMPLE 29 4- (3-methoxyimino-prop-1-y) 4- (3-methoxyimino-prop-1-y) 4- (3-methoxyimino-prop-1-y) 4- (3-methoxyimino-prop-1-yl) -2,5-methyl-1- (3,4,5-tri- hydroxy-6-m-ylsulfanyl-tetrahydro-pyran-2-yl) -propylamide -piperidine-2-carboxylic acid 1 1 e (R9 '= 3-methoxyimino-propyl, P = Alloc). To a solution of 11e (R9 '= 3-oxopropyl, P = Alloc) prepared in Example 26 (129 mg, 0.45 mmol) in ethanol (1.3 mL) was added methoxylamine hydrochloride and pyridine. The reaction mixture was refluxed for 2 h. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with 10% citric acid and brine, dried and concentrated to provide 1 e (R9 '= 3-methoxyimino-propyl, P = Alloc) (129' mg) as an oil. clear: MS (SPOS): 334.5 [M + Naf. 1- (3-methoxyimino-propyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester (R9 '= (3-methoxyimino-propyl), P = Alloc). To a mixture of ester 1 1 e (R 9 '= (3-methoxyimino-propyl), P = Alloc) (129 mg, 0.41 mmol, 1 equiv) in THF (1.5 ml) and water (0.5 ml) was added monohydrate of lithium hydroxide (69 mg, 1.6 mmol, 4 equiv). The mixture was stirred at RT overnight. The THF was removed under vacuum. The aqueous layer was taken up in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1x) and brine (1x), dried and concentrated to yield 1 f (R9 '= 3-methoxyimino-propyl, P = Alloc) (14mg, 93%) as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 7.31 (t, J = 6.2, 0.6H), 6.60 (t, J = 5. 4, 0.4H), 5.96-5.82 (m, 1), 5.30-5.16 (m, 2), 4.58 (d, J = 5.7, 2), 4.83 (t, J = 6. 5, 1), 3.83 (d, J = 0.3, 1.2H), 3.78 (d, J = 0.6, 1.8H), 3.77-3.62 (m, 1), 3.42-3.30 (m, 1), 2.38-2.26 (m, 1), 2.23-2.14 (m, 1), 2.08-1.85 (m, 2), 1.82-1.62 (m, 2), 1.33-1.35 (m, 3); MS (SPOS): 321.2 [M + Na] +.

R 2 -methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-in-propylamide of 4- (3-methoxy-1-propyl) -piperidine-2-acid carboxylic acid To a mixture of 2b (R2 '= H) (109.8 mg, 0.38 mmol, 1 equiv) in dry DF (0.9 ml), at 0 ° C, triethylamine (0.26 ml, 1.91 mmol, 5 equiv) was added. followed by bis (trimethylsilyl) trifluoroacetamide (0. mi, 0.57 mmol, 1.5 equiv.) The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 50 minutes. they added the protected amino acid 11f (R9 '= 3-methoxyimino-propyl, P = Alloc) (1 13.6 mg, 0.38 mmol, 1.0 equiv) and HATU (182 mg, 0.48 mmol, 1.26 equiv.) The reaction mixture was stirred at RT for 3 h The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with 10% citric acid (1 x), water (1 x), sat'd NaHCO 3 (1 x) and brine. The organic layer was dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography to provide l lincosamide product protected with Alloc (107 mg, 53%): MS (ESPOS): 532.4 [+ H] +. To a mixture of the above-mentioned protected lincosamide with Alloc (107 mg, 0.20 mmol, 1 equiv) in THF (2.6 ml) were added dimedone (282 mg, 2.01 mmol, 10 equiv) and tetrakis (triphenylphosphine) palladium (46.5 mg). , 0.04 mmol, 0.2 equiv). The mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was purified by chromatography to give the title compound of Example 29 (28 mg, 31%) as a white solid: 1 H NMR (300 MHz, CD3OD) d 7.36 (t, J = 6.2 , 0.68H), 6.66 (t, J = 5.4, 0.32H), 5.23 (d, J = 5.7, 1), 4.16 (dd, J = 3.2, 10.1 J), 4.10-4.01 (m, 2), 3.81 (s, 1), 3.79 (d, J = 3.3, 1), 3.74 (s, 2), 3.50 (dd, J = 3.3, 9.9, 1), 3.30-3.22 (m, 1), 3.18-3.10 ( m, 1), 2.67-2.55 (m, 1), 2.40-2.31 (m, 1), 2.25-2.12 (m, 2), 2.10 (s, 3), 1.97-1.88 (m, 1), 1.76- 1.65 (m, 1), 1.59-1.38 (m, 3), 1.14-1.01 (m, 2), 0.90 (d, J = 6.9, 6); S (SPOS): 448.4 [M + H] + EXAMPLE 30 4- (3-Ethoxyimino-prop-1-yl) -piperidine- r (4-methyl-1- (3,4,5-hydroxy-6-thiethylsulfanyl-tetrahydro-pyran-2-H) -propiH- amide of 4- (3-ethoxyimino-prop-1-yl) -piperidine- 2-carboxylic The synthesis of the title compound of Example 30 was carried out as described in Example 29, from intermediate 1 e (R9 ' 3-oxopropyl, P Alloc) which replaces the ethoxylamine hydrochloride in the mine formation step: MS (ESPOS): 462.4 [M + H] +.

EXAMPLE 31 r2-Methyl-1- (3,415-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-H) -proph-amide of 4-f2- (5-ethyl-isoxazol-3-yl) -ethyl-1-piperidine -2-carboxylic The synthesis of the title compound of example 31 was carried out as in example 29, starting from intermediate 11 e (R9 '= 3-oxopropyl, P = Alloc) which replaces the hydroxylamine hydrochloride in the step of forming Mine to produce 11 e (R9 '= 3-hydroxy-propyl, P = Alloc). The soxazole heterocycle was installed by preparing intermediate 11 e (R9 '= 3-hydroxyimino-propyl, P = Alloc) by cycloaddition of -butine in the presence of N-chlorosuccinimide and TEA. Coupling and deprotection were carried out as described in Example 29: MS (ESPOS): 486.3 [M + H] +.

EXAMPLE 32 r2-Chloro-1- (3-4-trihydroxy-6-methylsulfanM-tetra-idro-pyran-2-yl) -propylamide of fluoro-4-propyl-pyrrolidine-2-carboxylic acid: stereoisomer in 4-position and stereoisomer in position 4 II 4-fluoro-4-propyl-pyrrolidine-2-carboxylic acid 4-fluoro-4-propylamino-4-fluoro-4-propylamide (stereoisomer in position 4 I high Rf and stereoisomer in position 4 II under Rf). To a solution of the amino acid protected with Boc 12d (P = Boc, R 9 = propyl, m = 1) prepared in the general method Q, synthetic sequence represented in scheme 12 (310 mg 1, mmol) in DMF (3 ml), at 0 ° C, 7-CI MTL 6b (R2 = H, R3 = CI) (306 mg, 1, mmol), HBTU (469 mg, 1.3 mmol) and DIEA (290 μ? _, 2.3 mmol) were added. , and allowed to stir at room temperature overnight. The DMF was removed by rotary evaporation at high vacuum. The residue obtained was purified by column chromatography on silica gel (3% MeOH in DCM) to obtain 4-F-protected Boinc lincosamide (451 mg, 75%) as a brown oil: 1 H NMR (300 MHz, CD 3 OD) d 5.29 (d, J = 5.7, 1), 4.30 (m, 3), 4.10 (m, 1), 3.60 (m, 3), 2.51 (m, 1), 2.1 1 (m, 4), 1. 70 (m, 2), 1.50 (m, 9), 0.96 (t, J = 7.2, 3); MS (SPOS): 529 [+ H] +. To a solution of the above-exposed Boc-protected 4-fluoro-lincosamide (451 mg, 0.85 mmol) in DCE (6 ml), triethylsilane (0.16 ml), TFA (2 ml) and water (0.16 ml) were added and stirred at room temperature for 1.5 h. The reaction solvent was removed in vacuo. The resulting residue was purified by column chromatography on silica gel, using 10% MeOH in DCM as the eluent to obtain the title compound of example 32 stereoisomer 4 I (high TLC Rf) (165 mg, 45%): 1 H NMR (300 MHz, CD3OD) d 5.29 (d, J = 5.7, 1), 4.39 (m, 2), 4.32 (d, J = 9.9, 1), 4.07 (dd, J = 5.7, 10.2, 1), 3.81 (d, J = 3.3, 1), 3.59 (m, 3), 3.01 (d, J = 3.0, 1), 2.83 (m, 1), 2.14 (m, 4), 1.86 (m, 2), 1.50 (m, 5), 0.99 (t, J = 7.2, 3); MS (SPOS) 429 [M + H] +; and stereoisomer 4 II (under TLC Rf) (165 mg, 45%); H NMR (300 MHz, CD3OD) d 5.29 (d, J 5.7, 1), 4.59 (m, 3), 4.29 (d, J = 10.2, 1), 4.08 (dd, J = 5.7, 10.2, 1), 3.85 (d, J = 3.3, 1), 3.59 (m, 4), 2.60 (m, 1), 2.1 1 (m, 3), 1.88 (m, 2), 1.50 (m, 5), 0.99 (t , J = 7.2, 3); MS (SPOS); 429 [M + H] +.

EXAMPLE 33 4-Fluoro-4-propyl-piperidine-2-carboxylic acid f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl) -amide 1-tert-butyl ester of 4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid, 12d (P = Boc, R9 = n-propyl, m = 2). The synthesis of the protected 4-fluoro amino acid with Boc 12d from the starting material 1-tert-butyl ester of (2S) -4-oxo-piperidine-1,2-dicarboxylic acid employs the general method Q, represented in the scheme 12. The preparation of the starting material 1-tert-butyl ester of (2S) -4-oxo-piperidine-1,2-dicarboxylic acid is described by Bousquet, Y.; Anderson, P. C; Bogri, T .; Duceppe J .; Grenier, L .; Guse, L; Tetrahedron, 1997, 53 15671-15680. A rapidly stirred solution of 1-tert-butyl ether of 4-oxo-piperidine-1,2-dicarboxylic acid 12a (m = 2, P = H, P2 = Boc) (16.0 g, 0.066 mol) (prepared by the method described by Bousquet et al. Tetrahedron, 1997, 53, 15671) in DMF (200 ml) with solid cesium carbonate (10.7 g, 0.033 mol) and methyl iodide (4.5 ml, 0.072 mol). The reaction mixture was stirred for 5 h, diluted with EtOAc and extracted with saturated aq. Sodium bicarbonate, citric acid aq. At 10% and brine, the organic layer was separated and dried over sodium sulfate, filtered and evaporated to dryness. The product obtained after removal of the solvent was dried azeotropically by evaporation from dry benzene to yield 14.8 g (98%) of the desired product-tert-butyl ester 2-methyl ester of 4-oxo-piperidine-1, 2- dicarboxylic acid 12a (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 5.3 (flared m, 0.5) rotamer, 5.06 (flared 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 (s widened, 9). A stirred solution at 0 ° C of 1-tert-butyl ester 2-methyl ester of 4-oxo-piperidine-1,2-dicarboxylic acid 12a (m = 2, P = Me, P2 = Boc) (5.17 g, 0.02 mol) in DCM (60 ml) was treated with tetraalyltin (Aldrich) (5.3 ml, 0.022 mol) followed by the dropwise addition of BF3 «OEt2 (2.5 ml, 0.02 mol). The reaction mixture was stirred 1 h, then aq. Potassium fluoride was added. 1 M (38.0 ml) and celite (5 g), and the reaction mixture was stirred for 3 h. The reaction mixture was filtered and concentrated to dryness, the residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and evaporated to dryness. The residue obtained was purified by column chromatography on silica gel (DCM 100% to DCM: acetone 9: 1) to yield 3.85 g (64%) of the product 1-tert-butyl ester 2-methyl ester of 4-allyl acid Desired -4-hydroxy-piperidine-1,2-dicarboxylic acid 12b (m = 2, P = Me, P2 = Boc, R9 '= allyl) as an oil. 1 H NMR (300 MHz, CDCl 3) d 6.11-5.97 (m, 1), 5.42-5.32 (m, 2), 5.06 (d widened, J = 6.0, 0.5) rotamer, 4.87 (widened 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,); S (SPOS): 322.0 [M + Na] +. A stirred suspension of 12b (m 2, P = Me, P 2 = Boc, R9 '= allyl) (3.80 ml, 1.27 mmol) and 10% Pd / C (wet form degusa 50% w / w) (1.35 g, 1.3 mmol) in MeOH (80 ml) for 6 h under 1 atm hydrogen. The reaction mixture was filtered through celite and evaporated to dryness, dried azeotropically by evaporation of toluene, and the residue obtained (3, 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 2-methyl ester of 4-hydroxy-4-propyl-piperidine-1. , 2-dicarboxylic in DCM (30 ml). The reaction mixture was then stirred for 1 h, allowed to warm to -40 ° C for 5 h. More DAST (0.4 mL) was added and the reaction mixture was stirred an additional 2 h, sat. K2CO3 was added. ac. (20 ml) and water (60 ml) followed by diethyl ether (500 ml), the organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting crude fluorinated product was purified by column chromatography on silica gel (hexanes-EtOAc 9: 1). 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% aqueous solution) and 30% H2O (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), Na 2 SO 3 aq. 25% (2x100 ml) and brine (100 ml), dried over Na 2 SO 4 and evaporated to dryness. The residue obtained was purified by column chromatography on silica gel (hexanes-EtOAc 9: 1) to provide the desired product (1.08 g, 34%) 1-tert-butyl ester 2-methyl ester of 4-fluoro-4- propyl-piperidine-1,2-dicarboxylic acid 12c (m = 2, P = Me, P2 = Boc, R9 n-propyl) as 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, 9), 0.92 (t, J = 7.1, 3); MS (ESPOS): 204.1 (M + H-Boc), 326.3 [M + Na] +. The synthesis of the title compound of Example 33 from 12d (P = Boc, R9 = n-propyl, m = 2) is easily achieved using the coupling and deprotection conditions of Example 32. MS (SPOS): 443.1 [M + Hj; HPLC: C18 3.5 μ, column 4.6 x 30 mm; gradient eluent 2% -98% MeCN for 10 min; 1.5 ml / min): Rt = 3738 min.

EXAMPLE 34 r 2 -hydroxy-1 - (S 4,6-tri- hydroxy-S-methylsulfanyl-tetrahydro-pyran ^ -iD-propylamide of 4-fluoro-4-propyl-pyrrole »d. 2-carboxylic 4-Fluoro-4-propyl-pyrrolidine 2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide -2-carboxylic acid. A stirred suspension of 12d (P = Boc, R9 = C3H7, m = 1) (164 mg, 0.57 mmol) prepared by the general method Q, shown in scheme 12, 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 1 a (151 mg, 0.57 mmol) in 1: 1 acetone: water (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 (95: 5 dichloromethane / MeOH at 95: 8 dichloromethane / MeOH) to give the product as a colorless oil (137 mg, 45%): TLC Rf = 0.32 (9 : 1 dichloromethane / MeOH); MS (ESPOS): 411 [M + H-Boc] +, 51 1 [M + H] +. To a solution of the aforementioned 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). my). The reaction mixture was stirred at RT for 40 min, then diluted with DCE (25.0 ml). The solvent was removed in vacuo and co-evaporated twice with DCE. The residue was purified by chromatography on fluorosil (20% MeOH 0.25 M NH 3 / DCM) to provide the title compounds as a colorless solid (30 ,. mg, 30%): MS (ESPOS): 411.6 [M + H] + .

EXAMPLE 35 4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid f2-chloro-1- (3,415-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide: stereoisomer in position 4 I and stereoisomer in position 4 II Methyl ester of 4-hydroxy-4-butylproline 12b (P = Boc, m = 1, R9 = n-butyl). To a stirred solution of n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL), at -78 ° C, was added 12a (P = Boc, P2 = Me, m = 1) (570 mg , 2.3 mmol) in THF (5 mL). The reaction mixture was stirred at -78 ° C for 2 h and then at -40 ° C for an additional 1 h. EtOAc (20 mL) was added, followed by NH 4 Cl (5 mL, 10%) and water (10 mL). The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The obtained residue was purified by column chromatography on silica gel, using 50% EtOAc in hexanes as the eluent to provide methyl ester of 4-hydroxy-4-butylproline 12b (P Boc, m = 1, R9 = n-butyl) as a colorless oil (0.52 g, 73%): 1 H NMR (300 MHz, CDCl 3) d 4.33 (m, 1), 3.76 (d, J = 4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13 (m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (SPOS): 324 [+ Na] +.

Methyl ester of 4-Fluoro-4-butylproline 12c (P = Boc, m = 1, R9 = n-butyl). To a stirred solution of DAST (0.55 g, 3.4 mmol) in DCM (5 mL), at -78 ° C, was slowly added 4-hydroxyproline 12b (P = Boc, m 1, R9 = n-butyl) (520 mg, 1.7 mmol) in dry DCM (5 mL). The mixture was stirred at -78 ° C for 1 h and then at -10 ° C for 1 h more. DCM (50 ml) was added followed by 10 ml of NH4CI aq. (10%, 30 mi). The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by column chromatography, using 5% EtOAc in hexanes to obtain 4-fluoro-4-butylproline methyl ester 12c (P = Boc, m = 1, R9 = n-butyl) (270 mg, 52% ) as a colorless oil: 1 H NMR (300 MHz, CDCl 3) d 4.41 (m, 2), 3.83 (m, 1), 3.71 (s, 3), 3.45 (dd, J = 12.3, 32.7, 2), 2.48 (m, 1), 1 .73 (m, 2), 1.40 (m, 12), 0.89 (m, 3); MS (ESPOS): 326 [M + Na] +. 4-Fluoro-4-butylproline 12d (P = Boc, m = 1, R9 = n-butyl). To a solution of 12c (0.27 g, 0.89 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide monohydrate (45 mg, 1.06 mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was purified by column chromatography, using 0% MeOH in DCM as the eluent to obtain 4-fluoro-4-butylproline 12d (P = Boc, m = 1, R9 = n-butyl) (0.26 g, 100%) as a colorless oil: 1 H NMR (300 MHz, CD 3 OD) d 4.30 (m, 1), 3.72 (m, 1), 3.49 (m, 1), 3.39 (m, 1), 2.58 (m , 1), 2.02 (m, 2), 1.72 (m, 13), 0.93. (t, J = 6.6, 3); MS (ESNEG): 288 [M-1] \ 4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi-amide; co: stereoisomer 4 and stereoisomer 4 II. To a solution of 12d (P = Boc, m = 1, R9 n-butyl) (125 mg, 0.43 mmol) in DMF (3 mL), at 0 ° C, 7-CI MTL, 6b (R2 = H, R3 = Cl) (17 mg, 0.43 mmol), HBTU (180 mg, 0.47 mmol) and DIEA (1.1 mg, 0.86 mmol) and allowed to stir at room temperature overnight. The solvent was removed and the residue was purified by column chromatography on silica gel, using 2% MeOH in DCM to obtain the desired intermediate of Boc protected lincosamide (170 mg, 72%) as a light brown liquid: 1 H NMR ( 300 MHz, CD3OD) d 5.29 (d, J 5.4, 1), 4.57 (m, 3), 4.39 (m, 1), 4.03 (m, 2), 3.74 (m, 3), 3.25 (m, 1) , 2.51 (m, 1), 2.12 (m, 3), 1.85 (m, 3), 1.46 (s, 9), 1.36 (m, 6), 0.93 (t, J = 6.6, 3); MS (ESPOS): 543 [M + H] +. To a solution of the aforementioned Boc-protected lincosamide (170 mg, 0.31 mmol) in DCE (6 mL) was added triethylsilane (0.16 mL), TFA (2 mL) and water (0.16 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was purified by column chromatography on silica gel using 10% MeOH in DCM to obtain [2-chloro-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran 2-yl) -propyl] -amide of 4-fluoro-4-butyl-pyrrolidine-2-carboxylic acid, stereoisomer 4 I (14 mg, 10%); H NMR (300 MHz, CD3OD) d 5.30 (d, J = 6.0, 1), 4.54 (m, 3), 4.29 (d, J = 10.2, 1), 4.09 (dd, J = 5.6, 10.2, 1) , 3.80 (d, J = 3.0, 1), 3.56 (m, 3), 2.70 (m, 1), 2.14 (m, 4), 1.87 (m, 2), 1.43 (m, 7), 0.94 (t, J = 7.2, 3); MS (ESPOS): 443 [M + H] +. 4-Fluoro-4-butylpyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide, stereoisomer 4 II (3 mg, 2%); H NMR (300 MHz, CD3OD) d 5.30 (d, J = 6.0, 1), 434 (m, 3), 4. 29 (d, J = 10.2, 1), 4.09 (dd, J - 5.6, 10.2, 1), 3.80 (d, J = 3.0, 1), 3.56 (m, 3), 2.70 (m, 1), 2.14 (m, 4), 1.87 (m, 2), 1.43 (m, 7), 0.94 (t, J = 7.2, 3); (SPOS): 443 [M + H] +.

EXAMPLE 36 f2-chloro-1- (3,4,5-hydroxy-6-methylsulfanyl-tetrahydro-pi an-2-H) -propyl-4-fluoro-4-ethyl-piperidine-2-carboxylic acid 1-tert-butyl ester of 4-fluoro-4-ethyl-piperidine-1,2-dicarboxylic acid, 12d (P Boc, m = 2. R9 = n-eti). The synthesis of the protected 4-fluoro amino acid with Boc 12d from the starting material 1-tert-butyl ester of (2S) -4-oxo-piperidine-, 2-dicarboxylic acid employs the general method Q, represented in Scheme 12, using trimethylsilylacetylene anion as a two-carbon synthon in the alkylation step of 4-ketone. The preparation of the starting material, 1-tert-butyl ester of 4-oxo-piperidin-1,2-dicarboxylic acid, is described by Bousquet, Y .; Anderson, P. C; Bogri, T .; Duceppe J .; Grenier, L .; Guse, I .; Tetrahedron, 1997, 53 15671-15680. The synthesis of the title compound of example 36 from 12d (P = Boc, m = 2, R9 = ethyl) is easily achieved using the coupling and deprotection conditions of example 34. MS (SPOS): 429.1 [M + H ] +.

