KR20090099594A - 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

Novel LINCOMYCIN DERIVATIVES POSSESSING ANTIMICROBIAL ACTIVITY

The present invention relates to lincomycin derivatives exhibiting antimicrobial activity and methods of using these derivatives.

Reference to related application

This application is part of US Patent Application No. 10 / 777,455 (filed February 11, 2004), which is part of US Patent Application No. 10 / 642,807, filed August 15, 2003, US Patent Act 119 (e Claims priority based on U.S. Provisional Patent Application Nos. 60 / 479,296 (filed June 17, 2003) and 60 / 479,502 (filed June 17, 2003), incorporated herein by reference.

Lincomycin is a biosynthetic product that adversely affects the growth of various microorganisms, in particular gram positive bacteria. Features and methods of making lincomycin are disclosed in US Pat. No. 3,086,912. Likewise, various derivatives of lincomycin with antimicrobial activity have also been prepared. These derivatives include clindamycin, for example described in US Pat. No. 3,496,163.

Lincomycin derivatives are still a target of interest in antimicrobial drug discovery. Therefore, lincomycin derivatives having antimicrobial activity are preferred as possible antimicrobial agents.

Summary of the Invention

The present invention provides lincomycin derivatives having antimicrobial activity. In some embodiments, the novel lincomycin derivatives exhibit antimicrobial activity against gram positive and anaerobic pathogens. Surprisingly, selected novel lincomycin derivatives described herein, when compared to known compounds such as clindamycin, enterococcus species such as Enterocci faecium and Enterocci faecalis, and / or under It has anomalous efficacy against demanding Gram-negative pathogens such as Haemophilus influenzae .

In one of the subject matter of the composition, the present invention relates to a compound of formula (I), or a prodrug and / or a pharmaceutically acceptable salt thereof:

<Formula I>

Where

(여기에서의 위치는 질소에서 "1"로 시작하여 시계 반대 방향으로 연속적으로 번호를 매김)이고,W is a nitrogen-containing ring

(Position here is numbered consecutively in the counterclockwise order starting with "1" in nitrogen),

m is 0, 1, 2 or 3,

when m is 2, the nitrogen-containing ring may optionally contain a double bond between positions 4 and 5,

when m is 3, the nitrogen-containing ring may optionally contain a double bond between positions 4 and 5 or between positions 5 and 6,

R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl and substituted alkylsulfanyl,

R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent,

R ⁶ is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl , -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl,-(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 -N (R ⁶ )-fragment is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure,

R ⁷ is H or alkyl,

R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen , Halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclic sulfanylalkyl, heteroarylsulfanyl and heterocyclic sulfanyl, propylidene ( = CHCH ₂ CH ₃ ), azido,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -NR ⁴ R ⁵ and branched chain isomers thereof, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted Independently selected from the group consisting of alkenyl and -S (O) _q R ¹³ ,

n is an integer from 1 to 8,

R ⁴ and R ⁵ are H or alkyl,

q is an integer of 0, 1 or 2,

R ¹³ 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 Selected,

-S (O) _q R ¹³ groups are present on up to one nitrogen-containing ring.

In another of the subject matter of the composition, the invention relates to a compound of formula (II), or a prodrug and / or a pharmaceutically acceptable salt thereof:

<Formula II>

Where

(여기에서의 위치는 질소에서 "1"로 시작하여 시계 반대 방향으로 연속적으로 번호를 매김)이고,W is a nitrogen-containing ring

(Position here is numbered consecutively in the counterclockwise order starting with "1" in nitrogen),

m is 0, 1, 2 or 3,

when m is 2, the nitrogen-containing ring may optionally contain a double bond between positions 4 and 5,

when m is 3, the nitrogen-containing ring may optionally contain a double bond between positions 4 and 5 or between positions 5 and 6,

R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl and substituted alkylsulfanyl,

R ²⁰ and R ²¹ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ²⁰ and R ²¹ is = NOR ⁷ and the other is absent, or one of R ²⁰ and R ²¹ is = CH ₂ and the other is absent, or R ²⁰ and R ²¹ together are cycloalkyl, Aryl, substituted aryl, heterocyclic or heteroaryl,

R ⁶ is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl , -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl,-(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 -N (R ⁶ )-fragment is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure,

R ⁷ is H or alkyl,

R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen , Halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclic sulfanylalkyl, heteroarylsulfanyl and heterocyclic sulfanyl, propylidene ( = CHCH ₂ CH ₃ ), azido,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -NR ⁴ R ⁵ and branched chain isomers thereof, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted Independently selected from the group consisting of alkenyl and -S (O) _q R ¹³ ,

n is an integer from 1 to 8,

R ⁴ and R ⁵ are H or alkyl,

q is an integer of 0, 1 or 2,

R ¹³ 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 Selected,

-S (O) _q R ¹³ groups are present on up to one nitrogen-containing ring.

In another of the subject matter of the composition, the present invention relates to a compound of formula (IA), or a pharmaceutically acceptable salt and / or prodrug thereof:

<Formula IA>

Where

는 이중 결합 또는 단일 결합일 수 있는 결합이고,

Is a bond which may be a double bond or a single bond,

R ¹ is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo,

R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent,

로 이루어진 군으로부터 선택되거나, 또는 -N(R⁶)- 단편은 아미딘, N-사이아노아미딘, N-하이드록시아미딘 또는 N-알콕시아미딘 구조의 일부이고,R ⁶ is hydrogen, alkyl, substituted alkyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl , -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl,-(carboxamido) alkyl, (carbamoyl) alkyl,

Or the -N (R ⁶ )-fragment is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure,

R ⁷ is selected from the group consisting of hydrogen and alkyl,

R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, aryl, substituted Independently selected from the group consisting of aryl, alkenyl, substituted alkenyl and -S (O) _q R ¹³ ,

q is an integer of 0, 1 or 2,

R ¹³ 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 Selected,

m ¹ is 0 to 2,

t is 0 to 3, provided

A. In compounds of formula I,

가 단일 결합이고,

Is a single bond,

m ¹ is 0 or 1,

R ² and R ³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkyl, or one of R ² and R ³ is = NOR ⁷ and the other is absent, or of R ² and R ³ One is = CH ₂ and the other does not exist,

R ⁶ is hydrogen, alkyl, hydroxyalkyl, -C (O) O-alkylene-cycloalkyl, -C (O) O-alkylene-substituted alkyl, -C (O) O-alkyl, -C ( O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, -C (O) O-substituted heterocycle,-[C (O) O] _p -alkylene-heterocycle,-[C (O) O] _p -alkylene -A substituted heterocycle,

p is 0 or 1,

R ⁷ is selected from the group consisting of hydrogen and alkyl,

R ⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -NR ⁴ R ⁵ , -alkylene-R ^a and branched isomers thereof,

R ^a is selected from monofluorophenyl and monochlorophenyl,

n is an integer from 1 to 8,

When R ⁴ and R ⁵ are hydrogen or alkyl,

R ¹ is not —S-alkyl;

B. In compounds of formula I

이 단일 결합이고,

Is a single bond,

R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent, provided that both R ² and R ³ are hydrogen If one of R ² and R ³ is halo, the other is not hydrogen or hydroxy; if one of R ² and R ³ is hydroxy, the other is not hydrogen or hydroxy,

R ⁶ is hydrogen, alkyl, substituted alkyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl , -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl,-(carboxamido) alkyl, (carbamoyl) alkyl, or -N (R ⁶ ) -Fragment is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure,

R ⁷ is selected from the group consisting of hydrogen and alkyl,

When R ¹ is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo,

At least one R ⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,- (CH ₂ ) _n —NR ⁴ R ⁵ , -alkylene-R ^a and its branched isomers,

R ^a is selected from monofluorophenyl and monochlorophenyl,

n is an integer from 1 to 8,

R ⁴ and R ⁵ are hydrogen or alkyl;

C. In compounds of formula (I)

이 단일 결합이고,

Is a single bond,

R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent, provided that both R ² and R ³ are hydrogen If one of R ² and R ³ is halo, the other is not hydrogen or hydroxy; if one of R ² and R ³ is hydroxy, the other is not hydrogen or hydroxy,

R ⁷ is selected from the group consisting of hydrogen and alkyl,

R ¹ 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 ,

R ⁹ is independently hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,- (CH ₂ ) _n -NR ⁴ R ⁵ , not -alkylene-R ^a and its branched isomers,

R ^a is selected from monofluorophenyl and monochlorophenyl,

n is an integer from 1 to 8,

When R ⁴ and R ⁵ are hydrogen or alkyl,

, (카복스아미도)알킬, 및 아미딘, N-사이아노아미딘, N-하이드록시아미딘 또는 N-알콕시아미딘 구조의 일부인 -N(R⁶)- 단편으로 이루어진 군으로부터 선택되며,R ⁶ is substituted alkyl (not a monosubstituted or substituted heterocycle),

, (Carboxamido) alkyl, and -N (R ⁶ )-fragment which is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure,

The following specific terms used only in these clues have the following specific meanings:

Substituted alkyls include halogen, oxygen, hydroxy, amine (primary), amine (secondary-alkyl substituted with alkyl as defined above), amine (tertiary substituted with alkyl as defined above) at least one of the hydrogen atoms. Alkyl), sulfur, -SH or phenyl;

Substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, wherein alkyl is as defined above, or at least one of the hydrogen atoms is halogen, oxygen, hydroxy, amine (primary), amine (as defined above). Secondary-alkyl substituted with alkyl), amine (tertiary-alkyl substituted with alkyl as defined above), sulfur, -SH or a group substituted with alkyl substituted with -phenyl;

Substituted oxygen refers to the group -OR ^d where R ^d is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, cycloalkyl and substituted cycloalkyl;

Substituted amino is a nitrogen or R ^a and R ^b are independently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, and the group -NR ^a To R ^b ;

Substituted aryl is aryl 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. Ring, wherein alkylthio refers to the group -S-alkyl, and thioalkyl refers to an alkyl group having at least one -SH group;

Substituted heteroaryl is 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 Refers to a heteroaryl ring, where alkylthio is a group -S-alkyl, and thioalkyl refers to an alkyl group having at least one -SH group.

In another of the subject matter of the composition, the present invention relates to a compound of formula (IB), or a prodrug thereof and / or a pharmaceutically acceptable salt thereof:

<Formula IB>

Where

R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo and substituted alkylsulfanyl,

R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or One of R ² and R ³ is = NOR ⁷ and the other is absent,

R ⁶ is H, alkyl or hydroxyalkyl,

R ⁷ is H or alkyl,

R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, Independently selected from the group consisting of-(CH ₂ ) _n -OH,-(CH ₂ ) _n -NR ⁴ R ⁵ and branched chain isomers thereof,

n is an integer from 1 to 8,

R ⁴ and R ⁵ are H or alkyl,

m is 1 or 2.

In some embodiments, the nitrogen-containing ring is saturated and R ² and R ³ are independently hydrogen, hydroxy, halo, alkoxy, alkylsulfanyl, substituted alkylsulfanyl, alkyl, substituted alkyl, hydroxyalkyl , R ⁶ is hydrogen, alkyl, hydroxyalkyl, R ⁹ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-( CH ₂ ) _n -OH,-(CH ₂ ) _n NR ⁴ R ⁵ , and its branched isomers, n is an integer from 1 to 8, and R ⁴ and R ⁵ are hydrogen or alkyl, R ¹ is -S -Not alkyl.

In some embodiments, the nitrogen containing ring is saturated, m is 0, 1, 2 or 3 and R ² and R ³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkyl, or R ² and One of R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent, and R ⁶ is hydrogen, alkyl, hydroxyalkyl, -C (O ) O-alkylene-cycloalkyl, -C (O) O-alkylene-substituted alkyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O- Aryl, -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, -C (O) O-substituted heterocycle,-[C (O) O] _p -alkylene-heterocycle,-[C (O) O] _p -alkylene-substituted heterocycle, p is 0 or 1, R is ⁷ is selected from the group consisting of hydrogen and alkyl, R ⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted Nitrogen, halo, phenyl, substituted _{phenyl, - (CH 2) n -OH} , - (CH 2) n NR 4 R 5, - alkylene, and -R ^a and its branched isomers, R ^a is a mono-fluorophenyl And monochlorophenyl, where n is an integer from 1 to 8 and R ⁴ and R ⁵ are hydrogen or alkyl, then R ¹ is not -S-alkyl.

In some embodiments, the nitrogen containing ring is saturated, m is 1 or 2, and R ² and R ³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkyl, or one of R ² and R ³ Is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent, and R ⁶ is hydrogen, alkyl, hydroxyalkyl, -C (O) O-alkyl Ylene-cycloalkyl, -C (O) O-alkylene-substituted alkyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, -C (O) O-substituted Heterocycle,-[C (O) O] _p -alkylene-heterocycle,-[C (O) O] _p -alkylene-substituted heterocycle, p is 0 or 1, R ⁷ is hydrogen and Selected from the group consisting of alkyl, R ⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted vagina Bovine, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,-(CH ₂ ) _n NR ⁴ R ⁵ , -alkylene-R ^a and branched isomers thereof, R ^a is monofluorophenyl And monochlorophenyl, where n is an integer from 1 to 8 and R ⁴ and R ⁵ are hydrogen or alkyl, then R ¹ is not -S-alkyl.

In some embodiments, the nitrogen containing ring is saturated and R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, arylsulfanyl, substituted Alkylsulfanyl, hydroxy, halo, or one of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent, Provided that if R ² and R ³ are not both hydrogen and one of R ² and R ³ is halo, the other is not hydrogen or hydroxy, and if one of R ² and R ³ is hydroxy the other is hydrogen or hydroxy R ⁶ is hydrogen, alkyl, substituted alkyl, -C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O -Substituted aryl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl,-(carboxamido) alkyl, (carbamoyl) alkyl, or -N (R ⁶ )-fragment is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure, R ⁷ is selected from the group consisting of hydrogen and alkyl, R ^{When 1} is selected from the group consisting of -S-alkyl, -S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo, at least one of R ⁹ Hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,-(CH ₂ ) _n Is not NR ⁴ R ⁵ , -alkylene-R ^a and its branched isomers, R ^a is selected from monofluorophenyl and monochlorophenyl, n is an integer from 1 to 8, and R ⁴ and R ⁵ are hydrogen Or alkyl.

, (카복스아미도)알킬, 및 아미딘, N-사이아노아미딘, N-하이드록시아미딘 또는 N-알콕시아미딘 구조의 일부인 -N(R⁶)- 단편으로 이루어진 군으로부터 선택된다.In some embodiments, the nitrogen-containing ring is saturated and R ² and R ³ are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, Substituted alkylsulfanyl, hydroxy, halo, or one of R ² and R ³ is = NOR ⁷ and the other is absent, or one of R ² and R ³ is = CH ₂ and the other is absent , If both R ² and R ³ are not hydrogen, one of R ² and R ³ is halo, the other is not hydrogen or hydroxy, and if one of R ² and R ³ is hydroxy, the other is hydrogen or hydroxy Not oxy, R ⁷ is selected from the group consisting of hydrogen and alkyl, R ¹ is -S-alkyl, -S-substituted alkyl, (heteroaryl) alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkoxy, substituted alkoxy and halo, R ⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl,-(CH ₂ ) _n -OH,-(CH ₂ ) _n NR ⁴ R ⁵ , independently selected from -alkylene-R ^a and its branched isomers, R ^a is selected from monofluorophenyl and monochlorophenyl, n is an integer from 1 to 8, and R ^{If 4} and R ⁵ are hydrogen or alkyl, then R ⁶ is substituted alkyl (not a monosubstituted or substituted heterocycle),

, (Carboxamido) alkyl, and -N (R ⁶ )-fragment that is part of an amidine, N-cyanoamidine, N-hydroxyamidine or N-alkoxyamidine structure.

When used only in these clues, the following specific terms have the following specific meanings:

Substituted alkyls include halogen, oxygen, hydroxy, amine (primary), amine (secondary-alkyl substituted with alkyl as defined above), amine (tertiary substituted with alkyl as defined above) at least one of the hydrogen atoms. Alkyl), sulfur, -SH or phenyl substituted alkyl group;

Substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, wherein alkyl is as defined above, or at least one of the hydrogen atoms is halogen, oxygen, hydroxy, amine (primary), amine (also referred to as alkyl above). Substituted secondary-alkyl), amine (tertiary-alkyl substituted by said alkyl), sulfur, -SH or phenyl substituted group;

Substituted oxygen refers to the group -OR ^d where R ^d is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, cycloalkyl and substituted cycloalkyl;

Substituted amino is a nitrogen or R ^a and R ^b are independently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, and the group -NR ^a To R ^b ;

Substituted aryl is aryl 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. Ring, wherein alkylthio refers to the group -S-alkyl, and thioalkyl refers to an alkyl group having at least one -SH group;

Substituted heteroaryl is 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 Heteroaryl ring wherein alkylthio is a group -S-alkyl and thioalkyl refers to an alkyl group having at least one -SH group.

In some embodiments, R ² and R ³ are not both hydrogen. In some embodiments, if one of R ² and R ³ is halo, the other is not hydrogen or hydroxy. In some embodiments, if one of R ² and R ³ is hydroxy the other is not hydrogen or hydroxy.

임). 다른 실시태양에서, m은 1이다(W는

임). 한 실시태양에서, m은 2이다. 다른 실시태양에서, m은 2이고, 질소-함유 고리는 포화된다(W는

임). 다른 실시태양에서, m은 2이고, 질소-함유 고리는 4번과 5번 위치 사이에 이중 결합을 함유한다(W는

임). 한 실시태양에서, m은 3이다. 다른 실시태양에서, m은 3이고, 질소-함유 고 리는 포화된다((W는

임). 또 다른 실시태양에서, m은 3이고, 질소-함유 고리는 4번과 5번 위치 사이에 이중 결합을 함유한다((W는

임). 다른 실시태양에서, m은 3이고, 질소-함유 고리는 5번과 6번 위치 사이에 이중 결합을 함유한다((W는

임). 한 실시태양에서, 질소-함유 고리는 포화된다.In one embodiment, m is 0 (W is

being). In another embodiment, m is 1 (W is

being). In one embodiment, m is 2. In another embodiment, m is 2 and the nitrogen-containing ring is saturated (W is

being). In another embodiment, m is 2 and the nitrogen-containing ring contains a double bond between positions 4 and 5 (W is

being). In one embodiment, m is 3. In another embodiment, m is 3 and the nitrogen-containing ring is saturated ((W is

being). In another embodiment, m is 3 and the nitrogen-containing ring contains a double bond between positions 4 and 5 ((W is

being). In another embodiment, m is 3 and the nitrogen-containing ring contains a double bond between positions 5 and 6 ((W is

being). In one embodiment, the nitrogen-containing ring is saturated.

In a preferred embodiment, the invention provides that the nitrogen-containing ring in the formula

It provides a compound selected from.

In one embodiment, R ¹ 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 ¹ 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, R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkoxy, cycloalkylalkyl, alkylsulfanyl and substituted alkylsulfanyl. In one embodiment, R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkoxy, cycloalkylalkyl and substituted alkylsulfanyl. In a preferred embodiment, R ¹ is hydrogen, -S-methyl, -S-iso-propyl, -S-tert-butyl, propyl, 2,2,2-trifluoro-ethyl-sulfanyl, 2-e Selected from the group consisting of oxy-eth-1-yl, butoxy, 2-hydroxy-ethyl, 3-hydroxy-propyl, hydroxy-methyl, 2- (methyl-sulfanyl) -ethyl and cyclopropyl-methyl do. In another preferred embodiment, R ¹ is hydrogen, -S-iso-propyl, -S-tert-butyl, propyl, 2,2,2-trifluoro-ethyl-sulfanyl, 2-ethoxy-eth- 1-yl, butoxy, 2-hydroxy-ethyl, 3-hydroxy-propyl, hydroxy-methyl, 2- (methyl-sulfanyl) -ethyl and cyclopropyl-methyl. In another preferred embodiment, R ¹ is -S-methyl. Preferred R ¹ groups can be found in Tables I, II and III. In other embodiments, R ¹ is not -S-alkyl. In some embodiments, R ¹ is not -S-methyl. In other embodiments, R ¹ is not —S-substituted alkyl.

In other embodiments, R ¹ is preferably -SR ⁰ and R ⁰ is preferably C _1-4 alkyl, more preferably methyl, 2-hydroxyethyl or 2-ethyl salicylate. In other embodiments, R ¹ is preferably hydrogen, alkyl, substituted alkyl or 2,2,2-trifluoroethylsulfanyl. More preferably, R ¹ is hydrogen, propyl, 2-ethoxyethyl or 2,2,2-trifluoroethylsulfanyl.

In one embodiment, R ² and R ³ are independently selected from the group consisting of hydrogen, alkyl, hydroxy and halo. In a preferred embodiment, R ² and R ³ are independently selected from the group consisting of hydrogen, methyl, hydroxy and chloro. In another preferred embodiment, R ² and R ³ are hydrogen and hydroxy. In another preferred embodiment, R ² and R ³ are hydrogen and chloro. In another preferred embodiment, R ² and R ³ are hydrogen and methyl. Preferred R ² and R ³ groups can be found in Tables I, II and III.

In one embodiment, R ²⁰ and R ²¹ are independently alkyl or alkenyl, or R ²⁰ and R ²¹ together are cycloalkyl, aryl, substituted aryl, heterocyclic or heteroaryl. In one embodiment, one of R ²⁰ and R ²¹ is H and the other is alkyl or alkenyl. In a preferred embodiment, one of R ²⁰ and R ²¹ is H and the other is ethyl or ethenyl. In other embodiments, R ²⁰ and R ²¹ together are cycloalkyl or aryl. In a preferred embodiment, R ²⁰ and R ²¹ together are cyclopropyl, cyclopentyl, phenyl or 4-chloro-phenyl. Preferred R ²⁰ and R ²¹ The groups can be found in Tables I, II and III. In one embodiment, when one of R ²⁰ and R ²¹ is hydrogen, the other is not hydrogen, alkyl, hydroxy, cyano, alkylsulfanyl or substituted alkylsulfanyl.

In one embodiment, R ⁶ is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, substituted alkyl, iminomethyl, -C (O) O-substituted alkyl, 5-alkyl- [1,3] dioxol- 2-one-4-yl-methyl and 5-alkyl- [1,3] dioxol-2-one-4-yl-methoxy-carbonyl. In other embodiments, R ⁶ is selected from hydrogen and alkyl. In one embodiment, R ⁶ is 1H-imidazol-2-yl-methyl; 2- [HC (O)]-eth-1-yl; 2-amino-eth-1-yl; 2-hydroxyethyl; 2-methoxy-eth-1-yl; 5-Methyl-2-oxo- [l, 3] dioxol-4-yl-methoxy-carbonyl; 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl; Aminocarbonylmethyl; Aminocarbonylethyl; Cyanomethyl; Cyclopropyl; Hydrogen; Iminomethyl; Methyl and methoxycarbonylmethyl. In one embodiment, R ⁶ is 1H-imidazol-2-yl-methyl; 2-hydroxyethyl; 5-Methyl-2-oxo- [l, 3] dioxol-4-yl-methoxy-carbonyl; 5-Methyl-2-oxo- [1,3] dioxol-4-yl-methyl; Aminocarbonylmethyl; Cyanomethyl; Cyclopropyl; Hydrogen; It is selected from the group consisting of iminomethyl and methyl. In a preferred embodiment, R ⁶ is 1H-imidazol-2-yl-methyl; 2- [HC (O)]-eth-1-yl; 2-amino-eth-1-yl; 2-hydroxyethyl; 2-methoxy-eth-1-yl; Aminocarbonylmethyl; Aminocarbonylethyl; Cyanomethyl; Cyclopropyl; Hydrogen; Iminomethyl; Methyl and methoxycarbonylmethyl. In a preferred embodiment, R ⁶ is hydrogen or methyl. In another preferred embodiment, R ⁶ is 5-methyl- [1,3] dioxol-2-one-4-yl-methyl and 5-methyl- [1,3] dioxol-2-one-4-yl -Methoxy-carbonyl. Preferred R ⁶ groups can be found in Tables I, II and III.

In other embodiments, R ⁹ is alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, substituted alkenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclic Sulfanylalkyl, halogen, propylidene (= CHCH ₂ CH ₃ ), azido, substituted oxygen, heteroarylsulfanyl and heterocyclic sulfanyl. In other embodiments, R ⁹ is alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, substituted alkenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclic Sulfanylalkyl, halogen, propylidene (= CHCH ₂ CH ₃ ) and azido. In a preferred embodiment, R ⁹ is alkyl. In another preferred embodiment, R ⁹ is halogen.

In other embodiments, R ⁹ is (2-fluorocyclopropyl) methoxy; (3-fluoropropoxy) methyl; 1H-pyrrolylmethyl; 2- (4-ethylthiazol-2-yl) -eth-1-yl; 2- (4-methylthiazol-2-yl) -eth-1-yl; 2- (5-ethyl-isoxazol-3-yl) -eth-1-yl; 2,2,2-trifluoroethyl-sulfanyl; 2,2-difluoroethoxymethyl; 2- [1,3] dithiolan-2-yl-eth-1-yl; 2-chlorophenyl-methylsulfanyl; 2-cyclobutylethyl; 2-cyclobutylidene-ethyl; 2-cyclopropylethyl; 2-mercaptoethoxy-ethyl-sulfanyl; 2-fluoroethoxy; 2-propoxyethyl; 3- (1H- [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-trifluoroprop-1-yl-sulfanyl; 3,3,3-trifluoropropoxy; 3,3-difluoroallyl; 3,3-difluorobutyl; 3,3-difluoropropyl; 3-[(cyclopropyl) methoxy] propyl; 3-cyanoprop-1-yl; 3-cyclohexyloxypropyl; 3-cyclopropyl-propyl; 3-ethoxyiminoprop-1-yl; 3-ethylsulfanylprop-1-yl; 3-fluoropropoxy; 3-fluoropropoxymethyl; 3-fluoropropyl; 3-imidazol-1-yl-prop-1-yl; 3-mercaptopropylsulfanyl; 3-methoxyimino-prop-1-yl; 3-methylbuty-1-yl-sulfanyl; 3-methylbutyl; 3-pyridin-4-yl-allyl; 3-pyridin-4-yl-propyl; 3-pyrrolidin-2-onyl-prop-1-yl; 3-thiophen-2-ylsulfanylprop-1-yl; 4- (methoxy) butyl; 4,4-difluorobutyl; 4,4-difluoropentyl; 4-fluoro butoxy; 5,5-difluoropentyl; Azido; Butoxy; Butyl; Butylsulfanyl; Chloro; Cyclobutylmethyl; Cyclohexylmethyl; Cyclopropyl; Cyclopropylmethyl; ethyl; Ethylsulfanyl; Fluoro; Isobutyl; methyl; m-methylbenzylsulfanyl; n-butylsulfanyl; o, p-dichlorobenzylsulfanyl; Pentoxy; Pentyl; p-fluorobenzylsulfanyl; p-fluorophenylsulfanyl; p-methylbenzylsulfanyl; Propoxy; profile; Propylidene (= CHCH ₂ CH ₃ ); p-trifluoromethoxybenzyl-sulfanyl; Pyrazin-2-yl-methyl-sulfanyl; Pyridin-2-yl-methyl-sulfanyl; Pyridin-4-yl-sulfanyl; And thiophen-2-yl-methylsulfanyl.