EXAMPLE 37 F2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-propylidene-piperidine-2-carboxylic acid amide -tert-butyl ester 2-methyl ester of 4-oxo-piperidine-1, 2-dicarboxylic acid. To (2S) -4-oxo-piperidine-1, 2-dicarboxylic acid 1-tert-butyl ester (0.52 g, 2.15 mmol) in methanol (10 mL), a 2 M solution of TMS-diazomethane ( 2 ml, 4 mmol) in hexane and stirred at room temperature for 15 min. The reaction solvent was removed and the obtained methyl ester product, (1-tert-butyl ester 2-methyl ester of 4-oxo-piperidine-1,2-dicarboxylic acid), was used as such in the following reaction (0.55). g, 100%): MS (ESPOS): 258 [M + H] +; 1 H NMR (300 MHz, CD 3 OD) d 5.13, 4.86 (bs, 1), 4.02-4.1, 1 (m, 1), 3.73 (s, 3), 3.67-3.72 (m, 1), 2.78 (d, J = 4.2 Hz, 2), 2.51 (bs, 2), 1.46 (bs, 9). 1-tert-butyl ester 2-methyl ester of 4-propylidene-piperidine-1,2-dicarboxylic acid. Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to sodium hydride washed with hexane (123 mg, 3.22 mmol), in THF (10 mL), and stirred at room temperature for 3 h. Methyl ester 12a (P = Boc, m = 2, P2 = Me) (0.55 g, 2.15 mmol) in THF (5 ml) was slowly added to the above reaction mixture and then allowed to stir for an additional 2 h. It was then poured into water and extracted with ethyl acetate (30 ml). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness, the resulting residue was chromatographed using 20% EtOAc in hexanes to provide the product 1-tert-butyl ester 2-methyl ester of 4-propylidene -piperidine-1, 2-dicarboxylic. (0.100 g, 16%): MS (ESPOS): 284 [M + H] +; 1 H NMR (300 MHz, CD 3 OD) d 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3), 2.94-3.04 (m, 2), 2.40- 2.48 (m, 2), 1 .99-2.06 (m, 1), 1.85- .97 (m, 2), 1.38 (bs, 9), 0.85 (t, J = 5 Hz, 3).

Ester 1-tert-butyl of 4-propylidene-piperidine-1,2-dicarboxylic acid. To the 1-tert-butyl ester 2-methyl ester of 4-propylidene-piperidine-1,2-dicarboxylic acid (0.100 g, 0.353 mmol) in THF (10 mL) was added lithium hydroxide (0.50 g, 1 1.6 mmol) in water (2 ml) and the reaction mixture was stirred at room temperature for 16 h. It was then poured into water and extracted with ether (20 ml). The water layer was then acidified with 10% HCl (5 mL) and extracted with ethyl acetate (30 mL). The product carboxylic acid tert-butyl ester of 4-propylidene-piperidine-1,2-dicarboxylic acid obtained after drying and removing the solvent was absorbed as such for the next step. MS (ESNEG): 268 [M-1] '; 1 H NMR (300 MHz, CD 3 OD) d 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9), 0.85 (t, J 5 Hz, 3). i 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-propylidene-piperldine-2-carboxylic acid. To a solution of 2b (R21 = H) (32 mg, 0.12 mmol), DIEA (0.2 mL, 1.2.20 mmol), 1-tert-butyl ester of 4-propylidene-piperidine-1,2-d-carboxylic acid (37 mg, 0.14) mmol) in DMF (5 mL) was added HBTU (57 mg, 0.16 mmol) and the mixture was stirred at room temperature for 2 h.Most of the DMF was removed under high vacuum and the crude material was absorbed in acetate of ethyl (50 ml) and washed with saturated sodium bicarbonate (10 ml) The solvent was removed in vacuo and the product was purified by column chromatography on silica gel using ethyl acetate as the eluent to obtain the protd lincosamide. with desired Boc (50 mg, 83%): S (ESPOS): 503 (M-1); 1 H NMR (300 MHz, CD3OD) d 5.19-5.27 (m, 2), 4.10-4.26 (m, 2), 3.90-4.05 (m, 2), 3.83-3.90 (m, 2), 3.49-3.88 (m, 2), 3.06 (m, 2), 2.57 (m, 2), 1.90 (s, 3), 1.4 7 (bs, 9), 0.88-0.95 (m, 9). To the aforementioned Boc-protd Iincosamide (50 mg, 0.10 mmol) in dichloroethane (6 mL), triethylsilane (0.15 mL) was added followed by aq. Trifluoroacetic acid. to 93% (2.15 mi). After stirring at RT for 1 h, the solvent was removed at 45 ° C under reduced pressure. The obtained crude product was purified by column chromatography on silica gel using 10% MeOH in DCM as the eluent to provide the title compound (5 mg, 12%): 1 H NMR (300 MHz, CD 3 OD) d 5.40 (m, 1), 5.24 (d, J = 3.8 Hz, 1), 4.16-4.20 (m, 1), 4.04-4.09 (m, 2), 3.81 (t, J = 2.2 Hz, 1), 3.49-3.55 (m , 2), 2.50-2.92 (m, 3), 2.00- 2.25 (m, 6), 2.10 (s, 3), 0.89-0.98 (m, 9). MS (SPOS): 403 [M + Hf.

EXAMPLE 38 f2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin amide of 4-propyl-1, 2,3,6-tetrahydro-pyridine- 2-carboxylic Amino acid coupling protd with Boc a 2b (R = H). To a solution of the amino acid Boc 21 k (R9 = n-propyl, R9b = H, m = 1) prepared by the general method S, represented in scheme 21 (69 mg, 0.26 mmol, 1 equiv), 2b (R2, = H) (74 mg, 0.26 mmol, 1 equiv) and HBTU (107 mg, 0.28, 1.1 equiv) in DMF (2.5 ml) at 23 ° C was added N, N-düsopropylethylamine (89 μL, 0.51 mmol, 2 equiv). The reaction was stirred at 23 ° C for 2.5 h, then concentrated in vacuo to remove the DMF. The resulting residue was dissolved in EtOAc (70 mL), then washed with 1: 1 brine: 10% aqueous citric acid (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (30 mL), dried (MgSO4). ), filtered and concentrated to yield 107 mg of the desired coupled product. This material was used without further purification in the final deproton step. H NMR (300 MHz, CD3OD) d 5.39 (br d, J = 14.4 Hz, 1 H), 5.19 (d, J = 5.7 Hz, 1 H), 4.10-3.82 (m, 4H), 3.55-3.48 (m , 1 H), 2.45 (brs, 2H), 2.05 (s, 3H), 2.04-1.94 (m, 2H), 1.47 (s, 9H), 1.46-1.37 (m, 2H), 0.96-0.83 (m, 9H); MS (SPOS): 503.3 [M + Hf.

Boc deproton to produce 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-propyl-1, 2,3 acid, 6-tetrahydro-pyridine-2-carboxylic acid To a solution of the previously exposed Boc-protd carbamate lincosamide (35 mg, 0.070 mmol, 1 equiv) in DCE (5.0 ml), at 23 ° C, H20 (0.20) was added. mi) followed by TFA (2.0 ml) The reaction was stirred at 23 ° C for 30 min, then treated with toluene (40 ml), concentrated to a volume of 10 ml, treated with a second portion of toluene ( 40 mL) and concentrated to dry The crude product was purified via semi-prep HPLC (Waters Nova-Pak® HR C18, 6 μ? T? Particle size, 60 A pore size, 25 mm diameter x 100 mm length , 5-60% acetonitrile in H2O / OI% AcOH for 30 min, 20 ml / min flow) to yield 16 mg of [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran 4-propyl-1, 2,3,6-tetrahydro-pyridine-2-carboxylic acid-2-yl-propyl] -amide pure: 1 H NMR (300 MHz, D20) d 5.51 (br s, 1 H), 5.33 (br d, J = 5.4 Hz, 1 H), 4.18 (s, 2 H), 4.13-3.98 (m, 2 H), 3.86 (br s, 1 H), 3.55-3.58 (m, 3H), 2.58-2.39 (m, 2H), 2.12 (s, 3H), 2.12-2.00 (m, 3H), 1.50-1.37 (m, 2H) ), 0.94-0.78 (m, 9H); 3C NMR (300 MHz, D20): d 170.9, 136.5, 114.5, 88.4, 70.9, 69.3, 68.8, 68.2, 55.1, 53.0, 42.3, 38.3, 29.9, 27.7, 20.0, 19.9, 14.7, 13.3, 13.1; MS (SPOS): 403.3 [M + H] +.

EXAMPLE 39 f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-ii) -propylamide of 4-propyl-1,213,6-tetrahydro-pyridine-2-carboxylic acid Coupling of the amino acid protected with Boc to 6b (R2 = H R3 = Cl). To a solution of the amino acid Boc 21 k (R9 = n-propyl, m = 1) prepared by the general method S, represented in scheme 21 (131 mg, 0.49 mmol, 1 equiv), 7-CI MTL 6b (R2 = H, R3 = Cl) (132 mg, 0.49 mmol, 1 equiv) and HBTU (203 mg, 0.54, 1.1 equiv) in DMF (4.0 ml), at 23 ° C, was added N, N-diisopropylethylamine (170 μ ? _, 0.97 mmol, 2 equiv). The reaction was stirred at 23 ° C for 2.5 h, then concentrated in vacuo to remove the DMF. The resulting residue was dissolved in EtOAc (70 mL), then washed with 1: 1 brine: 10% aqueous citric acid (50 mL), NaHCC > 3 saturated aqueous (25 ml) and brine (30 ml), dried (MgSO), filtered and concentrated to provide 276 mg of the desired coupled product. This material was used without further purification in the final deprotection stage: H NMR (300 Hz, CD3OD) d 5.41 (br s, 1 H), 5.28 (d, J = 6.0 Hz, 1 H), 4.65-4.52 (m, 1 H), 4.46-4.36 (m, 1 H), 4.25-4.16 (m, 1 H), 4.15-3.97 (m, 2H), 3.93-3.74 (m , 2H), 3.55 (dd, J = 3.3, 10.2 Hz, 1 H), 2.62-2.40 (m, 2H), 2.13 (s, 3H), 2.10-1.95 (m, 2H), 1.49 (s, 9H) , 1.46-1.32 (m, 5H), 0.90 (br t, J = 7.2 Hz, 3H); MS (SPOS): 523.2 [M + H] +. [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 4-propyl-1, 2,3,6-tetrahydro-pyridine- 2-carboxylic. To a solution of the Boc protected carbamate lincosamide (225 mg, 0.43 mmol, 1 equiv) in DCE (25 mL), at 23 ° C, H20 (1.0 mL) was added followed by TFA (10 mL). The reaction mixture was stirred at 23 ° C for 30 min, then treated with toluene (150 ml), concentrated to a volume of 30 ml, then treated with a second portion of toluene (150 ml) and concentrated to dry up. The crude product was purified via semi-prep HPLC (Waters Nova-Pak® HR C-iB, 6 μm particle size, 60 Á pore size, 25 mm diameter x 100 mm length, 5-60% acetonitrile in H 2 O /0.1 AcOH for 30 min, 20 ml / min flow) to yield 90 mg of [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] - 4-propyI-1, 2,3,6-tetrahydro-pyridine-2-carboxylic acid pure amide: H NMR (300 Hz, D20) d 5.53 (br s, 1 H), 5.39 (br d, J = 6.0 Hz, 1 H), 4.66-4.55 (m, 1 H), 4.46 (dd, J = 1.2, 10.2 Hz, 1 H), 4.33 (d, J = 9.9 Hz, 1 H), 4.19-4.07 (m, 2H), 3.88 (d, J = 2.7 Hz, 1 H), 3.74 (br s, 2H), 3.66 (dd, J = 3.0, 10.2 Hz, 1 H), 2.70-2.44 (m, 2H), 2.18 ( s, 3H), 2.08 (br t, J = 7.2 Hz, 3H), 1.52-1.37 (m, 2H), 1.42 (d, J = 6.9 Hz, 3H), 0.85 (t, J = 6.9 Hz, 3H); MS (SPOS): 423.1 [M + H] +.

EXAMPLE 40 1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid F2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide To a stirred solution of 4-pentyl [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -pyrrolidine-2-carboxylic acid (200 mg, 0.48 mmol, 1 equiv), in anhydrous acetonitrile (3 mL), at room temperature, under nitrogen atmosphere, triethylamine (0.2 mL, 1.44 mmol, 3 equiv) was added followed by bromoacetamide (80 mg, 0.58 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue obtained was first purified on silica gel, with an eluent of 7% methanolic ammonia / dichloromethane. The desired fractions were collected, evaporated to dryness and repurified by HPLC (to remove the by-product of the reaction of the base with bromoacetamide). After lyophilization, the desired title compound of Example 40 (2.0 mg) was obtained as a white fluffy powder: HPLC: R t = 4.11 min (220.0 nm); 1H R N (300 MHz, CD3OD) d (rotamers) 5.46 (d, J = 5.5, 1), 4. 47 (dd, J = 3.02, 2.7, 1.1), 4.31-4.25 (m, 3.3), 4.1 1 (d, J = 3.02, 1.6), 2.31 (s, 3), 1 .65-1 .52 (m , 9.5), 1.12-1.09 (m, 10.3). MS (ESPOS): 476.5 [M + H] (ESNEG): 474.5 [M - H] \EXAMPLE 41 f2-methyl-1- (3,4,5-dihydroxy-6-methylsulfanyl-etrahydro-pyran-2-yl) -propin- A stirred solution of 4-pentyl-pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide was treated. -carboxylic crude (210 mg, 0.50 mmol, 1 equiv) and triethylamine (0.21 ml, 1.51 mmol, 3 equiv), in anhydrous acetonitrile (3 ml) with bromoacetonitrile (42 pi, 0.60 10 mmol, 1.2 equiv), at RT and under nitrogen. The resulting reaction mixture was stirred at RT for 18 h, evaporated to dryness and purified by chromatography on silica gel, with an eluent of 2.5% methanol in dichloromethane. The desired fractions were combined, evaporated to dryness and lyophilized to give the title compound (1.2 mg, 10%) as a fluffy white powder: TLC Rf = 0.2 (5% methanol in dichloromethane); 1 H NMR (300 Hz, CD 3 OD) d 5.44 (d, J = 5.49, 1), 4.38-4.23 (m, 4), 2.29 (s, 3), 1.52 (m, 1), 1.16-1.09 (m, 12 ); MS (ESPOS): 458.5 [M + H, MS (ESNEG): 456.5 [M - H] ".

EXAMPLE 42 [1- (1 H-lmidazole-2-i < methyl) 2-methyl-1 -O ^^ - trihydroxy-e-methylsulfanyl-tetrahicyl-pyran-yl) -propyl-amide pentiol-pyrrolidine-2-carboxylic acid 1- (1-Benzyl-1 H -imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester. The amino acid protected with Boc 7d (R9 '= 4-pent-2-enyl) (433 mg, 1.16 mmol, 1 eq.) Was stirred in 4M HCl in dioxane (50 mL) for 2 h, then evaporated to dryness . The obtained residue was co-evaporated to dryness from DCM (3 x 20 mL). The crude HCl salt was dissolved in acetone (8 ml) and the resulting solution was treated with diisopropylethylamine (0.61 ml, 3.50 mmol, 3 equiv) followed by 1-benzyl-2- (chlorometho [-1 H-imidazole (Maybridge ) (338 mg, 1.39 mmol, 1.2 equiv) The reaction mixture was stirred at room temperature for 48 h and evaporated to dryness The residue obtained was diluted with EtOAc (200 ml), washed sequentially with citric acid to 10% brine, dried over Na 2 SO 4, filtered and evaporated to dry The crude material obtained was purified by chromatography on silica gel, eluting with CH 2 Cl 2 / hexanes / MeOH (6: 5: 1), to provide the desired N-alkylated product: 1- (1-benzyl-1 H -imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester (257 mg, 50%): Rf = 0.7 (7: 2: 1, CH2Cl2 / hexanes / eOH); MS (ESPOS): 444.3 [M + Hf. 1 - (1-Benzyl-1 H-imidazol-2-ylmethyl) -4-pent-2-en-1-pyrrolidine 2-carboxylic acid. To a stirred solution of 1- (1-benzyl-1 H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester (257.2 mg, 0.6 mmol, 1 equiv. ) at 4: 1 THF / H20 (8 mL), at room temperature, lithium hydroxide monohydrate (250 mg, 5.96 mmol, 10 equiv) was added. The resulting reaction mixture was stirred at room temperature overnight and evaporated to dryness. The obtained residue was dissolved in water (10 ml) and the pH of the resulting solution was adjusted between 3 and 4, and extracted with EtOAc (3 x 100 ml). The combined organic extracts were washed with brine, dried. Na2SO4, filtered and evaporated to dryness, yielding the product 1- (1-benzyl-1 H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid (202 mg, 98 mg). %): Rf = 0.4 (7: 2: 1 CH2Cl2 / hexanes / eOH), visualization spot K n04; MS (ESPOS): 355 [M + H] +; MS (ESNEG): 352 [M-H] \ r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 1- (1- benzyl-1 H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid. To a solution of 2b (R2 '= H) (96.4 mg, 0.33 mmol, 1 equiv), in anhydrous DMF (1.5 ml), under N2, at 0 ° C, triethylamine (0.4 ml, 2.9 mmol, 8.7 ml) was added. equiv), followed by BSTFA (0.4 ml, 1.51 mmol, 4.6 equiv). The resulting mixture was stirred at 0 ° C for 10 min, then at room temperature for 30 min and re-cooled. To the reaction was added a solution of 1- (1-benzyl-1 H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid (194 mg, 0.55 mmol, 1.7 equiv) followed by solid HATU (261 mg, 0.69 mmol, 2.1 equiv). The resulting mixture was stirred at room temperature for 3 h and evaporated to dryness. The resulting residue was dissolved in EtOAc, then washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The crude persilylated compound was dissolved in MeOH (60 ml) and treated with Dowex H + resin resin (250 mg) at room temperature for 45 min, the reaction mixture was filtered and evaporated to dry to give the lincosamide product. [1- methyl-1- (3,4,5-tñhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (1-benzyl-1H-imidazole) -2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid. A solution of [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide was added to a tube with dry-oven closure. of the aforementioned crude 1- (1-benzyl-1 H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid (280 mg, 0.48 mmol) in anhydrous EtOH (5 mL), 10% Pd on carbon (560 mg) and 1,4-cyclohexadiene (1.5 ml). The reaction vessel was purged with N2, sealed and stirred at room temperature for 18 h. The reaction mixture was filtered through celite, washed several times with reactive alcohol and the combined washings and filtrate evaporated to dryness. The resulting residue was purified by chromatography on silica gel (1: 9 methanolic ammonia / CF ^ C). The desired fractions were evaporated to dryness and lyophilized to give the title compound of Example 42 (29.3 mg, 18%): TLC Rf 0.7 (14% methanolic ammonia / CH2Cl2), visualization spot KMn04; MS (SPOS): 499.4 [M + Hf EXAMPLE 43 1-iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide A stirred suspension of 4-pentyl-pyrrolidine-2- 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide was treated. carboxylic [(153 mg, 0.34 mmol, 1 equiv) and ethyl formimidate (Aldrich) (44 mg, 0.40 mmol, 1.2 equiv) in dioxane (1 mL) with 1 M aqueous NaOH (0.74 mL, 0.74 mmol, 2.2 equiv) ). After 1 h, additional ethyl formimidate (44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture and stirring was continued for 30 min. The reaction mixture was frozen and lyophilized. The lyophilized powder was purified by column chromatography to provide the title compound (8 mg): TLC Rf = 0.48 CHCl3 / MeOH / 32% aqueous AcOH (5: 3: 1); MS (ESPOS): 447.7 [M + H] +, 469.7 [M + Na] +; MS (ESNEG): 481.6 [M-H + HCl] -.

EXAMPLE 44 4-Butyl-1, 2,3,6-tetrahydro-pyridine r2-Cioro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide -2-carboxylic The amino acid Boc 21 k (R9 = n-butyl, R9b = H, m = 1), prepared by the general method S, was coupled to 7-CI MTL 6b (R2 = H, R3 = Cl). This material was used without further purification in the final deprotection step. Deprotection and purification to provide the title compound were carried out as in the previous example 38. 1 H NMR (300 Hz, CD3OD) d 5.52 (br s, 1 H), 5.29 (br d, J = 5.7 Hz; H), 4.63-4.52 (m, 2H), 4.30 (d, J = 9.6 Hz, 1 H), 4.08 (dd, J = 5.7 Hz, 1 H), 4.00 (dd, J = 4.8, 1.4 Hz, 1 H), 3.81 (d, J = 2.1 Hz, 1 H), 3.69 (br s, 2 H), 3.56 (dd, J = 3.3, 10.2 Hz, 1 H), 2.66-2.35 (m, 2H), 2.20 -2.06 (m, 2H), 2.14 (s, 3H), 1 .54-1.28 (m, 7H), 0.93 (t, J = 7.2 Hz, 3H); MS (SPOS): 437.2 [M + Hf.

EXAMPLE 45 4-butyl-1,2, 3,6-tetrahydroxy-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide pyridine-2-carboxy »co The amino acid Boc 21 k (R9 = n-butyl, R9b = H, m = 1), prepared by the general method S, was coupled to lincosamine 2b (R2 '= H). This material was used without further purification in the final deprotection step. The deprotection and purification to provide the title compound were carried out as in the previous example 38. H NMR (300 MHz, D20) d 5.52 (br s, 1 H), 5.24 (d, J = 5.7 Hz, 1 H), 4.23 (dd, J = 3.6, 10.2 Hz, 1 H), 4.13-4.04 (m, 2H), 3.95 (dd, J = 5.1, 11.1 Hz, 1 H), 3.81 (d, J = 2.7 Hz, 1 H), 3.68 (br s, 2 H), 3.51 (dd, J = 3.3, 10.2 Hz, 1 H), 2.59-2.34 (m, 2H), 2.24-2.06 (m, 3H), 2.11 (s) , 3H), 1.52-1.28 (m, 4H), 0.98-0.87 (m, 9H) S (SPOS): 417.3 [+ H] +.

EXAMPLE 46 r2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide of 5-propyl-2,3,6,7-tetrahydro-1 acid H-azepine-2-carboxylic acid To a solution of the protected cyclic amino acid 22h (R = H, R9 = propyl) (340 mg, 0.88 mmol) in DMF (3 mL), was added 6b 7-CI MTL (R2 = H, R3 = Cl) ( 367 mg, 0.88 mmol) TEA (332 μl, 1.76 mmol), HBTU (496 mg, 0.97 mmol) at 0 ° C, stirring at room temperature overnight. Then the solvent was removed. Purification was carried out by column chromatography on silica gel at 50-100% EtOAc / Hexane to provide the desired protected lincosamide 13a (R9 = propyl, R9b = H, m = 2, R2 = H, R3 = Cl, P1 = H, P2 Boc) (575 mg, 90%). MS (SPOS): 537 [MA a solution of lincosamide protected with Boc 13a (R9 = propyl, R9b = H, m = 2, R2 = H, R3 = Cl, P = H, P2 = Boc) (575 mg, 1.07 mmol) in DCE (15 mL) was added (0.5 mL), TFA (5 mL) and water (0.5 mL), stirring at room temperature for 1.5 h. The reaction solvents were removed and the resulting residue was purified by chromatography on silica with 5--0% MeOH / DCM to provide the title compound (433 mg, 92%) as a colorless solid. MS (HOOKS): 437 [M + 1f EXAMPLE 47 G2 - ??? G? -1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide of acid 5 -propyl-2-carboxylic acid The unsaturated titer compound of Example 46, [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide acid 5-propyl-2,3,6,7-tetrahydro-1 H-azepine-2-carboxylic acid (433 mg, 0.99 mmol) and 10% Pd / C (80 mg), were absorbed in hydrogenated MeOH (10 ml) 3.5153 kgf / cm2 (50 psi) overnight. The solvent was removed to obtain the crude material. Purification was carried out by column chromatography on silica gel (20% MeOH / DCM) followed by preparative HPLC (general method AC) to provide isomer 1 Rt = 18.3 min (10 mg, 2.3%) and isomer 2 Rt = 18.6 min (58 mg, 13.3%). Isomer 1: 1 H NMR (300 MHz, CD 3 OD) d 5.29 (d, J = 5.4, 1), 4.88 (m, 1), 4.42 (dd, J = 1.8, 10.2, 1), 4.23 (d, J = 9.9 , 1), 4.10 (dd, J = 5.7, 10.2, 1), 3.78 (d, J = 3.3, 1), 3.71 (t, J 6.0, 1), 3.58 (dd, J = 3.3, 10.2, 1) , 3, (m, 1), 2.83 (m, 1), 2.13 (m, 2), 2.03 (m, 2), 1.86 (m, 2), 1.73 (m, 1), 1.50 (m, 4) , 1.42 (m, 6), 0.92 (t, J = 6.6, 3); MS (SPOS): 439 [M + Hf.