In other embodiments, R ⁹ is 2- (4-methylthiazol-2-yl) -eth-1-yl; 2- (5-ethyl-isoxazol-3-yl) -eth-1-yl; 2- [1,3] dithiolan-2-yl-eth-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-difluoroallyl; 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-yl; 3-methylbuty-1-yl-sulfanyl; 3-methylbutyl; 3-pyridin-4-yl-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; o, p-dichlorobenzylsulfanyl; Pentyl; p-fluorophenylsulfanyl; p-methylbenzylsulfanyl; profile; Propylidene (= CHCH ₂ CH ₃ ); Pyrazin-2-yl-methyl-sulfanyl; And thiophen-2-yl-methylsulfanyl. In one embodiment, at least one R ⁹ group is not hydrogen.

In a preferred embodiment, R ⁹ is propyl. Preferred R ⁹ 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 other embodiments, Z is phosphate. In other embodiments, Z is palmitate.

(여기에서, R은 H 또는 Me임)로부터 선택되는 치환기를 포함하도록 개질된 화학식 I, II, IA 및 IB의 화합물을 포함한다.Compounds of the invention also include prodrugs of formulas (I), (II), (IA) and (IB). Such prodrugs are those in which one of the hydroxyl groups of R ⁶ or sugar is phosphate, palmitate or

Compounds of formula (I), (II), (IA) and (IB) modified to include substituents selected from wherein R is H or Me.

로부터 선택되는 치환기를 포함하도록 개질된 화학식 I, II, IA 및 IB의 화합물을 포함한다. Preferred prodrugs are those wherein R ⁶ or one of the hydroxyl groups of the sugar

Compounds of formula (I), (II), (IA) and (IB) modified to include substituents selected from.

Preferred compounds of formulas (I), (II), (IA) and (IB) are streptococcus pneumoniae (Streptococcus pneumoniae), Staphylococcus aureus (Staphylococcus aureus), Staphylococcus epidermis (Staphylococcus epidermidis), Enterococcus paecalis (Enterococcus faecalis), Enterococcus paesum (Enterococcus faecium), Haemophilus influenza (Haemophilus influenzae), Moraxella Catalanis (Moraxella catarrhalis), Eglisia Coli (Esherichia coli), Bacteroides fragilis (Bacteridees fragilis), Bacteroides tetaiotaomicron (Bacteridees thetaiotaomicron), And Clostridium difficile (Clostridium difficileHave a minimum inhibitory concentration of 32 μg / mL or less for one or more of the organisms selected from the group consisting of

In one embodiment, the compounds of Formulas (I), (II), (IA) and (IB) have a minimum inhibitory concentration of 4 μg / mL or less for one or more of the organisms selected from the group consisting of Haemophilus influenzae and Moraxella catarrhalis. . In one embodiment, the compounds of Formulas (I), (II), (IA) and (IB) have a minimum inhibitory concentration of 4 μg / mL or less for one or more of the organisms selected from the group consisting of enterococcus faecalis and enterococcus faesium. Have In one embodiment, compounds of Formulas (I), (II), (IA) and (IB) are 4 μg / mL or less for one or more of the organisms selected from the group consisting of VHIN1003 for Haemophilus influenzae and VHIN1004 for Haemophilus influenzae, which are gram negative organisms. Has a minimum inhibitory concentration of.

Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound described herein.

Another aspect of the invention is a method of treating a bacterial infection in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein. In one embodiment, the bacterial infection is caused by one or more of the following pathogens: Haemophilus influenzae, Moraxella catarrhalis, Enterococcus paecalis and Enterococcus paesium. The compound to be administered may be formulated into a pharmaceutical composition as described herein. The compound may be administered to the mammal in oral, parenteral, transdermal, topical, rectal or intranasal form as a pharmaceutical composition. In one embodiment, the compound may be administered in an amount of about 0.1 to about 100 mg / kg body weight / day.

), 하기 표 I(본원에서 "표 I"은 하기 표 Ia 내지 Ie를 의미한다)에 기재된 화학식 I의 화합물이다.Lincomycin derivatives falling within the scope of the present invention are characterized in that the nitrogen-containing ring position is numbered (ie

), A compound of formula I as described in Table I below ("Table I" herein means Tables Ia to Ie).

TABLE Ia

TABLE Ib

TABLE Ic

TABLE Id

TABLE Ie

In Table I, unless otherwise indicated, the R ⁹ substituents are substituted at the 4-position when m is 0 or 1.

Additional lincomycin derivatives within the scope of the present invention include compounds of formula (II) as described in Table II below, wherein the positions of the nitrogen-containing rings are numbered as in formula (I).

TABLE II

Additional lincomycin derivatives within the scope of the present invention include compounds of formula III, shown in Table III below, wherein the positions of the nitrogen-containing rings are numbered as in Formula I:

<Formula III>

TABLE III

In Tables I, II and III the following abbreviations are used:

S: single bond

D: double bond

D 4,5: double bond between positions 4 and 5 of the nitrogen-containing ring

Me: methyl

Pr: profile

Bu: Butyl

i: iso

t: Class 3

As used below these compounds are named based on amine derivatives, but alternatively the names of these compounds may be determined based on the 1-thio-L-threo-α-D-galactooctopyranoside derivatives.

Preferred compounds within the scope of the invention include the following compounds or their prodrugs and / or pharmaceutically acceptable salts:

4- (3,3-Difluoro-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

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;

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;

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (4-Fluoro-phenylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

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;

4- (3-Methyl-butylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (2,4-Dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide;

4- (thiophen-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

4- (Pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4- (2,4-Dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4-azido-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4- [3- (Furan-2-ylmethylsulfanyl) -prop-1-yl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

4- (3-Imidazol-1-yl-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl -Tetrahydro-pyran-2-yl) -propyl] -amide;

4- [3- (thiophen-2-ylsulfanyl) -prop-1-yl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

4- (3-Ethylsulfanyl-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide;

4- (3-Cyano-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide;

4- (3-Difluoromethylsulfanyl-prop-1-yl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl -Tetrahydro-pyran-2-yl) -propyl] -amide;

4- (3-Difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

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;

4- [2- (4-Methyl-thiazol-2-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan Yl-tetrahydro-pyran-2-yl) -propyl] -amide;

4- (3-methoxyimino-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide;

4- (3-Ethoxyimino-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide;

4- [2- (5-ethyl-isoxazol-3-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-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-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-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

4-Fluoro-4-ethyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

4-propylidene-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide ;

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

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-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

1- (1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra Hydro-pyran-2-yl) -propyl] -amide;

1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

4-propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide ;

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2- Methyl-propyl] -amide;

4-propyl-piperidine-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] Amide;

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -5-propyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-tri Hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

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;

5-Methyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

5-Ethyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

5-Cyclopropylmethyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide ;

5-cyclopropyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

5-Ethyl-4-methyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

4-Ethyl-5-methyl-azepan-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

5-Ethyl-6-methyl-azepan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

4-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

5-Fluoro-5-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] -Amide;

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-tri hydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4-Fluoro-1- (2-hydroxy-ethyl) -4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl -Tetrahydro-pyran-2-yl) -propyl] -amide;

4-Butyl-4-fluoro-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

4- (2-Cyclobutyl-ethyl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4-cyclopropylmethyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4- (2-Cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (2-Cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (2-Cyclobutyl-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

4-Cyclobutylmethyl-piperidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

5-propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide;

4- (2-Cyclopropyl-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

4-Cyclopropylmethyl-4-fluoro-piperidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

5-propyl-azpan-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

1-Cyclopropyl-5-propyl-azepane-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] -Amide;

4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

5-propyl-azane-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

5-propyl-azane-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl]- Amides;

3-cyclopropylmethyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide ;

3- (2-Cyclobutyl-ethyl) -azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydoxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

3- (2-Cyclopropyl-ethyl) -azetdine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

3- (3-Cyclopropyl-propyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

3-propyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

3-Butyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

3-Butyl-1- (2-hydroxy-ethyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

3-Pentyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

3- (3-Methyl-butyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

3- (3,3-Difluoro-propyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

3-Butyl-1-methyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide;

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide ;

4-propyl-piperidine-2-carboxylic acid [cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide;

5-propyl-azane-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;

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [phenyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide;

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-azpan-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-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (3,4,5-trihydroxy-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) -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-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Methyl] -amide;

4-propyl-piperidine-2-carboxylic acid [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl]- Amides;

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide;

5-propyl-azane-2-carboxylic acid [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide ;

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) -propyl] -amide;

4-propyl-piperidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) -tetrahydro- Pyran-2-yl] -propyl} -amide;

4-pentyl-pyrrolidine-2-carboxylic acid [1- (6-ethoxyethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide;

1- (2-Hydroxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4-Pentyl-pyrrolidin-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydropyran-2-yl) -propyl] -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]- Amides;

Phosphoric acid mono- (4,5-dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro- Pyran-3-yl) ester;

Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran 3-yl ester;

Phosphoric acid mono- (4,5-dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro- Pyran-3-yl) ester;

Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran 3-yl ester;

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide;

2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester;

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide;

2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester;

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl]- Propyl} -amide;

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl]- Propyl} -amide;

4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propyl] -amide;

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-methylsulfanyl-ethyl) -tetrahydro-pyran-2-yl] -Propyl} -amide;

4-propyl-pyrrolidine-2-carboxylic acid [1- (6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide.

Additional compounds falling within the scope of the present invention include the following compounds, or their prodrugs and / or pharmaceutically acceptable salts:

4- (thiophen-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide;

4- (4-Fluoro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (Pyridin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4- (Pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

4- (2,4-Dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

4- (3,3-Difluoro-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

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-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide;

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;

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;

1- (2-Methoxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

1- (1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra Hydro-pyran-2-yl) -propyl] -amide;

1- (2-Formylamino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

1- (2-Amino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4- (3-Cyclohexyloxy-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-pentyl-pyrrolidine- 1-yl} -acetic acid methyl ester;

1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide;

4- (2- [1,3] dithiolan-2-yl-ethyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan Yl-tetrahydro-pyran-2-yl) -propyl] -amide;

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] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl- Tetrahydro-pyran-2-yl) -propyl] -amide;

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;

4- [3- (thiophen-2-ylsulfanyl) -propyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl- Tetrahydro-pyran-2-yl) -propyl] -amide;

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;

4- [3- (2-Oxo-pyrrolidin-1-yl) -propyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

4- [2- (4-Methyl-thiazol-2-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan Yl-tetrahydro-pyran-2-yl) -propyl] -amide;

4- (3-methoxyimino-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2- Yl) -propyl] -amide;

4- [2- (4-ethyl-thiazol-2-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

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-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2- Yl) -propyl] -amide;

4-Pyrrole-1-ylmethyl-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 9H-fluorene-9-ylmethyl ester;

2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1 Carboxylic acid ethyl esters;

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 esters;

2- [2-Methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-piperidine-1 Carboxylic acid phenyl esters;

4- (2- [1,2,3] triazol-1-yl-ethyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

4-propylidene-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amides;

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -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-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

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)- 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-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide;

4- (3-Difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide;

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide;

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide;

4- (3-Difluoromethylsulfanyl-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.

Additional compounds of the present invention include the following compounds:

Phosphoric Acid Mono- (6- {2-Chloro-1-[(5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro -Pyran-2-yl) ester;

Phosphoric Acid Mono- (6- {2-chloro-1-[(5-fluoro-5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methyl Sulfanyl-tetrahydro-pyran-3-yl) esters;

Phosphoric acid mono- (6- {2-chloro-1-[(5-cyclopropylmethyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl- Tetrahydro-pyran-3-yl) ester;

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;

Hexadecanoic acid 6- {2-chloro-1-[(5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro- Pyran-3-yl ester;

Hexadecanoic acid 6- {2-chloro-1-[(5-fluoro-5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methyl Sulfanyl-tetrahydro-pyran-3-yl ester;

Hexadecanoic acid 6- {2-chloro-1-[(5-cyclopropylmethyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetra Hydro-pyran-3-yl esters; And

Hexadecanoic acid 6- {2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methyl Sulfanyl-tetrahydro-pyran-3-yl ester.

Additional compounds of the present invention include the following compounds:

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;

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -5-fluoro-5-propyl- Azepan-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester;

5-Fluoro-1- (5-methyl-2-oxo- [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;

5-cyclopropylmethyl-1- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -azepane-2-carboxylic acid [2-chloro-1- (3,4,5 -Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide;

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propylcarbamoyl] -5-cyclopropylmethyl-azepane- 1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester;

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-fluoro-4-propyl- Piperidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester; And

4-Fluoro-1- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3 , 4,5-Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.

Compounds, prodrugs and pharmaceutically acceptable salts thereof as defined herein may have activity against bacteria, protozoa, fungi and / or parasites.

In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined herein. The pharmaceutical composition of the present invention may further comprise one or more additional antibacterial agents. In one embodiment, one or more of the additional antimicrobials may be active against Gram negative bacteria. In one embodiment, one or more of the additional antimicrobials may be active against gram positive bacteria. In other embodiments, one or more of the antimicrobials may be active against both gram negative bacteria and gram positive bacteria.

In one of the subject matter of the invention, the present invention relates to a method of treating a bacterial infection in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the invention. The compounds of the present invention can be administered orally, parenterally, transdermally, topically, rectally or intranasally in pharmaceutical compositions to mammals.

Method In another aspect, the present invention relates to a method of treating a bacterial infection in a mammal comprising administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. The pharmaceutical composition of the present invention may further comprise one or more additional antibacterial agents. In one embodiment, one or more of the additional antimicrobials may be active against Gram negative bacteria. In one embodiment, one or more of the additional antimicrobials may be active against gram positive bacteria. The pharmaceutical composition can be administered orally, parenterally, transdermally, topically, rectally or intranasally to a mammal.

In a preferred embodiment, the bacterial infection to be treated is a gram positive infection. In other embodiments, the infection is a Gram negative infection. In other embodiments, the infection can be mycobacterium infection, mycoplasma infection or chlamydia infection.

In another aspect, the present invention provides novel intermediates and methods for preparing the compounds described herein.

As described above, the present invention relates to lincomycin derivatives which exhibit antimicrobial activity, in particular gram positive antimicrobial activity. In some embodiments, the novel lincomycin derivatives exhibit antimicrobial activity against gram positive and anaerobic pathogens. Surprisingly, selected novel lincomycin compounds described herein, when compared to known compounds such as clindamycin, enterococcus species such as enterococcus paesium and enterococcus paecalis and / or tricky Gram-negatives such as Haemophilus influenzae Show anomalous efficacy against pathogens. However, before describing the present invention in more detail, the following terms are first defined.

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, quoting a “pharmaceutically acceptable carrier” includes a plurality of such carriers; Reference to "additional antimicrobial agents" refers to one or more antimicrobials and their equivalent compounds known to those skilled in the art.

Justice

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

"Acyl" refers to the group -C (O) R ¹⁴ , wherein R ¹⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, heterocyclic ring or substituted heterocyclic ring.

"Acylamino" refers to -NR ^a C (O) R ¹⁴ , wherein R ^a and R ¹⁴ are as defined above.

"Alkenyl" is a linear unsaturated monovalent hydrocarbon radical having 2 to 8 carbon atoms or 3 to 8 carbon atoms, containing at least one double bond (-C = C-), preferably 1 or 2 double bonds. By branched monovalent hydrocarbon radical with carbon atoms is meant. Examples of alkenyl groups include, but are not limited to, allyl, vinyl, 2-butenyl, and the like.

"Alkoxy" is for example methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, secondary-butoxy, n-pentoxy, n-hexoxy, 1, Group “alkyl-O—” including 2-dimethylbutoxy and the like.

"Alkyl" means a linear saturated monovalent hydrocarbon radical having 1 to 8 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secondary-butyl, t-butyl, n-pentyl and the like.

"Alkylene" means a linear divalent hydrocarbon group having 1 to 8 carbon atoms or a branched divalent hydrocarbon group having 3 to 8 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, 2-methylpropylene, and the like.

"Alkylsulfanyl" is a group "alkyl-S-" including, for example, methylsulfanyl, butylsulfanyl, and the like, wherein alkyl is as defined herein.

"Alkynyl" is a linear monovalent hydrocarbon radical having 2 to 8 carbon atoms or having 3 to 8 carbon atoms, containing at least one triple bond (-C≡C-), preferably one triple bond By branched monovalent hydrocarbon radical. 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 "-NR ^a R ^b ", wherein R ^a and R ^b are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl , Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclic ring.

"Aminoacyl" refers to -C (O) NR ^a R ^b .

"Aminocarbonylalkyl" refers to the group "-R ^c C (O) NR ^a R ^b ", where R ^c is alkylene and R ^a and R ^b are as defined above.

"Aryl" means a monovalent monocyclic or bicyclic aromatic carbocyclic group having 6 to 14 ring atoms. Examples include, but are not limited to, phenyl, naphthyl and anthryl. The aryl ring may be optionally fused to a 5-, 6- or 7-membered monocyclic non-aromatic ring optionally containing one or two heteroatoms independently selected from oxygen, nitrogen or sulfur, with the remaining ring atoms Is C, wherein one or two C atoms are optionally substituted with carbonyl. Representative aryl groups with fused rings are 2,5-dihydro-benzo [b] oxepin, 2,3-dihydrobenzo [1,4] dioxane, chromman, isochroman, 2,3-dihydro Benzofuran, 1,3-dihydroisobenzofuran, benzo [1,3] dioxol, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3 -Dihydro-1H-indole, 2,3-dihydro-1H-isoindole, benzimidazol-2-one, 2H-benzoxazol-2-one and the like, but are not limited to these.

"Carboxy" means the group "C (O) OH".

"Cyanoalkyl" is an alkyl substituted with one or more cyano (-CN) groups, but only one or more cyano groups are 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 containing 3 to 8 ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

"Cycloalkylalkyl" refers to the group -R ^c R ^d where R ^c is an alkylene group as defined above and R ^d is a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropylmethylene, cyclohexylethylene, and the like.

"Halo" or "halogen" means fluoro, chloro, bromo or iodo.

"Haloalkyl" means alkyl substituted with one or more, preferably one to six, identical or different halo atoms. Examples of haloalkyl groups include, for example, trifluoromethyl, 3-fluoropropyl, 2,2-dichloroethyl, and the like.

"Heteroaryl" is a monovalent monocyclic or bicyclic aromatic radical containing 5 to 10 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O or S (the remaining ring atoms are C) Means.

"Heterocyclic" or "heterocyclic" means 1 to 10 carbon atoms in the ring and 1 to 1 selected from the group consisting of nitrogen, oxygen or S (O) _q , wherein q is 0, 1 or 2; Refers to a saturated or unsaturated group having one ring or a plurality of condensed rings, containing four heteroatoms, wherein at least one of the rings in the fused ring system may be aryl or heteroaryl.

Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, Isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine , Isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indolin, phthalimide, 1,2,3,4-tetrahydro-isoquinoline, 4 , 5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), Piperidinyl, pyrrolidine, tetrahydrofuranyl and the like, but are not limited to these.

"Hydroxy" means the group -OH.

"Hydroxyalkyl" refers to alkyl substituted with one or more -OH groups, but with only one hydroxy (-OH) group 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 mammals, including humans, livestock, and pets.

“Arbitrary” or “arbitrarily” means that the event or situation described later may or may not occur, and this description includes when an event or situation occurs and when it does not. For example, "an aryl group optionally monosubstituted or disubstituted with an alkyl group" means that alkyl may be present but is not necessarily present, and this description refers to situations where an aryl group is mono- or disubstituted with an alkyl group and that the aryl group is not substituted with an alkyl group. Includes situations that do not.

"Pharmaceutically acceptable carrier" means a carrier that is generally safe, non-toxic and useful for preparing a pharmaceutical composition that is biologically or otherwise desirable, and includes carriers that are acceptable for veterinary as well as human pharmaceutical use. As used herein and in the claims, a "pharmaceutically acceptable carrier" includes one carrier and more than one carrier.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. These salts are prepared from (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or 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, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedinsulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene -1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butyl acetic acid, lauryl sulfuric acid, Made with organic acids such as Gluconic Acid, Glutamic Acid, Hydroxynaphthoic Acid, Salicylic Acid, Stearic Acid, Muconic Acid, etc. Acid addition salts; Or (2) acidic protons present in the parent compound are replaced with metal ions, for example alkali metal ions, alkaline earth metal ions or aluminum ions or ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. Salts formed when coordinated with an organic base.

(여기에서, R은 H 또는 Me임)."Prodrug" means any compound which, when administered to a mammal, releases the active parent drug according to the compound of the invention in vivo. Prodrugs of the compounds of the invention are prepared by modifying functional groups present in the compounds of the invention in such a way that modifications in vivo can be cleaved to release the parent compound. Prodrugs include compounds of the invention wherein the hydroxy, sulfhydryl or amino group of the compound is bonded to any group capable of cleaving in vivo to regenerate free hydroxy, sulfhydryl or amino groups, respectively. Examples of prodrugs include esters of the hydroxy functional groups of the compounds of the present invention (eg, acetate, formate, palmitate and benzoate derivatives), carbamates (eg, N, N-dimethylaminocarbonyl), and the like. It is not limited to these. Preferred prodrug substituents include the following substituents attached at the N-position of the 5- or 6-membered nitrogen-containing heterocycle: phosphate, palmitate or

Wherein R is H or Me.

"Substituted alkyl" refers to cyano, halogen (ie, Cl, Br, F or I), acyl, substituted oxygen, hydroxy, alkylsulfanyl, substituted alkylsulfanyl, cycloalkyl, substituted cycloalkyl, amino Carbonylalkyl, carboxy, -C (O) H, -C (O) OR ¹⁵ , wherein R ¹⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , Substituted aryl, heteroaryl, substituted heteroaryl, etc.), -C (O) NR ^a R ^b , substituted nitrogen, = N-OR ⁷ , wherein R ⁷ is hydrogen or alkyl, -SH, -S (O) _q R ¹⁶ where q is 0, 1 or 2, and R ¹⁶ is substituted with alkyl, haloalkyl, aryl, heteroaryl, heterocycle, and aryl, heteroaryl, cycloalkyl and heterocycle Alkyl), as defined above having 1 to 3 substituents independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle It means a kill. Examples of substituted alkyl groups include 1-fluoroethyl, 1-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 1-bromopropyl, 1-iodopropyl, 1-chlorobutyl, 4-fluorobutyl , 4-chlorobutyl, 2-ethoxyeth-1-yl, -CH ₂ -S (O) ₂ CH ₃ , and the like, but are not limited to these.

"Substituted alkenyl" means an alkenyl group as defined above wherein at least one of the hydrogen atoms, preferably 1 to 3, is replaced with a substituent defined for substituted alkyl.

"Substituted alkynyl" means an alkynyl group as defined above in which one or more, preferably 1 to 3, hydrogen atoms are replaced with a substituent defined for the substituted alkyl.

"Substituted alkylsulfanyl" refers to a group -S-substituted alkyl in which substituted alkyl is as defined above, for example 2-hydroxyethylsulfanyl and the like.

"Substituted alkoxy" refers to alkyl in which substituted alkyl is group -O-substituted as defined above.

"Substituted aryl" means alkyl, substituted alkyl, alkylsulfanyl, substituted alkylsulfanyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, alkoxy, substituted alkoxy, acyl, amino, Acylamino, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxy, carboxy, -C (O) OR ¹⁵ , -C (O) NR ^a R ^b , an aryl ring substituted with one or more substituents, preferably 1 to 3 substituents selected from the group consisting of cyano, nitro and sulfanylalkyl. The aryl ring optionally contains one or two heteroatoms independently selected from oxygen, nitrogen or sulfur (the remaining ring atoms are C and one or two C atoms are optionally replaced by carbonyl) 5-, 6 Or optionally fused to a 7-membered monocyclic non-aromatic ring.

"Substituted cycloalkyl" means a cycloalkyl substituted with an alkyl group or a group defined above 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 selected from the groups defined above for substituted aryl, preferably 1 to 3 substituents.

"Substituted heterocycle" refers to a heterocyclic group independently substituted with one to three substituents as defined for substituted cycloalkyl.

"Substituted oxygen" means that R ^d is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted Refer to the group "-OR ^d ", which is a heterocycle.

"Substituted phenyl" refers to a phenyl group having 1 to 3 substituents selected from the groups defined for substituted aryls.

"Sulfanylalkyl" refers to an alkyl group substituted with one or more -SH groups, provided that no two thiol groups are present on the same carbon atom. Examples of sulfanylalkyl groups include, for example, sulfanylmethyl, 2-sulfanylethyl, 2-sulfanylpropyl, and the like.

A "therapeutically effective amount" means an amount of a compound that is sufficient to exert such therapeutic effect on a disease when administered to a mammal to treat the disease. A "therapeutically effective amount" depends on the compound, the disease and severity, and the age, weight, etc. of the mammal being treated.

“Treatment” of a disease may include (1) preventing the disease, ie, preventing the clinical symptoms of the disease from appearing in mammals that may or may be exposed to the disease but have not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, ie, inhibiting or reducing the progression of the disease or its clinical symptoms; Or (3) alleviation of the disease, ie causing degeneration of the disease or its clinical symptoms.

The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature. Abbreviations well known to those skilled in the art can be used (for example, phenyl for "Ph", methyl for "Me", ethyl for "Et", time for "h", room temperature for " rt ").