Isomer 2: 1 H NMR (300 MHz, CD3OD) d 5.30 (d, J = 5.7, 1), 5.30 (d, J = 5.7, 1), 4.61 (m, 2), 4.29 (d, J = 9.9, 1), 4.10 (dd, J = 5.7, 10.2, 1), 4.00 (m, 1), 3.78 (d, J = 3.0, 1), 3.58 (dd, J = 3.3, 10.2, 1), 3.39 (m , 1), 3.08 (m, 1), 2.14 (m, 4), 1.96 (m, 3), 1.59 (m, 3), 1.45 (m, 3), 1.35 (m, 4 ), 0.93 (t, J = 6.9, 3); MS (ESPOS): 439 [M + H] +.

EXAMPLE 48 1-cyclopropyl-5-propyl-azepane-2-carboxylic acid f2-methyl-1- (3A54-dihydroxy-6-methylsulfuric acid amide To [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 5-propyl-azepane-2-carboxylic acid , prepared by the methods described in Examples 47, 48 (68 mg, 0.16 mmol) in MeOH (2 mL), acetic acid (0.1 mL) was added, followed by - [(etoxycyclopro-pyl) oxytrimethylsilane (0.2 mL, 0.96 mmol), sodium cyanoborohydride (41 mg, 0.64 mmol), and 3Á molecular sieves, heated to reflux for 3 h. The molecular sieves were filtered and the reaction solvent was removed to obtain the crude material. Purification was carried out by column chromatography on silica gel (10% MeOH / DCM) and HPLC to provide the title compound (44 mg, 59%).

H NMR (300 MHz, CD3OD) d 5.20 (d, J = 5.4, 1), 4.15 (d, J = 6.6, 1), 4.08 (dd, J = 5.4, 9.9, 1), 3.96 (d, J = 3.0, 1), 3.88 (t, J = 13.2, 1), 3.62 (m, 1), 3.56 (dd, J = 3.3, 10.2, I), 3.14 (m, 1), 2.82 (m, 1), 2.13 (m, 2), 2.05 (s, 3), 1.99-1.30 (m, 10), 0.96 (m, 9), 0.51 (m, 4); MS (ESPOS): 459 [M + H] +.

EXAMPLE 49 [2-chloro-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide of) 1 - (5-methyl-2-oxo-ri) , 3rdioxol-4-ylmethyl) -5-propyl-azepane-2- The reaction, either with isomer 1 or with isomer 2 of the title compound of example 46 1 (wherein R 2 = H, R 3 = Cl, R 6 = H, R 9 = 5-n-propyl, and m = 3 ) with 4-Bromomethyl-5-methyl- [1, 3] d -oxo-2-one (prepared as described in J. Alexander, et.al. J. Med. Chem, 1996, 39, 480-486 .) in DMF, in the presence of sodium carbonate.

EXAMPLE 50 2-12-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) 5-methyl-2-oxo-ri, 31-dioxol-4-ylmethic acid ester propylcarbamoyl-5-propyl-azepane-1-carboxylic acid The title compound was prepared by treatment, either of isomer 1 or of isomer 2 of the title compound of example 46 1 (wherein R2 H, R3 = Cl, Rs = H, R9 = 5-n-propyl, and = 3) with 5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester 4-nitro-phenyl ester of carbonic acid (prepared as described in F. Sakamoto, et.a /, Chem. Pharm. Bull. 1984, 32 (6), 2241-2348) in DMF, in the presence of potassium bicarbonate.

EXAMPLE 51 5-Methyl-azepane-2-carboxylic acid f2-chloro-1- (314,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide cyclic amino acid 22f (R9 = propyl, R9b H, m = 2) prepared by the general method T as represented in general method Z to provide the intermediate carbamate 13a (R9 = Methyl, R9b = H, m = 2, R2 = H, R3 = Cl, P = H, P2 = Boc) which was deprotected under acidic conditions to provide the crude unsaturated intermediate. Hydrogenation of the compound saturated with 10% Pd / C in MeOH at 3.5153 kgf / cm 2 (50 psi) H 2 yielded a crude mixture of 5-position isomers. The two 5-position isomers were separated by preparative HPLC. Isomer 1 (low Rt) H NMR (300 MHz, CD3OD) d 5.30 (d, J = 5.7, 1), 4.58 (dd, J 6.3, 10.8, 2), 4.30 (d, J = 9.9, 1), 4.10 (m, 1), 3.79 (m, 1), 3.58 (m, 1), 3.33 (m, 1), 3.13 (m, 1), 2.14 (m, 4), 1.92 (m, 3), 1.55 ( m, 1), 1.44 (d, J = 9.9, 6), 1.00 (d, J = 9.9, 3); Rt: 14.2 min; MS (ESPOS): 412 [M + H] + Isomer 2 (high Rt): 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J 5.7, 1), 4.59 (m, 2), 4.30 (d, J = 9.9, 1), 4.10 (m, 1), 3.99 (m, 1), 3.81 (m, 1), 3.58 (m, 1), 3.14 (m, 1), 2.14 (m, 4), 1.90 ( m, 3), 1.51 (m, 1), 1.44 (d, J 9.9, 6), 1.00 (d, J = 9.9, 3); Rt = 14.5 min; MS (SPOS): 412 [+ H] \ EXAMPLE 52 r2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin amide of 5-ethyl-azepane-2-carboxylic acid Lincosamine 6b 7-CI MTL (R2 = H, R3 = Cl) was coupled to cyclic amino acid 22f (R9 = propyl, R9b = H, m = 2) prepared by the general method T, as depicted in general method Z to provide the intermediate carbamate 13a (R9 = ethyl, R9b = H, m = 2, R2 = H, R3 = Cl, P1 = H, P = Boc) which was deprotected under acidic conditions to provide the crude unsaturated intermediate. Hydrogenation of the unsaturated compound with 10% Pd / C in MeOH at 3.5153 kgf / cm2 (50 psi) H2 gave a crude mixture of 5-position isomers. The two 5-position isomers were separated by preparative HPLC. Isomer 1 (low Rt): 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J, 6.0, 1), 4.59 (m, 1), 4.49 (m, 1), 4.27 (d, J = 9.9, 1 ), 4.10 (dd, J = 6.0, 10.2, 1), 3.92 (m, 1), 3.79 (m, 1), 3.55 (m, 1), 2.99 (m, 1), 2.14 (m, 4), 1.79 (m, 3), 1.45 (d, J = 9.9, 6), 1.38 (m, 3), 0.99 (m, 3); R = 14.6 min MS (ESPOS): 425.3 [M + H] +. Isomer 2 (high Rt): 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J = 6.0, 1), 4.80 (m, 2), 4.29 (d, J = 9.9, 1), 4.10 (dd, = 6.0, 10.2, 1), 3.98 (m, 1), 3.80 (d, J2.7, 1), 3.59 (dd, J = 3.0, 10.2, 1), 3.07 (m, 1), 2.14 (m, 4 ), 1.92 (m, 3), 1.52 (m, 1), 1.45 (d, J = 9.9, 6), 1.32 (m, 2), 0.93 (m, 3) Rt: 16 min; MS (SPOS): 425.3 [M + H] + EXAMPLE 53 5-Cyclopropylmethyl-azepane-2-carboxylic acid f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin amide The title compound was prepared by coupling the cyclic amino acid 22f (R9 = cyclopropylmethyl, R9b '= H, m = 2), prepared by the general method T, to lincosamine 6b 7-CI MTL (R2 = H, R3 = Cl) as represented in general method Z. Hydrogenation of the unsaturated compound with 10% Pd / C as in Example 47 provides the title compound as a mixture of 5-position isomers.

EXAMPLE 54 5-Cyclopropyl-azepane-2-carboxylic acid f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide The title compound was prepared by coupling cyclic amino acid 22f (R9 = cyclopropyl, R9b = H, m = 2), prepared by the general method T, to lincosamine 6b 7-CI TL (R2 = H, R3 = Cl) such as it is represented in the general method Z. Hydrogenation of the unsaturated compound with 0% Pd / C as in example 47 provides the title compound as a mixture of the 5-position isomers.

EXAMPLE 55 5-Ethyl-4-methyl-azepane-2-carboxylic acid 5-ethyl-4-methyl-azepane-2-carboxylic acid (5-chloro-1- (3-hydroxy-5-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide) The title compound was prepared by coupling the cyclic amino acid 22f (R9 = ethyl, R9b = methyl, m = 2), prepared by the general method T, to lincosamine 6b 7-CI MTL (R2 = H, R3 = Cl) such as is represented in general method Z. Hydrogenation of the unsaturated compound with 10% Pd / C as in example 47 provides the title compound as a mixture of isomers.

EXAMPLE 56 4-ethyl-5-methyl-azepane-2-carboxylic acid r2-chloro-1 -f3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide The title compound was prepared by coupling the cyclic amino acid 22f (R9 = methyl, R9b = ethyl, m = 2), prepared by the general method T to lincosamine 6b 7-CI MTL (R2 = H, R3 Cl), such as is represented in general method Z. Hydrogenation of the unsaturated compound with 10% Pd / C as in example 47 provides the title compound as a mixture of isomers.

EXAMPLE 57 5-ethyl-6-methyl-azepane-2-carboxylic acid 5-ethyl-6-methyl-azepane-2-carboxylic acid f2-chloro-1-Q ^^ - trihydroxy-e-methylsulfanyl-tetrahydro-pyran- -D-propylamide The title compound was prepared by coupling the cyclic amino acid 22f (R9 = methyl, R9b = ethyl, m = 1), prepared by the general method T, to the lincosamine 6b 7-CI MTL (R2 = H, R3 = Cl), as represented in general method Z. Hydrogenation of the unsaturated compound with 10% Pd / C as in example 47 provides the title compound as a mixture of isomers.

EXAMPLE 58 G2 - ??? G? -1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrah.) 4-propyl-azepane-2-hydroxy-2-in-propylamide. carboxy The title compound was prepared by coupling the cyclic amino acid 22f (R = H, R = propyl, m = 2), prepared by the general method T to Nncosamine 6b 7-CI MTL (R2 = H, R3 = Cl), such as it is represented in general method Z. Hydrogenation of the unsaturated compound with 10% Pd / C as in example 47 provides the title compound as a mixture of 4-position isomers.

EXAMPLE 59 r2 parlor-1 - (3A5-5-fluoro-5-propyl-azepane-2-carboxylic acid 5-fluoro-5-propyl-azepane-2-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide The title compound was prepared by coupling amino acid 12d (R9 = propyl, m = 2) to lincosamine 6b 7-CI MTL (R2 = H, R3 = Cl) as depicted in general method Z.

EXAMPLE 60 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-yran-2-yl) »methylamide Lincosamide 23g (R20 + R21 = cyclopropyl, R = SMe) was coupled to 4-n-propylhydric acid, prepared by the method of Hoeksema, H. et. to the.

Journal of the American Chemical Society, 1967, 89-2448-2452, as depicted in general method Z to provide the title compound. H NMR (300 MHz, D20) d 5.37 (d, J = 5.7 Hz, 1 H), 4.26-4.18 (m 2H), 4.10 (dd, J = 5.7, 9.9 Hz, 1 H), 3.98 (d, J = 3.0 Hz, 1 H), 3.82 (dd, J 6.6, 1 1 .1 Hz, 1 H), 3.72 ( d, J = 8.7 Hz, 1 H), 3.67 (dd, J = 3.3, 7.2 Hz, H), 2.96-2.83 (m, 1 H), 2.90 (s, 3H), 2.45-2.16 (m, 3H) , 2.10 (s, 3H), 1.50-1.22 (m, 4H), 1.10-0.98 (m, 1 H), 0.86 (t, J = 7.2 Hz, 3H), 0.67-0.56 (m, 1 H), 0.50 -0.40 (m, 1 H), 0.32-0.14 (m, 2H). MS (ESPOS): 403.3 [M + H]; MS (ESNEG): 437.2 [M + Cl].

EXAMPLE 61 rc} 4-propyl-piperidine-2-carboxylic acid (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide Lincosamide 23g (R20 + R21 = cyclopropyl, R1 = SMe) was coupled to the ester-tert-butyllic 4-propyl-piperidine-1,2-dicarboxylic acid 27b (R9 = propyl) as represented by general method Z to provide the title compound. Intermediate 13a (R1 = SMe, R20 + R2 = cyclopropyl, R9 propyl, P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 2) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, D 20) d 5.37 (d, J = 5.7 Hz, 1 H), 4.20 (d, J = 9.0 Hz, 1 H), 4.09 (dd, J 5.7, 10.2 Hz, 1H), 3.96 ( d, J = 3.3 Hz, 1 H), 3.85 (dd, J = 3.0, 12.9 Hz, 1 H), 3.75-3.65 (m, 2H), 3.51-3.42 (m, 1 H), 3.07-2.96 (m , 1 H), 2.21-2.10 (m, 1 H), 2.10 (s, 3H), 1.99-1.90 (m, 1 H), 1.80-1.65 (m, 1 H), 1.46-1.23 (m, 6H) , 1.11 -0.98 (m, 1 H), 0.85 (t, J = 6.6 Hz, 3H), 0.66-0.55 (m, 1 H), 0.50-0.36 (m, 1 H), 0.30-0.12 (m, 2H) ); MS (ESPOS): 403.3 [M + H]; MS (ESNEG): 437.2 [M + Cl]. EXAMPLE 62 5-propyl-azepane-2-carboxylic acid 5-propyl-azepane-2-carboxylic acid cyclopropyl- (3,4,5-dihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl-amide Lincosamide 23g (R20 + R21 cyclopropyl, R1 = SMe) was coupled to 1-tert-butyl ester of 5-propyl azepine-1,2-dicarboxylic acid, as depicted in the general coupling method Z to provide the composed of the title. Intermediate 13a (R20 + R21 = cyclopropyl, R9 = propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 3) which was deprotected under acidic conditions to provide the title compound. MS (SPOS): 451.2 [M + H] +.

EXAMPLE 63 4-propyl-piperidine-2-carboxylic acid rphenyl- (3,4,5-hydroxy-6-methylsuiphanyl-tetrahydro-pyran-2-yl) -methyl-amide Lincosamide 23f (R20 + R21 Ph, R1 = SMe) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CDCl 3) d 7.41-7.26 (m, 5H), 6.90 (br d, J = 9.6 Hz , 1 H), 5.55 (d, J = 5.4 Hz, 1 H), 5.49 (dd, J = 1.2, 3.3 Hz, 1 H), 5.30-5.23 (m, 2H), 5.17 (dd, J = 3.3, 10.8 Hz, 1 H), 4.68 (dd, J = 0.9, 8.4 Hz, 1 14), 2.08 (s, 3H), 2.06 (s, 3H), 1.97 (s, 3H), 1.62 (s, 3H) ); MS (SPOS): 530.0 [M + Na]; 'MS (ESNEG): 506.0 [M - H]. Lincosamide 23g (R20 + R21 = Ph, R1 = SMe) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CD3OD) d 7.40-7.20 (m, 5H), 5.09 (d, J = 5.7 Hz, 1 H), 4.16-4.05 (m, 4H), 3.58 (dd, J = 3.3, 10.2 Hz, 1 H), 1.38 (s, 3H); MS (ESPOS): 286.0 [M + H]; MS (ESNEG): 284.2 [M - H]. Lincosamide 23g (R20 + R21 = Ph, R1 = SMe) was coupled to 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid 27b (R9 = propyl), as represented by the method general Z to provide the title compound. Intermediate 13a (R20 + R21 = Ph, R9 = propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 2) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 Hz, D 20) d 7.46-7.30 (m, 5H), 5.15 (d, J = 5.7 Hz, 1 H), 5. 1 (d, J 9.9 Hz, 1 H), 4.51 (d, J) = 10.2 Hz, 1 H), 4.13-4.03 (m, 2H), 3.91 (dd, J = 3.0, 12.9 Hz, 1H), 3.68 (dd, J 3.3, 10.2 Hz, 1 H), 3.49-3.40 (m , 1 H), 3.07-2.95 (m, 1 H), 2.10-2.01 (m, 1 H), 1.96-1.86 (m, 1 H), 1 .78-1.62 (m, 1 H), 1 .51 (s, 3H), 1.36-1.07 (m, 6H), 0.82 (t, J = 6.6 Hz, 3H) MS (SPOS): 439.3 [M + HJ; MS (ESNEG): 473.2 [M + Cl] EXAMPLE 64 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid, rhenyl- (3,4,5-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-in-methyl-1-amide Lincosamide 23g (R20 + R21 = Phenyl, R1 = SMe) was coupled to 4-n-represented in general method Z to provide the title compound. 1 H NMR (300 MHz, D 20) d 7.47-7.30 (m, 5 H), 5.15 (d, J = 5.7 Hz, 1 H), 5.1 (d, J = 10.2 Hz, 1 H), 4.50 (d, J = 9.9 Hz, 1 H), 4.28 (cid ,, J = 5.4, 9.3 Hz, 1H), 4.11-4.04 (m, 2H), 3.75 (dd, J = 6.0, 11.1 Hz, 1H), 3.68 (dd, J = 3.3, 10.5 Hz, 1 H), 2.91 (s, 3H), 2.90-2.80 (m, 1 H), 2.45-1.90 (m, 3H), 1.48 (s, 3H), 1 .44-1.10 (m , 4H), 0.78 (t, J = 7.2 Hz, 3H); MS (ESPOS): 439.3 [M + H]; MS (ESNEG): 473.2 [M + Cl].

EXAMPLE 65 4-propyl-piperidine-2-carboxyHC-4-propyl-piperidine-2-carboxy-4- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl-amide SMe) as shown in scheme 23. 1H NMR (300 MHz, CDCI3) d 6.29 (br d, J = 9.0 Hz, 1 H), 5.63 (d, J = 5.7 Hz, 1 H), 5.43 (d, J = 3.3 Hz, 1 H), 5.25 (dd, J = 5.4, 11.1 Hz, 1 H), 5.14 (dd, J = 3.3, 1 1.1 Hz, 1 H), 4.40-4.38 (m, 2H), 2.30-2.08 (m, 1 H), 2.14 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.97 (s, 3H), 1.86-1.48 (m, 6H), 1.27-1.12 (m, 2H); MS (ESPOS): 522.2 [M + Na]; MS (ESNEG): 498.2 [M - H]. Lincosamide 23g was prepared (R20 + R21 = cyclopentyl, R1 = SMe) as represented in scheme 23. 1 H NMR (300 MHz, CD3OD) d 5.28 (d, J = 5.7 Hz, 1 H), 4. 6-4.08 (m, 2H), 3.93 (dd, J = 0.9, 6.6 Hz, 1 H), 3.54 (dd, J = 3.0, 10.2 Hz, 1 H), 2.99 (t, J = 6.6 Hz, 1 H), 2.17-2.04 (m, 1 H), 2.07 (s) , 3H), 1.88-1.51 (m, 6H), 1.42-1.26 (m, 2H)

[0518] S (SPOS): 278.3 [M + H]; MS (ESNEG): 276.2 [M-H], Lincosamide 23g (R20 + R21 = cyclopentyl, R1 = SMe) was coupled to 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid. Co 27b (R9 = propyl) as represented by general method Z to provide the title compound. Intermediate 13a (R20 + R2 = cyclopentyl, R9 = propyl, P H, P2 = t-butyl ester of the carboxylic acid, m = 2) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, D 20) d 5.37 (d, J = 5.7 Hz, 1 H), 4.23 (dd, J = 5.4, 9.3 Hz, 1 H), 4. 5 (d, J = 9.3 Hz, 1 H) , 4.09 (dd, J = 5.7, 10.5 Hz, H), 3.90 (dd, J = 3.3, 13.2 Hz, 1 H), 3.63 (dd, J = 3.3, 10.5 Hz, 1 H), 3.49 (br d, J = 12.6 Hz, 1 H), 3.10-2.98 (m, 1 H), 2.32-2.12 (m, 2H), 2.13 (s, 3H), 2.10-1.91 (m, 1 H), I 80-1.04 (m, 16H), 0.87 (t, J = 6.6 Hz, 3H); MS (ESPOS): 431.3 [M + H]; MS (ESNEG): 465.2 [M + C!].

EXAMPLE 66 Cyclopentyl- (3A5 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid 1-methyl-4-propyl) -hydroxy-6-methylsulfamide Lincosamide 23g (R20 + R21 = cyclopentyl, R1 = SMe) was coupled to 4-n-propylhydric acid, as represented by general method Z to provide the title compound. 1 H NMR (300 MHz, D 20) d 5.35 (d, J = 6.0 Hz, 1 H), 4.31-4.22 (m, 2 H), 4. 6 (d; J = 9.0 Hz, 1 H), 4.09 (dd, J = 5.7, 10.5 Hz, 1 H), 3.94 (d, J = 3.0 Hz, 1 H), 3.85 (dd, J = 6.3, 11.1 Hz, 1 H), 3.63 (dd, J = 3.0, 10.5 Hz, 1 H), 2.95-2.85 (m, 1 H), 2.93 (s, 3H) 2.45-2.13 (m, 3H), 2.13 (s, 3H), 1.84-1.03 (m, 13H), 0.87 (t, J = 7.2 Hz, 3H); MS (ESPOS): 431.3 [M + H]; MS (ESNEG): 465.2 [M + Cl].

EXAMPLE 67 5-Propyl-azepane-2-carboxylic acid cyclopentyl- (3,4,5-trihydroxy-6-methylisulfanyl-tetrahydro-pyran-2-yl) -methi amide 1-tert-butyl ester of 5-propyl azepine-1,2-dicarboxylic acid, as represented by general method Z to provide the title compound. Intermediate 13a (R1 = SMe, R20 + R2 = cyclopentyl, R9 propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 3) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, D 20) d 5.33 (d, J = 5.7 Hz, 1 H), 4.24 (dd, J = 4.8, 9.0 Hz, 1 H), 4.19-4. 1 (m, 2H), 4.07 (dd, J = 5.7, 10.5 Hz, 1 H), 3.90 (d, J = 3.0 Hz, 1 H), 3.62 (dd, J = 3.3, 10.5 Hz, 1 H), 3.46 (dd, J = 4.2, 13.8 Hz, 1H), 3.19-3.08 (m, 1 H), 2.36-2.09 (m, 3H), 2.12 (s, 3H), 2.08-1.81 (m, 2H), 1.80 -1.40 (m, 8H), 1.36-1.01 (m, 7H), 0.83 (t, J = 6.6 Hz, 3H); MS (ESPOS): 445.2 [M + H]; MS (ESNEG): 479.0 [M + Clj.

EXAMPLE 68 RI- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -but-3-enyl-amide of 1-methyl-4-propyl -pyrrolidine-2-carboxylic acid Lincosamide 23f (R20 = vinyl, R2 = H, R1 = SMe) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CDCl 3) d 6.31 (br d, J = 9.3 Hz, 1 H), 5.80 -5.62 (m, 1 H), 5.64 (d, J = 5.4 Hz, 1 H), 5.41 (dd, J = 0.9, 3.0 Hz, 1H), 5.26 (dd, J = 5.4, 10.8 Hz, H), 5.23-5.10 (m, 3H), 4.42-4.25 (m, 2H), 3.56-2.44 (m, 1 H), 2.35-2.23 (m, 1 H), 2.14 (s, 3H), 2.09 (s, 3H) ), 2.08 (s, 3H), 1.97 (m, 3H); MS (ESNEG): 470.0 [M-H]. Lincosamide 23g (R20 = vinyl, R21 = H, R = SMe) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CD3OD) d 5.94-5.78 (m, 1 H), 5.27 (d, J = 5.7 Hz, 1 H), 5.20-5.10 (m, 2H), 4.09 (dd, J = 5.7, 10.2 Hz, 1 H), 4.04 (dd, J = 1.5, 3.3 Hz, 1 H), 3.82 (dd, J = 0.9, 8.1 Hz, H), 3.57 (dd, J = 3.3, 9.9 Hz, 1 H), 3.13 (dt, J = 3.9, 8.4 Hz, 1 H), 2.57-2.47 (m, 1 H), 2.14 -2.02 (m, 1 H), 2.07 (s, 3H); MS (SPOS): 272.0 [M + Na]; MS (ESNEG): 248.2 [M - H].

Lincosamide 23g (R20 = vinyl, R2 = H, R1 = SMe) was coupled to 4-n-propylhydric acid as depicted in general method Z to provide the title compound. 1 H NMR (300 Hz, D20) d 5.84-5.68 (m, 1 H), 5.37 (d, J = 5.7 Hz, 1 H), 5.16-5.07 (m, 2H), 4.28-4.18 (m, 2H), 4.14-4.07 (m, 2H), 3.93 (d, J = 3.3 Hz, 1 H), 3.82 (dd, J = 6.3, 1 1.1 Hz, 1 H), 3.66 (dd, J = 3.3, 10.5 Hz, 1 H), 2.91-2.83 (m, 1 H), 2.91 (s, 3H), 2.67-2.58 (m, 1 H), 2.40-2.10 (m, 4H), 2.1 1 (s, 3H), 1.52-1.22 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); MS (SPOS); 403.3 [M + H]; MS (ESNEG): 437.0 [M, + Cl].

EXAMPLE 69 n- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -but-3-enin-amide of 4-propyl-piperidine-2-carboxylic acid Lincosamide 23g (R20 R21 = H, R1 = SMe) was coupled to the 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid 27b (R9 = propyl), as depicted in general method Z to provide the title compound. Intermediate 13a (vinyl R20, R21 = H, R = SMe, R9 = propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 2) which was deprotected under acidic conditions to provide the title compound. HRN (300 Hz, D20) d 5.82-5.66 (m, 1 H), 5.37 (d, J = 5.7 Hz, 1 H), 5.16-5.07 (m, 2H), 4.24-4.05 (m, 3H), 3.92 (d, J = 3.3 Hz, 1 H), 3.85 (dd, J = 3.3, 12.9 Hz, 1 H), 3.66 (dd, J = 3.3, 10.5 Hz, 1 H), 3.47 (br d, J 12.3 Hz , 1 H), 3.08-2.96 (m, 1 H), 2.66-2.56 (m, 1 H), 2.22-2.10 (m, 2H), 2.1 1 (s, 3H), 1.99-1.89 (m, 1 H) ), 1.80-1.64 (m, 1 H), 1.41-1.22 (m, 6H), 0.87 (t, J = 6.6 Hz, 3H); MS (ESPOS): 403.3 [M + H]; MS (ESNEG): 437.2 [M + Cl]. Hydrogenation of the title compound from Example 69 afforded the title compound.

EXAMPLE 70 f1 - 5-Propyl-azepane-2-carboxylic acid (3,4,5-trihydroxy-6-methylsulfanH-tetrahydro-pyran-2-yl) -butyl-1-amide The title compound was prepared by coupling the cyclic amino acid 22f (R9 propyl, R9e = H, m = 2) prepared by the general method T to lincosamine 23g (R2 ° = ethyl, R21 = H, R1 = S e), such as it was represented in general method Z. Hydrogenation of the unsaturated intermediate gave the title compound. 1 H NMR (300 MHz, D 20) d 5.34 (d, J = 5.7 Hz, 1 H), 4.16-4.04 (m, 3 H), 4.01 (d, J = 9.3 Hz, 1 H), 3.89 (d, J = 3.3 Hz , 1H), 3.64 (dd, J = 3.3, 10.5 Hz, 1H), 3.45 (dd, J = 5.1, 13.2 Hz, 1H), 3.13 (t, J = 12.0 Hz, 1H), 2.20-1.16 (m, H), 2.08 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H), 0.83 (t, J = 6.9 Hz, 3H); MS (SPOS): 419.0 [M + HJ; MS (ESNEG): 453.2 [M + C!].

EXAMPLE 71 ri- (3,4,5-Rihydroxyl) -6-methylsulfanyl-tetrahydro-pyran-2-yl) -butylamide of 4-propyl-piperidine-2-carboxylic acid 1 H NMR (300 MHz, D 20) d 5.34 (d, J = 6.0 Hz, 1H), 4.14-4.04 (m, 2H), 4.00 (d, J 9.3 Hz, 1H), 3.91-3.83 (m, 2H), 3.64 (dd, J = 3.3, 10.5 Hz, 1H), 3.51-3.43 (m, 1H), 3.08-2.96 (m, 1H), 2.22-2.13 (m, 1H), 2.07 (s, 3H), 1.99- 1.89 (m, 1H), 1.83-1.65 (m, 2H), 1.48-1.13 (m, 9H), 0.85 (t, J = 7.5 Hz, 6H); MS (ESPOS): 405.4 [M + H]; MS (ESNEG): 439.2 [M + Cl].

EXAMPLE 72 ri- (3,4,5-trihydroxy-6-methylsulfann-tetrahydro-pyran-2-yl) -butyl-amid3 of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid Hydrogenation of the title compound of Example 68 afforded the title compound. 1H RN (300 MHz, D20) d 5.36 (d, J = 6.0 Hz, 1 H), 4.28-4.03 (m, 4H), 3.93 (d, J = 3.0 Hz, 1 H), 3.85 (dd, J = 6.9, 1 1.1 Hz, 1 H), 3.66 (dd, J = 3.0, 10.2 Hz, 1 H), 2.95-2.85 (m, 1 H), 2.93 (s, 3H), 2.47-2.19 (m, 3H) , 2.10 (s, 3H), 1.86-1.70 (m, 1 H), 1.54-1.16 (m, 7H), 0.87 (t, J = 6.9 Hz, 6 H); MS (ESPOS): 405.4 [M + H]; MS (ESNEG): 439.2 [M + CQ.

EXAMPLE 73 r (4-Chloro-phenyl) - (3,4,5-trihydroxy-6-methylsulfani [-tetrahydro-pyran-2-yl] -methyl] - 1-methyl-4-propyl-pyrrolidine-2-amide -carboxylic Lincosamide 23f (R20 + R2 = 4-chlorophenyl, R1 = SMe) was prepared as shown in scheme 23. H NMR (300 MHz, CDCl3) d 7.34 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8. 4 Hz, 2H), 7.16 (br d, J = 9.0 Hz, 1 H), 5.55 (d, J = 5.4 Hz, 1 H), 5.50 (d, J = 2. 1 Hz, 1 H), 5.30-5.13 (m, 3H), 4.66 (d, J = 8.7 Hz, 1 H), 2.09 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 1.65 (s, 3H); MS (ESPOS): 563.9 [M + Na]; MS (ESNEG): 539. 8 [M - H]. Lincosamide 23g (R20 + R21 = 4-chlorophenyl, R1 = SMe) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CD3OD) d 7.37 (d, J = 8.4 Hz, 2H), 7.31 (d , J = 9.0 Hz, 2H), 5.09 (d, J = 6.0 Hz, 1 H), 4.13-4.03 (m, 4 H), 3.58 (dd, J = 3.3, 10.2 Hz, 1 H), 1.41 (s) , 3H); MS (SPOS): 320.0 [M + H]; MS (ESNEG): 354.0 [M + CI].

Lincosamide 23g (R20 + R2 = R1 = SMe) was coupled to 4-n-propylhydric acid represented in general method Z to provide the title compound. 1 H NMR (300 MHz, D 20) d 7.43 (d, J = 8.1 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 5.18 (d, J 6.0 Hz, 1 H), 5.12 (d, J = 10.2 Hz, 1 H), 4.48 (d, J 9.9 Hz, 1 H), 4.29 (dd, J = 5.4, 9.0 Hz, 1 H), 4.14-4.05 (m, 2H), 3.78 (dd, J = 5.7, 10.8 Hz, 1 H), 3.70 (dd, J = 3.3, 10.2 Hz, 1 H), 2.92 (s, 3H), 2.87 (t, J = 10.8 Hz, 1 H), 2.26-2.11 (m, 2H), 2.07-1.94 (m, 1 H), 1.52 (s, 3H), 1.46-1.12 (m, 4H), 0. 81 - (t, J = 7.2 Hz, 3H); MS (SPOS): 473.2 [M + HJ; MS (ESNEG): 507.2 [M + CI].

EXAMPLE 74 ^ -chloro-phenin-fS ^^ - trihydroxy-S-methylsulfanyl-tetrahydro-pyran ^ -in-methylamide of 4-propyl-piperidine-2-carboxylic acid Lincosamide 23g (R20 + R21 = 4-chlorophenyl, R1 = SMe) was coupled to acid 27b (R9 = propyl) represented in general method Z to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 7.35 (s, 4 H), 5.20 (d, J = 9.6 Hz, 1 H), 5.14 (d, J = 6.0 Hz, 1 H), 4.36 (d, J = 9.3 Hz , 1 H), 4.10 (dd, J = 5.7, 10.2 Hz, 1 H), 3.99 (d, J = 3.0 Hz, 1 H), 3.89 (dd, J = 3.0, 12.6 Hz, 1 H), 3.59 ( dd, J = 3.3, 10.2 Hz, 1 H), 3.45-3.36 (m, 1 H), 3.04 (dt, J = 3.3, 13.2 Hz, H), 2.24-2.14 (m, 1 H), 1.98-1.88 (m, 1 H), 1.81-1.66 (m, 1 H), 1.52 (s, 3H), 1.46-1.13 (m, 6H), 0.94 (t, J = 7.2 Hz, 3H); MS (ESPOS): 473.2 [M + H]; MS (ESNEG): 507.2 [M + Cl].

EXAMPLE 75 1-Methyl-4-propy-pyrrolidine-2-carboxylic acid f2-metU-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) propyl-amide Lincosamide 23f (R methyl, R = methyl, R 1 = isopropylsulfanyl) was prepared as shown in scheme 23. H NMR (300 MHz, CDCl 3) d 6.10 (br d, J 10.5 Hz, 1H), 5.79 ( d, J = 5.4 Hz, 1 H), 5.36 (dd, J = 1.2, 3.3 Hz, 1 H), 5.20 (dd, J = 5.7, 1.1 Hz, 1 H), 5.09 (dd, J = 3.3, 10.8 Hz, 1 H), 4.36 (dd, J = 0.9, 9.9 Hz, 1 H), 4.26 (dt, J 3.0, 10.2 Hz, 1 H), 3.04-2.90 (m, 1 H), 2.13 (s, 3H ), 2.07 (s, 3H), 1.97 (s, 3H), 1.29 (d, J = 4.8 Hz, 3H), 1.27 (d, J = 5.1 Hz, 3H), 0.91 (d, J 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H) MS (HORMS): 524.0 [M + Na] MS (ESNEG): 500.0 [M-H] Unscosamide 23f was prepared (R20 methyl, R21 = methyl, R1 = isopropyl sulfanyl) as depicted in scheme 23. 1 H NMR (300 MHz, CD3OD) d 5.36 (d, J = 6.0 Hz, 1 H), 4.05 (dd, J = 5.7, 10.2 Hz, 1 H), 4.01 (dd, J = 1.5, 3.3 Hz, 1H), 3.95 (dd, J = 1.2, 8.7 Hz, 1 H), 3.48 (dd, J = 3.3, 10.5 Hz, 1 H), 3.04-2.93 (m, 1 H), 2.89 (dd, J = 3.6, 8.4 Hz, 1 H), 2.07-1.95 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.26 (d, J) = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); MS (ESPOS): 280.0 [M + H]; MS (ESNEG): 278.2 [M-H] 23g (R20 = methyl, R21 methyl, R1 = isopropyl sulfanyl) was coupled to 4-n-propylhydric acid, as depicted in general method Z to provide the title compound . 1 H NMR (300 MHz, D 20) d 5.47 (d, J = 6.0 Hz, 1 H), 4.25 (br t, J = 7.2 Hz, 1 H), 4.16 (br s, 2 H), 4.07 (dd, J = 5.7, 10.5 Hz, 1 H), 3.83 (dd, J = 8.1, 1 1.4 Hz, 2H), 3.56 (dd, J = 3.0, 10.5 Hz, 1 H), 3.1 1-2.99 (m, 1 H), 2.91 (s, 3H), 2.88 (br t, J = 11.1 Hz, 1 H), 2.45-2.20 (m, 3H), 2.15-2.00 (m, 1 H), 1.50-1.37 (m, 2H), 1.36 -1.23 (m, 8H), 0.90-0.80 (m, 9H); MS (ESPOS): 433.4 [M + H]; MS (ESNEG): 467.2 [M + Cl] EXAMPLE 76 r2-Methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl-4-propyl amide -piperidine-2-carboxylic acid Lincosamide 23g (R20 = methyl, R21 methyl, R1 = isopropyl sulfanyl) was coupled to 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid 27b (R9 = propyl) represented in general method Z for provide the title compound. Intermediate 13a (R1 = isopropyl sulfanyl, R20 = methyl, R2 = methyl, R9 = propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 2) which was deprotected under acidic conditions to provide the title compound . H NMR (300 MHz, D20) d 5.47 (d, J = 6.0 Hz, 1 H), 4.14 (br s, 2 H), 4.07 (dd, J = 6.0, 10.5 Hz, 1 H), 3.89 (dd, J = 3.0, 12.6 Hz, 1 H), 3.83 (d, J = 3.3 Hz, 1 H), 3.56 (dd, J = 3.3, 10.5 Hz, 1 H), 3.47 (br d, J = 13.5 Hz, 1 H ), 3.12-2.96 (m, 2H), 2.25-1.90 (m, 3H), 1.80-1.66 (m, 1H), 1.50-1.22 (m, 12H), 0.90-0.79 (m, 9H); MS (ESPOS): 433.4 [M + H]; MS (ESNEG): 467.2 [M + Cl].

EXAMPLE 77 1- (4-tert-Butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl-amide of 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid Tincosamide 23f (R methyl, R = methyl, R 1 = tert butyl sulfanyl) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CDCl 3) d 6.08 (br d, J = 9.3 Hz, 1 H), 5.81 (d, J = 5.7 Hz, 1 H), 5.34 (d, J = 3.0 Hz, 1 H), 5.19 (dd, J = 5.7, 11 .1 Hz, 1 H), 5.01 (dd, J = 3.3 , 11.1 Hz, 1 H), 4.34-4.18 (m, 2H), 2.20-2.05 (m, 1 H), 2.13 (s, 3H), 2.07 (s, 3H), 1.97 (s, 3H), 1.32 ( m, 9H), 0.89 (t, J = 6.6 Hz, 6H); S (SPOS): 15 538.0 [M + Na]; MS (ESNEG): 514.2 [M - H]. Lincosamide 23f (R20 = methyl, R2 = methyl, R1 = tert-butyl sulfanyl) was prepared as shown in scheme 23. 1 H NMR (300 MHz, CD3OD) d 5.39 (d, J = 5.7 Hz, 1 H) , 4.05 (dd, J = 6.0, 10.8 Hz, 1 H), 4.01 (dd, J = 1 .2, 3.3 Hz, 1 H), 3.90 (dd, J = 1.5, 8.7 Hz, 0 1 H), 3.39 (dd, J = 3.3, 10.5 Hz, 1 H), 2.88 (dd, J = 3.6, 8.1 Hz, 1 H), 2.08-1.95 (m, 1 H), 1 .36 (s, 9H), 0.98 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H); MS (ESPOS): 294.0 [M + H]; MS (ESNEG): 292.2 [M -H] Lincosamide 23g (R2 = isopropyl, R1 = tert-butyl sulfanyl) was coupled to 4-n-propylhydric acid as depicted in general method Z to provide the title compound. H NMR (300 MHz, D20) d 5.50 (d, J = 5.7 Hz, 1 H), 4.26 (br t, J = 7.5 Hz, 1 H), 4.15 (br s, 2 H), 4.08 (dd, J = 5.7, 10.5 Hz, 1 H), 3.90-3.82 (m, 2H), 3.50 (dd, J = 3.0, 10.8 Hz, 1 H), 2.93 (s, 3H), 2.91 (br t, J = 1 1.1 Hz , 1 H), 2.48-2.25 (m, 3H), 2.16-2.04 (m, 1 H), 1.52-1.26 (m, 4H), 1.37 (m, 9H), 0.88 (t, J = 6.9 Hz, 9H ); MS (ESPOS): 447.4 [M + H]; MS (ESNEG): 481.2 [M + CQ.

EXAMPLE 78? 4-propyl-p -peridine-2-carboxylic acid (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-yran-2-yl) -2-methylpropylamide Lincosamide 23g (R20-methyl, R21 methyl, R = tert-butyl sulfanyl) was coupled to 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid 27b (R9 = propyl) represented in general method Z to provide the title compound. Intermediate 13a (R = tert-butyl sulfanyl, R20 = methyl, 21 = methyl, R9 = propyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 2) which was deprotected under acidic conditions to provide the compound of the title. 1 H NMR (300 MHz, D 20) d 5.50 (d, J = 5.7 Hz, 1 H), 4.13 (br s, 2 H), 4.08 (dd, J = 5.7, 10.5 Hz, 1 H), 3.92 (dd, J = 3.0, 12.6 Hz, 1 H), 3.85 (d, J = 3.3 Hz, 1 H), 3.51 (dd, J = 3.0, 10.5 Hz, 2H), 3.06 (br t, J = 10.8 Hz, 1 H) , 2.28-2.19 (m, 1 H), 2.16-1.93 (m, 2H), 1.85-1.69 (m, 1 H), 1.54-1.27 (m, 6H), 1.38 (s, 9H), 0.94- 0.83 (m, 9H); MS (ESPOS): 447.4 [M + H]; MS (ESNEG): 481.0 [M + CI].

EXAMPLE 79 4- (2-cyclopropyl-ethyl) -piperidine r2-chloro-1- (3,4,5-hydrohydroxy-6-methylisulfanyl-tetrahydro-pyrn-2-in-propylamide) -2-carboxylic To a stirred solution of 11 b (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 triethylamine (7 ml) under dry nitrogen was added cyclopropyl acetylene (Aldrich) (0.25 g, 3.8 mmol, 2 equiv). The mixture was stirred at RT overnight. The solvent was removed under vacuum to produce a dark residue. The residue was purified by column chromatography 11c (R9 '= 2-cyclopropyl-et-1-ynyl) (0.39 g, 100%) as a yellow oil. 1 H NMR (300 Hz, 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 (HOOKS): 202.0 [M + H] +. To a solution of 11c (R9 '= 2-cyclopropyl-et-1-innyl) (0.39 g, 1.9 mmol) in methanol (5 mL) was added 10% palladium on carbon (0.2 g). The mixture was purged and charged with hydrogen (1 atm) and stirred at RT overnight. The palladium was removed by filtration and the filtrate was concentrated to yield 4- (2-cyclopropylethyl) -pyridine-2-carboxylic acid methyl ester (0.38 g, 97%) as a yellow oil, (intermediate not shown) 1H 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 (SPOS): 228.2 [M + Na. To a mixture of 4- (2-cyclopropyl) -pyridine-2-carboxylic acid methyl ester (0.38 g) in MeOH (8 ml) and water (8 ml) were added concentrated HCl (158). μ?) 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 yield a light yellow solid 11 d (R = 2-cyclopropylethyl) which was used without further purification. To the above-mentioned crude residue 1d (R 9 = 2-cyclopropylethyl) was added 2N NaOH (3.8 ml) and t-butylalcohol (2 ml). The reaction mixture was stirred at RT 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 the resulting residue was diluted with water, then washed with ether. The aqueous layer was acidified with 2N HCl until pH = 2.0, extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to yield 4- (2-cyclopropylethyl) -piperidine-1,2-dicarboxylic acid 1-f-ester (P = Boc, R9 = 2-cyclopropylethyl) ( 0.42 g, 77%) as a clear syrup. MS (ESPOS): 320.3 [M + Na] +; MS (ESNEG): 296.2 [M-H] \ Lincosamide 6b (R2 = H, R3 = Cl) was coupled to 4- (2-cyclopropylethyl) -piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 1 1f (P = Boc, R9 = 2-cyclopropylethyl) as represented by general method Z to provide the title compound. Intermediate 13a (R20 = methyl, R21 = methyl, R9 = propyl, P1 = H, P2 carboxylic acid t-butyl ester, m = 2) which was deprotected under acidic conditions to provide the title compound. MS (ESPOS): 451.3 [M + H] +.

EXAMPLE 80 [4-Cyclopropylmethyl-piperidine-2-carboxylic acid] 2-chloro-1 -O ^^ - trihydroxy-e-methylsuifanyl-tetrahydro-pfran ^ -iD-propylamide 4-Cyclopropylmethylpyridine-2-carboxylic acid, compound 10b (R9 = cyclopropylmethyl), was prepared using the O method, using the starting material 4-cyclopropylmethylpyridine prepared by alkylation of 4-picoline with cyclopropyl bromide by the method described by Osuch et al, Journal of the American Chemical Society, 1955, 78, 1723. The modified method is shown below. To a solution at -78 ° C of 4-picoline (1.1 g, 11.8 mmol) in THF (5 mL) was added a solution of 2M LDA in THF / heptane / ethylbenzene (Aldrich) (5.9 mL, 1.8 mmol). . The resulting mixture was stirred at -78 ° C for 3 h, then at -40 ° C for 1 h. Then cyclopropyl bromide (1.43 g, 1.8 mmol) was added at -78 ° C, allowed to warm to room temperature and stirred at room temperature for 1 h. Aqueous saturated NH CI (10 mL) was added to the reaction mixture, the aqueous phase was extracted with EtOAc (10 x 2 mL) and the combined organic extracts were dried over Na2SO4. The solvent was removed and the product 4-cyclopropylmethylpyridine (0.5 g, 31%) was obtained, which was used without further purification. Lincosamide 6b (R2 = H, R3 = Cl) was coupled to 4-cyclopropylmethylpyridine-2-carboxylic acid 10b (R9 = cyclopropylmethyl) as in general method AA to provide intermediate 13b (R = SMe, R2 = Me, R3 = H, R9 = cyclobutyl-ethyl, P1 = H) which was reduced by catalytic hydrogenation to the title compound. MS (SPOS): 437.2 [Mf.