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Before describing the compositions and methods of the present invention, it is to be understood that the present invention is not limited to the particular methods, processes, assays and reagents described (as these may vary). It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention, and is not intended to limit the scope of the invention described in the appended claims in any way.

Although any methods and materials similar or equivalent to those described herein can be used in the practice or teaching of the present invention, preferred methods, devices, and materials are described herein. All documents cited herein are incorporated herein by reference to describe and disclose the methods, reagents and means reported in the literature that may be used in connection with the present invention. It should not be considered that the present invention is not entitled to antedate such disclosure by prior invention.

In practicing the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology and pharmacology are used within the skill of the art. Such techniques are explained fully in the literature.

General Synthesis Overview

Compounds of the present invention can be prepared by the method shown in the scheme shown below.

Starting materials and reagents used to prepare these compounds include Toronto Research Chemicals (North York, Ontario), Aldrich Chemical Co. (Milwaukee, Wis.), Bachem ( Commercially available from commercial sources such as Bachem (Torrance, CA), Emka-Chemie or Sigma (St. Louis, MO), or Fieser and Fieser's Reagents for Organic Synthesis, 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Addendum (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), by methods known to those skilled in the art. These schemes merely illustrate some of the ways in which the compounds of the present invention can be synthesized, and they can be modified in various ways, as will be apparent to those skilled in the art having read the disclosure herein.

As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from causing undesirable reactions. Suitable protecting groups for various work vessels, and conditions suitable for protecting and deprotecting certain functional groups, are well known in the art. See, e.g., of a number of protecting groups Green (TW Greene) and wocheu (GM Wuts) [Protecting Groups in Organic Synthesis , 2nd edition, Wiley, New York, 1991 and references cited therein.

Starting materials and intermediates of the reaction can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like, if desired. Such materials may be characterized by conventional means, including physical constants and spectral data.

Compounds of the present invention typically contain one or more chiral centers. Thus, these compounds can be prepared or isolated as pure stereoisomers if necessary. All such stereoisomers (and mixtures rich in stereoisomers) are included within the scope of the invention unless otherwise indicated. Pure stereoisomers (or mixtures rich in stereoisomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated using, for example, chiral column chromatography, chiral splitting agents and the like.

Preparation of Compounds of the Invention

In general, to prepare the compounds of formula (I) of the present invention, suitably 7-substituted lincosamine intermediates and appropriately substituted pyrrolidinyl, piperidyl, azetidinyl or azepan carboxylic acids are preferred, under reactive conditions Preferably in an inert organic solvent in the presence of a coupling agent and an organic base. Such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT) Any number of known coupling agents can be used in combination with carbodiimide, isobutyl chloroformate and the like to carry out this reaction. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methyl morpholine and the like. Suitable 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 excess carboxylic acid for lincosamine at about 0 to about 50 ° C. Typically the reaction is continued until complete for about 2 to 12 hours.

Appropriate 7-substituted lincosamine intermediates as defined herein (ie, R ² / R ³ ) are described by Hoeksema, H. et al., Journal of the American Chemical Society , 1967, 89 2448-2452. Known to those skilled in the art from methyl 6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside, which may be prepared as described in Synthesized by the method. Exemplary synthesis methods for the 7-substituted lincosamine intermediates are shown in Schemes 1-6 below.

Further suitably 7-substituted lincosamine intermediates as defined herein (ie, R ² / R ³ ) are described in US Pat. No. 3,086,912 (R ² = OH, R ³ = H), 3,496,136, 3,502,646 Or preferably European Patent No. 0161794 (R ² = halogen, R ³ = H), US Patent 3,179,565 (R ² = SR, R ³ = H), 3,544,551 (R ² = SH, R ³ Methods well known to those skilled in the art from methyl 6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside as disclosed in = H). Synthesized by

Appropriately substituted pyrrolidinyl or piperidyl carboxylic acid intermediates as defined herein (ie, R ⁹ ) are also synthesized from proline and pyridine by methods known to those skilled in the art. Proline and pyridine that can be used in the synthesis of the carboxylic acid intermediates of the invention include, for example, 4-oxoproline and 4-substituted pyridine. Proline and pyridine used in the synthesis can be purchased from commercial sources such as Aldrich and Sigma. Alternatively, these prolines and pyridine can be prepared by methods well known in the art. Exemplary synthesis methods for suitably substituted pyrrolidinyl or piperidyl carboxylic acid intermediates are shown in Schemes 7-12 below.

Scheme 1 below illustrates the general synthesis of lincosamine intermediate (1c) where P is an N-protecting group, preferably Cbz or Boc and R ¹ is defined for Formula (I).

As it is shown in Scheme 1, methyl 6-amino-6, 8-dimethyl-1-deoxy-thio-erythro -α-D-galacto-fertile et blood hoek the Llano side (1a) Sema [Journal of the American Chemical Society , 1967, 89, 2448-2452. The amino and hydroxy functional groups of the product 1a are protected with suitable protecting groups. Suitable N-protecting group (P) can be formed by adding di-t-butyldicarbonate, N- (benzyloxycarbonyloxy) succinimide, and the like. The hydroxyl group can be protected as silyl ether. The hydroxyl group can be converted to trimethylsilyl (TMS) ether by reacting with N, O-bis- (trimethylsilyl) -trifluoroacetamide in the presence of a suitable organic base such as triethylamine or trimethylsilyl chloride. . Typically N-protection is achieved prior to O-protection. After evaporation of the solvent, the crude product is chromatographed on silica to provide the protected product 1b.

The 7-O-trimethylsilyl group of (1b) was chemiselectively deprotected and oxidized to give 7-keto-lincosamine derivative (1c). This selective modification is carried out by adding the protected product (1b) to dimethylsulfoxide and oxalyl chloride in an inert organic solvent such as dichloromethane and then adding an appropriate organic base such as triethylamine. Alternatively, (1b) can be modified in an inert organic solvent by addition to dimethyl sulfoxide and an appropriate activator such as trifluoroacetic anhydride. The reaction is typically carried out at about -70 ° C. The resulting reaction mixture is stirred at low temperature and then warmed to about -50 ° C. The reaction is maintained at this second temperature for about 1 to 3 hours. To the reaction mixture is added a suitable organic base such as TEA, pyridine and the like. The reaction mixture is properly worked up to give product 1c. The general class of conditions used for transformation from (1b) to (1c) is known in the art as sone oxidation conditions.

Scheme 2 shows that P is an N-protecting group, preferably Cbz or Boc, R ³ is hydrogen, R ^{2 ′} is consistent with R ² defined for Formula I and R ¹ is defined for Formula I The general synthesis of the same lincosamine intermediate (2b) is illustrated.

As shown in Scheme 2, alkenes are prepared by reacting keto-rincosamine intermediate (1c) using a Wittig or Horner-Wadsworth-Emmons reaction. In this reaction, strong bases are used to deprotect suitable phosphonium salts or phosphonates to produce phosphorus illides. Suitable phosphonium salts that can be used are alkyltriphenylphosphonium halides, which can be prepared by the reaction of triphenylphosphine with alkyl halides. Suitable phosphorus compounds include, for example, methyltriphenylphosphonium bromide, diethyl (cyanomethyl) phosphonate and the like. Suitable strong bases that can be used to produce the illide include organolithium reagents, tert-butoxylate, and the like. The formation of phosphorus ylide is typically carried out at low temperature under an inert atmosphere such as N _{2 in} an inert organic solvent such as toluene, THF and the like.

After producing the phosphorus illide, the product 1c is added to the reaction. The reaction may conveniently be carried out at −40 ° C. to room temperature, and the reaction is stirred for typically 1 to 4 hours until completion. The resulting organic solution is worked up and the crude product is chromatographed on silica to give the alkene product 2a.

The product 2a is then hydrogenated to give a saturated product 2b. Hydrogenation is typically performed in polar organic solvents such as methanol, ethanol and the like using 10% palladium on carbon in Parr bottles. The bottle is purged and filled with H ₂ to about 50-70 psi and then shaken for about 12-24 hours until complete. The resulting reaction mixture is filtered through celite for example and washed with a polar organic solvent such as methanol. The organic solution is worked up and shaken by transfer to a washed funnel containing anhydrous Dowex 50w-400 × H ⁺ form. The resin is washed with methanol and water, then eluted product 2b from the resin by washing with 5% TEA in MeOH. The product can also be purified by silica gel column chromatography.

Scheme 3 shows lincosamine intermediates in which P is an N-protecting group, preferably Cbz or Boc, one of R ² or R ³ is alkyl and the other is —OH, and R ¹ is defined for Formula (I). ) Shows a general synthesis method.

As shown in Scheme 3, a suitable carbon nucleophile in a suitable inert organic solvent is added to 7-ketorincosamine intermediate 1c to provide 7-hydroxy lincosamine intermediate 3b. Suitable carbon nucleophiles include methylmagnesium chloride, diethyl zinc, sodium acetylide and the like, and suitable inert organic solvents that may be used include THF, diethyl ether, toluene and the like. Typically the reaction is carried out at low temperature, suitably 0 ° C. for about 3 to 5 hours. The reaction is then quenched with a saturated aqueous acid solution such as saturated aqueous NH ₄ Cl / H ₂ O solution. The quenched mixture can be worked up and purified by chromatography to give the product 3b.

Scheme 4 shows that P is an N-protecting group, preferably Boc, R ¹ is as defined for Formula I, R ² / R ³ is oxime (= NOR ⁷ ), and R ⁷ is The general synthesis of lincosamine intermediate 4b as defined is shown.

As shown in Scheme 4, lincosamine intermediates are stirred by the presence of suitable reagents such as O-trimethylsilylhydroxylamine, O-alkylhydroxylamine hydrochloride (e.g., O-methylhydroxylamine hydrochloride) and the like. Convert (1c) to oxime. Typically the reaction is carried out in a polar organic solvent such as methanol. Conveniently, the reaction can be carried out at room temperature for about 8 to 24 hours. Solvent is removed to provide N-protected product 4a.

The protecting group can be removed using an acid 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. Typically removed at low temperature, such as 0 ° C., then gradually warmed to room temperature to give product 4b.

Scheme 5 below illustrates the general synthesis of lincosamine intermediate (5b) in which R ² and R ³ are both fluorine, P is an N-protecting group, preferably Cbz or Boc, and R ¹ is defined for Formula (I). To illustrate.

As shown in Scheme 5, lincosamine intermediate 1c is contacted with a suitable fluoride in an inert organic solvent. Suitable fluorides that may be used include tetrabutylammonium fluoride, Amberlite resin A-26 F ^- form, HF pyridine and the like. Suitable inert organic solvents include THF, acetonitrile, dichloromethane, dioxane and the like. The reaction can conveniently be carried out at room temperature for about 1 to 2 hours. The product (not shown) can be purified on a silica gel column.

Contact with acetic anhydride and dimethylaminopyridine (DMAP) in a suitable mixture of an inert organic solvent and an organic base such as dichloromethane and pyridine converts the O-protecting group of the product obtained from the column. The reaction can conveniently be carried out at room temperature for about 6-12 hours. The product can be purified on a silica gel column to give product 5a.

Product 5a is contacted with a suitable fluorinating agent and then the N-protecting group is removed to give product 5b. Suitable fluorinating agents that can be used include, for example, dimethylaminosulfurtrifluoride, [bis (2-methoxyethyl) -amino] sulfurtrifluoride and the like. Typically the reaction is carried out in about 6 to 12 hours at room temperature in an inert organic solvent such as dichloromethane, ethyl acetate, THF and the like.

The protecting group can be removed using an acid 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. Typically removed at low temperature, such as 0 ° C., then gradually warmed to room temperature to give product 5b.

Scheme 6 shows that P is an N-protecting group, preferably trifluoroacyl, one of R ² and R ³ is hydrogen and the other is Cl, Br or I, and R ¹ is defined for Formula I The general synthesis method of lincosamine intermediate 6b is illustrated.

As shown in Scheme 6, N-protect lincosamine intermediate (1a) with a suitable trifluoroacylating agent in the presence of a base in a suitable organic solvent. Suitable trifluoroacylating agents include methyltrifluoroacetate, ethyl trifluorothioacetate, trifluoroacetic anhydride, and the like. Suitable organic solvents include methanol, THF, acetonitrile, dichloromethane, dioxane and the like. The reaction can conveniently be carried out at ambient temperature for about 2 to 4 hours. Protected lincosamide intermediate 6a can be purified by crystallization or used in subsequent reaction in crude state.

Suitable Rydon reagents described in Magerlein, BJ, Kagen, F., Journal of Medicinal Chemistry, 1969, 12, 780-784, or European Patent No. 0161794 Halogenation of the 7-position of the protected intermediate 6a is achieved by contact with the amide halide salt disclosed in. Suitable lydon reagents include triphenylphosphene dichloride, triphenylphosphene dibromide and the like in an inert organic solvent such as acetonitrile, dichloromethane, dichloroethane or toluene. Suitable haloamide salt reagents include 1-N- (chloromethylene) -piperidine chloride, 1-N- (chloromethylene) -N- in an inert organic solvent such as acetonitrile, dichloromethane, dichloroethane or toluene. Methylmethanium chloride and the like. The reaction is typically carried out at about 24 to 70 ° C. for 16 to 24 hours using excess halogenation reagent. Hydrolysis of the halogenated product adduct (not shown) and removal of the protecting group in the aqueous base affords 7-deoxy-7-halolincosamide intermediate 6b. Suitable bases are NaOH, KOH and concentrated ammonia in water or in a mixture of water and miscible organic solvents such as methanol, acetonitrile, tetrahydrofuran, dioxane and the like. The reaction is typically carried out under conditions of precipitating crude 7-deoxy-7-halolincosamide intermediate 6b. The 7-deoxy-7-halolincosamide intermediate 6b can be purified by crystallization from a suitable solvent or solvent system.

Alternatively, by contact with a suitable lydon reagent or amide halide salt disclosed in European Patent No. 0161794, (1c) can be directly halogenated as disclosed in US Pat. No. 3,496,136 or 3,502,646. The halogenated product adduct (not shown) in the aqueous base is hydrolyzed to provide 7-deoxy-7-halolin cosamide intermediate 6b.

Scheme 7 below illustrates the general synthesis of trans R ^{9 ″} -proline intermediate (7d), wherein R ^{9 ″} is alkyl or substituted alkyl.

As shown in Scheme 7, protected 5-oxoproline (7a), as described in the procedures of Zhang, R. et al., Journal of the American Chemical Society, 1998, 120, 3894-3902. Is enolated with a suitable base and then alkylated with a suitable alkylating agent in an inert organic solvent to give lactam 7b (R ^{9 ′} is alkenyl). Compound (7a) can be purchased from a dealer such as Bachem. Alternatively, (7a) can be produced by methods well known in the art. Suitable basic enolating agents include LiHMDS, LiN (iPr) ₂ and the like, suitable alkylating agents include allyl bromide and benzyl bromide, for example 4-bromo-2-methyl-2-butene and cis-1-bromo-2 Pentene, allylbromide and the like.

Reduction of the lactam (7b) using a suitable reducing agent provides pyrrolidine (7c) wherein R ^{9 '} is alkenyl. Reduction is carried out in a two-step continuous reaction including Superhydride® reduction of lactam to hemiaminol and subsequent reduction of hemiaminol. Suitable reducing agents that may be used include Et ₃ SiH / BF ₃ · OEt ₂ , Et ₃ SiH / TiCl ₄ , and the like.

The pyrrolidine (7c) is then hydrogenated to remove the unsaturation of the R ^{9 '} substituent while at the same time removing the benzyl protecting group from the carboxylic acid to give the product (7d). Hydrogenation is typically performed in polar organic solvents such as methanol, ethanol and the like using 10% palladium on carbon in Parr bottles. The bottle is purged, filled with H ₂ to about 50 to 70 psi and shaken for typically 5 to 24 hours until complete. The reaction mixture is filtered through a pad of celite, for example and washed with a polar organic solvent such as methanol. The combined washes and filtrates are evaporated to give product 7d wherein R ^{9 ″} is alkyl or substituted alkyl.

Scheme 8 below illustrates the general synthesis of trans-R ⁹ -proline intermediates (8b, 8c) wherein R ^{9 '} is alkenyl or substituted alkenyl and R ^{9 "} is alkyl or substituted alkyl.

As shown in Scheme 8, the product 7c is ozonated to give an aldehyde, which is treated under Wittig conditions to give (8a). Typically in anhydrous inert organic solvents such as dichloromethane, dioxane, THF, etc., the ozone decomposition reaction is carried out at low temperature, eg -78 ° C, and then the reaction is quenched with a reducing agent such as DMS, Ph ₃ P.

Suitable phosphonium salts and aldehydes are reacted in the presence of a strong base in an inert organic solvent. Suitable phosphonium salts that can be used include, for example, fluorobenzyl phosphonium chloride, 4-chlorobenzyl phosphonium chloride, dibromofluoromethane, triphenylphosphine and the like. Suitable bases that can be used include t-butoxylated, 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 with vigorous stirring in an inert atmosphere (eg under nitrogen). The reaction is typically carried out at room temperature to about 110 ° C. for 1-2 hours. The resulting reaction mixture can be worked up appropriately and purified by chromatography to give (8b).

The intermediate 8b is then hydrogenated to give the product 8c. Hydrogenation is typically performed in polar organic solvents such as methanol, ethanol and the like using 10% palladium on carbon in Parr bottles. The bottle is purged and filled with H ₂ to about 40-70 psi and then shaken for about 4 to 24 hours until finished. The reaction mixture is filtered through, for example, a pad of celite and washed several times with a polar organic solvent (eg methanol). The combined washes and filtrates are evaporated to give product 8c, wherein R ^{9 "} is alkyl or substituted alkyl, which corresponds to the saturated form of product 8b.

Alternatively, the intermediate 8b is saponified by a method known to those skilled in the art by contact with an aqueous alkali solution and a miscible organic cosolvent to provide an R ^{9 ′} unsaturated amino acid intermediate 8c.

Scheme 9 below illustrates the general synthesis of proline intermediate (9d), wherein R ⁹ is defined for Formula (I).

Scheme 10 below shows a substituted pyridine carboxylic acid intermediate in which R ⁹ is defined for Formula I, as described in Shuman, RT, Journal of Organic Chemistry, 1990, 55, 741-750. The general synthesis method of (10b) is illustrated.

As shown in Scheme 10, suitably substituted pyridine is contacted with a suitable oxidant in an inert organic solvent. Properly substituted pyridine starting materials can be purchased from vendors such as Aldrich and Sigma. Alternatively, these pyridine can be prepared by methods well known in the art. Suitable oxidants which may be used include hydrogen peroxide, MCPBA and the like. The reaction is typically carried out at reflux for 6 to 12 hours. The reaction mixture is then contacted with a suitable cyanide reagent to provide the cyano-substituted pyridine 10a. Suitable cyanide reagents that may be used include trimethylsilyl cyanide, HCN and the like. Suitable inert organic solvents include dichloromethane, dioxane, THF and the like. The reaction can conveniently be carried out at room temperature for about 6-12 hours. The reaction mixture is worked up to give cyano-substituted pyridine (10a).

The cyano-substituted pyridine (10a) is then hydrolyzed by contact with a suitable acid to give the pyridin-2-yl carboxylic acid (10b). Acids suitable for hydrolyzing cyano groups to form carboxylic acids include hydrochloric acid, aqueous sulfuric acid solutions and the like. Typically the reaction is carried out at reflux for 6-12 hours.

Scheme 11 below illustrates the general synthesis of pyridine and piperidine intermediates in which R ⁹ is defined for Formula (I).

Scheme 12 below illustrates the general synthesis of proline intermediate 12d, wherein R ⁹ is defined for Formula (I).

As shown in Scheme 12, ketoproline 12a is allylated to produce hydroxy allyl proline and its hydroxy functional group is replaced by fluorine. Allyl double bonds are hydrogenated to give fluoro alkyl proline 12c, which is deprotected to yield 12d.

Scheme 13 below illustrates a coupling reaction of lincosamine intermediate prepared as described above in Schemes 1-6, and pyrrolidinyl or piperidyl carboxylic acid prepared as described above in Schemes 7-12, wherein R ¹ , R ² , R ³ , R ⁶ and R ⁹ are as defined for Formula I, P ¹ is a suitable O-protecting group and P ² is a suitable N-protecting group.

As shown in Scheme 13, a suitably 7-substituted lincosamine intermediate (such as prepared according to any one of Schemes 1-6) and an appropriately substituted pyrrolidinyl or piperidyl carboxylic acid (e.g. Prepared according to any one of 7 to 9 or 11 or 12) are condensed under reactive conditions, preferably in the presence of a coupling agent and an organic base in an inert organic solvent. The reaction was carried out with O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT Any number of known coupling agents, such as) may be used in combination with carbodiimide, isobutylchloroformate and the like. Suitable organic bases include diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N-methyl morpholine and the like. Suitable inert organic solvents that can be used include, for example, N, N-dimethylformamide, acetonitrile, dichloromethane and the like. Typically this reaction is carried out using excess carboxylic acid for lincosamine at about 0 to about 50 ° C. The reaction is continued until terminated (typically about 2 to 12 hours).

Removal of the protecting group can be carried out using an acid 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. Removal is typically performed at low temperature, for example 0 ° C., and then gradually warmed to room temperature to give the product.

As shown in Scheme 13, a suitably 7-substituted lincosamine intermediate (such as prepared according to any one of Schemes 1-6) and an appropriately substituted pyridin-2-yl carboxylic acid (such as prepared according to Scheme 10) Condensation under reactive conditions, preferably in the presence of a coupling agent and an organic base in an inert organic solvent as described above.

Pyridine (13b) is hydrogenated to give the piperidyl product. Hydrogenation is typically carried out in polar organic solvents such as methanol, ethanol and the like using platinum (IV) oxide in the presence of acids such as HCl, acetic acid and the like in Parr bottles. The bottle is purged, filled with H ₂ to about 40-70 psi and shaken until closed (typically about 24 hours). The reaction mixture is filtered through a pad of celite, for example and washed several times with a polar organic solvent such as methanol. The combined washes and filtrates are evaporated to give the piperidyl product.

Pyridine carboxylic acid and Lin is coupled to the kosamin was reduced after service pyridine (13b) to provide a piperidyl product, and Meyer et al., Beoken (Birkenmeyer, RD) [Journal of Medicinal Chemistry 1984, 27, 216-223.

Scheme 14 below illustrates a coupling reaction of lincosamine intermediate prepared as described above in Schemes 1-6 with pyrrolidinyl or piperidyl carboxylic acid prepared as described above in Schemes 7-12, wherein R ¹ , R ² , R ³ and R ⁹ are as defined for Formula I and P is a suitable N-protecting group. The coupling reactions described herein may also be used to couple azetidinyl and azepan carboxylic acids.

Scheme 15 is a protected 1-allyl intermediate (15b, 15c, 15e, 15f), wherein R ² , R ³ , R ⁹ are as defined for Formula I, and P ₁ and P ₂ are each suitable N- And O-protecting groups).

In Scheme 15, P ₁ and P ₂ are preferentially differentially removable protecting groups. By contacting DAST in the presence of N-bromosuccinimide (NBS) in a suitable solvent, such as dichloromethane (DCM), the methylsulfanyl (methylsulfanyl) group is replaced with a fluoro substituent, thereby compound (15b). 15e).

Again, the fluoro group is substituted by contact with trimethylallylsilane in the presence of a trifluoroborate diethyl ether complex to form an alkyl substituent. Subsequent removal of the Boc (t-butoxycarbonyl) protecting group with trifluoroacetic acid (TFA) gives the deprotected product. Alternatively, 1-des (methylsulfanyl) -1-fluoro-2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamine is typically defluorinated to yield 1-des ( Methylsulfanyl) -2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamine (ie, R ¹ is hydrogen).

O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate in dimethylformamide (DMF) and triethylamine (TEA) N-Boc-4 as 1-des (methylsulfanyl) -1-allyl-2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamine in the presence of a coupling promoter such as HATU). The carboxyl group of -pentyl-proline is typically amide coupled to provide compounds 15c and 15f. The allyl groups of compounds 15c and 15f provide an easy source for various modifications at the 1-position of lincosamine groups.

Scheme 16 wherein R ¹ is alkylsulfanyl, substituted alkylsulfanyl, R ² , R ³ , R ⁹ are as defined for Formula I, and P ₁ and P ₂ are suitable N- and O-protecting groups, respectively. The general synthesis method for preparing the compound showing

Scheme 16 indicates that nucleophilic substitution of the 1-fluoro group by a suitable sulfanyl moiety can be achieved on lincosamine residues to provide compound 16a, or on coupled lincosamine derivatives to provide compound 16b. Shows. Nucleophilic substitutions are carried out using conventional techniques well known in the art.

Scheme 17 wherein R ² , R ³ , R ⁹ are as defined for Formula I, P ₁ and P ₂ represent suitable N- and O-protecting groups, respectively, R is hydrogen, alkyl, substituted alkyl, aryl, Illustrative general synthesis methods for producing alcohol and ether substituents at the 1-position, which are substituted aryl, heteroaryl or substituted heteroaryl.

Scheme 17 oxidizes 1- (desulfanylmethyl) -1-allyl-lincosamine derivatives to produce the corresponding aldehydes, followed by conventional methods (e.g., after ozone decomposition, preferably sodium in a protic solvent such as methanol). Reduction with borohydride) to produce a primary alcohol. The primary alcohol is then contacted with a suitable base such as sodium hydride and a suitable alkyl halide to form the ether derivative, either as lincosamine itself or as a coupled lincosamine derivative, to provide compounds 17c and 17f, respectively.

Scheme 18 is a compound in which R ² , R ³ , R ⁹ are as defined for Formula I, P is a suitable N-protecting group, and R ¹ is consistent with Schemes 15, 16 and 17, respectively (15f, 16b, 17f) The deprotection scheme of is illustrated.

Scheme 18 shows that the compound of formula I is produced by conventional deprotection.

Scheme 19 below illustrates alkylation of nitrogen of a pyrrolidinyl or piperidyl ring, wherein R ⁶ is alkyl or hydroxyalkyl and R ¹ , R ² , R ³ and R ⁹ are defined for Formula (I).

(a) alkylating agents

As shown in Scheme 19, lincosamine 18a can be N-substituted by contact with an alkylating agent in the presence of a suitable base to provide product 18b. Suitable alkylating agents that can be used include epoxides, alkyl bromide and the like. Suitable bases that may be used include potassium carbonate, cesium carbonate triethylamine and the like. The alkylation reaction is typically carried out in a polar organic solvent such as methanol or DMF. The alkylation reaction is typically carried out for 10 to 20 hours at low temperatures of 0 to -10 ° C.

In Scheme 20, R ² , R ³ , R ⁶ and R ⁹ are as defined for Formula I and P ₂ is a suitable O-protecting group.

a. Raney Ni, EtOH, reflux.

Scheme 21 below illustrates a versatile synthetic sequence in which m and R ⁹ can synthesize an unsaturated N-protected amino acid (21k) ring as defined for Formula (I).

(a) NaH, R ⁹ Br, DMF; (b) KOH, H ₂ O, EtOH; (c) CH ₂ O (aqueous solution), piperidine, EtOH; (d) DIBALH, CH ₂ Cl ₂ ; (e) PBr ₃ , Et ₂ O; (f) ethyl bromoacetate; (g) HCl / dioxane; (h) LiOt-Bu, THF; (i) 21d, LiHMDS, LiCl, THF, 0 ° C; (j) Boc ₂ O, Et ₃ N, CH ₂ Cl ₂ ; (k) olefin metathesis catalyst CH ₂ Cl ₂ ; (l) 1M NaOH (aq), MeOH.

As shown in Scheme 21, suitable N-allyl amino esters 21f are added to pseudoephedrine acting as auxiliary chiral centers to enable stereospecific alkylation of carbon with suitable allyl bromide 21d. After protecting the secondary amine, olefin metathesis and cleavage of the auxiliary chiral centers are performed to provide 4,5-unsaturated N-protected cyclic amino acids (21k).

a. H ⁺ , MeOH; b. 2-nitrobenzenesulfonyl chloride, 2,4,6-collidine, dichloroethane; c. Cs ₂ CO ₃ , TBABr, DMF, 22c (Y = Br or OTs) or c. PPh ₃ , diisopropylazidodicarboxylate, 22c (Y = OH) by Mitsunobu alkylation; d. Benzylidene [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidineylidene] dichloro- (tricyclohexylphosphine) ruthenium; e. Organic base (7-methyl, 1,5,7-triazabicyclo [4.4.0] dec-5-ene), thiophenol; f. (Boc) ₂ O, TEA; g. LiOH aqueous solution, dioxane.

Pharmaceutical formulation

When used as a medicament, the compounds of the present invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, parenteral, transdermal, intravenous, intramuscular, topical, rectal and intranasal. These compounds are effective as injectable compositions and oral compositions. These compositions are prepared in a manner well known in the pharmaceutical art and comprise one or more active compounds.

The present invention also includes pharmaceutical compositions containing one or more compounds of the present invention as active ingredient, together with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually mixed with excipients, diluted with excipients or enclosed in a carrier which can be in the form of capsules, sachets, paper or other containers. The excipients used are typically excipients suitable for administration to humans or other mammals. If the excipient acts as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may contain tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) such as up to 10% by weight of the active compound. Ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In preparing formulations, the active compound may be milled to provide the appropriate particle size prior to mixing with other components. If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is typically adjusted by milling (eg, about 40 mesh) to be substantially uniformly distributed in the formulation.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Cellulose, sterile water, syrup and methyl cellulose. The formulation further comprises lubricants such as talc, magnesium stearate and mineral oil; Wetting agents; Emulsifying and suspending agents; Preservatives such as methyl- and propylhydroxy-benzoate; Sweetening and flavoring agents. Procedures known in the art can be used to formulate compositions of the invention to release the active ingredient rapidly, continuously or delayed after administration to a patient.

In pharmaceutical compositions and unit dosage forms thereof, the amount of active ingredient which is a compound according to the invention can be varied or adjusted widely depending upon the particular use, the potency of the particular compound and the desired concentration.

The compositions are preferably formulated in unit dosage forms, each dosage form containing about 5 to about 100 mg, more typically about 10 to about 30 mg of the active ingredient. The term “unit dosage form” refers to physically discrete units suited as single-dose forms for humans and other mammals, where each unit is calculated with a suitable pharmaceutical excipient to produce the desired therapeutic effect. Contains a quantity of active substance. Preferably, the compounds of the present invention are used in about 20% by weight or less, more preferably about 15% by weight or less of the pharmaceutical composition, with the remainder being pharmaceutically inert carrier (s).

The active compounds are effective in a wide range of dosages and are usually administered in pharmaceutically or therapeutically effective amounts. However, the actual amount of compound administered is dependent upon the relevant situation, including the condition to be treated, the severity of the bacterial infection being treated, the route of administration chosen, the active compound administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms. You should know that your doctor decides.

In therapeutic uses to treat bacterial infections or combat bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof allow to obtain and maintain concentrations of active ingredients, i.e. amounts or blood levels, which have antimicrobial effects upon treatment in animals. Doses are administered orally, topically, transdermally and / or parenterally. Generally, such an antimicrobial or therapeutically effective amount (ie, an effective dosage) of the active ingredient is about 0.1 to about 100 mg / kg body weight / day, more preferably about 1.0 to about 50 mg / kg body weight / day.

To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to prepare a solid preformulation composition containing a homogeneous mixture of the compounds of the invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is divided into unit dosage forms of this type, for example containing from 0.1 to about 500 mg of the active ingredient of the invention.

Tablets or pills of the invention may be coated or otherwise formulated to provide dosage forms that provide the benefit of long-term action. For example, a tablet or pill can include an internal dosage component and an external dosage component, wherein the external dosage component is in the form of an envelope over the internal dosage component. The two components can be separated into an enteric layer that resists disintegration in the stomach and allows the internal components to pass into the duodenum intact or to delay release. Various materials can be used in such enteric layers or coatings, and such materials include a plurality of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms into which the novel compositions of the present invention may be incorporated for oral administration or injection are aqueous solutions, syrups, aqueous or oil suspensions with appropriate addition of flavors, and edible oils (e.g. corn oil, cottonseed oil, sesame oil, coconut oil or Emulsions with peanut oil), and elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients. Preferably, the composition is administered by the oral or nasal breathing route for local or systemic effects. Preferably the composition in a pharmaceutically acceptable solvent can be sprayed by using an inert gas. The sprayed solution can be inhaled directly from the spraying device, or the spraying device can be attached to a face mask tent or an intermittent positive pressure respirator. The solution, suspension or powder composition may preferably be administered orally or nasal from the device for delivering the formulation in a suitable manner.

The following formulation examples illustrate representative pharmaceutical compositions of the present invention.

Formulation example  One

Hard gelatin capsules are prepared containing the following ingredients:

The active ingredients are mixed and filled into hard gelatin capsules in an amount of 340 mg.

Formulation example  2

Tablet formulations are prepared using the following ingredients:

The ingredients are combined and compressed to produce tablets each weighing 240 mg.

Formulation example  3

A dry powder inhalation formulation is prepared containing the following ingredients:

The active ingredient is mixed with lactose and the mixture is added to the dry powder inhalation device.

Formulation example  4

Tablets each containing 30 mg of the active ingredient are prepared as follows:

The active ingredient, starch and cellulose were treated with 20 mesh U.S. Pass through the sieve and mix thoroughly. A solution of polyvinylpyrrolidone is mixed with the resulting powder, which is 16 mesh U.S. Pass through the sieve. The granules thus prepared were dried at 50-60 ° C. and treated with 16 mesh U.S. Pass through the sieve. 30 mesh U.S. in advance Sodium carboxymethyl starch, magnesium stearate and talc passed through a sieve are added to the granules, mixed and tableted in a tableting machine to produce tablets each weighing 120 mg.

Formulation example  5

Capsules containing 40 mg of each drug are prepared as follows:

The active ingredient, starch and magnesium stearate are blended and mesh No. 20 U.S. After passing through a sieve, hard gelatine capsules are filled in an amount of 150 mg.

Formulation example  6

Suppositories each containing 25 mg of the active ingredient are prepared as follows:

The active ingredient is 60 mesh U.S. Pass through a sieve and suspend in the pre-melted saturated fatty acid glycerides using the minimum heat required. The mixture is then poured into suppository molds of nominal 2.0 g capacity and cooled.

Formulation example  7

A suspension containing 50 mg of drug per 5.0 mL dose is prepared as follows:

The active ingredient, sucrose and xanthan gum were formulated and mesh 10. U.S. Pass through a sieve and then mix with a solution of microcrystalline cellulose and sodium carboxymethyl cellulose in previously prepared water. Sodium benzoate, fragrances and colorants are diluted with some of the water and added with stirring. Add enough water to make the required volume.

Formulation example  8

The active ingredient, starch and magnesium stearate were blended and mesh 20. U.S. Pass through the sieve and fill the hard gelatin capsules in an amount of 425.0 mg.

Formulation Example 9

Subcutaneous formulations are prepared as follows:

Formulation example  10

Topical formulations are prepared as follows:

Heat the white soft paraffin until it melts. Liquid paraffin and 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 it is solid.

Formulation example  11

Intravenous formulations are prepared as follows:

Other preferred formulations used in the methods of the present invention utilize transdermal delivery devices (“patches”). Such transdermal patches can be used to inject a controlled amount of a compound of the invention continuously or discontinuously. The manufacture and use of transdermal patches for delivering drugs is well known in the art. See, eg, US Pat. No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference. Such patches may be prepared for delivery of medication continuously, pulsatingly or as needed.

Often, it is desirable or necessary to introduce the pharmaceutical composition directly or indirectly into the brain. Direct techniques typically involve placing drug delivery catheters within the ventricular system of the host to bypass the blood-brain barrier. One such implantable delivery system used to transport biological factors to specific anatomical regions of the body is described in US Pat. No. 5,011,472, which is incorporated herein by reference.

Typically preferred indirect techniques usually include formulating the composition to provide drug efficacy potential by converting the hydrophilic drug into a fat soluble drug. Drug potential is typically achieved by blocking hydroxy, carbonyl, sulfate and primary amine groups present on the drug to make the drug more soluble and compliant to transport across the blood-brain barrier. Alternatively, delivery of a hydrophilic drug can be enhanced by injecting a hypertonic solution into the artery that can 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 edition (1985).

As indicated above, the compounds described herein are suitable for use in the various drug delivery systems described above. In addition, to improve the plasma half-life of the administered compound, other conventional techniques can be encapsulated, introduced into the cavity of liposomes, prepared as a colloid, or to provide extended plasma half-life of the compound. It is available. Various methods can be used to prepare liposomes, as described, for example, in US Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 to Szoka et al., Each of which is incorporated herein by reference.

As noted above, the compound administered to the patient is in the form of the pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The resulting aqueous solution can be packaged for use by itself or can be combined with a sterile aqueous carrier prior to lyophilization and administration of the lyophilized formulation. The pH of the compound formulation is usually 3 to 11, more preferably 5 to 9, most preferably 7 to 8. It will be appreciated that the use of certain excipients, carriers or stabilizers described above results in pharmaceutical salts.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any mode of administration that is acceptable for agents that provide similar utility. Toxicity and therapeutic efficacy of these compounds can be determined, for example, in cell culture or experimental animals to determine LD ₅₀ (doses that are lethal to 50% of individuals) and ED ₅₀ (doses that are therapeutically effective at 50% of individuals). Can be determined by standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD ₅₀ / ED ₅₀ . Preferred are compounds that exhibit a large therapeutic index.

Dose ranges for use in humans can be determined using data obtained from cell culture assays and animal studies. Dosages of such compounds are preferably within a wide range of circulating concentrations including ED ₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. Dosages can be determined in animal models to achieve a range of circulating plasma concentrations including an IC ₅₀ (the concentration of test compound that achieves half of the maximum inhibition of symptoms) as determined in cell culture. This information can be used to more accurately determine useful dosages in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

Utility

Compounds, prodrugs and pharmaceutically acceptable salts thereof as defined herein have activity against one or more of a variety of bacteria, protozoa, fungi and parasites. By way of example, the compounds, their prodrugs and pharmaceutically acceptable salts may be active against gram positive and gram negative bacteria. Compounds, their prodrugs and pharmaceutically acceptable salts are the salts Muko (Mucor) and Candida (Candida) fungi from the genus, for example, Muko la triangle Versus (Mucor racemosus ) or Candida albicans , and can be active against a variety of fungi. The compounds, their prodrugs and pharmaceutically acceptable salts can be active against a variety of parasites, including malaria and cytosporidium parasites.

The compounds of the present invention may be active against one or more of a variety of bacterial infections, including, for example, Gram positive infections, Gram negative infections, Mycobacterium infections, Mycoplasma infections and Chlamydia infections.

Since the compounds of the present invention may exhibit potent activity against various bacteria, such as gram positive bacteria, the compounds of the present invention may be useful antimicrobial agents and are effective against one or more of many human and veterinary pathogens, including gram positive bacteria. Can be. Gram-positive organisms in which the compounds of the present invention may be effective include, for example, Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus paecalis, Enterococcus pae Cium, Haemophilus influenzae, Moraxella catarrhalis, E. coli, Bacteroides pragillis, Bacteroides tetaiotamicron, Clostridium difficile and the like.

Compounds of the invention can be combined with one or more additional antibacterial agents. One or more additional antimicrobials may be active against Gram negative bacteria. One or more of the additional antimicrobials may be active against gram positive bacteria. Combinations of compounds of the invention with one or more additional antimicrobials may be used to treat Gram negative infections. Combinations of compounds of the invention with one or more additional antimicrobials may be used to treat Gram positive infections. Combinations of compounds of the invention with one or more additional antibacterial agents may also be used to treat mycobacterium infections, mycoplasma infections or chlamydia infections.

In vitro activity of the compounds of the invention is described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", 3rd edition, 1993 published, National Committee for Clinical Laboratory standards, Villanova, Pa. As can be appreciated by standard test procedures such as determining the minimum inhibitory concentration (MIC) by agar dilution.

The amount administered to a mammalian patient will vary depending upon the compound being administered, the purpose of administration (eg, prophylactic or therapeutic), the condition of the patient, the mode of administration and the like. In one example, an amount of a composition sufficient to treat or at least partially arrest the symptoms of the disease and its complications is administered to a patient already suffering from the disease. Appropriate amounts to achieve this are defined as "therapeutically effective dosages". The amount effective for this use will depend on the judgment of the attending clinician, depending on factors such as the disease being treated, and the severity of inflammation, the age, weight and general condition of the patient.

The composition administered to the patient is in the form of the pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The resulting aqueous solution can be packaged for use on its own or can be lyophilized and mixed with a sterile aqueous carrier prior to administration of the lyophilized formulation. The pH of the compound formulation is typically about 3 to about 11, more preferably about 5 to about 9, most preferably about 7 to about 8. It will be appreciated that the use of certain excipients, carriers or stabilizers described above results in pharmaceutical salts.

The therapeutic dosage of a compound of the invention will depend, for example, on the particular use treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dosage is typically about 20 to about 500 μg / kg body weight, preferably about 100 to about 300 μg / kg body weight. Suitable dosage ranges for intranasal administration are typically about 0.1 to 1 mg / kg body weight. Effective dosages can be estimated from dose-response curves derived from in vitro or animal model test systems.

The following synthetic and biological examples are presented to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

Surprisingly, selected novel lincomycin compounds described herein, when compared to known compounds such as clindamycin, enterococcus species such as enterococcus faesium and enterococcus faecalis and / or tricky Gram-negative pathogens such as Haemophilus influenzae Exhibit anomalous efficacy for.

In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has a generally accepted meaning.

7-methylMTL: 1-methylsulfanyl-7-deoxy-7-methyllincosamine

Ac: Acetyl

apt: apparent triplet

Aq: aqueous

atm: barometric pressure

Bn: Benzyl

Boc: Class 3-Butyl Carbon Day Protector

br s: wide single line

BSTFA: N, O-bis (trimethylsilyl) trifluoroacetamide

¹³ C NMR: ¹³ carbon nuclear magnetic resonance

Cbz: carbonyloxybenzyloxy protecting group

CDCl ₃ : Deuterated Chloroform

CD ₃ OD: Deuterated Methanol

CD ₃ SOCD ₃ : deuterated dimethyl sulfoxide

cfu: colony forming unit

D ₂ O: deuterated water

d: doublet

DAST: Dimethylaminosulfurtrifluoride

dd: doublet of doublets

dddd: doublet of doublet of doublet

DIBALH: diisobutylaluminum hydride

dt: doublet of triplets

DCE: Dichloroethane

DCM: Dichloromethane

DIEA: diisopropylethylamine

DMAP: dimethylaminopyridine

DMF: Dimethylformamide

DMS: dimethyl sulfide

DMSO: Dimethyl Sulfoxide

DPPA: diphenylphosphoryl azide

ED ₅₀ : therapeutically effective dose in 50% of subjects

equiv: equivalent

ESMS: electrospray mass spectroscopy

Et: ethyl

EtOAc: ethyl acetate

Et ₂ O: diethyl ether

g: grams

h: hour

HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

HOBT: 1-hydroxybenzotriazole hydrate

¹ H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy

HPLC: High Pressure Liquid Chromatography

Hz: Hertz

IC ₅₀ : Concentration of Test Compounds Achieving Half of Maximum Inhibition of Symptoms

J: Coupling Constant (Hz)

L: liter

LD ₅₀ : A dose lethal to 50% of individuals

LiHMDS: Lithium hexamethyldisilazide

m: polyline

M: Mall

MCPBA: 3-chloroperoxybenzoic acid

Me: methyl

MeCN: acetonitrile

MeOH: Methanol

mg: mg

MHB: Mueller Hinton Broth

MHz: MHz

MIC: minimum inhibitory concentration

min: min

mL: milliliters

mm: mm

mmHg: millimeter mercury

mmol: mmol

MS (ESPOS): Mass spectrometry by positive electrospray ionization

MS (ESNEG): Mass spectroscopy by negative electrospray ionization

MTBU: 7-methyl-1,5,7-triazacyclocyclo- [4.4.0] dec-5-ene

MTL: 1-methylsulfanylincosamine (methyl 6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside)

N: normal

NBS: N-bromosuccinimide

NMR: nuclear magnetic resonance

OBz: benzyloxy protecting group

OtBu: tert-butoxy

Pd / C: Palladium / Carbon

pg: picogram

Ph: Phenyl

Pro: L-Proline

psi: Pounds per square inch

q: quartet

q.v .: Quantitative

R _f : retention factor

rt: room temperature

s: single line

sat .: Saturated

t: triplet

TCI: TCI America

TEA: triethylamine

TFA: trifluoroacetic acid

THF: Tetrahydrofuran

TLC: thin layer chromatography

TMS: trimethylsilyl

Ts: Chubby

Μg: microgram

μL: microliters

μM: micromolar

v / v: volume / volume

In addition, the term “Aldrich” indicates that the compound or reagent used in the following procedure is available from Aldrich Chemical Company, Inc. (West St. Paul Avenue 1001, Milwaukee, 53233, Wisconsin); The term “Fluka” indicates that a compound or reagent is commercially available from Fluka Chemical Corp. (11779 Ronconcoma South Second Street 980, NY, USA); The term “Lancaster” indicates that a compound or reagent is available from Lancaster Synthesis, Inc. (03087 Wyndham P. Box. 100, New Hampshire, USA); The term “sigma” indicates that the compound or reagent is commercially available from Sigma (63178 St. Louis P. Box 14508, Missouri, USA); The term “Chemservice” indicates that a compound or reagent is commercially available from Chemservice Inc. (Westchester, PA); The term “bachem” indicates that the compound or reagent is commercially available from Bachem Biosciences Inc. (19406 King of Prussia Renaissance at Gulf Mills Horizon Drive 3700, PA); The term "Maybridge" indicates that the compound or reagent is commercially available from Maybridge Chemical Co. (Pl 34 O. Double U. Tintagel Trevlet, Cornwall, UK); The term "RSP" is that a compound or reagent is commercially available from RSP Amino Acid Analogs, Inc. (01748 Hopkinton South Street 106, Maine, USA). Represents; The term “TCI” indicates that a compound or reagent is commercially available from TCI America (North Harborgate Street, 9211, 97203, Oregon); The term “Toronto” indicates that the compound or reagent is commercially available from Toronto Research Chemicals, Inc., Brisbane Road 2, New York, Ontario; The term "Alfa" indicates that a compound or reagent is commercially available from Johnson Matthey Catalog Company, Inc. (01835-0747 Word Hill Bond Street 30, Maine, USA). Represent; The term “Nova Biochem” denotes that a compound or reagent is commercially available from NovaBiochem USA (92039-2087 Lazola P. Box 12087 North Torrey Pines Road 10933, Calif.).

In the examples below, the temperatures are all ° C (unless otherwise indicated) and the following general procedure is used to prepare the indicated compounds.

General procedure

Method A

Methyl 6-amino-6,8-dideoxy-1-thio-erythro-α-D- as described in Hoexema et al., Journal of the American Chemical Society , 1967, 89, 2448-2452. Galacto-Octopyranoside (1a) (MTL) was prepared. 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 for 36 h under N ₂ atmosphere. The reaction mixture was cooled to 0 ° C. and then bis-N, O-trifluoroacetamide (15.7 mL, 59.0 mmol) was added by syringe over 2 minutes. The reaction mixture was allowed to warm to rt and stirred for 42 h. Toluene (100 mL) was added and the reaction mixture was evaporated to dryness. The residue was taken up in ethyl acetate (400 mL). The organic solution was washed quickly with 10% citric acid (200 mL), H ₂ O (3 × 100 mL), saturated NaHCO ₃ (100 mL) and brine (2 × 100 mL), then dried over Na ₂ SO ₄ and dried until dry. Evaporated. Protected product (1b) (P = Cbz) by chromatography of the crude product on silica with 10% EtOAc / hexanes containing 0.2% TEA after simultaneous evaporation from toluene (100 mL) and cyclohexane (2 × 100 mL). , R ¹ = SMe) (7.2 g, 54%) was obtained as a colorless oil. ¹ H NMR (300MHz, CD ₃ SOCD ₃ ) δ 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 DCM (1.5 mL) cooled to -72 ° C. 2M of oxalyl chloride in DCM (1.49 mL, 2.98 mmol) was added over 1 minute to dimethylsulfoxide (413 μL, 5.82 mmol). After 25 minutes, 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 minutes and then warmed to -50 ° C. (dry ice acetonitrile) and held at this temperature for 2 hours. To the reaction mixture was added TEA (1.29 mL, 3.30 mmol). After 25 minutes, the reaction mixture was diluted with EtOAc (300 mL). The resulting organic solution was washed quickly with 5% citric acid (300 mL), H ₂ O (2 × 300 mL), saturated NaHCO ₃ (100 mL), brine (100 mL), then dried over Na ₂ SO ₄ and toluene (100 mL) The product 1c was provided by evaporation to dryness using. Co-evaporation with n-pentane and removal of residual solvent under high vacuum yielded product 1c (P = Cbz, R ¹ = SMe) as a colorless crystalline solid (1.60 g, 94%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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

As outlined below, Boc-protected product 1c (P = Boc, R ¹ = SMe) can generally be prepared. Di-t-butyl die in (1a) (MTL) (dried at 50 ° C. and high vacuum) (21.8 g, 86 mmol) suspended in methanol (200 mL) and TEA (26 mL) and cooled to 0 ° C. on ice. Carbonate (57.0 g, 0.26 mol) was added. The reaction mixture was then stirred at rt overnight. Toluene (100 mL) was added to the resulting mixture and the solvent was removed to a total volume of 100 mL to give a viscous suspension, to which cyclohexane (300 mL) was added. The resulting solid precipitate was triturated and then filtered, washed with cyclohexane, ether and pentane and dried until constant weight. The crude Boc-protected product was used (87%) without further purification. TLC R _f = 0.75 (10% MeOH / DCM); MS (ESPOS): 354 [M + H] ⁺ ; ¹ H NMR (300MHz, CD ₃ OD) δ 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-methylthiorincosamide (240 mg, 0.68 mmol) in DMF (5 mL) was added BSTFA (0.52 mL, 2.0 mmol) and triethylamine (0.14 mL, 1.42 mmol) at 0 ° C., followed by room temperature. Stir overnight at. DMF was removed and the crude product was passed quickly through a silica gel column (pretreated with 2% triethylamine in ethyl acetate) eluting with 10% ethyl acetate in hexane (1b) (P = Boc, R ¹ = SMe) (350 mg, 95%) was obtained. Dimethyl sulfoxide (0.22 mL, 0.78 mmol) was slowly added to oxalyl chloride (0.16 mL, 0.78 mmol) in -60 ° C dichloromethane (5 mL), followed by stirring for 15 minutes. Then (1b) (370 mg, 0.65 mmol) in dichloromethane (5 mL) was slowly added. The reaction mixture was stirred for 45 minutes during which the reaction temperature was raised to -40 ° C. Triethylamine (0.70 mL, 3.25 mmol) was added and stirring was continued for additional 15 min at -40 ° C. Then extracted with dichloromethane (100 mL) and washed with 10% citric acid (50 mL). The residue obtained upon solvent removal was purified on a silica gel column using 10% ethyl acetate in hexane as eluent to afford (1c) (P = Boc, R ¹ = SMe) as a colorless oil (289 mg, 78% Obtained). TLC: Rf = 0.60 (10% EtOAc / hexanes); MS (ESPOS): 590 [M + Na] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 t-butoxylated potassium (715 mg, 6.4 mmol) were suspended in toluene (31 mL) under vigorous stirring under N ₂ atmosphere. After 4.0 h, protected product 1c (P = Cbz, R ¹ = SMe) (1.40 g, 2.36 mmol) in toluene (20 mL) was added by cannula. The resulting reaction mixture was stirred for 2 hours and then diluted with EtOAc (250 mL). The resulting organic solution was washed quickly with H ₂ O (2 × 100 mL), brine (1 × 100 mL), dried over Na ₂ SO _{4 and} then evaporated to dryness. Chromatography of the crude product on silica with 6% EtOAc / hexanes containing 0.2% TEA to give the alkene product 2a (P = Cbz, R ¹ = SMe, R ^{2 ′} = H) as a colorless oil, It was co-evaporated from toluene and cyclohexane and then crystallized (0.65 g, 46%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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).