EXAMPLE 81 4- (2-Cyclobutyl-ethyl) -piperidine-2-carboxylic acid f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide The 4- (cyclobutyl-ethyl) -pyridine-2-carboxylic acid, compound 10b (R9 = cyclobutyl-ethyl), was prepared using the general method O, using the starting material 4- (cyclobutyl-ethyl) -pyridine prepared by alkylation of 4-picoline with bromomethylcyclobutane as described in example 80.

Lincosamide 6b (R2 = H, R3 Cl) was coupled to 4- (cyclobutyl-ethyl) -pyridine-2-carboxylic acid 10b (R9 = cyclobutyl-ethyl) as in general method AA to provide intermediate 13b ( R = SMe, R2 = Me, R3 = H, R9 = cyclobutyl-ethyl, P1 = H) which was reduced by catalytic hydrogenation to the title compound. MS (SPOS): 465.2 [M] + EXAMPLE 82 4-Cyclobutylmethyl-piperidine-2-carboxylic acid f2-chloro-1- (3,4,5-hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide The 4-cyclobutylmethylpyridine-2-carboxylic acid, compound 10b (R9 = 4-cyclobutylmethyl) was made using the general method O, using the starting material 4-cyclobutylmethylpyridine prepared by alkylation of 4-picoline with cyclobutyl bromide, as described in Example 80. Lincosamine 6b (R2 = H, R3 = Cl) was coupled to 4-cyclobutylmethylpyridine-2-carboxylic acid, compound 10b (R9 = 4-cyclobutylmethyl) as in the general coupling method AA to provide intermediate 13b (R1 = SMe, R2 = Me, R3 = H, R9 = cyclobutylethyl P = H) which was reduced by catalytic hydrogenation to the title compound. MS (SPOS): 451.2 [M + H] +.

EXAMPLE 83 4-Cyclopropylmethyl-pyrrolidine-2-carboxylic acid r2-cioro-1- (3,4,5-tr? Hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide The protected amino acid intermediate (2S, 4R) -4-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester was prepared by the synthetic sequence described by Goodman et al. Journal of Organic Chemistry, 2003, 68, 3923 using cyclopropylmethyl triphenylphosphonium bromide (Aldrich) as the start material in the wittig olefination step. Lincosamine 6b (R2 = H, R3 = Cl) was coupled to 1-tert-butyl ester of (2S, 4R) -4-cydopropylmethyl-pyrrolidine-1,2-dicarboxylic acid, as depicted in the scheme of general coupling 11 to provide intermediate 13a (R1 = SMe, R2 = Me, R9 = cyclopropylmethyl, P1 = H, P2 = carboxylic acid t-butyl ester, m = 1) which was deprotected under acidic conditions to provide the Title. MS (SPOS): 423.2 [M + H] +.

EXAMPLE 84 4- (2-Cyclobutylidene-etii) -pyrrolidine-2-carboxylic acid f 2 -methyl-1- (3,4,54-hydrohydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide The amino acid intermediate 1-tert-butyl ester of (2S, 4R) -4- (2-cyclobutylidene-ethyl) -pyrrolidine-1,2-dicarboxylic acid was prepared by general method K, by alkylation of pyroglutamic acid ester 7a with (2-bromo-etiiidene) -cyclobutane. The allylic halide (2-bromoethylidene) -cyclobutane starting material was prepared from two-step cyclobutanone as described in US Patent 3,711,555. Lincosamine 2b (R1 = SMe, R2 = Me) was coupled to the protected amino acid 8c (R9 '= 2-cyclobutylidene-ethyl) to provide the intermediate carbamate 13a (R1 = SMe, R2 = Me, R9 = 2-cyclobutylidene-ethyl, P1 = H, P2 = Boc, m = 1) which was deprotected under acidic conditions to provide the title compound. MS (SPOS): 429.1 [+ H] +.

EXAMPLE 85 f 2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-n-propylamide of 4- (2-cyclobutylidene-ethyl) -pyrrolidin-2 -carboxylic The amino acid intermediate of (2S, 4R) -4- (2-cyclobutylidene-ethyl) -pyrrolidin-1,2-dicarboxylic acid-1-tert-butyl ester was prepared by the general method K, by alkylation of the 7a pyroglutamic acid with (2-bromoethylidene) -cyclobutane. AND! Allyl halide (2-bromoethylidene) -cic! obutan start material was prepared from two-step cyclobutanone, as described in US Pat. No. 5,7555. Lincosamine 6b (R2 = H, R3 = Cl) was coupled to the protected amino acid 8c (R9 '= 2-cyclobutylidene-ethyl) to provide the intermediate carbamate 13a (R1 = SMe, R2 Me, R9, = 2-cyclobutylidene-ethyl, P1 = H, P2 = Boc, m = 1) which was deprotected under acidic conditions to provide the title compound. MS (ESPOS): 450.1 [M + H] +.

EXAMPLE 86 4- (2-Cyclobutyl-ethyl) -pyrrolidine-2-carboxylic acid r2-chloro-1- (3,4,5-trihydroxy-6-methyl) -amide The (2S, 4R) -4- (2-cyclobutyl-ethyl) -pyrrolidine-1,2-dicarboxylic acid-tertiary butyl ester intermediate was prepared by the general method K, by alkylation of the pyroglutamic acid ester 7a with (2-bromoethylidene) -cyclobutane. The allylic halide (2-bromo-ethylidene) -cyclobutane starting material was prepared from two-step cyclobutanone, as described in U.S. Patent 3,711,555. Lincosamine 6b (R2 H, R3 = Cl) was coupled to the protected amino acid 7d (R9 = 2-cyclobutyl-ethyl) to provide the intermediate carbamate 3a (R1 = SMe, R2 = Me, R9 = cyclobutyl-ethyl, P1 = H, P2 = Boc, m = 1) which was deprotected under acidic conditions to provide the title compound.

MS (SPOS): 451.2 [M] +.

EXAMPLE 87 4- (2-Cyclopropyl-ethyl) -pyrrolidine-2- (2,4-chloro-ethyl) -3,5,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-in-propyl-amide carboxylic Lincosamine 2b (R1 = SMe, R2 = Me) was coupled to the protected amino acid 8c (R9 = 2-cyclopropyl-ethyl) prepared by the general method M to provide the intermediate carbamate 13a (R1 = S e, R2 Me, R9 = cyclopropyl -ethyl, P = H, P2 = t-butyl ester of the carboxylic acid, m = 1) which was deprotected under acidic conditions to provide the title compound. MS (SPOS): 437.2 [M + H] +.

EXAMPLE 88 f2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl-propionamide 4-fluoro-1- (2-hydroxy-ethyl) -4- propyl-p »'rrolidine-2- [4-fluoro-4-propyl] -3,14-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl! -amide was treated. ! -pyrrolidine-2-carboxylic acid 18a (Example 32) with ethylene oxide in methanol, as described in scheme 19 to provide the title compound. MS (SPOS): 473.3 [M + Hf.

EXAMPLE 89 [4-Butyl-4-fluoro-piperidine-2-carboxylic acid 2-chloro-1- (3,4,5-trihydroxy-6-rnethylsulfanH-tetrahydro-pyran-2-yl) -propyl-amide] The synthesis of 1-tert-butyl ester of 4-fluoro-4-butyl-piperidine-1,2-dicarboxylic acid protected with Boc 12d (P = Boc, m = 2, R9 = n-butyl) from the resulting material 1-tert-butyl ester of (2S) -4-oxo-piperidine-1,2-dicarboxylic acid uses the general method Q, represented in scheme 12, which uses the 1-butyne anion as a four-carbon synthon in the alkylation step of 4-ketone. The preparation of the starting material, 1-tert-butyl ester of 4-oxo-piperidine-1,2-dicarboxylic acid, is described by Bousquet, Y .; Anderson, P. C; Bogri, T .; Duceppe J .; Grenier, L; Guse, I .; Tetrahedron, 997, 53 5671-15680. Lincosamide 6b (R2 = H, R3 = Cl) was coupled to 12d (P = Boc, m = 2, R9 = butyl) to provide intermediate 13a (R2 = H, R3 = Cl, R9 = butyl, P1 = H, P2 = Boc, m = 2) which was deprotected under acidic conditions to provide the title compound, such as represented in the general method Z. MS (SPOS): 457.0 [M + H] +.

EXAMPLE 90 r2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra-4-cyclopropylmethyl-4-fluoro-piperidine-2-carboxylic acid idro-pyran-2-n-propylamide 2, R9 = cyclopropylmethio) to provide intermediate 13a (R2 = H, R3 Cl, R9 = cyclopropylmethyl, P = H, P2 = Boc, m = 2) which was deprotected under acidic conditions to provide the title compound, such as it is represented in the general method Z. MS (SPOS): 455.0 .- [M + H] +.

EXAMPLE 91 3-Butyl-azetidine-2-carboxylic acid r2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyltetrahydro-pyran-2-yl) -propyl-amide To a solution of azetidine acid 25f (R9 butyl) (52 mg, 0. 20 mmol, 1 equiv), 7-CI MTL 6b (R2 H, R3 = Cl) (58 mg, 0.20 mmol, 1 equiv) and HBTU (84 mg, 0.22 mmol, 1.1 equiv) in DMF (2.0 ml), a 23 ° C, DI PEA (88 μ ?, 0.51 mmol, 2.5 equiv) was added. After stirring for 12 h at 23 ° C, the DMF was removed in vacuo, then the residue was partitioned between EtOAc (100 mL) and 1: 1 brine: 10% aqueous citric acid (100 mL). The organic layer was separated and washed with 1: 1 brine / saturated aqueous NaHCO 3 (100 mL) and brine (50 mL), dried (MgSO 4), filtered and concentrated to give 82 mg (0.17 mmol, 84%) 13a (R2 = H, R3 = Cl, R9 = butyl, P = H, P2 = t-butyl ester of the carboxylic acid, m = 0) as a glassy solid which was used without further purification in the next step. To a solution of carbamate 13a (R2 = H, R3 = Cl, R9 = butyl, P = H, P2 = Boc, m = Q) (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 resulting solution was concentrated to dryness. The residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR Gis, 6 μ ?? particle size, 60 A pore size, 20 mm ID x 100 mm, 5-60% acetonitrile in H20 with 0.1% HCl for 30 min, 20 ml / min flow) to yield 41 mg of the title compound as a solid White. 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J = 6.0 Hz, 1 H), 4.64 (d, J = 7.8 Hz, 1 H), 4.63-4.52 (m, 2 H), 4.29 (d, J = 10.2 Hz, 1 H), 4.07 (dd, J = 5.7, 10.2 Hz, 1 H), 4.00 (t, J = 6.6 Hz, 1 H), 3.82 (d, J = 3.3 Hz, 1 H), 3.75 (dd) , J = 8.4, 9.9 Hz, 1 H), 3.56 (dd, J = 3.3, 10.2 Hz, 1 H), 2.92-2.76 (m, 1 H), 2.14 (s, 3H), 1.90-1.67 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H), 1.44-1.24 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H); MS (SPOS): 411.0 [M + H] +.

EXAMPLE 92 3-Cyclopropylmethyl-azetidine-2-carboxylic acid F2-chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi-amide Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetidine acid 25f (R9 = cyclopropylmethyl) as in the general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = cyclopropylmethyl, P1 = H, P2 = Boc, m = 0) which was deprotected under acidic conditions for provide the title compound. 1 H NMR (300 Hz, CD 3 OD) d 5.30 (d, J = 5.7 Hz, 1 H), 4.70 (d, J = 7.5 Hz, H), 4.63-4.54 (m, 2H), 4.29 (d, J = 9.9 Hz, 1 H), 4.08 (dd, J = 5.7, 10.2 Hz, H), 4.02 (t, J = 9.3 Hz, 1 H), 3.88-3.80 (m, 2H), 3.57 (dd, J = 3.3, 10.2 Hz, 1 H), 3.05-2.91 (m, 1 H), 2.14 (s, 3 H), 1.90-1.65 (m, 1 H), 1.57-1 .46 (m, 1 H), 1.47 (d, J = 6.6 Hz, 3H), 0.80-0.64 (m, 1 H), 0.58-0.47 (m, 2H), 0.16-0.10 (m, 2H); S (SPOS): 409.2 [+ H] +.

EXAMPLE 93 3-propyl-azetidine-2-carboxylic acid f2-chloro-1-3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-1-amide Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 25f (R9 = propyl) as in general method Z to provide the intermediate 13a (R2 = H, R3 = Cl, R9 = propyl, P1 = H, P2 = Boc, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.31 (d, J = 5.7 Hz, 1 H), 4.66 (d, J = 7.5 Hz, 1 H), 4.63-4.54 (m, 2 H), 4.31 (d, J = 9.9 Hz, 1 H), 4.09 (dd, J = 5.4, 10.2 Hz, 1H), 4.03 (t, J = 9.6 Hz, 1 H), 3.83-3.74 (m, 2H), 3.57 (dd, J = 3.3, 10.2 Hz, 1 H), 2.95-2.80 (m, 1H), 2.15 (s, 3H), 1.88-1.66 (m, 2H), 1.47 (d, J = 6.9 Hz, 3H), 1.46-1.30 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); MS (SPOS): 397.0 [M + H] +.

EXAMPLE 94 G2 - ??? G? -1 - (3A5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of 3-butyl-1- (2-hydroxy-ethyl) -azetidine -2-carboxylic A sample of 3-butyl-azetidine [2-chloro-1- (3,4,5-tri- hydroxy-6-methylisulfanyl-tetrahydro-pyran-2-yl) -propl] -amide was alkylated. 2-carboxylic acid, prepared in Example 91, with ethylene oxide as represented in scheme 19 (R6 = 2-hydroxyethyl) to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J = 5.4 Hz, 1 H), 4.67-4.57 (m, 1 H), 4.46-4.37 (m, 1 H), 4.29-4.24 (m, 1 H ), 4.13-4.06 (m, 1 H), 3.83-3.78 (m, 1 H), 3.67-3.55 (m, 3H), 3.44-3.32 (m, 1 H), 2.75-2.57 (m, 2H), 2.44-2.34 (m, 1 H), 2.14 (s, 3H), 1.80-1.40 (m, 6H), 1.39-1.20 (m, 5H), 0.95-0.86 (m, 3H); MS (HOOKS): 455.0 [M + H] +.

EXAMPLE 95 f2-Chloro-1- (3, 4,5-tr.) H-hydroxy-6-rnet-sulfonyl-tetrahydro-pyran-2-yl) -propyl-3-butyl-1-methyl-amide azetidine-2-carboxylic acid To a solution of Boc-carbamate 25f (R9 = butyl) (236 mg 0. 92 mmol, 1 equiv) in aqueous formaldehyde (37%, 2.0 ml), at 23 ° C, formic acid (95%, 1.0 ml) was added. The resulting mixture was heated to reflux for 4 h, then cooled to 23 ° C; treated with t-BuOH (5.0 mL) and concentrated. The crude residue was dissolved / suspended in H20 (15 ml), frozen and lyophilized. The resulting solid was dissolved in 1.0 N HCl (15 mL), filtered and concentrated. The resulting material was dissolved / suspended in H2O to produce a misty suspension which was filtered through a nylon membrane (0.2 μ) and concentrated to yield 186 mg of white solid, of which the main component is the salt of desired hydrochloride of 3-butyl-1-methyl-azetidine-2-carboxylic acid. This material was used without further purification. MS (SPOS): 172.3 [M + H].

Lincosamine 6b (R2 = H, R3 = Cl) was coupled to 3-butyl-1-methyl-azetidine-2-carboxylic acid hydrochloride salt as in general method Z to provide the title compound. 1 H NMR (300 MHz, D 20) d 5.40 (d, J = 5.7 Hz, 1 H), 4.73 (d, J = 7.8 Hz, 1 H), 4.66-4.56 (m, 1 H), 4.48 (dd, J = 1.2, 9.9 Hz, 1 H), 4.38-4.27 (m, 2H), 4.11 (dd, J = 5.7, 10.5 Hz, 1 H), 3.88 (d, J = 3.0 Hz, 1 H), 3.81 (t , J = 9.6 Hz, 1 H), 3.67 (dd, J = 3.3, 10.5 Hz, 1 H), 3.04-2.87 (m, 1 H), 2.94 (s, 3H), 2.18 (s, 3H), 1.90 -1.68 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.40-1.22 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H); MS (SPOS): 425.3 [M + H] +.

EXAMPLE 96 3-Pentyl-azetidine-2-carboxylic acid r2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl-amide Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 25f (R9 = pentyl) as in general method Z to provide intermediate 3a (R2 = H, R3 Cl, R9 = pentyl, P = H, P2 = carboxylic acid t-butyl ester, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.30 (d, J = 5.4 Hz, 1 H), 4.63-4.53 (m, 3 H), 4.30 (d, J = 9.6 Hz, 1 H), 4.08 (dd, J = 5.7 , 10.2 Hz, 1 H), 4.00 (t, J = 9.6 Hz, 1 H), 3.81 (d, J = 2.4 Hz, 1 H), 3.74 (dd, J = 7.8, 9.9 Hz, 1 H), 3.57 (dd, J = 3.3, 10.2 Hz, 1 H), 2.92-2.78 (m, 1 H), 2.15 (s, 3H), 1.90-1.67 (m, 2H), 1.46 (d, J = 6.9 Hz , 3H), 1.44-1.26 (m, 6H), 0.92 (t, J = 7.5 Hz, 3H); MS (SPOS): 425.0 [M + H] +.

EXAMPLE 97 r2 3- (3-Methyl-butyl) -zetidine-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-pyrn-2-yl) -propyl-amide of 3- (3-methyl-butyl) -zetidine-2- carboxylic Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 25f (R9 = 3-methyl-butyl) as in the general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = 3-methyl-butyl, P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.31 (d, J = 5.4 Hz, 1 H), 4.63-4.53 (m, 2 H), 4.30 (d, J = 10.5 Hz, 1 H), 4.08 (dd, J = 5.7, 10.5 Hz, 1 H), 4.00 (t, J = 9.6 Hz, 1 H), 3.81 (d, J = 2.4 Hz, 1 H), 3.74 (dd, J = 8.1, 9.9 Hz, 1 H), 3.57 (dd, J = 3.3, 10.2 Hz, 1H), 2.88-2.75 (m, 1H), 2.15 (s, 3H), 1.90-1.67 (m, 2H), 1.63- 1.50 (m, 1 H), 1.46 (d, J = 6.9 Hz, 3H), 1.39-1.10 (m, 3H), 0.94 (d, J = 1.5 Hz, 3H), 0.92 (d, J = 1.5 Hz, 3H); MS (SPOS): 425.0 [M + H] +.

EXAMPLE 98 3- (3-Cyclopropyl-propyl) -zetidine-2-f2-chloro-1- (3,4,5-tr »hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide -carboxylic Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 26f (R9 = 3-cyclopropylpropyl) as in general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = butyl, P1 = H, P2 = carboxylic acid t-butyl ester, = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.9 (d, J = 5.7 Hz, 1 H), 4.64-4.51 (m, 3 H), 4.29 (d, J = 10.2 Hz, 1 H), 4.07 (dd, J = 5.7, 10.2 Hz, 1 H), 3.99 (t, J = 9.9 Hz, 1 H), 3.79 (d, J = 3.3 Hz, H), 3.74 (dd, J = 8.4, 9.9 Hz, H), 3.55 ( dd, J = 3.3, 10.2 Hz, 1 H), 2.91-2.77 (m, 1 H), 2.13 (s, 3H), 1.93-1.68 (m, 2H), 1.60-1.32 (m, 2H), 1.44 ( d, J = 6.9 Hz, 3H), 1.24 (q, J = 10.2 Hz, 2H), 0.74-0.62 (m, 1 H), 0.44-0.36 (m, 2H), 0.04-0.02 (m, 2H); MS (SPOS): 437.2 [M + H] +.

EXAMPLE 99 3- (3-Cyclobutyl-propyl) -zetidine f2-Chloro-1- (3,4,5-trihydroxy-6-methylsuiphanyl-tetrahydro-pyran-2-yl) -propyl-1-amide -2-carboxylic Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 26f (R9 = 3-cyclobutylpropyl) as in general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = (3-cyclobutyl-propyl), P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 0) which was deprotected under acidic conditions to provide the title compound. H NMR (300 MHz, CD3OD) d 5.29 (d, J = 5.7 Hz, 1 H), 4.63-4.46 (m, 3H), 4.28 (d, J = 10.2 Hz, 1 H), 4.08 (dd, J = 5.4, 10.2 Hz, 1 H), 3.89 (t, J = 9.0 Hz, H), 3.79 (d, J = 3.6 Hz, 1 H), 3.65 (dd, J = 8.1, 9.6 Hz, 1 H), 3.56 (dd, J = 3.0, 10.2 Hz, 1H), 2.86-2.71 (m, 1 H), 2.38-2.20 (m, 1 H), 2.14 (s, 3H), 2.10-.96 (m, 2H), 1.90-1.52 (m, 6H), .44 (d, J = 6.9 Hz, 3H), .44- .14 (m, 4H). MS (SPOS): 451.2 [M + H] EXAMPLE 100 f2-Chloro-1- (314,5-trihydroxy-6-methylsulfanii-tetrahydro-pyran-2-yl) -propyl-1-amide of 3- (2-ci-obutil-ethyl) -zetidine-2- acid carboxylic Lincosamine 6b (R = H, R = Cl) was coupled to azetedine acid 26f (R9 = 2-cyclobutyl-ethyl) as in general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = 2-cyclobutyl-ethyl, P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 0) which was deprotected under acidic conditions to provide the title compound. NMR (300 MHz, CD3OD) d 5.29 (d, J = 5.7 Hz, 1 H), 4.63-4.50 (m, 3H), 4.29 (d, J = 10.2 Hz, 1 H), 4.08 (dd, J = 5.4 , 10.2 Hz, 1 H), 3.95 (t, J = 9.3 Hz, 1 H), 3.79 (d, J = 3.0 Hz, 1 H), 3.69 (dd, J = 8.4, 9.9 Hz, H), 3.56 ( dd, J = 3.3, 10.2 Hz, 1 H), 2.87-2.72 (m, 1 H), 2.38-2.20 (m, 1 H), 2.14 (s, 3H), 2.13-2.00 (m, 2H), 1 .94-1.55 (m, 6H), 1.54-1.34 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H); MS (SPOS): 437.2 [M + H] +.