Product (2a) (P = Cbz, R ¹ = SMe, R ^{2 ′} = H) in ethanol (50 mL) in 10% palladium on carbon (50% w / w water in degussa wet form) (700 mg) in a Par bottle ( 490 mg, 0.82 mmol) was added. The bottle was purged, filled with H ₂ to 65 psi and shaken for 24 hours. The reaction mixture was filtered through celite and washed with methanol. The organic solution was transferred to a resin funnel containing a washed dry Anhydrous Dows® 50w-400 × H ⁺ form (0.8 g) and shaken for 10 minutes. The resin was washed three times with methanol and twice with water, then eluted the saturated product (2b) from the resin by washing with 5% TEA in MeOH (35 mL × 10 min × 5). The combined filtrates were evaporated to dryness and co-evaporated twice from EtOH and then lyophilized from 1: 1 MeCN / H ₂ O to give the product (2b) (R ^{2 ′} = H) as a colorless powder (198 mg, 96%). Obtained as. ¹ H NMR (300 MHz, D ₂ O) δ 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 [MH] ⁻ .

Method D

Alternatively, when Boc-protecting groups are used in Scheme 1 (P = Boc), methyltriphenyl-phosphonium bromide (12 g, 33.6 mmol) and t-butoxylated (3 g, 26.7 mmol) are added at 0 ° C. Put in THF (70mL) and stirred for 4 hours at room temperature. Boc-protected product 1c (P = Boc, R ¹ = SMe) (4.7 g, 8.2 mmol) in THF (30 mL) was then added and stirred at room temperature for 2 hours. It was then extracted with EtOAc (300 mL), washed with brine (100 mL) and dried over sodium sulfate. Crude alkene product 2a (P = Boc, R ¹ = SMe, R ^{2 ′} = H) was purified by chromatography on a silica gel column using 10% EtOAc in hexane as eluent (4.1 g, 87.6%). ). TLC: R _f = 0.5 (10% EtOAc in hexanes); ¹ H NMR (300MHz, CD ₃ OD) δ 7.24 (m, 2), 5.22 (d, J = 5.7, 1), 4.21 (m, 1), 4.09 (m, 2), 3.87 (d, J = 2.4 , 1), 3.60 (dd, J = 2.7, 9.3, 1), 1.99 (s, 3), 1.76 (s, 3), 1.43 (s, 9); MS (ESPOS): 444 [M-2 TMS + Na] ⁺ .

To dox® H ⁺ resin (1 g) was added to product 2a (P = Boc, R ¹ = SMe, R ^{2 ′} = H) in methanol (30 mL) and stirred at room temperature for 1 hour. The resin was filtered and the product obtained upon removal of solvent (2.4 g, 6.8 mmol) was added to MeOH (30 mL) and Pd / C (2.5 g) was added and then hydrogenated overnight at 55 psi. The crude product obtained after filtration and solvent removal was purified by chromatography on a silica gel column using 10% MeOH in DCM to afford Boc-protected 7-methyl MTL as a white solid (2.06 g, 86%). : TLC R _f = 0.5 (10% MeOH in DCM); ¹ H NMR (300MHz, CD ₃ OD) δ 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 Boc-protected 7-methyl MTL (150 mg, 0.43 mmol) in dichloroethane (6 mL) was added dimethyl sulfide (0.16 mL, 2.5 mmol), TFA (2 mL), water (0.16 mL) and 1 h at room temperature. Was stirred. After purification by chromatography on a silica gel column using 30% MeOH in DCM as eluent, the product 2b (R ^{2 ′} = H) identical in all respects to the material obtained in process C was obtained.

Method E

Sodium hydride (80 mg, 3.3 mmol) was suspended in THF (4 mL) under vigorous stirring under N ₂ atmosphere. The suspension was cooled to −30 ° C. and diethyl (cyanomethyl) phosphonate (805 μL, 5.0 mmol) was added. After 30 minutes, protected product 1c (P = Cbz, R ¹ = SMe) in THF (3 mL) was added by cannula. The resulting reaction mixture was stirred for 4 hours and diluted with EtOAc (250 mL). The resulting organic solution was saturated with NaHCO _3. Aqueous solution (1 × 100 mL), brine (1 × 50 mL) was washed quickly, dried over Na ₂ SO ₄ and evaporated to dryness. The crude product is chromatographed on silica with 6% EtOAc / hexanes to 10% EtOAc / hexanes containing 0.2% TEA to give the protected alkene product 2a (P = Cbz, R ¹ = SMe, R ^{2 ′} = CN) was obtained as a colorless oil (0.38 g, 37%). MS (ESPOS): 625.5 [M + H] ⁺ , MS (ESNEG): 659.5 [M + Cl] ⁻ .

Product 2a (P = Cbz, R ¹ = SMe, R ^{2 ′} = CN) (180 mg, 0.29 mmol) in ethanol (15 mL) was added to 10% palladium on carbon (Degussa wet form 50% w / w) Water) (300 mg) and concentrated HCl (29 μL) was added. The bottle was purged, filled with H ₂ to 65 psi and shaken for 24 hours. The reaction mixture was filtered through celite and washed with methanol. The organic solution was placed in a resin funnel containing the washed anhydrous Dow's® 50w-400xH ⁺ form (1 g) and shaken for 10 minutes. The resin was washed with methanol (twice) and water and then washed with 5% TEA in MeOH (20 mL x 20 min x 3) and MeCN (20 mL x 20 min) from saturated resin (2b) (R ¹ = SMe, R ^{2 '} = CN) eluted. The combined organic filtrates were evaporated to dryness and lyophilized from 1: 1 MeCN / H ₂ O to give the product 2b (R ¹ = SMe, R ² = CH ₂ CN) as a colorless solid (70 mg, 91%). Obtained. MS (ESNEG): 275. 3 [M ⁻ H] ⁻ .

Method F

To protected product 1c (P = Cbz, R ¹ = SMe) (0.75 g, 1.3 mmol) in THF (7.3 mL) was added MeMgCl 3M (Aldrich) in THF (7.0 mL, 2.1 mmol) at 0 ° C. . Over 30 minutes, the reaction mixture was warmed to 4 ° C. and after 4 hours the reaction mixture was quenched with 1: 3 saturated aqueous NH ₄ Cl solution / H ₂ O (10 mL). The quenched mixture was diluted to 100 mL with water and extracted with DCM (4 × 50 mL). The combined organic phases were dried and evaporated. The residue was dissolved in 1: 2: 4 H ₂ O / HOAc / THF (100 mL), stirred for 20 h and then evaporated with toluene (2 × 100 mL). Chromatography (10: 1 to 10: 2 DCM / MeOH) afforded product 3a (P = Cbz, R ¹ = SMe, R ^{2 ″} = Me) (153 mg, 31%). MS (ESNEG) : 399.5 [M ⁻ H] ⁻ .

(3a) (P = Cbz, R ¹ = SMe, R ^{2 "} = Me) (79 mg, 0.2 mmol) in ethanol (10 mL) in 10% palladium on carbon (Degussa wet form 50% w / w water) (400 mg) The bottle was purged, H ₂ filled to 65 psi and shaken for 6 hours The reaction mixture was filtered through celite and washed with methanol The combined filtrates were evaporated to dryness and 1: Lyophilization from 1 MeCN / H ₂ O afforded product 3b (R ¹ = SMe, R ^{2 ″} = Me) as colorless powder (42 mg, 80%). ¹ H NMR (300MHz, D ₂ O) δ 5.33 (d, J = 5.8, 1), 4.83-4.06 (m, 3), 3.65-3.60 (m, 1), 3.06-3.03 (m, 1), 2.18 (s, 3), 1.30 (s, 3), 1.23 (s, 3); MS (ESPOS): 268.4 [M + H], MS (ESNEG): 266.2 [MH] ^- .

Method G

To Boc-protected product (1c) (P = Boc, R ¹ = SMe) (100 mg, 0.18 mmol) in methanol (3 mL), O-trimethylsilylhydroxylamine (0.10 mL, 0.8 mmol) was added and room temperature Stir overnight at. Solvent was removed to give crude Boc-protected product 4a (R ¹ = SMe, R ⁷ = H). To crude product 4a (95 mg, 0.15 mmol) was added 30% trifluoroacetic acid in dichloroethane (10 mL) and dimethyl sulfide (0.5 mL) and stirred for 1 hour. The solvent was removed and the product (4b) (R ¹ = SMe, R ⁷ = H) was taken by itself for the next step.

TLC: R _f = 0.35 (10% MeOH / DCM): MS (ESPOS): 267 (M + H); ¹ H NMR (300 MHz, CD ₃ OD) δ 1.96 (s, 3), 2.09 (s, 3), 3.58 (dd, J = 3.3, 10.2, 1), 3.90 (s, 1), 4.11 (dd, J = 5.7, 10.20, 1), 4.19 (d, J = 5.4, 1), 4.50 (d, J = 5.1, 1), 5.36 (d, J = 5.7, 1).

Method H

To Boc-protected product 1c (P = Boc, R ¹ = SMe) (100 mg, 0.176 mmol) in methanol (4 mL) and water (1 mL), O-alkylhydroxylamine hydrochloride (eg O -Methylhydroxylamine hydrochloride) (60 mg, 0.70 mmol) and sodium acetate (57 mg, 0.70 mmol) were added, heated at 80 ° C. for 3 hours and then stirred at room temperature overnight. The solvent was removed under high vacuum to afford crude Boc-protected product 4a (R ¹ = SMe, R ⁷ = Me). The crude product 4a was taken up in 30% trifluoroacetic acid in dichloroethane (10 mL) and dimethylsulfide (0.5 mL) and stirred at room temperature for 1 hour. The solvent was removed and the residue was kept under high vacuum for 1 hour, then product 4b (R ¹ = SMe, R ⁷ = Me) was taken by itself for the next step. TLC: R _f = 0.63 (10% MeOH / DCM); MS (ESPOS): 281 [M + H] ⁺ ; ¹ H NMR (300 MHz, CD ₃ OD) δ 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 a Boc-protected product (1c) (P = Boc, R ¹ = SMe) (500 mg, 0.88 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (2.5 mmol, 1M in THF) and the reaction mixture was allowed to stand at room temperature. Stirred for 1 h. The solvent was removed and the residue was purified on a silica gel column using 5% methanol in dichloromethane as eluent. The product obtained from the column (111 mg, 0.31 mmol) was added to a mixture of dichloromethane (3 mL) and pyridine (3 mL), to which acetic anhydride (0.5 mL, 10.6 mmol) and dimethylaminopyridine (80 mg, 1.7 mmol) were obtained. ) Was added and stirred overnight at room temperature. The solvent was removed and the crude product was purified on a silica gel column using 30% ethyl acetate in hexane as eluent to afford (5a) (P = Boc, R ¹ = SMe) (58 mg, 38%). . TLC R _f = 0.73 (50% EtOAc / hexanes); ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, R ¹ = SMe) (158 mg, 0.331 mmol) in DCM (5 mL) was added dimethylaminosulfurtrifluoride (732 μL, 3.31 mmol) and stirred overnight. Additional DCM was added and the organic portion was washed with sodium bicarbonate. The residue obtained upon removal of the solvent was purified by chromatography on a silica gel column using 20% ethyl acetate (100 mg, 60%) in hexane as eluent to give the protected product (P = Boc, R ¹ = SMe). ). Boc-protected product was added to 30% trifluoroacetic acid in dichloroethane and dimethyl sulfide and stirred at room temperature for 1 hour. Solvent was removed to give product 5b (R ¹ = SMe). TLC R _f = 0.63 (40% MeOH / hexanes); ¹ H NMR (300 MHz, CDCl ₃ ) δ 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

Compound (6a) (P = TFA Manufacture).

In a 1 L round bottom flask, anhydrous (1a) MTL (R ¹ = SMe) (dried overnight at 50 ° C. under vacuum) (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) was added. The reaction mixture was stirred at rt for 4 h and then evaporated to dryness to afford protected MTL (6a) (R ¹ = SMe, P = TFA) (26.2 g, 95%) which was itself Taken for next step.

Chloromethylene Piperidinium HCl (Scheme 6, reagent b)

To a 3 L three-necked round bottom flask equipped with a mechanical stirrer, organic stir bar (large Teflon paddle) under nitrogen atmosphere, diethyl ether (anhydrous, 1.8 L) and N-formylpiperidine (35.6 g, 0.315 mol) were added. . The reaction mixture was cooled to 0 ° C. and triphosgen (31.2 g, 0.105 mole) was added in portions of at least 5 times over 2 hours, kept at 0 ° C. and stirred vigorously. The reaction mixture was allowed to warm to room temperature (1 hour) to allow the triphosgen to react completely and again cool to 0 ° C. The reaction mixture was filtered under a stream of nitrogen or argon (very hygroscopic and malodorous) and washed with cold diethyl ether (2 x 100 mL). The white crystals obtained were dried in vacuo to afford chloromethylenepiperidinium HCl (46.4 g, 95%).

TFA  7- protected Cl MTL .

To a 3 L three-necked round bottom flask equipped with a mechanical stirrer, organic stir bar, Teflon paddle and reflux condenser under nitrogen atmosphere was added chloromethylene piperidinium HCl (44.4 g, 0.286 mol) and dichloroethane (anhydrous, 1 L). . The resulting slurry was vigorously stirred and the temperature was brought to 0 ° C. To the stirred reaction mixture was added crude (6a) (R ¹ = SMe, P = TFA) (20 g, 0.057 mol) over 1 minute. The reaction mixture was stirred for 1 hour, then the temperature was raised to 65 ° C. during which the reaction turned to a clear solution. The reaction mixture was then stirred at 65 ° C. for 18 hours. The reaction mixture was cooled to 0 ° C. and quickly poured into 4 L Erlenmeyer tubes equipped with a mechanical stirrer, to which water (1 L) and NaOH (22.9 g, 0.57 mol) were added and cooled to 0 ° C. The reaction mixture was stirred for 30 minutes, then the pH was adjusted to 10.5 (pH paper) with concentrated HCl (added over 5 minutes checking pH, and after each HCl addition, simply NaOH was added when the pH was reduced to less than 10.5). Addition is allowed to adjust to 10.5). The pH adjusted mixture was stirred for 2 hours while bringing the reaction to room temperature. The pH was adjusted to pH 7 with additional concentrated HCl and then stirred overnight or until the product appeared to have no adduct formed by the chlorinating agent and sugar OH functionality. The reaction mixture was then evaporated until dry by high vacuum attached to a rotary evaporator (to facilitate this process, solvents such as toluene can be co-evaporated). To the resulting solid was added a mixture of 10% methanol / DCM and stirred for 1 hour to liberate the product from the salt. The mixture was filtered and the filtrate was evaporated to dryness to give a syrup containing the product and N-formyl piperidine. Most of the N-formyl piperidine can be removed by grinding the mixture into hexane and decanting hexane from the product oil several times. The crude reaction product was then chromatographed using 10% methanol / DCM to give purified TFA protected 7-Cl MTL (21.1 g, 75%).

(6b) ( R ^One = SMe , R ² = Cl , R ³ = H).

To a 500 mL three-necked round bottom flask equipped with a mechanical stirrer was added TFA protected 7-Cl MTL (20 g, 0.054 mol) purified in a minimum amount of methanol (10 mL) and 1 M NaOH (250 mL) at 0 ° C. In order to prevent hydrolysis of the 7-chloro functional group, the reaction mixture was stirred for 12 hours at 0 ° C. with periodic harvesting of pure product crystals (the mixture initially appeared to form a sticky solid that was difficult to handle and eventually became a solution. Pure product crystals appear to form immediately thereafter, washed with a minimum amount of cold water and cold methanol to give 7-Cl MTL (6b) (R ¹ = SMe, R ² = Cl, R ³ = H) as a colorless solid ( 10 g, 50%).

Method K

Literature, etc. Section [Journal of the American Chemical Society , 1998, 120, 3894-3902, lactam (7b) (R ⁹ ) by enolation (LiHMDS) and alkylation of (7a) with 4-bromo-2-methyl-2-butene using the procedure described in A mixture (61%) of diastereomers of ^' = 2-methyl-2-butene) was obtained. Compound (7a) can be purchased from a dealer such as Bachem. Alternatively, (7a) can be prepared by methods well known in the art, such as by Baldwin JE et al., Tetrahedron , 1989, 45, 7449-7468.

The lactam (7b) is converted to pyrrolidin (7c) by a two-step reaction of superhydride (R) reduction of lactam to hemiaminol and subsequent reduction of hemiaminal using Et ₃ SiH / BF ₃ · OEt ₂ . Reduced to (R ^{9 ′} = 2-methyl-2-butene) (70%). Pyrrolidine (7c) (778 mg, 2.08 mmol), 10% palladium on carbon (230 mg) in dry methanol (25 mL) was parhydrolyzed at 50 psi for 5 hours. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washes and filtrates were evaporated to dryness to give a colorless oil (7d) (R ^{9 "} = 2-methyl-2-butene) without further purification. TLC R _f = 0.3 [solvent system: DCM / hexanes / MeOH (6: 5: 1)]; MS (ESNEG): 284.5 [M ⁻ H] ⁻ .

Method L

1 M solution of LiHMDS in THF (33 mmol, 33 mL, 1.1 equiv), cis-1-bromo, in a stirred solution of (7a) (9.47 g, 29.7 mmol, 1 equiv) in dry THF at −78 ° C. and N ₂ 2-pentene (4.21 mL, 35.6 mmol, 1.2 equiv) was added to give a mixture of diastereomers of lactam (7b) (R ^{9 ′} = 2-pentene) after silica gel purification. Superhydride® reduction of lactam to hemiaminol in anhydrous THF at −78 ° C. and subsequent reduction of hemiamine with Et ₃ SiH / BF ₃ · OEt ₂ in anhydrous DCM at −78 ° C. By two-step reaction, the lactam (7b) (3.96 g, 10.22 mmol) was reduced to pyrrolidine (7c) (R ^{9 '} = 2-pentene), after silica gel purification (7c) (R ^9' = 2-pentene) (71%). Pyrrolidine (7c) (2.71 g, 7.26 mmol) in dry methanol (30 mL) and 10% palladium on carbon were parhydrolyzed at 50 psi for 5 hours. The reaction mixture was filtered through a pad of celite and washed several times with methanol. The combined washes and filtrates were evaporated to dryness to give a colorless oil (7d) (R ⁹ = pentyl) (1.68 g, 80%) without further purification. TLC: R _f = 0.3 [solvent system: DCM: hexane: MeOH (6: 5: 1)]. MS (ESNEG): 284.5 [M ⁻ H] ⁻ .

Method M

(8a) ( R ^{9 '} = 3,3- Difluoroprop -2-yen).

The final aldehyde (8a) (77) was subjected to ozone decomposition treatment of (7c) (R ^{9 '} = 2-methyl-2-butene) in anhydrous dichloromethane followed by DMS at -78 ° C and slowly warmed to room temperature. %) Was obtained and used in the next step without further purification.

Dibromodifluoromethane (0.21 mL, 2.34 mmol, 2 equiv) was added to a solution of aldehyde (8a) (407 mg, 1.17 mmol, 1 equiv) from the reaction in 0 ° C dimethylacetamide (0.25 mL). Added. Under nitrogen, a solution of triphenylphosphine (0.61 g, 2.34 mmol, 2 equiv) in dimethyl acetamide (0.5 mL) was added over 20 minutes to the stirred mixture. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, then added to activated zinc (0.25 g, 3.82 mmol, 3.3 equiv) using dimethylacetamide (0.3 mL). The resulting reaction mixture was stirred at 110 ° C. for 1 hour, cooled to room temperature and filtered using 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) (R ^{9 '} = 3,3-difluoroprop-2-yne) (182 mg, 41%). MS (ESPOS): 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. 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 (1 ×), brine (1 ×), dried and concentrated to give (8c) (R ^{9 ′} = 3,3-difluoroprop-2-ene) as a clear glass (56 mg, 87 Obtained in%). MS (ESPOS): 192.3 [M-Boc + H] ⁺ ; MS (ESNEG): 290.3 [M ⁻ H] ⁻ .

(8b) (R ^{9 "} = 3,3-difluoropropane) The saturated product of Scheme 8 can be obtained, for example, by the hydrogenation method described in Method K for (7d).

Method N

(9b) (P = Boc , m = 1, LG = Ts ).

N-Boc- (2S, 4R) -4-hydroxyproline methyl ester (bachem) (9a) (P = Boc, m = 1) (5 g, 20.4 mmol, 1 equiv) and DMAP (0.25) in DCM (80 mL) Toluenesulfonic anhydride (8.65 g, 26.5 mmol, 1.3 equiv) was added to a solution of g, 2.04 mmol, 0.1 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 min and then at rt overnight. The solution was concentrated to dryness. The residue was taken up in ethyl acetate (400 mL) and washed with 10% aqueous citric acid solution (2 x 400 mL), saturated aqueous NaHCO ₃ solution (400 mL), brine, dried over Na ₂ SO ₄ and concentrated to give a yellow syrup (9b) ( P = Boc, m = 1, LG = Ts) (8.44 g, 100%). HPLC (method RV-1), C18 3.5 μm, 4.6 30 mm column; Gradient eluent 2% -98% MeCN over 5 minutes; 1.5 mL / min): Rt = 3.096.

(9c) (P = Boc , m = 1, R ⁹ = 2,4- Dichlorobenzyl sulfide ).

To a solution of tosylate (9b) (P = Boc, m = 1, LG = Ts) (1.02 g, 2.55 mmol, 1 eq) in anhydrous DMF (7.6 mL) under N ₂ , 2,4-dichlorobenzylthiol ( 1.48 g, 7.66 mmol, 3 equiv) was added followed by 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) and washed with 10% citric acid (50 mL) and brine and concentrated. The residue was purified by chromatography to give a clear syrup (9c) (P = Boc, m = 1, R ⁹ = 4- (2,4-dichlorobenzyl sulfide) (1.0 g) MS (ESPOS) ): 320.2 [M-Boc + H] ⁺ ; MS (ESNEG): 418.4 [MH] ⁻ .

Hydroxide in a solution of methyl ester (9c) (P = Boc, m = 1, R ⁹ = 2,4-dichlorobenzyl sulfide) (1.0 g, 2.38 mmol, 1 equiv) in THF (9 mL) and water (3 mL) Lithium (0.5 g, 11.9 mmol, 5 equiv) was added. The reaction mixture was stirred at rt overnight. THF was removed under vacuum. The residue was partitioned between ethyl acetate (150 mL) and 10% citric acid (100 mL). The organic layer was washed with water (1 ×), brine (1 ×), dried over Na ₂ SO ₄ and evaporated to a clear syrup (9d) (P = Boc, m = 1, R ⁹ = 2,4-die Chlorobenzylsulfide) (1.0 g) was obtained. MS (ESPOS): 306.3 [M-Boc + H] ⁺ ; MS (ESNEG): 404.2 [M ⁻ H] ⁻ .

Method O

4- Propylpyridine -2- Carboxylic acid (10b) ( R ⁹ = n-propyl).

30% hydrogen peroxide (2.4 g) was added to 4-propylpyridine (TCI) (2.5 g, 20 mmol) and refluxed overnight. Solvent was removed and the resulting residue was taken in DCM (30 mL). Trimethylsilyl cyanide (2.6 g, 26 mmol) was added to the solution followed by dimethyl carbamyl chloride (2.8 g, 26 mmol) and stirred overnight at room temperature. Potassium carbonate (10%, 100 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to give 4-propyl-2-cyanopyridine (2.5 g, 93%). It was refluxed overnight in hydrochloric acid (6N, 60 mL). After crystallization from acetonitrile 4-propylpyridinecarboxylic acid (10b) (R ⁹ = nPr) was obtained (2.0 g, 71%). MS (ESPOS): 166 [M + H]; ¹ H NMR (300 MHz, CD ₃ OD) δ 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) ( R ⁹ = 4-propyl- (3- Phenyl )).

Trimethylsilyl cyanide (1.3 mL, 10 mmol) and dimethylcarbamic chloride (1 mL, in 4-propyl- (3-phenyl) pyridine-N-oxide (1 g, 4.69 mmol) in dichloromethane (10 mL) 10 mmol) was added and stirred at room temperature for 24 hours. Aqueous potassium carbonate solution (10%, 10 mL) was added and extracted with dichloromethane (100 mL). The crude product obtained upon removal of the solvent was placed in hydrochloric acid (6N, 30 mL) and refluxed for 24 hours. After removal of the acid the crude product was crystallized from acetonitrile to yield acid 10b (1 g, 86%). MS (ESPOS): 240 [M-1]; ¹ H NMR (300 MHz, CD ₃ OD) δ 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 hours. Solvent was removed in vacuo. Anhydrous methanol (160 mL) was added and the mixture was stirred at rt for 30 min. The solvent was evaporated and the residue was taken up in 5% sodium bicarbonate and extracted with ethyl acetate (3 ×). The organic layers were combined, dried over MgSO ₄ and evaporated. The residue was purified by chromatography to give 4-chloropicolinic acid methyl ester (19.9 g, 72%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (11a).

A mixture of 4-chloropicolinate methyl ester (2.4 g, 14.1 mmol), 57% hydroiodic acid (13.3 mL) and 50% aqueous solution of phosphorous acid (0.66 mL) was stirred at 85 ° C. for 2 hours and then at 107 ° C. overnight. It was. The mixture was cooled to 95 ° C. At this temperature 10M sodium hydroxide solution (4.2 mL) was added within 30 minutes followed by water (15.2 mL). The mixture was cooled to rt and stirred at rt for 1 h. The precipitate was filtered off, washed with cold water and dried under high vacuum overnight to afford 4-iodopicolinic acid (3.5 g, 66%) as a yellow solid (11a). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 8.39 (d, J = 5.1, 1), 8.35 (d, J = 1.8, 1), 8.07 (dd, J = 1.7, 5.2, 1); MS (ESPOS): 250.2 [M + H] ⁺ .

4- Iodopicolinic acid methyl  Ester 11b.

To a solution of 4-iodopicolinic acid (11a) (7.0 g, 18.6 mmol) in MeOH (70 mL) at 23 ° C. was added concentrated sulfuric acid (350 μL) and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and concentrated to afford the desired product 4-iodopicolinate methyl ester (11b) (4.4 g, 90%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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- [3- (tert-butyl-dimethyl-silanyloxy) -prop-1-ynyl] -pyridine-2-carboxylic acid methyl ester (11c) (R ^{9 '} Tert-butyl-dimethyl-silanyloxy).