EXAMPLE 101 3- (2-Cyclopropyl-ethyl) -zetidine-2-carboxylic acid f2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 26f (R9 = 2-cyclopropyl-ethyl) as in general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 2-cyclopropyl-ethyl, P1 = H, P2 = t-butyl acid ester carboxylic, m = 0) that was deprotected under acidic conditions to provide the title compound. H NMR (300 MHz, CD3OD) d 5.29 (d, J = 5.7 Hz, 1 H), 4.62-4.50 (m, 3H), 4.29 (d, J = 10.2 Hz, 1 H), 4.07 (dd, J = 5.4, 10.2 Hz, 1 H), 3.99 (t, J = 9.6 Hz, 1 H), 3.82 -3.71 (m, 2H), 3.56 (dd, J = 3.3, 10.2 Hz, 1 H), 2.95-2.80 (m, 1 H), 2.13 (s, 3H), 2.00-1.77 (m, 2H) , 1.44 (d, J = 6.9 Hz, 3H), 1.35-1.20 (m, 2H), 0.74-0.62 (m, 1H), 0.48-0.40 (m, 2H), 0.09-0.02 (m, 2H); MS (SPOS): 423. 2 [M + H.

EXAMPLE 102 3- (3,3-D-Fluoropropyl-azetidine-2-carboxylic acid 3- (3,3-d-fluoropropyl-azetidine-2-carboxylic acid) r2-chloro-1- (3,415-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide Lincosamine 6b (R2 = H, R3 = Cl) was coupled to azetedine acid 26f (R9 = 3,3-difluoropropyl) as in general method Z to provide intermediate 13a (R2 = H, R3 = Cl, R9 = 2-cyclopropyl-ethyl, P1 = H, P2 = t-butyl ester of the carboxylic acid, m = 0) which was deprotected under acidic conditions to provide the title compound. 1 H NMR (300 MHz, CD 3 OD) d 5.93 (t, J = 57 Hz, 1 H), 5.29 (d, J = 5.7 Hz, 1 H), 4.64 (d, J = 7.5 Hz, 1 H), 4.60-4.51 (m, 2H), 4.29 (d, J = 10.2 Hz, 1 H), 4.07 (dd, J = 5.7, 10.2 Hz, 1 H), 4.02 (t, J = 8.7 Hz, 1 H), 3.82-3.74 (m, 2H), 3.55 (dd, J = 3.3, 10.5 Hz, 1 H), 2.96-2.82 (m, 1 H), 2.13 (s, 3H), 2.06-1.76 (m, 4 H), 1.44 ( d, J = 6.9 Hz, 3H); MS (SPOS): 433.0 [M + H] +.

EXAMPLE 103 r2-methyl-1- (3,4,5-hydroxy-6-propyl-tetrahydro-pyran-2-yl) ^ 4-pentyl-pyrrolidine-2-carboxylic acid 2-Methyl-1- (3,4,5-trihydroxy-tetrahydro-pyrn-2-yl) -propylcarbamoin-4-pentyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 2- (1-amino-2-methyl-propyl) -6-propyl-tetrahydro-pyran-3,4,5-triol prepared by the general method AB, (51.9 mg, 0.21 mmol, 1 equiv) in dry DMF (4.5 ml), at 0 ° C, triethylamine (17 μ ?, 0.84 mmol, 4 equiv) was added, followed by the addition of BSTFA (84 μ ?, 0.32 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C for 10 minutes and then stirred at RT for 45 minutes. 7d protected amino acid was added to the reaction mixture, as prepared in the general method L (R9 = n-pentyl, P = Boc) (72 mg, 0.25 mmol, 1.2 equiv) and HATU (120 mg, 0.32 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h, evaporated to dryness, taken up in Et20 (150 mL), washed with 10% citric acid (1x), saturated NaHCO3 (1x) and brine. The organic layer was dried over MgSO4 and concentrated to obtain the product (190 g) as a yellow oil. The residue was taken up in DCE (6 mL) and trifluoroacetic acid (4 mL) containing water (0.2 mL) was added thereto. The reaction mixture was stirred at RT for 1 h, then the solvent was removed in vacuo and repeatedly co-evaporated with DCE. The residue was purified by column chromatography on 10% NH3 0.25M silica gel in MeOH / DCM to obtain the product (38.4 mg, 43%). H NMR (300 MHz, D20) 5 4.37 (dd, J = 4.7, 9.1, 1), 4.14 (dd, J = 3. 0, 9.6, 1), 3.97-3.90 (m, 2), 3.70 (d, J = 2.8, 1), 3.62-3.51 (m, 3), 2.89 (dd, J = 9.1, 1 1.3, 1), 2.33-2.03 (m, 1), 1.64-1.55 (m, 2), 1.52-1.45 (m, 3), 1.36-1.25 (m, 6), 1.0-0.86 (m, 12); MS (SPOS): 416.6 [M + HJ.

EXAMPLE 104 r2-metM-1 - 4-propyl-piperidine-2-carboxylic acid (314,5-trihydroxy-6-propyl-tetrahydro-pyran-2-H) -propyl-amide The title compound of Example 2 was prepared according to the procedure described in Example 103, using intermediate 10b, prepared in the general method O (R9 = n-propyl). (SPOS): 401.7 [M + H] +.

EXAMPLE 105 (2-Methyl-1 3 ^, 5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) etrahydro-pi-n-propyl > 4-propyl-piperidine-2-carboxylic acid amide Intermediate 27a, prepared in the general method * 1-tert-butyl ester of 4-propyl-piperidine-, 2-dicarboxylic acid. MS (ESNEG): 270.2 [M-H] The title compound was prepared according to the procedure described in general method R and illustrated in Scheme 16; 1, 1, 1 trifluoroethanol was used as the thiol nucleophile. The coupling of the protected amino acid intermediate 1-tert-butyl ester of 4-propyl-piperidine-1,2-dicarboxylic acid and the deprotection were carried out as in example 103. (ESPOS): 473.7 [M + Hf.

EXAMPLE 106 fl-e-ethoxyethyl-S ^ .S-trihydroxy-tetra idro-pyran ^ -yl ^ -Z-methyl-propyl-amide of 4-pentii-pyrrolidine-2-carboxylic acid 2-R - (6-Allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-iQ-2-methyl-propiicarbamoyl) tert-butyl ester To a stirred solution of the building block 15c (650 mg, 1.26 mmoi, 1 equiv) and protected amino acid 7d (R9 = pentiio, P = Boc) (395 mg, 1.39 mmol, 1.1 equiv) in dry DMF (5.0 ml), at 0 ° C, DIEA was added (0.88). mi, 5.0 mmol, 4 equiv), with subsequent addition of solid HATU (956 mg, 2.52 mmol, 2.0 equiv.) The reaction mixture was stirred at RT for 3 h, evaporated to dryness, absorbed in ethyl acetate, was washed with 10% citric acid (1x), water (1x), saturated NaHCO3 (1x) and brine.The organic layer was dried over a2SO4 and concentrated to produce a yellow syrup. residue was purified by column chromatography on silica 10% EtOAc / Hexanes at 20% EtOAc / Hexanes to obtain the product 2- [1- (6-allyl-3,4,5-tris-benzyloxy) tert-butyl ester tetrahydro-pyran-2-yl) -2- methyl-propylcarbamoyl] -4 -pentyl-pyrrolidine-1-carboxylic acid as a colorless oil (897 mg, 89%). 2- (2-Methyl-1 - [3,4,5-tris-benzyloxy-6- (2-hydroxy-ethyl-tetrahydro-pyran-2-n-propylcarbamoyl) -4-tert-butyl ester -pentyl-pyrrolidine-1-carboxylic acid A stirred solution of (634 mg, 0.81 mmol, 1 equiv) in DCM (60 ml) was treated at -78 ° C with a stream of ozone in oxygen for 20 min; Persistent pale blue color After 30 min the excess ozone was removed with a stream of N2 and a solution of DMS (3 mL) in DCM (10 mL) was added, the solution was allowed to warm to RT overnight. The solution was evaporated to dryness and the residue was dissolved in EtOH (50 mL) cooled to 0 ° C and treated with NaBH (300 mg 8.1 mmol, 0 equiv.) After 1 h, the excess NaBH 4 was destroyed by acidifying the reaction mixture The solvent was removed and the crude product was purified by column chromatography on silica gel 20% EtOAc / Hexanes to obtain the alcohol product (304 mg, 47%). 2- Tertiary butyl ester. { 2-methyl-1- [3,4,5-ths-benzyloxy-6- (2-ethoxy-ethyl) -tetrahydro-pyran-2-yn-propylcarbamoyl-4-pentyl-pyrrolidine-1-carboxylic acid. To a stirred solution of washed NaH (4.4 mg 0.183 mmol, 1 equiv) in THF (0.8 ml), at 0 ° C, was added the intermediate of tert-butyl alcohol ester of 2-acid. { 2-methyl-1- [3,4,5-tris-benzyloxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid (144 mg, 0.183 mmol, 1 equiv) after 10 min, Etl (73 μm, 0.92 mmol, 5.0 equiv) was added and the reaction mixture was stirred throughout the night. The reaction mixture was evaporated to dryness. The filtrate was concentrated and the residue was purified by 30% EtOAc / Hexanes prep. to obtain the product 2- tertiary butyl ester. { 2-methyl-1 - [3,4,5-tris-benzyloxy-6- (2-ethoxy-ethyl) -tetrahydro-pyran-2-yl] -pro-pilcarbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid (33.8 mg 22%) as a colorless oil. 4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-ethoxymethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl-amide. 2- tertiary butyl ester. { 2-methyl-1- [3,4,5-tris-benzyloxy-6-2-ethoxy-ethyl) -tetrahydro-pyran-2-yl] -propyl-carbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid (33.8 mg) degussa 50% w / w 10% wet palladium on carbon (80 mg) suspended in MeOH (3 mL) was stirred for 20 h under H2 at 1 atm pressure. The reaction mixture was filtered through Celite, evaporated to dryness to provide the crude product which was purified by column chromatography on silica 3% to 5% MeOH / DCM to obtain the ether product protected with boc (19 mg), which was absorbed in DCE (1 ml). , trifluoroacetic acid (1 ml) containing water (0.05 ml) was added with stirring. The reaction mixture was stirred at RT for 1 h, then the solvent was removed in vacuo and repeatedly co-evaporated with DCE. Freeze drying of the TFA salt from diluted 1: 1 HCl containing excess MeCN / water yielded the title compound (13.0 mg 66%).

H NMR (300 Hz, D20) d 4.47-4.38 (m, 1), 4.21-4.16 (m, 1), 4.1 1-4.06 (m, 1), 3.96 (dd, J = 6.3, 9.6, 1), 3.81 (s, 1), 3.61-3.50 (m, 7), 2.92 (dd, J = 9.9, 9.9, 1), 2.33-1.98 (m, 7), 1.96-1.82 (m, 1), 1.47-1.33 (m, 11), 1.18 (t, J = 6.9, 3), 0.97-0.89 (m, 2); MS (ESPOS): 446.4 [M + H].

EXAMPLE 107 1-2-Hydroxy-ethyl-4-pentyl-pyrrolidine-2-carboxylic acid r2-methyl-1- (314,5-trihydroxy-6-propyl-4-tetrahydro-pyran-2-yl) -propinamide The title compound was prepared according to the procedure illustrated in Scheme 19. Ethylene oxide was used as the alkylating agent. To a solution of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide (example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μ! _) In MeOH (2 mL), at 0 ° C, condensed ethylene oxide (200 μl_) was added and the reaction mixture was stirred for 48 h. The reaction mixture was evaporated to dryness and the resulting residue was purified by column chromatography on silica 20% NH3 0.25M in MeOH / DCM to obtain the crude product N-alkylated. The crude product was taken up in Et20, filtered and the filtered was treated with 2M HCl in Et20, the precipitated HCI salt was collected, washed with Et20 and lyophilized to yield the title compound as a colorless powder (4.4 mg 34%).

MS (SPOS): 473.6 [+ H] +.

EXAMPLE 108 f2-Rethyl-1- (3,4,5-tri- hydroxy-tetrahydro-pyran-2-yl) -propyl-1-arnide of 4-pentyl-pyrrolidine-2-carboxylic acid 2- Tertiary butyl ester. { 2-methyl-H3,4,5-tris-hydroxy-tetrahydro-pyran-2-in-propylcarbamoyl > -4-pentyl-pyrrolidine-1-carboxylic acid. To a stirred solution of wet Raney nickel R1 (300 mg) suspended in EtOH (5 ml) under N2 was added a solution of 1- (2- (S) -4- (R) -n-pentylpyrrolidin-2-yl. ) -N-. { 1 - (R) - [2- (S) -3- (S), 4- (S), 5- (R) -trihydroxy-6- (R) -methithio) tetrahydropyran-2-yl] -2- metilprop-1-il} acetamide (85.0 mg 0.164 mmol, 1 equiv) in EtOH (5 mL). The reaction mixture was refluxed for 2 h cooled to RT, filtered through Celite and evaporated to dry to provide the crude product (66 mg) which was purified by column chromatography on silica 3% MeOH / DCM obtain the des-thiomethyl product protected with N-Boc (42.7 mg 55%). TLC R 0.27 (10% MeOH / DCM); MS (ESPOS): 473.6 [M + Hf, (ESNEG): 507.5 [M + HCl]. 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propin-amide. The de-thiomethyl product protected with N-Boc was absorbed in DCE (5 ml), trifluoroacetic acid (5 ml) containing water (0.1 ml) was added with stirring. The reaction mixture was stirred at RT for 40 min, then the solvent was removed in vacuo by repeated coevaporation from DCE. The residue was dissolved in 1: 1 MeCN / water cooled to 0 ° C and 1 M ECI (0.5 ml) was added, the solution was filtered and lyophilized to obtain the title compound (26 mg, 43%) as a colorless powder. . TLC (CHCl3: MeOH: 32% AcOH aq.) Rf = 0.58; MS (SPOS) 387. 3 [M + H] +. Examples 109-127, 142 and 143 can be made according to the methods described herein.

EXAMPLE 109 4-propyl-1, 2,3,6-tetrahydro-pyridine r2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylamide -2-carboxylic EXAMPLE 110 f2-Cioro-1- (3,4,5-trihydroxy-6-methylisulfanyl tetrahydro-pyran-2-yl) -propyl-1-propyl-azepane-2-carboxylic acid amide EXAMPLE 111 r2-Methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propylamide of 5-propyl-azepane-2-carboxylic acid EXAMPLE 112 [1 - (6-tert-Butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propylamide of 5-propyl-azepane-2-carboxylic acid EXAMPLE 113 F (5-propyl-azepane-2-carboxylic acid 4-chloro-phenylM3A5-trihydroxy-6-methylsulfani ^ amide EXAMPLE 114 4-pentii-pyrrolidine-2-carboxylic acid r2-methyl-1- (3,4,5-trihydroxy-6-propy1-tetrahydro-pyrn-2-yl) -propyl-1-amide EXAMPLE 115 G1 - (4-Pentyl-pyrrolidine-2-carboxylic acid 6-butoxy-3 ^, 5-trihydroxy-tetrahydro-pyran-2-in-2-methyl-propylamide EXAMPLE 116 4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid r2-methyl-1- (314,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl-1-amide EXAMPLE 17 mono- (4,5-dihydroxy-6-f2-methyl-1-r (4-pentyl-pyrrolidine-2-carbonyl) -aminopropyl> 2-propyl-tetrahydro-pyran-3-ester ilo) of phosphoric acid EXAMPLE 118 4,5-dihydroxy-6-ester. { 2-methyl-1-r (4-pentyl-pyrrolidine-2-carbonyl) -amino-1-propyl > -2-propyl-tetrahydro-pyran-3-yl of hexadecanoic acid EXAMPLE 119 mono- (4,5-dihydroxy-6- 2-methyl-1-r (4-propyl-pyrrolidine-2-carbonyl) -amino-1-propyl> 2-propyl-tetrahydro-pyran-3-yl ester ) of phosphoric acid EXAMPLE 120 4,5-Dihydroxy-6-ester. { 2-methyl-1-r (4-propyl-pyrrolidine-2-carbonyl) -amino-propyl > -2-propH-tetrahydro-pyran-3-yl acid EXAMPLE 121 r2-Methyl-1 - (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl-1-ai-trifluoride of 1 - (5-methyl-2-oxo-r 1 , 31-dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid EXAMPLE 122 2-f2-Methyl-1 - (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl 5-methyl-2-oxo-M, 31-dioxol-4-ylmethyl ester) ) -propylcarbamoin-4-pentyl-pyrrolidine-1-carboxylic acid EXAMPLE 123 r2-Methyl-1- (314,5-trihydroxy-6-pyrrol-4-tetrahydro-pyran-2-yl) -propin-amide of 1- (5-methyl-2-oxo-f1,31-dioxol-4- ilmethyl) -4-propyl-pyrrolidine-2-carboxylic acid EXAMPLE 124 2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl-1-5-methyl-2-oxo-f-1, 3-dioxol-4-ylmethyl ester 4-propyl-pyrrolidine-1-carboxylic acid EXAMPLE 125 (4-propyl-pyrrolidine-2-carboxylic acid 2-methyl-1-f3,415-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl-1-propyl-amide EXAMPLE 126. { 4-propyl-pyrrolidine-2-carboxylic acid 2-methyl-1-f3,4,5-trihydroxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl-propiD-amide EXAMPLE 127 f2-Methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyrn-2-yl-propylamide 4-propyl-pyrrolidine-2-carboxylic acid EXAMPLE 142. { 2-Methyl-1-r3,4,5-trihydroxy-6- (2-methylsulfanyl-etn-tetrahydro-pyran-2-yl-propyl> 4-propyl-pyrrolidine-2-carboxylic acid amide EXAMPLE 143 G1 - 4-propyl-pyrrolidine-2-carboxylic acid (6-cyclopropylmethyl-3,4,5-trihydro-amide Examples of specific prodrugs 128-141 below are prepared from the respective parent compounds (see above) using the methods already described herein.

EXAMPLE 128 phosphoric acid mono- (6-. {2-Gloro-1-r (5-propyl-azepane-2-carbonyl) -aminol-propyl) -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran 3-il) ester EXAMPLE 129 6-. { 2-chloro-1-f (5-propyl-azepane-2-carbonyl) -amino-1-propyl > -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester EXAMPLE 130 phosphoric acid mono- (6-. {2-chloro-1-f (5-fluoro-5-propyl-azepane-2-carbonyl) -amino-1-propyl> 5-dihydroxy-2-methylsu [ fanil etrahidro-píran-3-i ester EXAMPLE 131 Hexadecanoic acid 6- < 2-chloro-1-r (5-fluoro-5-propyl-azepane-2-carbonyl) -amino-1-propyl > ^ t5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester ,) MCH, EXAMPLE 132 2-R 2 -chloro-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran 5-methyl-2-oxo-ri, 31-dioxoi-4-ylmethyl ester) -2 l) -propylcarbamoin-5-fluoro-5-propyl-azepane-1-carboxylic acid EXAMPLE 133 r2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amide of S-fluoro-l-fS-methyl-oxo-n.SldioxoM- ilmetiD-S-propyl-azepano-2-carboxylic acid EXAMPLE 134 5-Cyclopropylmethyl-1- (5-metH-2-oxo-) -3,5-chloro-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propin-amide n, 31-dioxol-4-ylmethyl) - azepane-2-carboxylic acid EXAMPLE 35 2- [2-Chloro-1- (3, i5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) 5-methyl-2-oxo-n, 31-dioxol-4-ylmethyl acid) -propylcarbamoyl-5-cyclopropylmethyl-azepane-1-carboxylic acid EXAMPLE 136 hexadecanoic acid 6-f2-chloro-1-r (5-cyclopropylmethyl-azepane-2-carbonyl) -am ^ no propyl > 5-dihydroxy-2-methylsu ^ fanyl-tetrar? Idro-p ^ ran-3- ^ l ester EXAMPLE 137 Phosphoric acid mono- (6-. {2-chloro-1-r (5-cyclopropylmethyl-azepane-2-carbonyl) -amino-1-yl) -pyril, 5-dihydroxy-2-rnetilsu > fanyl-tetrahydro-pyran-3 in ester EXAMPLE 138 6- hexadecanoic acid. { 2-chloro-1-r (4-fluoro-4-propyl-piperidine-2-carboni-aminol-propyl) 4,5-dihydroxy-2-methylsuiphanyl-tetrahydro-pyran-3-yl ester CHs EXAMPLE 139 phosphoric acid mono- (6- (2-chloro-1-f (4-fluoro-4-propyl-piperidine-2-carbonyl) -amino-1-propyl) ^, 5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran -3-H) ester EXAMPLE 140 5-Methyl-2-oxo-ri, 31-dioxol-4-ylmethyl ester of 2-f2-cyoro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) ) -propylcarbamoyl-1-4-fluoro-4-propyl-piperidine-1-carboxylic acid EXAMPLE 141 4-Fluoro-1- (5-methyl-2-oxo-4-fluoro-1- (3,4-trihydroxy-6-rnethylsulfanyl-tetrahydro-pyran-2-yl) -propylamide ri, 3ldioxol-4-ymethyl) -4-propyl-piperidine-2-carboxylic acid Example A Susceptibility test Compounds were tested following the NCCLS microdilution method (National Committee for Clinical Laboratory Standards for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approved Standard - fifth edition, document NCCLS M7-A5, NCCLS, Wayne, PA 2000. National Committee for Clinical Laboratory Standards, Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved Standard - fifth edition, document NCCLS MI 1-A4, NCCLS, Wayne, PÁ. 2001). The tests were carried out in 96-well plastic sterile microtitre trays with round bottom wells (Greiner).

Preparation of compounds The stock solutions of the test compounds and the control antibiotics are prepared at 10 mg / ml in DMSO. Dilutions are carried out in half in series of each drug in a microtitre plate through each row, using DMSO as the solvent at a concentration of 100 times the desired final concentration. The wells in columns # 1-11 contain the drug and column # 12 was maintained as a proliferation control for the organism without drug. Each well in the mother plate is diluted with sterile deionized water, mixed and the volumes of 10 μ? they are distributed to each well in the test plates.

Inoculation preparation Stock cultures were prepared using the icrobankIM method (Pro-Lab Diagnostics) and stored at -80 ° C. To propagate the aerobic strains, a bead was removed from the frozen vial and aseptically lined in Soy Agar (Difco), Chocolate Agar (Remel) or Blood Agar (Remel), which were incubated at 35 ° C overnight. The anaerobes were cultured in Brucella Agar (Remel) enriched with hemin and vitamin K, incubated in anaerobiosis using an anaerobic flask (Mitsubishi) at 35 ° C for 24 to 48 h. Standardized inocula were prepared using the direct colony suspension method according to the NCCLS guidelines (National 20 Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approved Standard - fifth edition, document NCCLS M7 -A5, NCCLS, Wayne, PA 2000. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, Approved Standard-Fifth Edition, NCCLS document M1 1-A4, NCCLS, Wayne, PA, 2001. Isolated colonies were selected from an 18-24 h agar plate and resuspended in sterile 0.9% saline to match the 0.5 McFarland turbidity standard. The suspension was used within 15 minutes of the preparation.

Streptococcus pneumoniae VSPN1001 Streptococcus pneumoniae ATCC 49619 Streptococcus pneumoniae VSPN3026 Streptococcus pneumoniae R6x Streptococcus pneumoniae VSPN4054 Streptococcus pneumoniae 488 K Streptococcus pneumoniae VSPN4021 Streptococcus pneumoniae 9 Staphylococcus aureus VSAU 017 Staphylococcus aureus Smith Staphylococcus aureus VSAU 1003 Staphylococcus aureus ATCC 25923 Staphylococcus aureus VSAU4020 Staphylococcus aureus125 Staphylococcus aureus VSAU4048 Staphylococcus aureus 85-EPI Staphylococcus aureus VSAU4065 Staphylococcus aureus VSAU4065 Staphylococcus eptdermidis VSEP1001 Staphilococcus epidermidis ATCC 12228 Enterococcus faecalis VEFL1003 Enterococcus faecalis ATCC 51299 Enterococcus faecium VEFA1005 Enterococcus faecium BM4147.1 Haemophilus influenzae VHIN1003 Haemophilus influenzae ATCC 49766 Haemophilus influenzae VHI 1004 Haemophilus influenzae ATCC 31517 Haemophilus influenzae VHIN1005 acr Haemophilus influenzae LS-2 Moraxella catarrhalis VMCA1001 Moraxella catarrhalis ATCC 25238 Escherichia coli VEC02096 Escherichia coli MG1655 Escherichia coli VEC02526 tolC Escherichia coli MGI 655 tolC Bacteroides fragilis VBFR1001 Bacteroides fragilis ATCC 25285 Bacteroides thetaiotaomicron VBTH Bacteroides thetaiotaomicron ATCC Clostridium difficiiee VODI1001 Clostridium difficiiee ATCC 9689 Preparation of test plates for preparation of MIC Media were prepared at a concentration of 1.1 x. Mueller-Hinton MHB broth (Difco) enriched with Ca ++ and Mg ++ as recommended by NCCLS, MHB enriched with 5% equine blood lye, HTM broth (Remel) or Brucella broth (Remel) enriched with hemin and vitamin K. For each organism , the standardized suspension was diluted in the appropriate proliferation medium in a sterile container. After mixing, the wells were inoculated into the test plates containing the drug with a volume of 90 μ ?. Therefore, for each MIC determination, each well contains a final volume of 100 μ? with an inoculum size of approximately 5 * 105 cfu / ml and not more than 1% DMSO.

Interpretation of MIC Complete microtiter plates were incubated for 16-20 h at 35 ° C in ambient air for aerobes, and at 35 ° C for 46-48 h or in an anaerobic flask (Mitsubishi) for anaerobes. The optical density of each well was determined at 600 nm using a VersaMax microplate reader (Molecular Devices, Sunnyva! E, CA). MIC was defined as the minimum drug concentration that causes the complete suppression of visible bacterial proliferation. Isomer I of Example 47 and isomer II of Example 47 had in vitro potency against the gram negative organism Haemophilus influenzae with a MIC < 4 μ§ / t ?. Isomers 1 and 2 of Example 47 also exhibit a MIC of 0.5 μg / m \ against the strain of H. influenzae ATCC 31517, compared to clindamycin, which exhibits a MIC of 8 9 / ??? against strain of H. influenzae ATCC 31517.

Example B Efficacy in septicemia by murine S. aureus Efficacy studies were carried out in the model of murine septicemia by S. aureus according to other published models (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 MM 63,246, a new semisynthetic glycopeptide antibiotic Antimicrob Agents Chemother., 39: 1580-588; Mislek,., 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-ylthio methy) 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 administration or 0.9% NaCl solution for intravenous administration. The compounds were administered 1 hour after bacterial inoculation. Vancomycin or ampicillin were used as controls.

Efficacy model Male or female ICR mice weighing 22 ± 2 g of NOS Pharma Services were used for the evaluation. They were given water at will. For the experiment, 6 mice weighing 22 ± g were used.