(11b) (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), acetic acid in dried flask Palladium (184.5 mg, 0.82 mmol, 0.04 equiv) and triethylamine (74 mL) were added. The mixture was degassed with nitrogen and t-butyldimethyl (2-propynyloxy) silane (Aldrich) (8.34 mL, 41.14 mmol, 2 equiv) was added. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo resulting in a dark residue. The residue was purified by chromatography to give ester (11c) (R ^{9 '} = 3- (tert-butyl-dimethyl-silanyloxy) -prop-1-ynyl) (6.07 g, 97%). Obtained as a brown oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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- [3- (tertiary- Butyl - Dimethyl - Silanyloxy ) -Propyl] -piperidine-2- Carboxylic acid methyl  Ester (11d) ( R ^{9 '} = 3- (3rd class- Butyl - Dimethyl - Silanyloxy )-profile).

(11c) (R ^{9 '} = 3- (tert-butyl-dimethyl-silanyloxy) -prop-1 in MeOH (60 mL), water (60 mL) and acetic acid (1.14 mL, 19.8 mmol, 1 equiv) To a mixture of 6.05 g, 19.8 mmol, 1 equiv) was added platinum oxide (2.0 g). The mixture was purged and filled with hydrogen (50 psi) and shaken overnight at room temperature. The platinum oxide was removed by filtration and the filtrate was concentrated to give product 11d (R ^{9 ′} = 3- (tert-butyl-dimethyl-silanyloxy) -propyl) (5.0 g, 80%). . MS (ESPOS): 316.6 [M + H] ⁺ .

4- [3- (tertiary- Butyl - Dimethyl - Silanyloxy ) -Propyl] -piperidine-1,2- Dicarboxylic acid  Class 1-3-Butyl Ester 2- methyl  Ester (11e) ( R ^{9 '} -3- (3rd class- Butyl - Dimethyl - Silanyloxy ) -Profile, P = Boc ).

Triethylamine (4.42 mL, 31.7 in (11d) (R ^{9 '} = 3- (tert-butyl-dimethyl-silanyloxy) -propyl) (4.99 g, 15.8 mmol, 1 equiv) in methanol (60 mL) Mmol, 2 equiv) and di-t-butyldicarbonate (4.7 mL, 20.6 mmol, 1.3 equiv) were added. The mixture was stirred at rt overnight. The solvent was removed in vacuo. Purification of the residue by chromatography gave carbamate (11e) (R ^{9 '} = 3- (tert-butyl-dimethyl-silanyloxy) -propyl, P = Boc) (2.75 g, 42%) transparent. Served as a syrup. ¹ H NMR (300MHz, CDCl ₃ ) δ 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 (ESPOS): 316.6 [M + H-Boc] ⁺ .

4- [3- (tertiary- Butyl - Dimethyl - Silanyloxy ) -Propyl] -piperidine-1,2- Dicarboxylic acid  Class 1-3-butyl ester (11f) R ^{9 '} = 3- (3rd class- Butyl - Dimethyl - Silanyloxy ) -Profile, P = Boc ).

Lithium hydroxide monohydrate (306 mg, in a mixture of (11e) (R ^{9 '} = 3- (tert-butyl-dimethyl-silanyloxy) -propyl, P = Boc) in THF (12 mL) and water (4 mL) 7.29 mmol, 1.1 equiv) was added. 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. THF was removed under vacuum. The aqueous layer was placed in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1 ×), brine (1 ×), dried and concentrated to give a yellow syrup which was purified by chromatography to give the desired acid (11f) (R ^{9 ′} = 3- (3). Tert-Butyl-dimethyl-silanyloxy) -propyl, P = Boc) (1.83 g, 69%) was provided as a colorless syrup. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (ESPOS): 424.7 [M + Na] ⁺ .

Method Q

(2S, 4R) -N- Boc -4- Hydroxyproline methyl  Ester.

To a stirred solution of (2S, 4R) -4-hydroxyproline (bachem) (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 ° C for 1 h. The residue obtained upon removal of solvent was purified by column chromatography using 50% ethyl acetate in hexanes to give (2S, 4R) -N-Boc-4-hydroxyproline methylester (27 g, 100%). Obtained as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (ESPOS): 268 (M + Na).

(2S, 4R) -N- Boc -4- Ketoproline Methyl ester (12a) (P = Boc , P ₂ = Me , m = 1).

DMSO (18.6 mL, 236 mmol) was slowly added over 15 minutes to oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) at -78 ° C. After the addition, (2S, 4R) -N-Boc-4-hydroxyproline methyl ester (26.5 g, 108 mmol) in DCM (100 mL) was added dropwise and stirred at -78 ° C for 20 minutes, followed by triethyl Amine (54.6 g, 540 mmol) was added and stirred for 2 hours. The reaction mixture was washed with 10% aqueous HCl solution (200 mL). The organic layer was separated and dried over sodium sulfate. The crude product obtained upon removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexane to give (12a) (P = Boc, P ₂ = Me, m = 1) (20 g, 78%). Was obtained as a brown solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (ESPOS): 244 (M + H).

N- Boc -4- Hydroxy -4- Allylproline Methyl ester (12b) (P = Boc , P ₂ = Me , m = 1, R ^{9 '} = Alyl).

To a stirred solution of (12a) (P = Boc, P ₂ = Me) (1 g, 4.11 mmol) in THF (10 mL) was added tetraallyltin (1.08 mL, 4.52 mmol) in dry THF and then cooled to 0 ° C. Boron trifluoride etherate (0.520 mL, 4.11 mmol) was added slowly. The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in 5 mL water) and celite (1 g) were added and the reaction mixture was stirred for 1 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), then dried over MgSO ₄ and evaporated to dryness. The residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexane (12b) (P = Boc, P ₂ = Me, m = 1, R ⁹ = allyl) (0.94 g, 80 %) Was obtained as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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] ⁺ .

N- Boc -4- Fluoro -4- Allylproline Methyl ester (12c) (P = Boc , P ₂ = Me , m = 1, R ^{9 '} = Alyl).

To a stirred solution of DAST (1.06 g, 6.58 mmol) in DCM (10 mL) at −78 ° C. (12b) (P = Boc, P ₂ = Me, R ⁹ = allyl) in anhydrous DCM (10 mL) (940 mg, 3.3 Mmol) was added slowly. The mixture was stirred at -78 ° C for 1 hour and then at -10 ° C for a further 1 hour. DCM (50 mL) was added and quenched with NH ₄ Cl (10%, 150 mL), then the organic layer was separated, dried over sodium sulphate and evaporated to dryness. Purification of the residue by silica gel column chromatography using 5% EtOAc in hexane as eluent gave the desired product 12c (P = Boc, P ₂ = Me, m = 1, R ⁹ = allyl) ( 330 mg, 34%) was obtained as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.82 (m, 1), 5.12 (m, 2), 4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1 ), 2.43 (m, 4), 1.37 (dd, J = 4.5, 13.8, 9); MS (ESPOS): 310 [M + Na] ⁺ .

N- Boc -4- Fluoro -4- Propylproline methyl  Ester 12c (P = Boc , P ₂ = Me , m = 1, R ⁹ = Profile).

To a solution of (12c) (P = Boc, P ₂ = Me, m = 1, R ⁹ = allyl) (0.33 g, 1.15 mmol) in MeOH (15 mL) was added 10% Pd / C (40 mg). The reaction mixture was stirred for 3 h at room temperature under hydrogen (30 atm). The catalyst was filtered through celite and washed with methanol. The filtrate was concentrated to give the desired protected amino acid ester 12c (P = Boc, P ₂ = Me, R ⁹ = propyl) (0.33 g, 100%) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (ESPOS): 190 [M-Boc] ⁺ .

N- Boc -4- Fluoro -4- Propylproline (12d) (P = Boc , R ⁹ = Propyl, m = 1).

To a solution of methyl ester (12d) (330 mg, 1.15 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 rt overnight. THF was removed and the residue was taken up in ethyl acetate (50 mL) and washed with 10% citric acid (100 mL) and brine (20 mL). The organic portion was concentrated to give the desired protected amino acid 12e (P = Boc, R ⁹ = propyl, m = 1) (310 mg, 100%) as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 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 .

Ethyl trifluoroacetate (4.8 mL, in a solution of 4-tert-butyloxyproline (bachem) (5.0 g, 27 mmol, 1 equiv) and TEA (11.2 mL, 80 mmol, 3 equiv) in anhydrous MeOH (30 mL) 40 mmol, 1.5 equiv) was added. The mixture was stirred at 24 ° C. overnight. The solution is concentrated to dryness and dissolved in DCM (200 mL), then the organic phase is washed with 0.2 M aqueous KHSO ₄ solution (2 × 100 mL) and brine (1 × 100 mL), dried over MgSO ₄ and evaporated to dryness. I was. The resulting residue was triturated with cyclohexane and pentane to give the product (2S, 4R) -N-trifluoroacyl-4-tert-butyloxyproline as light yellow powder (5.5 g, 72%). .

(14a) (P = CF ₃ CO , m = 1, R ² = H, R ³ = OH ).

To a solution of MTL (1a) (1.32 g, 5.3 mmol, 1 equiv) in dry DMF (16 mL) at 0 ° C., triethylamine (2.20 mL, 15.9 mmol, 3 equiv) followed by bis- (trimethylsilyl) trifluoro Loacetamide (2.81 mL, 10.6 mmol, 2.0 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture was added (2S, 4R) -N-trifluoroacyl-4-tert-butyloxyproline (1.8 g, 6.3 mmol, 1.2 equiv), HATU (3.02 g, 8.0 mmol, 1.5 equiv). The reaction mixture was stirred for 3 hours. The reaction mixture was evaporated to dryness, placed in ethyl acetate (500 mL) and washed with 10% citric acid (100 mL), water (100 mL), half saturated NaHCO ₃ (200 mL) and brine. The organic layer was dried over Na ₂ S0 ₄ and evaporated to give a yellow syrup, which was dissolved in MeOH (100 mL). Dried Dodds® H + form resin (500 mg) was added and the resulting suspension was stirred for 50 minutes, filtered and evaporated to dryness to give a yellow solid (2.89 g). Purify the product by silica chromatography using DCM / hexanes / MeOH 6: 5: 1 to 7: 2: 1 to give product 14a (P = CF ₃ CO, m = 1, R ² = H, R ³ = OH) was obtained as a colorless solid (1.7 g, 51%).

(14b) (P = CF ₃ CO , m = 1, R ² = H, R ³ = Oac ).

(14a) (P = CF ₃ CO, m = 1, R ² = H, R ³ = OH) (1.63 g, 3.1 mmol), pyridine (3 mL, 30 mmol) and DMAP in dry DCM (10 mL) at 0 ° C. To a solution of (38 mg, 0.31 mmol) acetic anhydride (3 mL, 31 mmol) was added. The reaction temperature was raised to 24 ° C. over 1 h and stirred for 48 h. The reaction mixture was diluted with chloroform (200 mL) and the organic phase washed with 10% aqueous acetic acid solution (3 × 200 mL), 10% citric acid (200 mL), half-saturated NaHCO ₃ aqueous solution (200 mL) and brine (1 × 100 mL). , Dried over Na ₂ SO ₄ and evaporated to afford the hyperacylated intermediate 14b (P = CF ₃ CO, m = 1, R ² = H, R ³ = OAc) (2.14 g, 99%) as colorless crystals. It was.

Solution of the above acylated intermediate 14b (P = CF ₃ CO, m = 1, R ² = H, R ³ = OAc) (2.1 g, 3.1 mmol) in DCE (64 mL) with methylsulfide (1.4 mL) To this was added trifluoroacetic acid (21 mL) and water (1.4 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and co-evaporated twice with DCE. The residue was purified by chromatography with 5% MeOH in DCM to afford the intermediate alcohol (1.6 g, 83%) as a colorless solid, which was used in the next step without determining its characteristics.

(14b) (P = CF ₃ CO , m = 1, R ² = H, R ³ = Oac ).

To a solution of the 4-alcohol intermediate (1.5 g, 2.38 mmol, 1 equiv) and DMAP (29 mg) in DCE (9.5 mL) was added p-toluenesulfonic anhydride (1.01 g, 3.09 mmol, 1.3 equiv). 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 and then at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was taken up in ethyl acetate (200 mL) and washed with 10% citric acid (2 × 200 mL), saturated NaHCO ₃ (200 mL) and brine, dried over Na ₂ SO ₄ and concentrated to give a yellow syrup, which was 4: Purification by chromatography with 1 hexanes / EtOAc yielded p-toluenesulfonic acid ester product 14b (P = CF ₃ CO, m = 1, R ² = H, R ³ = OAc) (1.7 g, 92 %) Was obtained as a colorless solid.

Method S

Diethyl  n- Propyl Malone .

Diethyl malonate in DMF (100 mL) via cannula over 10 minutes in a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 eq) in 23 ° C. at DMF (300 mL) (45.5 mL, 300 mmol, 1 equiv) of solution was added. When added, mild exotherm was generated, H ₂ gas was observed to be generated and cooling was not required. After addition, the reaction was stirred at 23 ° C. for 45 min and then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23 ° C. for 25 minutes and then heated to 65 ° C. for 3 hours and stirred at 23 ° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) and then extracted with diethyl ether (700 mL). The ether extract was washed with H ₂ O (400 mL), brine (200 mL), dried (MgSO ₄ ), filtered and concentrated to give 65.1 g of product as a clear oil. ¹³ C NMR showed about 4: 1 mono: bis-alkylated product. The product diethyl n-propylmalonate was used without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) 4.18 (q, J = 6.9 Hz, 4H), 3.32 (t, J = 7.8 Hz, 1H), 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 ) ( ^* indicates signal due to trace product of bis-alkylation): 169.6, 61.2, 60.9 ^* , 51.8, 34.4 ^* , 30.7, 20.5, 17.3 ^* , 14.4 ^* , 14.0, 13.7.

Ethyl n- Propyl Malone (21b) ( R ⁹ = n-propyl).

A solution of 1.0M KOH in a solution of diethyl n-propylmalonate (containing about 20% diethyl bis (n-propyl) malonate, 65.0 g, 273 mmol, 1 equiv) in EtOH (500 mL) at 23 ° C. (273 mL, 273 mmol, 1 equiv) was added. After addition, the reaction was heated to 80 ° C. (internal temperature) for 4 hours. After cooling to 23 ° C., EtOH was removed in vacuo. The remaining mixture was partitioned between diethyl ether (400 mL) and H ₂ O (200 mL). The layers were separated and the ether layer was extracted with saturated aqueous NaHCO ₃ (100 mL). The NaHCO ₃ aqueous layer was combined with the original aqueous layer, and this solution was acidified to pH 1 with 1.0N HCl and then extracted with EtOAc (2 × 600 mL). The EtOAc extract was dried (MgSO ₄ ), filtered and concentrated to give 41.3 g (237 mmol, 79% for 2 steps) of pure product (21b) (R ⁹ = n-propyl) as a clear oil. ¹ H NMR (300MHz, CDCl ₃ ) 4.43 (q, J = 7.2 Hz, 2H), 3.60 (t, J = 7.5 Hz, 1H), 2.18-2.02 (m, 2), 1.66-1.50 (m, 2H) , 1.49 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.5 Hz, 3H).

Ethyl n- Propyl acrylate (21c) ( R ⁹ = n-propyl).

To a solution of ethyl n-propylmalonate (41.3 g, 237 mmol, 1 equiv) in 23 ° C. EtOH (500 mL), piperidine (28.1 mL, 284 mmol, 1.2 equiv) followed by aqueous formaldehyde solution (37%, 88 mL) Was added. After addition, the reaction was refluxed for 29 hours. After cooling to 23 ° C., the mixture was partitioned between diethyl ether (500 mL) and 1.0 N HCl (800 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL). The combined organic layers were washed with H ₂ O (500 mL), brine (300 mL), dried (MgSO ₄ ), filtered and concentrated (rotovap only, product may be volatile). The product was vacuum distilled (boiling point 70 ° C. at 15 mm Hg) to give 16.4 g (115 mmol, 49%) of desired product 21c (R ⁹ = n-propyl). ¹ H NMR shows unidentified material incorporated; The product was used for next step without further purification. ¹ H NMR (300MHz, CDCl ₃ ) 6.12 (s, 1H), 5.50 (s, 1H), 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- Prof -2-en-1-ol.

DIBALH (1.0 M in hexane, 403 mL, 403 mmol, 3.5 equiv) in a solution of (21c) (R ⁹ = n-propyl) (16.4 g, 115 mmol, 1 equiv) in CH ₂ Cl ₂ (500 mL) at 78 ° C. ) Was added via cannula over 20 minutes. After addition, the reaction was stirred at 78 ° C. for 30 minutes and then warmed to 55 ° C. over 60 minutes. When the reaction bath temperature reached 55 ° C., EtOAc (15 mL) was added to quench excess DIBALH. After stirring for 5 minutes, the quenched reaction mixture was slowly added via cannula to a stirred mixture of 1: 1 saturated aqueous sodium tartrate: saturated NaHCO ₃ aqueous solution (1 L) at 23 ° C. After stirring the biphasic mixture for 1 hour the layers were separated. The aqueous layer was extracted with diethyl ether (500 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated (rotochet only, product may be volatile). The product was vacuum distilled (boiling point 100-120 ° C. at 15 mm Hg) to give 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 (300MHz, CDCl ₃ ) 5.22 (s, 1H), 5.06 (s, 1H), 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-en (21d) ( R ⁹ = n-propyl).

Pyridine (0.58 mL) was added to a solution of n-propyl allyl alcohol (7.58 g, 75.8 mmol, 1 equiv) in Et ₂ O (65 mL) at 0 ° C. A solution of PBr ₃ (4.28 mL, 45.5 mmol, 0.6 equiv) in Et ₂ O (20 mL) was added via cannula over 15 minutes. After the addition, the reaction was stirred at 0 ° C. for 75 minutes, then the cold reaction mixture was slowly added to the stirred ice cold saturated aqueous NaHCO ₃ solution (500 mL). The resulting biphasic mixture was extracted with diethyl ether (250 mL). The organic extracts were washed with saturated aqueous NaHCO ₃ solution (2 × 100 mL), brine (100 mL), 1.0 N HCl (100 mL), brine (100 mL), dried (MgSO ₄ ), filtered and concentrated (rototoxin at 0 ° C.). , Product is volatile). Purification of the product via flash column chromatography on silica gel using pentane as eluent to give 5.97 g (36.8 mmol, 49%) of the desired product (21d) (R ⁹ = n-propyl) as a clear oil. It was. ¹ H NMR (300MHz, CDCl ₃ ) 5.16 (s, 1H), 4.95 (s, 1H), 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- Allylglycine  Ethyl ester.

Ethyl bromoacetate (36.9 mL, 333 mmol, 1 equiv) in a solution of allylamine (21e) (R ^9b = H, m = 1) (50 mL, 666 mmol, 2 equiv) in Et ₂ O (167 mL) at 0 ° C. ) Was added. White precipitates and exothermic reactions were observed immediately after addition; The exotherm caused the solvent to boil for about 2 minutes. After addition, the reaction was stirred for 2.5 hours, the ice water bath was removed and the reaction was stirred at 23 ° C. overnight. After 15 hours at 23 ° C., the reaction mixture was filtered through glass frit to remove precipitated allylamine hydrobromide salt by-product. The collected solid was washed with Et ₂ O (200 mL) and then the combined filtrates were concentrated. The product was vacuum distilled (boiling point 48-55 ° C. at 1.0 mm Hg) to give 35.5 g (249 mmol, 75%) of the desired product N-allylglycine ethyl ester as a yellow oil. ¹ H NMR (300MHz, CDCl ₃ ) 5.93-5.79 (m, 1H), 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 (ESPOS): 144.1 [M + H] ⁺ .

N- Allylglycine  Ethyl ester Hydrochloride (21f) ( R ^9b = H, m = 1).

4.0 in dioxane (16.6 mL, 66.5 mmol, 0.95 equiv) in a solution of N-allylglycine ethyl ester (10.0 g, 70.0 mmol, 1 equiv) in Et ₂ O (260 mL) and hexane (1.3 L) at 23 ° C. M HCl was added slowly through the addition funnel over 35 minutes. After addition, the suspension was stirred for an additional 40 minutes, then the product was isolated by filtration through glass frit and washed with hexane (200 mL). The collected white solid was transferred to a flask and placed under vacuum (0.5 mm Hg) for 1 hour to give 11.5 g of the desired product as a white solid. The reaction was repeated on the same scale to give a total of 22.73 g (127 mmol, 90%) of the desired amine hydrochloride (21f) (R ^9b = H, m = 1) as a white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) 9.50 (s, 2H), 5.95-5.81 (m, 1H), 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 (ESPOS): 144.1 [M + H] ⁺ .

Pseudoephedrine N- Allylglycineamide (21h) ( R ^9b = H, m = 1).

THF (130 mL) was added to a flask containing (21f) (R ^9b = H) (20.3 g, 113 mmol, 1.3 equiv) and (1R, 2R)-pseudoephedrine (21 g) (14.4 g, 86.9 mmol, 1 equiv) Added. The resulting mixture was stirred vigorously at 20 ° C. for 20 minutes to produce a uniform slurry and treated with solid tert-butoxylithium (9.74 g, 122 mmol, 1.4 equiv) added all at once. The reaction was stirred at 20 ° C. for 2 days and then analyzed to reveal that both starting materials were still present. The incomplete reaction was treated with H ₂ O (200 mL) and then THF was removed in vacuo. The resulting aqueous solution was extracted with CH ₂ Cl ₂ (2 × 150 mL), saturated with NaCl and further extracted with CH ₂ Cl ₂ (2 × 100 mL). The organic extract was dried (K ₂ CO ₃ ), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using 2: 2: 96 MeOH / Et ₃ N / CH ₂ Cl ₂ as eluent to give 18 g of product. This material still contained N-allylglycine ethyl ester, which was gently heated (60 ° C.) for 15 hours under vacuum (1.0 mmHg) to remove the desired glycineamide product (21h) (R ^9b = H, m = 1) 14.88 g (56.8 mmol, 65%) were obtained as a viscous oil. ¹ H NMR (300 MHz, CDCl ₃ ) (spectrum indicates rotamer) 7.41-7.24 (m, 5H), 6.00-5.80 (m, 1H), 5.29-5.07 (m, 2H), 4.64-4.44 (m, 1H), 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 (ESPOS): 263.2 [M + H] ⁺ . HPLC (Symmetry C18, 35 μm particle size, 100 μm pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN / 0.1% TFA in H ₂ O over 10 minutes, 2 mL / min flow rate): Rt = 3.10 min.

Pseudoephedrine N- Of allyl glycine amide  Alkylation.

Pseudoephedrine N-allyl glycineamide (21h) (R ^9b = H, m = 1) in THF (50 mL) in a flask containing LiCl (flame dried in vacuum, 3.14 g, 74.1 mmol, 4 equiv) at 0 ° C. 4.85 g, 18.5 mmol, 1 equiv) was added. The resulting mixture was stirred for 25 min at 0 ° C. and then treated with a solution of LiHMDS (1.0 M in THF, 37.0 mL, 37 mmol, 2 equiv) slowly added via cannula over 40 min. After addition of LiHMDS, the enolate solution was stirred for an additional 30 minutes at 0 ° C., then allyl bromide (3.00 g, 18.5 mmol, 1 equiv) was added dropwise via syringe over 30 seconds. The reaction was stirred for additional 90 min at 0 ° C., then quenched with H ₂ O (200 mL) and extracted with CH ₂ Cl ₂ (3 × 150 mL). The organic extract was dried (K ₂ CO ₃ ), filtered and concentrated to afford 8.0 g of yellow oil. A small amount of crude product was purified via flash column chromatography on silica gel using 3: 2: 95 MeOH / Et ₃ N / CH ₂ Cl ₂ as eluent to provide a pure product sample for analysis. The remaining material was used for the next step without purification. ¹ H NMR (300 MHz, CDCl ₃ ) (spectrum indicates rotamer) 7.40-7.24 (m, 5H), 5.90-5.76 (m, 1H), 5.20-5.02 (m, 2H), 4.92-4.75 (m, 2H), 4.66-4.45 (m, 2H), 4.20-4.00 (m, 1H), 3.62 (t, J = 6.3 Hz, 1H), 3.34-3.16 (m, 1H), 3.05-2.94 (m, 2H) , 2.84 (s, 3H), 2.55 (q, J = 7.2 Hz, 1H), 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, 1H), 0.96 (d, J = 6.9 Hz, 1H), 0.89 (t, J = 7.2 Hz, 2H); MS (ESPOS): 345.0 [M + H] ⁺ . HPLC (Symmetry C18, 3.5 μm particle size, 100 μm pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN / 0.1% TEA in H ₂ O over 10 minutes, 2 mL / min flow rate): Rt = 4.28 min.

Diene  Amino Amide (21i) (R ⁹ = n-propyl, R ^9b = H, m = 1) Boc -protect.

Triethylamine (2.83 mL, 20 mmol, 1.1 equiv) in a solution of amine (crude product from the previous step, 8.0 g, about 18 mmol, 1 equiv) in CH ₂ Cl ₂ (100 mL) at 23 ° C., followed by (Boc ) ₂ O (8.07 g, 37 mmol, 2 equiv) was added. The resulting mixture was stirred at 23 ° C. for 13.5 h and then concentrated. Gradient on silica gel (column packed to 5.5 cm diameter 17 cm high) first eluting with 25% EtOAc / hexanes (1 L), then 30% EtOAc / hexanes (600 mL), then 40% EtOAc / hexanes (400 mL) The crude product was purified by flash column chromatography. This gave 5.20 g (11.7 mmol, 65% over two steps) of pure product 21i (R ⁹ = n-propyl, R ^9b = H, m = 1). Some mixed fractions containing small amounts of product were discarded. ¹ H NMR (300 MHz, CDCl ₃ ) (Spectrum represents rotamer) 7.52-7.24 (m, 5H), 5.90-5.62 (m, 1H), 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, 1H), 3.79 (d, J = 5.7 Hz, 1H), 2.91 (s, 1H), 2.87 (s, 2H), 2.52-2.29 (m, 2H), 2.10-1.96 (m, 2H), 1.54-1.35 (m, 9H), 1.13-1.00 (m, 2H), 0.96-0.86 (m, 3 H); MS (ESPOS): 467.3 [M + Na] ⁺ . HPLC (Symmetry C18, 3.5 μm particle size, 100 μm pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN / 0.1% TFA in H ₂ O over 10 minutes, 2 mL / min flow rate): Rt = 6.85 min.

Closure Diene Double decomposition (21j) ( R ⁹ = n-propyl, R ^9b = H, m = 1).

Benzylidene [1,3-bis in a solution of diene (21i) (R ⁹ = n-propyl, R ^9b = H) (5.20 g, 11.7 mmol, 1 equiv) in CH ₂ Cl ₂ (700 mL) at 23 ° C. (2,4,6-trimethylphenyl) -2-imidazolidineylidene] dichloro- (tricyclohexylphosphine) ruthenium [Grubbs 2nd generation catalyst, 320 mg, 0.38 mmol, 0.03 equiv] It was. The reaction was refluxed for 2 hours then cooled to 23 ° C. and concentrated. The resulting product was first purified via flash column chromatography on silica gel (40% EtOAc in hexane as eluent) to afford the desired product containing some unidentified material. This product was dissolved in hot hexane (100 mL) and crystallized over 2 days. The crystallized product was isolated by filtration through glass frit and washed with ice cold hexane (100 mL) to yield 3.425 g (8.23 mmol, 70%) of the desired tetrahydropyridine. The mother liquor was concentrated to give 0.57 g of brown oil which was then flash column chromatography on silica gel (40-50% EtOAc in hexane as eluent) to give the desired product (21j) (R ⁹ = n-propyl, R ^9b = H, m = 1) 392 mg (0.94 mmol, 8%) were further provided. ¹ H NMR (300 MHz, CDCl ₃ ) (spectrum shows rotamer) 7.50-7.25 (m, 5H), 5.52-5.26 (m, 1H), 5.05-4.96 (m, 1H), 4.63-4.35 (m, 2H), 4.30-3.58 (m, 3H), 2.91 (s, 3H), 2.50-2.34 (m, 1H), 2.20-1.94 (m, 3H), 1.46 (s, 7H), 1.41 (s, 2H) , 1.19-1.01 (m, 2H), 0.94-0.85 (m, 3H); MS (ESPOS): 439.3 [M + Na] ⁺ . HPLC (Symmetry C18, 3.5 μm particle size, 100 μm pore size, 4.6 mm diameter 30 mm length, 2% -98% MeCN / 0.1% TFA in H ₂ O over 10 minutes, 2 mL / min flow rate): Rt = 6.29 min.

Pseudoephedrine supplements (21k) R ⁹ = n-propyl, R ^9b = H, m = 1) cleavage.

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., 0.1 M aqueous NaOH solution (41.1 mL, 41.1 mmol, 5 equiv) was added. The reaction was refluxed for 24 hours (oil bath temperature 100 ° C.), then cooled to 23 ° C. and concentrated via rotary evaporation to remove most of MeOH. The resulting aqueous solution was transferred to a separatory funnel, diluted with H ₂ O (100 mL) and extracted with Et ₂ O (100 mL). The ether extract was washed with 0.5M aqueous NaOH solution (70 mL) and then discarded. The combined basic aqueous layers were acidified to pH 2 with 1.0 N HCl and extracted with EtOAc (2 × 200 mL). The organic extract was dried (MgSO ₄ ), filtered and concentrated to give 2.46 g of the desired Boc-protected amino acid (21k) (R ⁹ = n-propyl, R ^9b = H, m = 1). ¹ H NMR (300 MHz, CDCl ₃ ) (spectrum shows rotamer) 5.36 (d, J = 22.8 Hz, 1H), 5.09 (d, J = 4.8 Hz, 0.5H), 4.90 (br s, 0.5H) , 4.14-3.97 (m, 1H), 3.83-3.67 (m, 1H), 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

SOCl ₂ (1.58 mL, 21.6 mmol) was added dropwise to 0 ° C. anhydrous MeOH (20 mL), the solution was stirred at 0 ° C. for 10 min, and then solid L-2-amino-4-pentenoic acid (22a) (R ^9b = H) (Aldrich) (1.0 g, 8.7 mmol) was added. The reaction mixture was stirred at ambient temperature for 48 hours and the solvent was removed in vacuo. Purification by silica gel column chromatography (10% MeOH / DCM) affords L-2-amino-4-pentenoic acid methyl ester 22b (R ^9b = H) (0.95 g, 85%).

To a solution of L-2-amino-4-pentenoic acid methyl ester in dichloroethane (32 mL) at 0 ° C., 2,4,6-collidine (2.3 mL, 19.1 mmol, 2.2 equiv) and solid 2-nitrobenzene Sulfonyl chloride was added. The reaction was stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (200 mL) and saturated aqueous NH ₄ Cl solution. The organic layer was washed with 1.0M aqueous KHSO ₄ solution, saturated aqueous NaHCO ₃ solution, brine, dried (MgSO ₄ ) and concentrated to give a residue, which was then column chromatography on silica (gradient 10-20% EtOAc / hexanes). Purification by) yielded 0.70 g (26%) of the desired product (22b) (R ^9b = H) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10-8.06 (m, 1H), 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) (R ^9b = H) (685 mg, 2.18 mmol), Cs ₂ CO ₃ (710 mg, 2.18 mmol) and tetrabutylammonium bromide (702 mg, 2.18 mmol) in DMF (5.0 mL). 3-methylenehex-1-yl-toluenesulfonate (22c) (R ⁹ = propyl) {702 mg, 2.61 mmol in DMF (1.0 mL); Kelvin H. Yong et al., Journal of Organic Prepared according to Chemistry , 2001, 66, 8248, and the reaction mixture was heated to 60 ° C. overnight. The reaction solvent is removed by evaporation, the resulting residue is taken up in EtOAc and washed with 10% aqueous citric acid solution and brine, the organic phase is dried over MgSO ₄ and concentrated to give a residue, which is column chromatography on silica. Purification by (17-20% EtOAc / hexanes) afforded the desired product 22d (R ⁹ = propyl, R ^9b = H) (0.38 g, 42%) as an oil.

MS (ESPOS): 433 [M + Na] ⁺ .

Benzylidene [1,3-bis (2,4,6-trimethylphenyl) -2 in a solution of (22d) (R ⁹ = propyl, R ^9b = H) (0.38 g, 0.92 mmol) in anhydrous DCM (40 mL) -Imidazolidinylidene] dichloro- (tricyclohexylphosphine) ruthenium (23.3 mg, 0.0276 mmol) was added and the resulting reaction mixture was refluxed under N ₂ for 2.5 hours, then cooled to room temperature and concentrated I was. The product was purified by flash column chromatography on silica gel (35% ethyl acetate / hexanes) to afford the desired compound 22e (R ⁹ = propyl, R ^9b = H) (0.29 g, 81%).

MS (ESPOS): 383 [M + Na] ⁺ .

Stirring of thiophenol (183 μL, 1.79 mmol) and 7-methyl-1,5,7-triazacyclo- [4,4,0] dec-5-ene (214 μL, 1.49 mmol) in anhydrous DMF (3 mL) To the resulting solution was added a solution of alkene (22e) (R ⁹ = propyl, R ^9b = H) (228 mg, 0.596 mmol) in anhydrous DMF (3.0 mL) via cannula and the resulting reaction mixture was added under N _2. Stir for hours and then concentrate to give a residue. The residue was taken up in ether and stirred for 5 min with 1N HCl aqueous solution (15.0 mL). The aqueous phase was washed with ether and then made basic with solid potassium carbonate. The resulting basic aqueous phase was washed three times with ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, cooled to 0 ° C., treated with 2M HCl in ether (0.8 mL), the resulting mixture was stirred for 5 minutes and then evaporated to dryness. , Desired product (22f) (R ⁹ = propyl, R ^9b = H) was obtained as hydrochloride salt (144 mg, 103%).

MS (ESPOS): 198 [M + H] ⁺ .

To a solution of amine (22f) (R ⁹ = propyl, R ^9b = H) (143 mg, 0.61 mmol) in anhydrous dichloromethane (2.0 mL) triethylamine (170 μL, 1.22 mmol) and di-t-butyldi Carbonate (350 mg, 1.6 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature under N ₂ and evaporated to dryness and then purified by flash column chromatography on silica gel using 20% ethylacetate in hexane as eluent to give the desired compound (22 g). (R ⁹ = propyl, R ^9b = H) (176 mg, 86%).

MS (ESPOS): 320 [M + Na] ⁺ .

To a solution of ester (22 g) (R ⁹ = propyl, R ^9b = H) (175 mg, 0.59 mmol) in dioxane / water (6: 1) (4 mL) was added 1 M aqueous lithium hydroxide solution (0.65 mL, 0.648 mmol). It was. The resulting reaction mixture was stirred at rt under N ₂ overnight 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 over sodium sulfate and evaporated to dryness to afford the desired protected cyclic amino acid (22h) (R ⁹ = propyl, R ^9b = H) (175 mg, 105%).

MS (ESNEG): 292 [M ⁻ H] ⁻ .

Common way u

Nitron (23a) in Et ₂ O (200 mL) at 23 ° C. (Dondoni et al., Synthetic Communications , 1994, 24, 2537-2550) (5.96 g, 16.4 mmol, 1 equiv) in a solution of Et ₂ AlCl (1.0M in heptane, 16.4 mL, 16.4 mmol, 1 equiv) ) Was added. The reaction was stirred at 23 ° C. for 15 minutes and then cooled to −78 ° C. and treated with a solution of cyclopropylmagnesium bromide (0.5M in THF, 99 mL, 49 mmol, 3 equiv) added via cannula over 25 minutes. It was. After stirring for an additional 1.7 h at -78 ° C, the reaction was quenched with 1.0M aqueous NaOH solution (80 mL) at low temperature. The resulting mixture was stirred at 23 ° C. for 25 minutes and then transferred to a separatory funnel to separate the layers. The organic layer was washed with brine (100 mL, gently shaken to form no emulsion). The original aqueous layer was extracted with Et ₂ O (3 × 150 mL) and each extract was washed with brine (100 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give 5.89 g (14.5 mmol, 89%) of the desired product (23b) (R ²⁰ + R ²¹ = cyclopropane) as a white solid. This material was used without further purification.

MS (ESPOS): 406.0 [M + H].

Hydroxylamine (23b) (R ²⁰ + R ²¹ = cyclopropane) (5.89 g, 14.5 mmol, 1 equiv) and Et ₃ N (12.2 mL, 87.3 mmol, 6 in CH ₂ Cl ₂ (200 mL) at 0 ° C. To the solution of eq) methanesulfonyl chloride (2.25 mL, 29.1 mmol, 2 eq) was added. The reaction was stirred at 0 ° C. for 20 minutes and then further stirred at 23 ° C. for 25 minutes and added to 1.0M aqueous NaOH solution: brine (1: 1, 200 mL). The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 50 mL) and then the combined organic phases were dried (MgSO ₄ ), filtered and concentrated. The resulting residue was dissolved in 1: 1 EtOAc: hexane (200 mL), washed with H ₂ O (150 mL), saturated aqueous NaHCO ₃ solution (200 mL), brine (150 mL), dried (MgSO ₄ ), filtered and Concentration gave 5.95 g of brown oil whose main component is the desired imine. MS (ESPOS): 388.2 [M + H].

To a solution of crude imine (5.95 g) in MeOH (150 mL) at 23 ° C. was added Girard reagent T (2.84 g, 16.9 mmol, 1.1 equiv). After stirring for 70 minutes, the solution was concentrated. The residue was partitioned between EtOAc (150 mL) and 1: 1: 1 H ₂ O: brine: saturated aqueous NaHCO ₃ solution (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated to yield 4.70 g of a yellow oil whose main component was the desired amine.

MS (ESPOS): 300.0 [M + H] ⁺ .

Trifluoroacetic anhydride (3.28 mL, 23.6 mmol, 1.5) in 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. Equivalent)) was added. The reaction was stirred at 0 ° C. for 1 h and then at 23 ° C. for 3 h and then quenched with H ₂ O (100 mL). The quenched reaction mixture was stirred for 10 minutes and partitioned between 1: 1 EtOAc: hexane (300 mL) and brine (200 mL). The layers were separated and the organic layer was washed with 1.0N HCl (300 mL), saturated aqueous NaHCO ₃ (300 mL), brine (200 mL), dried (MgSO ₄ ), filtered and concentrated. 4.50 g of the desired trifluoroacetamide (23c) (R ²⁰ + R ²¹ = cyclopropane) was purified by flash column chromatography on silica gel using 25% EtOAc in hexane as eluent. (11.3 mmol, 78% from hydroxylamine) were obtained.

MS (ESPOS): 418.0 [M + Na] ⁺ .

To a solution of diacetonide (23c) (R ²⁰ + R ²¹ = cyclopropane) (4.50 g, 11.3 mmol, 1 equiv) at 23 ° C. was added an aqueous solution of TFA (80%, 100 mL, precooled to 0 ° C.) It was. The reaction was stirred at 23 ° C. for 35 minutes and then concentrated to yield 3.87 g of a white solid whose main component is the desired deprotected galactose.

MS (ESPOS): 338.1 [M + Na] ⁺ .

Ac ₂ O (7.65 mL, 81.1 mmol) in a solution of crude galactose (3.65 g, 11.6 mmol, 1 equiv) and Et ₃ N (16.1 mL, 116 mmol, 10 equiv) in CH ₂ Cl ₂ (130 mL) at 23 ° C. , 7 equiv) followed by DMAP (141 mg, 1.2 mmol, 0.1 equiv). The reaction was stirred at 23 ° C. for 2 hours and then quenched with MeOH (5 mL). The quenched reaction mixture was stirred for 5 minutes and then diluted with Et ₂ O (300 mL). The resulting solution was washed with H ₂ O (2 × 300 mL), 1.0 N HCl (300 mL), saturated aqueous NaHCO ₃ solution (300 mL), brine (300 mL), dried (MgSO ₄ ), filtered and concentrated to acetylated. 5.07 g of product was obtained as a mixture of alpha / beta isomers and pyranose / furanose isomers.

MS (ESPOS): 506.1 [M + Na] ⁺ .

To a solution of peracetate isomer (5.07 g) in CH ₂ Cl ₂ (150 mL) at 0 ° C. was added a solution of HBr (33%, 30 mL) in acetic acid. The reaction was stirred at 0 ° C. for 30 minutes and then warmed to 23 ° C. After stirring for an additional 3.5 h, the reaction mixture is diluted with CH ₂ Cl ₂ (50 mL), ice water (2 × 300 mL), ice cold 50% NaHCO ₃ saturated aqueous solution (2 × 300 mL), ice cold 50% saturated brine (300 mL). ), Dried (MgSO ₄ ), then filtered and concentrated to give 4.33 g (8.60 mmol, 76% from diacetonide) of α-bromide (23d) (R ²⁰ + R ²¹ = cyclopropane). . This material was used without further purification.

AgOAc (1.44 g, 8.60 mmol, 1 equiv) was added to a solution of bromide (23 d) (R ²⁰ + R ²¹ = cyclopropane) (4.33 g, 8.60 mmol, 1 equiv) in AcOH (100 mL) at 23 ° C. . After 45 min stirring at 23 ° C., the reaction mixture is diluted with CH ₂ Cl ₂ (350 mL), H ₂ O (2 × 400 mL), ice cold 50% NaHCO ₃ saturated aqueous solution (3 × 300 mL), brine (400 mL). After washing, drying (MgSO ₄ ), filtration and concentration provided 3.76 g (7.78 mmol, 91%) of the desired β-acetate as white foam. This material was used without further purification.

MS (ESPOS): 506.1 [M + Na].

To a solution of β-acetate (3.76 g, 7.78 mmol, 1 equiv) in CH ₂ Cl ₂ (50 mL) at 23 ° C. was added PCl ₅ (1.70 g, 8.17 mmol, 1.05 equiv) followed by BF ₃ · OEt ₂ (50 μL). Added. After stirring for 1 hour, the reaction was diluted with CH ₂ Cl ₂ (300 mL), washed with ice cold brine (500 mL), saturated ice cold 50% NaHCO ₃ aqueous solution (2 × 500 mL), and ice cold brine (500 mL), Drying (MgSO ₄ ), filtration and concentration gave 3.72 g of the desired β-chloride (23e) (R ²⁰ + R ²¹ = cyclopropane). The product was used without further purification.

MS (ESNEG): 458.2 [M-H].

MeSNa (1.70 g, in a solution of galactosyl chloride (23e) (R ²⁰ + R ²¹ = cyclopropane) (3.72 g, 8.10 mmol, 1 equiv) in DMF (30 mL) and HMPA (7.5 mL) at 23 ° C. 24.3 mmol, 3 equiv) was added. After stirring for 35 min at 23 ° C., the reaction mixture was partitioned between Et ₂ O (150 mL) and 1: 1 H ₂ O / brine (70 mL). The layers were separated and the aqueous layer was reextracted with Et ₂ O (150 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (130 mL), Et ₃ N (11.3 mL, 81.0 mmol, 10 equiv), Ac ₂ O (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 quenched reaction mixture was stirred for 10 minutes and partitioned between Et ₂ O (200 mL) and H ₂ O (200 mL). The layers were separated and the organic layer was washed with 1.0 M aqueous HCl solution (200 mL), saturated aqueous NaHCO ₃ solution (200 mL), brine (100 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using 30% EtOAc in hexane as eluent to give the desired product (23f) (R ²⁰ + R ²¹ = cyclopropane, R ¹ = SMe). 2.03 g (4.30 mmol, 53%) was obtained as a white solid.

¹ H NMR (300MHz, CDCl ₃ ) β 6.52 (br d, J = 9.3Hz, 1H), 5.65 (d, J = 5.4Hz, 1H), 5.56 (dd, J = 0.9, 3.0Hz, 1H), 5.27 (dd, J = 5.4, 11.1Hz, 1H), 5.20 (dd, J = 3.0, 10.5Hz, 1H), 4.43 (dd, J = 0.9, 7.5Hz, 1H), 3.66 (q, J = 9.0Hz, 1H), 2.15 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 0.94-0.78 (m, 1H), 0.70-0.61 (m, 1H), 0.57 -0.33 (m, 3 H); MS (ESPOS): 493.9 [M + Na]; MS (ESNEG): 470.2 [M ⁻ H] ⁻ .

1.0 M NaOH in a solution of triacetyl trifluoroacetamide (23f) (R ²⁰ + R ²¹ = cyclopropane, R ¹ = SMe) (2.03 g, 4.30 mmol, 1 equiv) in MeOH (35 mL) at 23 ° C. An aqueous solution (43 mL, 43 mmol, 10 equiv) was added. The reaction was stirred for 100 minutes and then acidified to pH 2 with 1.0M aqueous HCl solution (48 mL). The resulting solution was concentrated in vacuo until dry and the residue was dissolved / suspended in EtOH (40 mL) and then filtered through a medium pore glass frit to remove NaCl. The solid was washed with EtOH (2 x 20 mL). The combined filtrates were treated with Amberlite IRA400 (OH ^- form) resin (60 mL resin phase in MeOH) and the resin was transferred to MeOH (2 × 20 mL). The resulting mixture was stirred at 23 ° C. for 1 hour and then filtered. The resin was washed with MeOH (3 × 100 mL), CH ₃ CN (100 mL). The combined filtrates were concentrated to give 1.04 g of the desired galactoside (23 g) (R ²⁰ + R ²¹ = cyclopropane, R ¹ = SMe) as a white solid (4.19 mmol, 97%). The product was used without further purification.

¹ H NMR (300 MHz, CD ₃ OD) β 5.28 (d, J = 5.7 Hz, 1H), 4.13-4.06 (m, 2H), 3.97 (d, J = 6.6 Hz, 1H), 3.59 (dd, J = 3.3, 9.9 Hz, 1H), 2.33 (dd, J = 6.9, 9.0 Hz, 1H), 2.05 (s, 3H), 0.91-0.77 (m, 1H), 0.58-0.43 (m, 2H), 0.39-0.31 (m, 1 H), 0.28-0.19 (m, 1 H); MS (ESPOS): 272.0 [M + Na]; MS (ESNEG): 248.2 [M−H].

Common method V

According to the general method of Scheme 24, in a solution of compound (1) hydrochloride (9.90 mmol, 1 equiv) in THF (70 mL) at 23 ° C., H ₂ O (70 mL), followed by KHCO ₃ (12.9 mmol, 1.3 equiv), Then (Boc) ₂ O (12.0 mmol, 1.3 equiv) was added. After stirring for 5 hours, 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 ). Biotage® column chromatography system (40 + M cartridge) using solvent removed under reduced pressure and linear gradient (75% EtOAc / hexane-100% EtOAc) over a total of 1.2 L eluent at 50 mL / min. The crude product was purified by 40 mm ID x 150 mm) to give carbamate 24a (8.91 mmol, 90%).

To a solution of carbamate (24a) (15.9 mmol, 1 equiv) in benzene (300 mL) at 23 ° C., p-anisaldehyde dimethyl acetal (4.06 mL, 23.8 mmol, 1.5 equiv) followed by PPTS (199 mg, 0.79 mmol, 0.05 equivalents) was added. The reaction mixture was heated to reflux. After 4 hours, a second portion of p-anisaldehyde dimethyl acetal (2.0 mL, 11.7 mmol, 0.74 equiv) was added. After 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 further refluxed for 3 hours and cooled to 23 ° C., then partitioned between EtOAc (300 mL) and H ₂ O (300 mL). The organic layer was washed with 50% saturated NaHCO ₃ aqueous solution (300 mL), brine (150 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica gel flash column chromatography using 40% EtOAc in hexane as eluent to give 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. add pyridine (3.90 mL, 48.2 mmol, 10 equiv) followed by POCl ₃ (0.88 mL, 9.65 mmol, 2 equiv) Add over 60 seconds. Other acylating agents such as acid anhydride (R ¹¹ CO) ₂ O or acid chloride R ¹¹ COCl may be used in this step in the presence of a suitable base to provide different R ¹¹ acyl substituents. After addition, the reaction was held at 0 ° C. for 2 hours, after which triethylammonium bicarbonate buffer (1.0M, pH 8.5, 40 mL) was added carefully to quench the reaction. H ₂ O (60 mL) was then added and the resulting reaction was stirred at 0 ° C. for 30 minutes and warmed to 23 ° C. The quenched reaction mixture was stirred at 23 ° C. for 2 hours and then heated in a water bath (40-45 ° C.) to remove volatiles in vacuo. The resulting crude product was azeotropically dried by co-evaporation with DMF (3 × 100 mL) followed by toluene (150 mL, bath temperature = 40-45 ° C.) to give a white solid. Crude product 24c (R ¹¹ = PO (OH) ₂ ) contained substantially triethylammonium salts, but proceeded without purification.

Solution of protected phosphate 24c (R ¹¹ = PO (OH) ₂ ) (crude from previous step, about 4.8 mmol) prepared as described above in 1,2-dichloroethane (600 mL) at 0 ° C. To H ₂ O (25 mL) was added followed by TFA (200 mL). After addition, the reaction was held at 0 ° C. for 5 minutes and then warmed to 23 ° C. After stirring for 25 minutes at 23 ° C., the volatiles were removed in vacuo to yield 16.2 g of oil. The crude product was dissolved in 1: 1 H ₂ O / MeOH (70 mL) and filtered, then the resulting solution was prepared using HPLC [Waters Nova-Pak® HR C ₁₈ , 6 μm particle size. , 60 μs pore size, 40 mm ID × 200 mm, 5-60% acetonitrile / 0.1% AcOH in H ₂ O over 30 minutes, 75 mL / min flow rate] to purify desired 2-phosphate (5) (R ¹¹ ). = PO (OH) ₂ ) (3.10 mmol, 64% from free alcohol) was obtained as a white solid.

Method W

Β-lactam (24a) {2.92 g, 12.8 mmol, 1 equivalent in THF (30 mL) at 0 ° C .; Solution of benzyl (S)-(-)-4-oxo-2-azetidine-carboxylate (Aldrich) as described in Baldwin et al., Tetrahedron , 1990, 46, 4733). Over 20 minutes, a solution of LDA (2.0 M, 14.0 mL, 28.1 mmol, 2.2 equiv) was added via syringe pump. 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 about 1.5 min, the mixture was stirred at 0 ° C. for 2 h, then 1.0 M KHSO ₄ partitioned between aqueous solution (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with 1.0M aqueous KHSO ₄ solution (100 mL), brine (100 mL), dried (MgSO ₄ ), filtered and concentrated to give a light green solid (25b) (R ^{9 ′} = 2-butenyl). 3.65 g (100%) were obtained. This material was used without further purification.

MS (ESNEG): 282.2 [M ⁻ H] ⁻ .

Trimethylsilyldiazomethane (2.0M in Et ₂ O, 25.0 mL, 50 mmol, 3.9 equiv) was converted to acid (25b) (R ^{9 ′} = 2-butenyl) in methanol (70 mL) at 0 ° C. (3.65 g , 12.9 mmol, 1 equiv) was added slowly to the solution. The solvent was removed in vacuo to yield 3.53 g (11.9 mmol, 92%) of the desired ester product as a yellow oil. This material was used in the subsequent reaction without further purification.

Pd / C (10 wt.%, 482 mg) was added to a solution of alkene (25c) (R ^{9 ′} = 2-butenyl) (3.53 g, 11.9 mmol, 1 equiv) in EtOAc at 23 ° C. The reaction vessel was filled with hydrogen (balloon) and the mixture was mixed vigorously. After 2.5 hours, the reaction mixture was filtered through a pad of celite. Celite was washed with EtOAc (200 mL) and the filtrate was concentrated to give 3.51 g (11.7 mmol, 99%) of (25c) (R ⁹ = butyl) as a yellow oil. This material was used without further purification.

MS (ESPOS): 300.4 [M + H] ⁺ .

Et ₃ N · 3HF (0.95 mL, 5.85 mmol, 0.5 equiv) in a solution of N-TBS β-lactam (25c) (R ⁹ = butyl) (3.51 g, 11.7 mmol, 1 equiv) in THF (50 mL) at 23 ° C. ) Was added. After stirring at 23 ° C. for 60 minutes, 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), then dried (MgSO ₄ ) filtered and concentrated. The product was purified via flash column chromatography on silica gel using 50% EtOAc in hexane as eluent to give 1.48 g (8.0 mmol, 68%) of (25d) (R ⁹ = butyl) as a clear oil. .

MS (ESPOS): 578.3 [3M + H] ⁺ .