Mice were intraocclusively inoculated with Staphilococcus aureus Smith at 4 104 CFU in 0.5 ml of Brain and Heart Infusion Broth (Difco) containing 5% mucin (Sigma). Mortality was recorded once a day for 7 days after bacterial inoculation. While the invention has been described and illustrated herein by references to various specific materials, methods and examples, it is to be understood that the invention is not limited to the combinations of particular materials or the methods selected for that purpose. Numerous variations of said details may be involved, as will be appreciated by the person skilled in the art.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of Formula (IA): (IA) where: he represents a link that can be a double link or a single link; R is selected from the group consisting of -S-alkyl, -S-substituted alkyl, SMe, S- (2-hydroxyethyl), (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenniium, substituted alkenylene, alkoxy, alkoxy substituted, cycloalkylalkyl, halo and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkeniio, substituted alkeniio, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido) alkyl, (carbamoyl) alkyl, alkoxycarbonyl, (alkoxycarbonyl) alkyl, (alkoxycarbonylamino) alkyl, or the fragment -N (R6) - is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl) alkenyl and - S (0) qR13 wherein q is an integer equal to zero, one or two and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocycle and substituted heterocycle; and where m = 0-2; and where t = 0-3; or their pharmaceutically acceptable salts and / or prodrugs; with the exception of the following compounds: the compounds when it is a single bond and each R9 is hydrogen; and the compounds when it is a single bond, R9 is substituted alkyl having a simple substituent, said simple substituent being other than halo, oxygen, hydroxy, primary amine, amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as above), sulfur, -SH, phenyl, or - (CH2), NR'R "wherein n is an integer between 1 and 8, and R 'and R" are hydrogen or I rent; and the compounds when - is a single bond, R9 is halo. 2 - A compound of Formula (IA): (IA) represents a link that can be a double link or a single link; R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, SMe, S- (2-hydroxyethyl), (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, alkoxy substituted, cycloalkylalkyl, halo and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido) alkyl, (carbamoyl) alkyl, alkoxycarbonyl, (alkoxycarbonyl) alkyl, (alkoxycarbonylamino) alkyl, or the fragment N (R) - is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl) alkenyl and - S (0) qR13 wherein q is an integer equal to zero, one or two, and R13 is selected from the group consisting of alkyl, substituted alkyl, alkeniio, substituted alkeniio, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and where m = 0-2; and where t = 0-3; or their pharmaceutically acceptable salts and / or prodrugs; with the exception of the following compounds: the compounds when it is a single bond and each R9 is hydrogen; and the compounds when z is a single bond, R9 is substituted alkyl having a simple substituent, said simple substituent being other than halo, oxygen, hydroxy, primary amine, amine (secondary alkyl substituted with alkyl such as above), amine (tertiary alkyl substituted with alkyl as above), sulfur, -SH, phenyl, or - (CH2) nNR'R "wherein n is an integer between 1 and 8 and R 'and R" are hydrogen or alkyl; and the compounds when it is a single bond, R9 is halo. 3. The compound according to claim 1 or 2, further characterized in that the nitrogen-containing ring in the formulas (I) and (II) is selected from: 4. - A compound selected from the group consisting of: 1- (2- (S) -4- (S) - (ethylthio) pyrrolidin-2-yl) -N-. { 1 - (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (RHmethylsulfanyl) tetrahydropyran-2-yl] -2-hydrox -prop-1-il} acetamide; 1- (2- (S) -4- (R) - (ethylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-i ^] - 2-hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (R) - (ethylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] - 2-chloro-prop-1-yl} acetamide; 1 - (2- (S) -4- (S) - (ethylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -chloro-prop-1-il} acetamide; 1 - (2- (S) -4- (S) - (3-p-fluorophenyl) thiopyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1 -yl} acetamide; 1 - (2- (S) -4- (S) - (n-butylthio) pyrrolidin-2-yl) -N-. { 1 - (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropylan-2-i1] -2 -hydroxy-prop-1-yl} Acetami 1 - (2- (S) -4- (S) - (3,3,3-trifluoroprop-1-yl-thio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (S) - (2- (2-chlorophenyl) -ethylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (S) - (3-methylbut-1 -ylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (S) - (2-ethoxythiol) -ethylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran- 2-yl] -2 -hydroxy-prop-1 -yl} acetamide; 1 - (2- (S) -4- (S) - (2,2,2-trifiuoroetiitio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methanesulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (S) - (m-methylphenyl) methylsulfanylpyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -tnhydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-ii] -2 -hydroxy-prop-1-yl} acetamide; 1 - (2- (S) -4- (S) - (p-pyridinylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydro 1- (2- (S ) -4- (S) - (p-trifluoromethoxyphenyl) methylsulfanyl) -N-. { 1- (R) - [2- (s), 3- (s), 4- (s), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1 - (2- (S) -4- (S) - (o, p-dichlorophenyl) methylsulfanyl) -N-. { 1 - (R) - [2- (S), 3- (S), 4- (S), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2 -hydroxy-prop-1-yl} acetamide; 1- (2- (S) -4- (S) - (p-pyridinylthio) pyrrolidin-2-yl) -N-. { 1- (R) - [2- (S), 3- (S), 4- (S), 5- (R) -trihydroxy-6- (R) - (methylsulfanyl) tetrahydropyran-2-yl] -2-hydroxy-prop-1-yl) acetamide; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi!] -amide of 4- (thiophen-2-ylmethyl-suifanil) -p Rhodidine-2-carboxylic acid; [2 - ??? G ??? '- 1- (3,4,5-? P ??? G ??? - 6-G ????! 3 ??? 3 ??? - ?? G3 - G3 - G3? -2 -?) - propyl] -amide of 4- (4-fluoro-benzyl-sulfanyl) -pyrrolidine-2-carboxylic acid; 4- (4-Methyl-benzylsulfanyl) -3- (4-methyl-benzylsulfanyl) -2- hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-3-amide ) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (pyridin-2-ylmethylsulfanyl) -pyrrolidine -2-carboxylic; [4- (pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl-pyrrolidine-2- carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4-dichloro-benzylsulfanyl) -pyrrolidine-2 -amide -carboxylic; 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pirari-2-yl) -propyl] -amide; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3,3-difluoro-allyl) -pyrrolidine -2-carboxylic; 1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 1-Cyanomethyl-4-pentyl-pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; [4- (3-pyridin-4-yl-allyl) -pyrrolidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsuifanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [2-methyl-1- (3, 4, 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-pyridin-4-yl-propyl) ) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-methoxy-ethyl) -4 -pentii-pyrrolidine-2-carboxylic acid; [1- (H-imidazole-2-methyl-2-methyl-1- (3,4,5-triahydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide il-methyl) -4-pentyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 1- (2-formylamino-ethyl) -4 -pentyl-pyrrolidine-2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-amino-ethyl) -4-pentyl-pyrrolidine -2-carboxylic; [4- (3-Cyclohexyloxy-propyl) -piperidine-2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] carboxylic; acid methyl ester. { 2- [2-methyl-1- (3 ^> 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbam pentyl-pyrrolidin-1-yl} -acetic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 1-methylcarbamollmethyl-4-pentyl-pyrrolidine-2-acid carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2- [1, 3] dithiolan- 2-yl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid; [4- (3- (furan-2-ylmethylsulfanyl) - [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] - propyl] -piperidine-2-carboxylic acid; [4- methyl-3-imidazol-1-yl-propyl] -piperidine -2-carboxylic; [4- (3- (thiophen-2-ylsulfanyl) -propyl] -2- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -piperidine-2-carboxylic acid; [4- (3-imidazol-1-yl-propyl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propi!] -amide of 4- [3- (2-oxo-pyrrolidin-1- il) -propyl] -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (4-methyl-thiazol-2-yl)] ) -ethyl] -piperine-2-carboxylic acid; 2- (3-Methoxyimino-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tert.); [2-methyl] 4- (2- (4-ethyl-thiazole-2) - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of the acid 4- (3-Ethylsulfanyl-propyl) -piperidine-2-carboxylic acid; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 4- (3-ethoxyimino-propyl) -piperidine-2-carboxylic acid; [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] 2- (2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl) -amino-pyrrol-1-ylmethyl-2-carboxylic acid ester, 9H-fluoren-9-ylmethyl tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-) ethyl ester 2-yl) -propylcarbam 4-propyl-p-peridine-1-carboxylic acid; [4- (3-Cyano-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; Phenyl ester of 2- [2-methyl-1- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydropyran-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-piperidine-1-carboxylic acid phenyl ester; [2-Methyl-1 - (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (2- [1 , 2,3] triazol-1-yl-ethel) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylidene-piperidine-2-carboxylic acid; [2- (5-methyl-2-oxo) -amide (2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfani! -tetrahydro-pyran-2-yl) -propl] -amide - [1,3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5, -trihydroxy-6-methylsulfani! -tetrahydro-pyran-2-yl) -propyl-J-amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -anhydride of 4-fluoro-4-propyl-piperidine-2 -carboxylic; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-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) -propN] -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- (3-difluoromethylsulfanyl-propyl) -piperidine [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide] -2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4-propyl-1, 2,3,6-tetrahydro -pyridine-2-carboxylic acid; [2-chloro-1- (3 ^, 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6- tetrahydro-pyridine-2-carboxylic acid; and 4- (3-difluoromethylsulfanyl-propyl) -piperidine-2 [2-methyl- - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -annide -carboxylic; [2-hydroxy-1 - (3,4,5-tríh id roxi-6-metilsu Ifan il-tetra h id ro-pira n-2-ii) -propyl] -amide of 4-ethylsulfanyl-pyrrolidine -2-carboxylic; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-ethylsulfan-N-pyrrolidine-2-carboxylic acid; [4- (4-Fluoro-phenylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-hydroxy-1- (3 ^, 5-trihydroxy-6-methyl-sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amine of 4-butylsulfanyl-pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3,3,3- trifluoro-propylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-chloro-benzylsulfanyl) -pyrrolidine- 2-carboxylic; [4- (3-Methyl-butylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4- [2- (2-mercapto-ethoxy) - ethylsulfanyl] -pyrrolidine-2-carboxylic acid; [2- (Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,2,2-Trifluoro-ethylsulfanyl) -pyrrolidine] -2-carboxylic; [2-Hydroxy-1- (3,4,5-trihydroxy-6-methylsu! Fanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-methyl-benzylsulfanyl) -pyrrolidine- 2-carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (pyridin-4-ylsulfanyl) -pyrrolidine-2-carboxylic acid; [4- (4-trifluoromethoxy-benzylsulfanyl) -pyrrolidine [2-hydroxy-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4-dichloro-benzylsulfanyl) -pyrrolidine -2-carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-rriethylsulfanyl-teirahydro-pyran-2-yl) -propi!] -amide of 4- (thiophen-2-ylmethylsulfanyl) -pyrrolidine-2- carboxylic; [4- (4-Fluoro-benzylsulfanyl) -pyrrolidine-2- [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-y!) -propyl] -amide] carboxylic; [4- (4-Methyl-benzylsulfanyl) -pyrrolidine [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [2-Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4- (pyridin-2-ylmethylsulfanyl) -pyrrolidine-2 -amide -carboxylic; [2- (Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (pyrazin-2-ylmethylsulfanyl) -pyrrolidine- 2-carboxylic acid; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-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- (2,4-dichloro-benzylsulfanyl) -pyrrolidine -2-carboxylic; 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide; [4- (3,3-difluoro-allyl) -pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; [1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] carboxylic; 1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl] sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -ami of 4- (3-pyridin-4-yl-) allyl) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-pyridyl-4-yl- propyl) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propyl] -amide of 1- (2-methoxy-ethyl) -4-pentyl-pyrrolidine -2-carboxylic; [1- (1H-imidazol-2-ylmethyl) -4- [2-methy] -1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -pentyl-pyrrolidine-2-carboxylic acid; 1- (2-formylamino-ethyl) -4- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 1- (2-formylamino-ethyl) pentiol pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3 ^, 5-trihydroxy-6-methylsulfani) -tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-amino-ethyl) -4-pentyl -pyrrolidine-2-carboxylic acid; [4- (3-Cyclohexyloxy-propyl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propl] -amide] -2-carboxylic; acid methyl ester. { 2- [2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidin-1-yl} -acetic; [2-methyl-1- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 1-methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-rnethylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2- [1, 3] dithiolan-2] -l-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-iminomethyl-4-pentyl-pyrrolidine- 2-carboxylic; [4- (3- (furan-2-ylmethylsulfariyl) -propyl] 2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -piperidine-2-carboxylic acid; [4-methyl-3- (3-1-midazol-1-yl) -2- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -propyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (iiophen-2- ilsulfanyl) -propyl] -piperidine-2-carboxylic acid; [4- methyl-3-imidazol-1-yl-propyl] -piperidine -2- carboxylic; [2-Rethyl-1 - (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (2-oxo- pyrrolidin-1-yl) -propyl] -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (4-methyl- thiazol-2-yl) -ethyl] -p -peridine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-methoxyiminopropyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -prapyl] -amide of 4- [2- (4-ethyl-t Azole-2-yl) -ethyl] -piperidine-2-carboxylic acid; [4- (3-Ethylsulfanyl-propyl) -pipendin-2-methyl-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (3-Ethoxyimino-propyl) -piperidine-2-methoxy-3 - (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-pyrrol-1-methyl-piperidine-2-carboxyl co; 9-Fluoren-9-ylmethyl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine- 1 -carboxylic; 2- [2-methyl-1- (3,4,5-tn ^ idroxy-6-methy1-sulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1 ethyl ester -carboxylic; [4- (3-Cyano-propyl) -piperidine-2-methyl-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-p-peridine-1-carboxylic acid phenyl ester; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-p-peridine-1-carboxylic acid phenyl ester; [4- (2- [1,2,3] triazole-1] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. - il-etl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylidene-piperidine-2-carboxylic acid; [2-methyl-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl-piperidine-2-carboxylic acid; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-piyan-2-yl) -propyl] -amide -carboxylic; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (3-difluoromethylsulfanyl-propyl) -piperidine [2-chloro-1- (3,4,5-trihydroxy-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 4-propyl-1, 2,3,6-tetrahydro-pyridine -2-carboxylic; [2-Chloro-1- (3,4,5-tri- hydroxy-6-rriethylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6-tetrahydroamide -pyridine-2-carboxylic acid; and 4- (3-difluoromethylsulfanyl-propyl) -2- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -piperidine-2-carboxylic acid. 5. A compound of Formula (IB): (IB) wherein: R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is H, alkyl or hydroxyalkyl; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) n-NR4R5 and their branched chain isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl; and m is 1 or 2 or its prodrug and / or pharmaceutically acceptable salt; with the proviso that the compound of formula I has a minimum inhibition concentration of 32 pg / ml or lower 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. 6. A compound selected from the group consisting of: [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propi] -amide of 4-pentyl-pyrrolidine-2-acid -carboxylic; 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Propyl-piperidine-2-carboxylic acid [2-methy1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; [1- (2-Hydroxy-ethyl) -4-pentyl-pyrrolidine [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-piperidine-2-carboxylic acid amide; 4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide; 4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; mono- (4,5-dihydroxy-6-. {2-methyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl] -2-propyl-tetrahydro-pyran- 3-yl) ester of phosphoric acid; 4,5-dihydroxy-6-. { 2-methyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; mono- (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl.} 2-propyl-tetrahydro-pyran-3- il) phosphoric acid ester; 4,5-dihydroxy-6-. { 2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propl] -amide of 1- (5-methyl-2-oxo- [1 , 3] d -oxo-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-meityl-1- (3,4,5-tri- hydroxy-6-propyl-tetrahydro-pyran-2) acid -yl) -propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid; [2-methyl-1 - (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide of - (5-methyl-2-oxo- [1 , 3] dioxol-4-ylmethyl) -4-propyl-pyrrolidine-2-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran 2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid; . { 2-methyl-1 - [3,4,5-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-pyrrolidine-2-carboxylic acid amide; . { 2-methyl-1- [3,4,5-tr'h'droxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl] -propyl} -amide of 4-propyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propy] 4-propyl-pyrrolidine-2-carboxylic acid. { 2-methyl-1 - [3,4,5-trihydroxy-6- (2-methylsulfanyl-ethyl) -tetrahydro-pyran-2-yl] -propyl} -amide of 4-propyl-pyrrolidine-2-carboxylic acid; [1- (6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide of 4-propyl-pyrrolidine-2-carboxylic acid; or its prodrug and / or pharmaceutically acceptable salt. 7. - A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined in any of claims 1, 2 6 5. 8. - The use of a compound as defined in any one of claims 1, 2 or 5, for preparing a medicament for the treatment of a microbial infection in a mammal. 9. The use claimed in claim 8, wherein the medicament is administrable in oral, parenteral, transdermal, topical, rectal or intra nasal form. 10. The use claimed in claim 8, wherein the medicament is administrable in an amount of about 0.1 to about 100 mg of the compound / kg of body weight per day. 11. - A compound of formula (I): wherein: W is a ring containing nitrogen:, m is 0, 1, 2 or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5; wherein when m is 3, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5 or between the positions of the nitrogen-containing ring 5 and 6; wherein the positions of the nitrogen containing ring are numbered consecutively in the counterclockwise direction, starting with "1" in the nitrogen; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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; R 6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0-anhole, -C (0) 0-substituted aryl, -C (0) 0-heteroaryl, -C (0) -O-substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, 5-alkyl- [1, 3] dioxol -2-one-4-yl-methyl, 5-alkyl- [1, 3] dioxol-2-one-4-yl-methoxy-carbonyl or the fragment -N (R6) - is part of the amidine structure, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, oxygen substituted, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclic sulfanylalkyl, heteroarylsulfanyl and heterocyclosulfanyl, propylidene (= ???? 2 ?? 3), azido, - (CH2) nOH, - (CH2) n-NR4R5 and its branched chain isomers, wherein n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13 where q is an integer equal to zero, one or two, and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl their substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocycium, and wherein not more than one group -S (0) qR13 is present in the nitrogen-containing ring; and where t = 0-3; or its prodrug and / or pharmaceutically acceptable salt; with the exception of the following compounds: the compounds when it is a single bond and each R9 is hydrogen; and the compounds when it's a simple link, R9 is substituted alkyl having a simple substituent, said substituents being simple other than halo, oxygen, hydroxy, primary amine, amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl such as above), sulfur, -SH, phenyl, or - (CH2) nNR'R "wherein n is an integer between 1 and 8 and R 'and R" are hydrogen or alkyl; and the compounds when: =: = is a single bond, R9 is halo. 12. A compound of Formula (IA): 0A) where: the represents a link that can be a double link or a single link; R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, SMe, S- (2-hydroxyethyl), (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido) alkyl, (carbamoyl) alkyl, alkoxycarbonyl, (alkoxycarbonyl) alkyl, (alkoxycarbonylamino) alkyl, or the fragment -N (R6) - is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl) alkenyl and - S (0) qR13 where q is an integer equal to zero, one or two and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocycle and substituted heterocycle; and where m = 0-2; and where t = 0-3; or their pharmaceutically acceptable salts and / or prodrugs; with the exception of the following compounds: the compounds when it is a single bond and each R9 is hydrogen; and the compounds when it is a single bond, R9 is substituted alkyl having a simple substituent, said simple substituent being other than halo, oxygen, hydroxy, primary amine, amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl) substituted with alkyl as above), sulfur, -SH, phenyl, or - (CH2), NR'R "wherein n is an integer between 1 and 8, and R 'and R" are hydrogen or alkyl; and the compounds when it is a single bond, R9 is halo. 3. A compound of Formula (IA): where it represents a link that can be a double link or a simple link; R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, SMe, S- (2-hydroxyethyl), (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, alkoxy substituted alkoxy, cycloalkylalkyl, halo and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido) alkyl, (carbamoyl) alkyl, alkoxycarbonyl, (alkoxycarbonyl) alkyl, (alkoxycarbonylamino) alkyl, or the fragment -N (R6) - is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from e! group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl) alkenyl and - S (0) qR13 wherein q is an integer equal to zero, one or two and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocycle and substituted heterocycle; and where m = 0-2; and where t = 0-3; or its pharmaceutically acceptable salts and / or prodrugs acceptable; with the exception of the following compounds: the compounds when it is a single bond and each R9 is hydrogen; and the compounds when it is a single bond, R9 is substituted alkyl having a simple substituent, said simple substituent being other than halo, oxygen, hydroxy, primary amine, amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as above), sulfur, -SH, phenyl, or - (CH2) nNR'R "wherein n is an integer between 1 and 8 and R 'and R" are hydrogen or alkyl; and the compounds when it is a single bond, R9 is halo. 14. A compound of Formula (IA): where: the represents a link that can be a double link or a single link; R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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; R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -substituted aryl, -C (0) -heteroaryl, -C (0) -substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, or the fragment N (R6) - is part of the amidine structure, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, nitrogen substituted, halo, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13 wherein q is an integer equal to zero, one or two and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and where m = 0-2; and where t = 0-3; or their pharmaceutically acceptable salts and / or prodrugs; with the following caveats: A. that in the compounds of formula (I) when it is a single bond, m is zero or one, R2 and R3 are independently hydrogen, alkyl, hydroxy, fluoro, 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, R6 is hydrogen, alkyl, hydroxyalkyl, -C (0) 0 -alkylenecycloalkyl, -C (0) 0 -alkylene-substituted alkyl, -C (0) 0-alkyl, -C (0) 0-substituted alkyl, -C (0) 0-aryl, -C (0) 0-substituted ary, -C (0) 0-heteroaryl, -C (0) 0-substituted heteroaryl, -C (0) 0-heterocycle, -C (0) 0 -substituted heterocycle, - [C (0) 0] p alkylene-heterocycle, - [C (0) 0] p-substituted heterocycle alkylene, wherein p is zero or one, and R7 is selected from the group consisting of hydrogen and alkyl; R9 is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) nOH, - (CH2) nNR4R5, -alkylene-Ra wherein Ra is selects between monofluorophenyl or monochlorophenyl, and their branched isomers wherein n is an integer between 1 and 8 inclusive and R 4 and R 5 are hydrogen or alkyl; and then R1 is not -S-alkyl, B. in the compounds of formula (I), when it is a single bond, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano , alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, 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 caveats that both R2 and R3 do not be hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -C (0) 0 -alkyl, -C (0) 0 -substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -substituted aryl, -C (0) -heteroaryl, C (0) -substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, or the fragment N (R6) - is part of the amidine structure, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is selected from the group consisting of hydrogen and alkyl; and R is selected from the group consisting of -S-alkyl, substituted S-alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; then at least one of R9 is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) nOH, - (CH2) nNR4R5, -alkylene -Ra in which Ra is selected from monofluorophenyl or monochlorophenyl, and their branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl, C. in the compounds of formula (I), when it is a single bond, R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the another is absent, or one of R2 and R3 is = CH2 and the other is absent, with the provisos that both R2 and R3 are not hydrogen; when one of R2 and R3 is halo, the other is not hydrogen or hydroxy; and when one of R2 and R3 is hydroxy, the other is not hydrogen or hydroxy; R7 is selected from the group consisting of hydrogen and alkyl; and R1 is selected from the group consisting of -S-alkyl, -S-substituted alkyl, (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo; R9 is independently selected from another that is not hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) nNR4R5, -alkylene-Ra in which Ra is selected from monofluorophenyl or monochlorophenyl, and their branched isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are hydrogen or alkyl, then R6 is selected from the group consisting of in substituted alkyl (which are not monosubstituted heterocycle or substituted heterocycle), (carboxamido) alkyl, and a fragment -N (R6) - which is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure; wherein, as used in these provisos only, the following specific terms and expressions have the following specific meanings: substituted alkyl refers to alkyl groups in which one or more of the hydrogen atoms have been replaced with a halogen , oxygen, hydroxy, amine (primary), amine (secondary alkyl substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl), substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, wherein alkyl is as defined above or a group in which one or more of the hydrogen atoms have been replaced with a halogen, oxygen, hydroxy, amine (primary), amine (secondary alkyl) substituted with alkyl as above), amine (tertiary alkyl substituted with alkyl as defined above), sulfur, -SH or phenyl, substituted oxygen refers to the group -ORd wherein Rd is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aikenyl, cycloalkyl and substituted cycloalkyl, substituted nitrogen or amino refers to the group NRaR wherein Ra and Rb are each independently hydrogen, alkyl, haloalkyl, aikenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, substituted aryl refers to an aryl ring substituted with one or more substituents selected from the group consisting of alkyl, aikenyl, alkynyl , halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioaikyl in which alkylthio refers to the group -S-alkyl and thioaikyl refers to an alkyl group having one or more -SH groups, and substituted heteroaryl refers to a heteroaryl ring substituted with one or more substituents selected from the group consisting of alkyl, aikenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioaikyl, those which alkylthio refers to the group -S-alkyl and thioaikyl refers to an alkyl group having one or more -SH groups. 15. The compound according to any of claims 1-14, further characterized in that the nitrogen-containing ring in the formulas (I) and (IA) is selected from: A compound of Formula (IB) GB) wherein: R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is H, alkyl or hydroxyalkyl; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) n-NR4R5 and their branched chain isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl; and m is 1 or 2 or its prodrugs and / or pharmaceutically acceptable salts. 17. A compound of Formula (II): m is 0,, 2 or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5; wherein when m is 3, the nitrogen-containing ring may optionally contain a double bond between the positions of the nitrogen-containing ring 4 and 5 or between the positions of the nitrogen-containing ring 5 and 6; wherein the positions of the ring containing nitrogen are numbered consecutively in a counter-clockwise direction, beginning with "1" in the nitrogen; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyou, halo, alkylsulfanyl and substituted alkylsulfanyl; R and R are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo or one of R20 and R21 is = NOR7 and the other is absent, or one of R20 and R21 is = CH2 and the other is absent, or R20 and R21 taken together are cycloalkyl, aryl or a heterocycle group, R6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyo, cycloalkyl, substituted alkyl, iminomethyl, - C (0) 0-alkyl, -C (0) 0-substituted alkyl, -C (0) 0 -aryl, -C (0) 0 -substituted aryl, -C (0) -heteroaryl, -C (0 ) 0-substituted heteroaryl, - (carboxamido) alkyl, (carbamoyl) alkyl, 5-alkyl- [, 3] dioxol-2-one-4-yl-methyl, 5-alky1- [1, 3] dioxol-2-one-4-yl-methoxycarbonyl or the fragment -N (R6) - is part of the structure of amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, sulfanylalkyl heterocyclic, heteroarylsulfanyl and heterocyclosulfanyl, propylidene (= CHCH2CH3), azido, - (CH2) nOH, - (CH2) n- NR4R5 and its branched chain isomers, wherein n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl and -S (0) qR13 in the q is an integer equal to zero, one or two, and R13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted lquinyl, aryl, substituted aryl, heteroanium, substituted heteroaryl, heterocycle and substituted heterocycle, and in which no more than one group -S (0) qR13 is present in the nitrogen-containing ring; or its prodrug and / or pharmaceutically acceptable salt. 18. A compound selected from the group consisting of: [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (thiophene) acid -2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid; [4- (4-Fluoro-benzylsulfanyl) -pyrrolidine-2-hydroxy-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -carboxylic; [4- (4-Methyl-benzylsulfanyl) -pyrrolidine [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -2-carboxylic; [2-Hydroxyl- (3,4,5-trih idroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (pyridin-2-ylmethylsulfanyl) -pyrrolidine-2 -carboxyl- (2- (hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (pyrazin-2-ylmethylsulfanil) ) -pyrrolidine-2-carboxylic acid; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-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- (2,4-dichloro-benzylsulfanyl!) -pyrroiidine- 2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-butylsulfanyl-pyrrolidine-2-carboxylic acid; 4- (3,3-difluoro-allyl) -pyrrolyl [2-methyl- - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; dina-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsu! Fanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 1-carbamoylmethyl-4-pent 1-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1-cyanomethyl-4 -pentii-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -am of 4- (3-pyridin-4-yl-allyl) -pyrrolidine -2-carboxylic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (3-pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-methoxy-ethyl) -4-pentyl-pyrrolidine -2-carboxylic; [1- (1 H -imidazol-2-ylmethyl) - [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] - 4-pentyl-pyrrolidine-2-carboxylic; 1- (2-formylamino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid p-methyl-l-S S ^. S-trihydroxy-O-methylsulfanyl-tetrahydro-pyran ^ -yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propl] -amide of 1- (2-amino-ethyl) - 4-pentyl-pyrrolidine-2-carboxylic acid; [4- (3-Cyclohexyloxy-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; acid methyl ester. { 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbam pentyl-pyrrolidin-1-yl} -acetic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 1-methylcarbamoylmethyl-4-pentyl-pyrrolidine-2 acid -carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-H) -propylj-amide of 4- (2- [1, 3] dithiolan-2-yl- ethyl) -piperidine-2-carboxylic acid; [2-Methylsulfanyl-tetrahydro-pyran-2-yl] -propyl] -amide of 1-phenylmethyl-4- (3,4,5-triv] -droxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide pentyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [3- (furan-2- ilmetysulfanyl) -propyl] -piperidine-2-carboxylic acid; [4- (3-imidazole-1-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] il-propyl) -piperidine-2-carboxylic acid; [4- (3- (thiophen-2-ylsulfanyl) - [2-methyll-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] - propyl] -piperidine-2-carboxylic acid; [4- (3-imidazole-1-yl-4- (3-imidazole-1-yl) -amide] - 2-methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide propyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3 ^, 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyj-amide of 4- [3- (2-oxo-pyrrolidine- 1-yl) -propyl] -piperidine-2-carboxylic acid; [2- (4-methyl-thiazole-2-1- (3,4-methyl-thiazole-2-metho1-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] l) -ethyl] -piperidine-2-carboxylic acid; [4- (3-methoxyimino-propyl) -3- (3-methoxyimino-propyl) - [2-methyl-1- (3,4,5-t-Hydroxy-6-methyl-sulfanyl-tetGahidGO-iran-2-yl) -pGopyl] -amide] - piperidine-2-carboxylic; [2- (4-ethyl-thiazoyl) -2- methyl- 1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. -2-yl) -ethyl] -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-ethylsulfanyl-propyl) -piperidine-2-acid -carboxylic; [4- (3-Ethoxyimino-propyl) -piperidine [2-methyl-1- (3,4,5-trihydroxy-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-4-pyrrol-1-ylmethyl-piperidine-2-carboxylic acid; 9-Fluoren-9-ylmethyl 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propylpi peridine-1-carboxylic acid; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamo 4-propyl-piperidine-1-carboxylic acid ethyl ester; 4- (3-Cyano-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid phenyl ester; - 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-p-peridine-1-carboxylic acid phenyl ester; [4- (2- [1,2,3] triazole-1] -2- Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. ethyl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylidene-piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-l-IS] .s-trihydroxy-e-methylsulfanyl-tetrahydro-piYan ^ - ^ - propyl-J-amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-teirahydro-pyran-2-yl) -propyl] -amide; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-teirahydro-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-Fluoro-4-propyl-pyrrolidine-2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; [4- (3-difluoromethylsulfanyl-propyl) -piperidine-2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. -carboxylic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-, 2,3,6- tetrahydro-pyridine-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propl] -amide of 4-propyl-1, 2,3 6-tetrahydro-pyridine-2-carboxylic acid; and 4- (3-difluoromethylsulfanyl-propyl) -piperidine-2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid; [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-ethylsulfanyl-pyrrolidine-2-carboxylic acid; [4- (4-Fluoro-phenylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3 ^, 5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [4- (3,3,5-trifluoro-trifluoro-4-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (3,3,3-trifluoro- propylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2-chloro-benzylsulfanyl) -p. R-rolidine-2-carboxylic acid; 4- (3-Methyl-butylsulfanyl) -pyrrolidine- [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 2-carboxylic; [2- (2-mercapto-ethoxy) -ethylsulfanyl] -2- hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methyl-sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,2,2-Trifluoro-) ethylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-methyl) acid l-benzylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (pyridin-4-ylsulfanyl) -pyrrolidine-2-carboxylic acid; [2-hydroxy-1 - (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 4- (4-trifluoromethoxy-benzylisulfanyl) -pyrrolidine-2-acid -carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (2,4-dichloro-benzylsulfanyl) - pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (thiophen-2-methylmethylsulfanyl) -pyrrolidine- 2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra-idro-pyran-2-yl) -propyl] -amide of 4- (4-fluoro-benzylsulfanyl) -pyrrolidine-2- carboxylic; [4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2- [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] carboxylic; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (pyridin-2-ylmethylsulfanyl) - pyrrolidine-2-carboxylic acid; [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (p -razin-2-ylmethylsulfanyl) - pyrrolidine-2-carboxylic acid; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Methyl-1- (3,4,5-trlhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl-amida of 4- (2,4-dichloro) -benzylsulfanyl) -pyrrolidine-2-carboxylic acid; 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4- (3,3-difluoro-allyl) -pyrrolidine-2- [2-methyl- - (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-piYan-2-yl) -propyl] -anhydride] carboxylic; [1-Carbamoylmethyl-4-pentyl-pyrrolidine-2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide] carboxylic; [1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] co; [4- (3-pyridin-4- (3-pyridin-4-methoxyphenyl-tetrahydro-pyran-2-yl) -propyl] -amide il-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3- pyridin-4-yl-propyl) -pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-methoxy-ethyl) -4-pentyl -pyrrolidine-2-carboxylic acid; [1- (1 H -imidazol-2-ylmethyl) - [2-methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] - 4-pentyl-pyrrolidine-2-carboxylic acid; [2-methyll-1- (3 ^, 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-formylamino-ethyl) -4-pentyl- pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -am of 1- (2-amino-ethyl) -4-pentyl-pyrrolidine -2-carboxylic; [4- (3-Cyclohexyloxy-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; acid methyl ester. { 2- [2-methyl-1- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl-pentyl-pyrrolidin-1-yl} -acotic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 1-methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -annide of 4- (2- [1, 3] dithiolan-2-yl] ethyl) -piperidine-2-carboxylic acid; 1-iminomethyl-4-pentyl [2-methyl-1- (3,4,5-tri] idroxy-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- [3- (furan-2-ylmethylsulfanyl) -propyl] -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4- (3-imidazol-1 -amide); 1-propyl) -piperidine-2-carboxylic acid; [4- (3- (thiophen-2-ylsulfanyl) -propyl] -2- methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] -piperidine-2-carboxylic acid; [4- (3-imidazole-1-yl-) -2- methy1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide propyl) -piperine-2-carboxylic acid; [4- (3- (2-Oxo-pyrrolidin-1-yl) -2- methyl- 1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. ) -propyl] -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- [2- (4-methyl-thiazol-2-yl) ) -eti] -piperidine-2-carboxylic acid; [4- (3-methoxyimino-propyl) -piperidine-2-methoxyimino-propyl] -2- (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 of 4- [2- (4-ethyl-thiazole-2 -amide] -yl) -ethyl] -piperidine-2-carboxylic acid; [4- (3-Ethyl-sulfanyl-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; [4- (3-Ethoxyimino-propyl) -piperidine- [2-methi-1- (3,4,5-trihydroxy-6-methylsuiphanyl-tetrahydro-pyran-2-yl) -propyl] -amide] 2-carboxylic; [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide 4-pyrrol-1-ylmethyl-p -peridine-2-carboxylic acid; 9-Fluoren-9-ylmethyl ester of 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine- 1 -carboxylic; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbam 4-propyl-piperidine-carboxylic acid ethyl ester; [4- (3-Cyano-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide]; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid phenyl ester; 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydropyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1-carboxylic acid phenyl ester; [4- (2- [1,2,3] triazole-2-methyl-2- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide] ethyl-ethyl) -piperidine-2-carboxylic acid; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propylidene-piperidine-2-carboxylic 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; 4-Fluoro-4-propyl-p -peridine-2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide -carboxylic; 4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-tnhydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-4-propyl-pyrrolidine-2- carboxylic; 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-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; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4- (3-d-fluoromethylsulfanyl-propyl) -piperidine -2-carboxylic; [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-1, 2,3,6-tetrah D-pyridine-2-carboxylic acid; [2-Chloro-1- (3,4,5-tnh-hydroxy-6-methylsulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide of 4-propyl-1, 2,3 acid, 6-tetrahydro-pyridine-2-carboxylic acid; 3- (3-Cyclobutyl-propyl) 2-chloro- (3,4,5-trihydroxy-6-methylsulfaryl-tetrahydro-pyrid-2-yl) -propyl] -amide -zetidine-2-carboxylic acid; [4- (3-difluoromethylsulfanyl-propyl) -piperidine-2-methyl-2-methyl-1- (3,4,5-trihydroxy-6-methiisulfanyl-tetrahydro-pyrn-2-yl) -propyl] -amide. -carboxylic; and 4- (2-cyclopropyl-ethyl) -piperidine- [2-chloro-1- (3,4,5-tri- hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. 2-carboxylic acid 19. A compound selected from the group consisting of: mono- (6-) {2-chloro-1 - [(5-propyl-azepane-2-carbonyl) -amino] -propyl.} -4.5- dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl) ester of phosphoric acid; mono- (6- { 2-chloro-1 - [(5-fluoro-5-propyl-azepane-2-carbonyl) -amino] -propyl.} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro -piran-3-yl) ester of phosphoric acid; mono- (6- {2-chloro-1 - [(5-cyclopropylmethyl-azepane-2-carbonyl) -amino] -propyl.} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3 -il) ester of phosphoric acid; mono- (6-. {2-chloro-1 - [(4-fluoro-4-propyl-piperidine-2-carbonyl) -amino] -propyl.) -4,5-dihydroxy-2 -methylsulfanyl-tetrahydro-pyran-3-yl) ester of phosphoric acid; 6- { 2-chloro-1 - [(5-propyl-azepane-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; 6- { 2-Chloro-1 - [(5-fluoro-5-propyl-azepane-2-carbonyl) -amino] -propyl} 4,5-dihydroxy-2-methylsulfanyl-tetrahydropyran-3-yl ester of hexadecanoic acid; 6- { 2-chloro-1 - [(5-cyclopropylmethyl-azepane-2-carbonyl) -amino] -propl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; 6- { 2-Chloro-1 - [(4-fluoro-4-propyl-piperidine-2-carbonyl) -amino] -propyl} 4,5-Dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid. 20. A compound selected from the group consisting of: 5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (3,4,5-trihydroxy) -6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -5-propyl-azepane-1-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) ) -propylcarbamoyl] -5-fluoro-5-propylazene-1-carboxylic acid; 5-Fluoro-1- (5-methyl-2-oxo-) 2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide [1, 3] dioxol-4-ylmethyl) -5-propyl-azepane-2-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 5-cyclopropylmethyl-1- (5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl) -azepane-2-carboxylic acid; 5-Methy! -2-oxo [1,3] dioxol-4-ylmethyl ester of 2- [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) ) -propylcarbamoyl] -5-cyclopropylmethyl-1-carboxylic acid; 5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl 2- [2-chloro- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) ester -propylcarbamoyl] -4-fluoro-4-propyl-piperidine-1-carboxylic acid; [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-fluoro-1- (5-methyl-2- oxo- [1, 3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid. 21. - A compound of Formula (IB): wherein: R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R2 and R3 is = NOR7 and the other is absent; R6 is H, alkyl or hydroxyalkyl; R7 is H or alkyl; R9, which may be substituted simply or multiply in the ring in the same carbons or in different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, - (CH2) n-OH, - (CH2) n-NR4R5 and their branched chain isomers in which n is an integer between 1 and 8 inclusive, and R4 and R5 are H or alkyl; and m is 1 or 2 or its prodrug and / or pharmaceutically acceptable salt; with the proviso that the compound of formula I has a minimum inhibition concentration of 32 pg / ml or lower 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. 22. A compound selected from the group consisting of: [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propyl] -amide of 4-pentyl-pyrrolidine-2 acid -carboxylic; 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-Propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propl] -amide; [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide of 1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine -2-carboxylic acid; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) -tetrahydro-pyran-2-y-propyl} 4-propyl-piperidine-2-carboxylic acid amide; 4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide; 4-Butyl-1-methy1-pyrroiidine-2-methyl-1- (3,4,5-dihydroxy-6-propyl-tetrahydro-pyrn-2-yl) -propyl] -amide -carboxylic; mono- (4,5-dihydroxy-6-. {2-rnethyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl.} 2-propyl-tetrahydro-pyran-3- il) phosphoric acid ester; 4,5-dihydroxy-6-. { 2-methyl-1 - [(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran-3-yl ester of hexadecanoic acid; mono- (4,5-dihydroxy-6-. {2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl.} 2-propyl-tetrahydro-pyran- 3-yl) ester of phosphoric acid; hexadecanoic acid 4,5-dihydroxy-6- (2-methyl-1 - [(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl.] -2-propy] -tetrahydro-pyran-3-yl ester: 1- (5-methyl-2-oxo) - [2-methyl-1- (3,4,5-tri- hydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide - [1, 3] dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid 2- [2-methyl] -3-methyl-2-oxo- [l, 3] dioxol-4-ylmethyl ester -1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid; [2-methyl-1- (3,4 , 1- (5-Methyl-2-oxo- [1, 3] dioxol-4-ylmethyl) -4-propyl, 5-dihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide. -pyrrolidine-2-carboxylic acid; 5-methyl-2-oxo- [1, 3] dioxol-4-ylmethyl ester of 2- [2-methyl-1- (3,4l5-trihydroxy-6-propyl- tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid;. {2-methyl-1- [3,4,5-trihydroxy-6- (2-hydroxy-ethyl ) -tetrahydro-pyran-2-yl] -propyl.} - 4-propyl-pyrrolidine-2-carboxylic acid:. {2-methyl-1 - [3,4,5-trihydroxy} - 6- (3-hydroxy-propyl) -tetrahydro-pyrn-2-yl] -propyl} 4-propyl-pyrrolidine-2-carboxylic acid amide; [2-methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propyl] -amide of 4-propyl-pyrrolidine-2-carboxylic acid; . { 2-methyl-1- [3,4,5-trihydroxy-6- (2-methylsulfanyl-ethyl) -tetrahydro-pyran-2-yl] -propyl} 4-propyl-pyrrolidine-2-carboxylic acid amide; 4-Propyl-pyrrolidine-2-carboxylic acid [1 - (6-cidopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl, or its prodrug and / or pharmaceutically acceptable salt. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined in any one of claims 11-22. 24. - The use of a compound as defined in any one of claims 1 1-22, for preparing a medicament for the treatment of a microbial infection in a mammal. 25. - The use claimed in claim 24, for the treatment of a bacterial infection caused by any of the following bacterial pathogens: H. influenzae, E. faecalis and E. faecium. 26. - The use claimed in claim 24 or 25, wherein the medicament is administrable orally, parenterally, transdermally, topically, rectally or intranasally. 27. The use claimed in claim 24 or 25, wherein the medicament is administrable in an amount of about 0.1 to about 100 mg of the compound / kg of body weight per day.