A solution of LiAlH ₄ (1.0M in THF, 22.9 mL, 22.9 mmol, 2.06 in a solution of β-lactam (25d) (R ⁹ = butyl) (2.06 g, 11.1 mmol, 1 equiv) in THF (150 mL) at 23 ° C. Equivalent) was added via syringe over 2 minutes. After stirring at 0 ° C. for 10 minutes, the reaction was warmed to 23 ° C. and stirred for 15 minutes and then refluxed for 3 hours. The mixture was then cooled to 0 ° C. and quenched by careful addition of H ₂ O (1.0 mL), then 15% aqueous NaOH solution (1.0 mL), and then H ₂ O (2.5 mL). The resulting suspension was stirred at 23 ° C. for 1.5 h, diluted with Et ₂ O (250 mL), filtered through celite and washed with Et ₂ O (250 mL). The filtrate was concentrated to give 1.42 g (9.93 mmol, 89%) of the desired product (25e) (R ⁹ = butyl) as a clear oil. The product was used without further purification.

MS (ESPOS): 287.4 [2M + H] ⁺ .

To a solution of amino alcohol 25e (R ⁹ = butyl) (1.41 g, 9.86 mmol, 1 equiv) in dichloromethane (50 mL) at 23 ° C. was added Boc ₂ O (2.59 g, 11.9 mmol, 1.2 equiv) It was. After 2 hours of stirring at 23 ° C., the reaction mixture was concentrated. The product was purified by flash column chromatography on silica gel using 33% EtOAc in hexane as eluent to give 1.53 g (6.31 mmol, 64%) of (25f) (R ⁹ = butyl) as a clear oil.

MS (ESPOS): 266.0 [M + Na] ⁺ .

To a solution of NaIO ₄ (8.81 g, 41.2 mmol, 10 equiv) in H ₂ O (60 mL) at 23 ° C. RuCl ₃ · xH ₂ O (350 mg, catalytic amount) followed by alcohol (25f) in acetone (60 mL) (R ⁹ = Butyl) (1.00 g, 4.12 mmol, 1 equiv) was added. The biphasic mixture was stirred at 23 ° C. for 30 min, then extracted with EtOAc (250 mL) and the organic layer was decanted. The aqueous residue was extracted with two portions of EtOAc (2 × 150 mL). The combined organic extracts were treated with 2-propanol (75 mL) and stirred at 23 ° C. After stirring for 2 hours, the mixture was filtered through celite and washed with EtOAc (300 mL). The filtrate was concentrated to give 0.78 g (3.04 mmol, 74%) of the desired product (25 g) (R ⁹ = butyl) as a dark oil. The product was used without further purification.

MS (ESPOS): 280.0 [M + Na] ⁺ .

Method X

Imidazole (2.21 g, 32.5 mmol, 2.5 equivalents) in a solution of alcohol (25f) (R ^{9 ′} = 2-methyl-2-butenyl) (3.31 g, 13.0 mmol, 1 equiv) in DMF (100 mL) at 23 ° C. TBSCl (2.93 g, 19.5 mmol, 1.5 equiv) was then added. The reaction was stirred for 35 minutes and then quenched with MeOH (2.0 mL). After stirring for 5 minutes, the resulting mixture was partitioned between Et ₂ O (500 mL) and H ₂ O (400 mL). The organic layer was separated, washed with H ₂ O (400 mL), brine (200 mL), dried (MgSO ₄ ), filtered and concentrated to afford the desired product (26a) (R ^{9 ′} = 2-methyl-2-). Butenyl) 4.13 g (11.2 mmol, 86%) was obtained as a clear oil.

MS (ESPOS): 392.4 [M + Na] ⁺ .

A solution of intermediate 26a (R ^{9 ′} = 2-methyl-2-butenyl) (2.03 g, 5.50 mmol, 1 equiv) in dichloromethane (80 mL) was introduced at −78 ° C. through a gas dispersion tube. Treated with ozone (1.2 L / min) until blue was observed (20 min). An oxygen stream (1.2 L / min) was passed through the reaction mixture to release excess ozone. After 15 minutes, the oxygen flow was stopped and PPh ₃ (2.16 g, 8.25 mmol, 1.5 equiv) was added. The reaction mixture was stirred at −78 ° C. for 30 minutes and then at 0 ° C. for 15 minutes and warmed to 23 ° C. After stirring at 23 ° C. for 10 minutes, silica gel was added and the resulting mixture was concentrated to dryness in vacuo to give a free-flowing powder which was immediately placed in a silica gel column. Flash column chromatography using 30-33% EtOAc in hexane as eluent gave 1.52 g (4.42 mmol, 80%) of aldehyde 26b as a clear oil.

MS (ESPOS): 398.0 [M + MeOH + Na] ⁺ .

In a suspension of cyclopropylmethyltriphenylphosphonium bromide (1.22 g, 3.06 mmol, 1.5 equiv) in THF (10 mL) at 0 ° C., inject a solution of NaHMDS (1.0 M in THF, 3.06 mL, 3.06 mmol, 1.5 equiv) Was added dropwise over 1 minute. The resulting solution was stirred at 0 ° C. for 20 min and then treated with a solution of aldehyde (26b) (700 mg, 2.04 mmol, 1 equiv) in THF (3.0 mL; 2 × 1.0 mL flush) transferred via cannula. After 15 minutes at 0 ° C., the reaction was warmed to 23 ° C. and stirred for an additional 10 minutes and then quenched with saturated NH ₄ Cl (30 mL). The resulting mixture was partitioned between Et ₂ O (120 mL) and H ₂ O (50 mL). The organic layer was separated, washed with brine (50 mL), dried (MgSO ₄ ), filtered and concentrated. Flash column chromatography using 10% EtOAc in hexane as eluent gave 588 mg (1.54 mmol, 76%) of (26c) (R ^{9 '} = cyclopropyl-prop-3-enyl) as a clear oil. .

MS (ESPOS): 404.3 [M + Na] ⁺ .

To a solution of alkene (26c) (R ^{9 ′} = 3-cyclopropyl-prop-3-enyl) (191 mg, 0.50 mmol, 1 equiv) in dioxane (5.0 mL) at 23 ° C. (dipotassium azodicarboxylate ( After addition of 973 mg, 5.01 mmol, 10 equiv), a solution of AcOH (573 μL, 10.0 mmol, 20 equiv) in dioxane (5.0 mL) was added slowly through a syringe pump over 16 hours. After the addition, the reaction was stirred for an additional 6 hours and then filtered through a glass frit using Et ₂ O (150 mL) to remove the precipitate. The resulting solution was washed with saturated aqueous NaHCO ₃ (2 × 100 mL), brine (80 mL), dried (MgSO ₄ ), filtered and concentrated. The procedure was repeated three times on the obtained crude material to completely convert the alkene to give 183 mg (0.48 mmol, 96%) of saturated product 26d (R ⁹ = 3-cyclopropyl-propyl) as a clear oil.

MS (ESPOS): 406.0 [M + Na] ⁺ .

A solution of TBAF (1.0 M in THF, 0.55 mL, 0.55) in a solution of TBS ether 26d (R ^{9 ′} = 3-cyclopropyl-propyl) (190 mg, 0.50 mmol, 1 equiv) in THF (10 mL) at 23 ° C. Mmol, 1.1 equiv) was added. The resulting solution was stirred at 23 ° C. for 40 minutes and then partitioned between Et ₂ O (50 mL) and H ₂ O (50 mL). The organic layer was separated, washed with brine (50 mL), then dried (MgSO ₄ ) filtered and concentrated to give (26e) (R ⁹ = 3-cyclopropyl-propyl) 133 mg (0.50 mmol, 100%) as a clear oil. Obtained as

MS (ESPOS): 290.2 [M + Na] ⁺ .

As described in the previous examples, (26e) was oxidized with catalytic ruthenium to give the desired carboxylic acid product 26f (R ⁹ = 3-cyclopropyl-propyl).

MS (NEG): 282 [M ⁻ H] ⁻ .

Method Y

Racemic (27a) (R ⁹ = n-propyl)  synthesis.

To a solution of (10b) (R ⁹ = n-propyl) (22 g, 0.13 mol) in methanol (30 mL) and concentrated HCl (10 mL) was added platinum (IV) oxide (5 g). The reaction mixture was hydrogenated at 50 psi for 16 hours, the catalyst was removed by filtration through Celite® and the filtrate was evaporated to dryness. Crude pipecolic acid was used without further purification.

19 g of crude pipepelic acid residue was dissolved in acetonitrile (200 mL), tetramethylammonium hydroxide.5H ₂ O (33 g) was added and the reaction mixture was stirred for 30 minutes, then di-t-butyl pyrocarbonate (39 g, 0.46 mol) was added and the reaction mixture was stirred at rt for 72 h. Additional tetramethylammonium hydroxide.5H ₂ O (8 g) and di-t-butyl pyrocarbonate (9 g) were added and the reaction mixture was stirred for 24 hours. The reaction solvent was removed in vacuo and the resulting oil 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 × 200 mL). The combined organic layers were dried over MgSO _4, filtered and the solvent removed to give (27a) (R ⁹ = n-propyl) (19 g, 77%) as a yellow oil which crystallized upon standing.

¹ H NMR (300 MHz, CD ₃ OD) δ 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 (R ⁹ = n-propyl) is diluted with acetonitrile (5 vol) and S-α-methylbenzyl amine (0.5 equiv), heated until reflux and the seed is added To cool. Allow the mixture to stand overnight. The resulting first portion of salt is filtered off and left until finally recrystallized.

The liquid from the filtration is concentrated in vacuo and then placed in DCM (4 vol) and the DCM washed with 1M citric acid (2/3 volume of DCM). DCM is then separated, dried over magnesium sulphate, filtered and concentrated in vacuo. The free acid, rich in 2R, 4S enantiomers, is placed in 5 volumes of acetonitrile, 0.85 equivalents of R-α-methylbenzyl amine is added, the mixture is heated to reflux, and then seeded to cool. Allow the mixture to stand overnight. The resulting salt is filtered off (the ee of the salt is usually 85 to 90%).

The procedure for obtaining the second portion of the 2S, 4R salt is the same as in the previous paragraph, except that the R-α-methylbenzyl amine is replaced with S-α-methylbenzyl amine. The second amount of salt formed is filtered (usually having about 80-90% ee) and left until finally recrystallized.

The liquid from filtration (2S, 4R salt forming liquid, second portion) is concentrated in vacuo. The salts are separated by the method described previously. In this step, the impurities are concentrated to such a level that salt formation is impossible. The free acid is column chromatographed (30% EtOAc / hexanes), thereby removing unwanted impurities. The column used silica to compound in a 10: 1 weight to weight ratio. In addition, the compound was absorbed onto 3 equivalents (weight: weight) of silica.

The free acid from the column (rich in 2R, 4S enantiomers) is diluted with acetonitrile (5 volumes), R-α-methylbenzyl amine is added and recrystallization is repeated.

Salt separation and formation of the 2S, 4R salt is the same as described above. The third portion of salt formed usually has an ee of 80-90%.

Combine three portions of 2S, 4R salt and dilute with acetonitrile (7 volumes). The mixture is heated to reflux until all salts are dissolved. The mixture is then cooled to room temperature and allowed to stand overnight by addition of seed. The salt precipitated out of the solution is filtered. Salt represents about 97% ee. The process is repeated to provide salts with ee greater than 99%. The salt is poured into DCM (4 volumes), washed twice with 1M citric acid (about 2/3 volume of DCM), dried over magnesium sulfate, filtered and concentrated in vacuo. By this procedure, 77% of the 2S, 4R enantiomer of theoretical yield is obtained as a tan oil (98% ee).

Method Z

The conditions below are representative of the general coupling and deprotection scheme shown in Method Z where P ¹ = H and P ² = carboxylic acid-t-butyl ester (Boc).

Azetedinic acid (25f) (R ⁹ = butyl) (52 mg, 0.20 mmol, 1 equiv), 7-Cl MTL (6b) (R ² = H, R ³ = Cl) in DMF (2.0 mL) at 23 ° C. 58 mg, 0.20 mmol, 1 equiv) and DIPEA (88 μL, 0.51 mmol, 2.5 equiv) were added to a solution of HBTU (84 mg, 0.22 mmol, 1.1 equiv). After stirring for 12 h at 23 ° C., DMF was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and 1: 1 brine: 10% aqueous citric acid solution (100 mL). The organic layer was separated and washed with 1: 1 brine / saturated aqueous NaHCO ₃ solution (100 mL), brine (50 mL), dried (MgSO ₄ ), filtered and concentrated to give (13a) (R ² = H, R ³ =). Cl, R ⁹ = butyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0) 82 mg (0.17 mmol, 84%) were provided as a glassy solid which was used without purification in the next step. .

Carbamate (13a) (R ² = H, R ³ = Cl, R ⁹ = butyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, in 1,2-dichloroethane (10 mL) at 23 ° C), m = 0) (82 mg, 0.17 mmol, 1 equiv) was added H ₂ O (0.40 mL) followed by TFA (4.0 mL). Stir at 23 ° C. for 20 min, then toluene (50 mL) was added and the resulting solution was concentrated to dryness. Semi-preparative HPLC (Waters Nova-Pak® HR C ₁₈ , 6 μm particle size, 60 μs pore size, 20 mm ID × 100 mm, 5-60% acetonitrile / 0.1% HCl in H ₂ O over 30 minutes , 20 mL / min flow rate) to purify the residue to give the title compound 3-butyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl- 41 mg of tetrahydro-pyran-2-yl) -propyl] -amide was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 5.30 (d, J = 6.0 Hz, 1H), 4.64 (d, J = 7.8 Hz, 1H), 4.63-4.52 (m, 2H), 4.29 (d, J = 10.2Hz, 1H), 4.07 (dd, J = 5.7, 10.2Hz, 1H), 4.00 (t, J = 6.6Hz, 1H), 3.82 (d, J = 3.3Hz, 1H), 3.75 (dd, J = 8.4, 9.9 Hz, 1H), 3.56 (dd, J = 3.3, 10.2 Hz, 1H), 2.92-2.76 (m, 1H), 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 (ESPOS): 411.0 [M + H] ⁺ .

Way AA

To pyridine-2-carboxylic acid (10b) (0.5 mmol) in DMF (2 mL) was added lincosamine (0.5 mmol) as defined in general coupling scheme 13, followed by HBTU (214 mg, 0.55 mmol) and DIEA (132 mg, 1 mmol). ) Was added. The reaction mixture was stirred at rt for 2 h. The solvent (13b) was obtained by removing the solvent and purifying the crude material by silica gel column chromatography.

PtO ₂ (200 mg) is added to a solution of pyridine (13b) (0.46 mmol) in water (10 mL), AcOH (3 mL) and MeOH (2 mL) and the resulting reaction mixture is shaken under 55 psi hydrogen or lower hydrogen It was shaken for longer periods in pressure. The residual catalyst was removed by filtration through celite and the solvent was removed to give the crude product. Purification by silica gel column chromatography using MeOH in DCM afforded type 1 lincosamide analogs as defined in Scheme 13.

In general, silica chromatography readily separates cis-2S diastereomers from unwanted isomers. In some cases, separation of the isomers requires semi-preparative HPLC. A representative set of conditions is as follows: Waters Nova-Pak® HR C ₁₈ column, 6 μm particle size, 60 mm pore size, 20 mm ID × 100 mm, 5-60% acetonitrile 0.1% AcOH / over 30 minutes H ₂ O 0.1% AcOH, 20 mL / min flow rate.

Way AB

[2- methyl -1- (3,4,5- Tris - Benzyloxy -6- Methylsulfanyl - Tetrahydro -Pyran-2-yl) -propyl]- Carbam  Level 3 Butyl  Ester 15b (step a) ( P _One = Boc , P ₂ = Bn , R ² = Me , R ³ = H) Synthesis (Intermediate) Not shown ).

To a rapidly stirred solution (2 g, 5.7 mmol) of (2a) (P = Boc, R ¹ = Me, R ² = H) in benzene (40 mL) was added 50% aqueous KOH solution (12.8 mL) and N ₂ In the atmosphere, tetrabutylammonium bisulfate (0.67 g) and benzyl bromide (6.77 mL, 57.0 mmol) were suspended with vigorous stirring. After 3.5 hours, benzyl amine (6.0 mL) was added and the reaction mixture was stirred for an additional 20 seconds, then toluene (300 mL) was added and the organic layer was H ₂ O (2 × 100 mL), 2M KHSO ₄ (3 X 100 mL), saturated aqueous NaHCO ₃ (1 x 100 mL), brine (1 x 100 mL), then dried over MgSO ₄ and evaporated to dryness. Product 15b (step a) 2-methyl-1- (3,4,5-tris-benzyloxy- by chromatography of the crude product on silica using 10% EtOAc / hexanes to 15% EtOAc / hexanes. 6-Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -carbamic acid tert-butyl ester was obtained as a colorless foam (2.6 g, 72%). MS (ESPOS): 522.8 [M + H-Boc] ⁺ .

[2- methyl -1- (3,4,5- Tris - Benzyloxy -6- Fluoro - Tetrahydro -Pyran-2-yl) -propyl] -ca Bamsan  Level 3 Butyl  Ester (15b) ( P _One = Boc , P ₂ = Bn , R ² = Me , R ³ = H) (step b) synthesis.

Intermediate 2-methyl-1- (3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -carbamic acid tert-butyl in DCM (25 mL) DAST (0.599 mL, 4.46 mmol) was added to the stirred solution cooled to −16 ° C. of ester (1.54 g, 2.5 mmol) and suspended under vigorous stirring under N ₂ atmosphere. After 5 minutes, solid NBS (0.599 mL, 4.46 mmol) was added over 5 minutes, the reaction mixture was stirred for an additional 45 seconds, then DCM (300 mL) was added and the organic layer was saturated aqueous NaHCO ₃ solution (1 ×). 100 mL), dried over MgSO ₄ and evaporated to dryness. Crude product was chromatographed on silica using 15% to 30% Et ₂ O / hexanes to give 1-α and β fluorinated [2-methyl-1- (3,4,5-tris-benzyloxy-6 Mixture of -fluoro-tetrahydro-pyran-2-yl) -propyl] -carbamic acid tert-butyl ester (15b) (P ₁ = Boc, P ₂ = Bn, R ² = Me, R ³ = H) Was isolated as a colorless oil (0.85 g, 58%). TLC (20% Et ₂ O / hexane) R _f isomer 1 = 0.2, R _f isomer 1 = 0.05. ¹⁹ F NMR (CDCl ₃ ) δ Isomer 1: -132.78, -132.96, Isomer 2: -145.05, -145.13, -145.23, -145.31, HPLC (C ₁₈ 3.5 μm, 4.6 × 30 mm column; for gradient over 10 minutes Lize 2% -98% MeCN; 1.5 mL / min): Retention time = 7.93 min, 7.98 min; MS (ESPOS): 494.7 [M + H-Boc] ⁺ ; MS (ESNEG): 592.7 [M−H] ⁺ .

2- methyl -1- (6-allyl-3,4,5- Tris - Benzyloxy - Tetrahydro -Pyran-2-yl) -propylamine (15c) ( P _One = H, P ₂ = Bn, R ^One = Allyl, R ² = Me, R ³ = H)  synthesis.

To the stirred solution cooled to −32 ° C. of the intermediate (15b) (831 g, 2.5 mmol) in DCM (30 mL) under N ₂ atmosphere was added allyltrimethylsilane (1.12 mL, 7.0 mmol). After 10 minutes, BF ₃ · Et ₂ O (0.36 mL, 2.8 mmol) was added over 2 minutes and the reaction mixture was stirred for an additional 1.5 hours, then warmed to 0 ° C. for 30 minutes. Water (1 mL) and TFA (15 mL) were added to the reaction mixture and the reaction mixture was allowed to warm to room temperature, stirred for 1 hour and evaporated to dryness. The residue was dissolved in Et ₂ O (200 mL), washed with 1M K ₂ CO ₃ aqueous solution (50 mL) and brine, dried over Na ₂ SO ₄ and evaporated to dryness to yield product (15c) (P ₁ = H , P ₂ = Bn, R ¹ = allyl, R ² = Me, R ³ = H) was isolated as colorless oil (0.69 g, 96%). TLC (20% EtOAc / hexanes) R _f = 0.05; MS (ESPOS): 516.4 [M + H-Boc] ⁺ .

2- (1-amino-2- methyl -Propyl) -6-propyl- Tetrahydro -Pyran-3,4,5- Triol .

160 mg 2-methyl-1- (6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl) -propylamine (15c) and degussa 50% w / w wet 10% palladium 100 mg / carbon was suspended in NF (5 mL) and 1M HCl aqueous solution (1 mL) under N ₂ , then the reaction mixture was stirred for 24 h under 1 atmosphere H ₂ . The reaction mixture was filtered through celite and evaporated to dryness to give the product 2- (1-amino-2-methyl-propyl) -6-propyl-tetrahydro-pyran-3,4,5-triol (60.8 mg, 89%) was obtained as the HCl salt. TLC (CHCl ₃ : MeOH: 32% AcOH aqueous solution) R _f = 0.35. MS (ESPOS): 248 [M + H] ⁺ .

Way AC

In general, the final purification of the compounds and the separation of diastereoisomers described in detail in the Examples below can be achieved by semi-preparative HPLC. The final product was mounted on a Waters Prep LC 4000® system equipped with a Waters 2487® dual λ absorbance detector set at 214 nm and a SEDERE Sedex 55® vaporized light scattering detector in series. Purified. The general conditions used to separate diastereomers are as follows: Waters Nova-Pak HR C ₁₈ column, 6 μm particle size, 60 mm pore size, 20 mm ID × 100 mm, 5-60% over 30 minutes Acetonitrile 0.1% AcOH / H ₂ O 0.1% AcOH, 20 mL / min flow rate. Collect the collected fractions and lyophilize until dry.

The following examples were made according to the method described above.

Example 1

4- (3,3-Difluoro-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide

4- (3,3-Difluoro-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide.

To a solution of (2b) (R ^{2 ′} = H) (45 mg, 0.18 mmol, 1 equiv) in dry DMF (0.5 mL) at 0 ° C., add triethylamine (79.4 μL, 0.57 mmol, 3.2 equiv) , Bis- (trimethylsilyl) trifluoroacetamide (71.2 μL, 0.27 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. The reaction mixture was added to the protected amino acid ( 8c ) (R ⁹ = 3,3-difluoroallyl) (56 mg, 0.19 mmol, 1.1 equiv) in a 25 mL round bottom flask made by the general method M, followed by solid HATU (91.2 mg, 0.24 mmol, 1.3 equiv) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, poured into ethyl acetate (60 mL), washed with 10% citric acid (2 x 40 mL), water (40 mL), 50% saturated aqueous NaHCO ₃ (40 mL) and brine. . Organic layer over Na ₂ S0 ₄ Dry and evaporate to give yellow syrup.

To a solution of the crude coupling product in DCM with methylsulfide (0.2 mL) (9 mL) was 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 twice with toluene. The residue was purified by chromatography to give the title compound 4- (3,3-difluoroallyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6- Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (55.6 mg, 73%) was obtained as a white solid:

Example 2

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

The title compound of Example 2, 4- (3-pyridine-4), using the ylide derived from triphenyl (4-pyridylmethyl) phosphonum chloride in the Whitig olefination step shown in Scheme 8 -Yl-allyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydoxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -Amides were prepared according to the procedures described in Example 1 and General Method M. HPLC: C ₁₈ 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 minutes; 1.5 mL / min): R _t = 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) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide

Protected amino acid (8b) (R ⁹ = 3-pyridin-4-yl-propyl) after use of an lide derived from triphenyl (4-pyridylmethyl) phosphonum chloride in the Whitig olefination step shown in Scheme 8 , R ₂ = H), with reductive deprotection to give the title compound of Example 3, 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 was prepared according to the procedure described in Example 1 and General Method M. The desired final product was obtained by the coupling and deprotection procedure described in Example 1. HPLC: C ₁₈ 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 minutes; 1.5 mL / min): R _t = 2.99 min; MS (ESPOS): 466.4 [M + H] ⁺ ; MS (ESNEG): 468.3 [M ⁻ H] ⁻ , 502.4 [M + HCl] ⁻ .

 Example 4

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

N-Cbz- (2S), (4S)-(n-butylsulfanyl) pyrrole (9d) (P = Cbz, m = 1, R9 = n-butylsulfanyl).

The title intermediate was prepared according to general method N. In a stirred solution of intermediate (9b) (P = Cbz, m = 1, LG = Ts) (1.34 g, 3.08 mmol) in DMF (10 mL) under N ₂ , 1-butanethiol (0.7 mL, 6.16 mmol, 2 equivalents), followed by 7-methyl-1,5,7-triazacyclo [4.4.0] dec-5-ene (0.7 mL, 4.87 mmol, 1.6 equiv). After addition, the resulting mixture was stirred at rt for 18 h and then partitioned between EtOAc and H ₂ O. 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 give methyl ester (9c) (P = Cbz, m = 1, R ⁹ = n-butylthio) (470 mg, 44%). Obtained.

Methyl ester (9c) was treated with lithium hydroxide in 4: 1 THF / H ₂ O overnight. The pH of the reaction solution was adjusted to 3 with aqueous 1M HCl and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the product (9d) N-Cbz- (2S), (4S)-(n-butylthio) proline (463 mg, quantitative). ) Was obtained.

To a suspension of MTL (1a) (140 mg, 0.56 mmol, 1 equiv) in anhydrous DMF (2 mL) under N ₂ was added triethylamine (0.3 mL, 2.2 mmol, 3.9 equiv) followed by BSTFA (0.3 mL, 1.1 mmol, 2 equivalents) was added. The resulting mixture was stirred at 0 ° C. for 10 minutes, then at room temperature for 30 minutes and cooled to 0 ° C. Protected amino acids N-Cbz- (2S), (4S)-(n-butylthio) proline (218 mg, 0.64 mmol, 1.2 equiv) in anhydrous DMF (1 mL), followed by solid HATU (320 mg, 0.84 mmol) , 1.5 equiv) was added, the cooling bath was removed and stirred at rt for 2 h. The reaction mixture was evaporated under high vacuum, the residue obtained was diluted with ethanol acetate (150 mL), washed successively with 10% citric acid (2x50 mL), 0.5M saturated aqueous NaHCO ₃ (2x50 mL), brine (50 mL) , Dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The obtained persylated intermediate was treated with Doex® 50w-400 × H ⁺ form resin (Aldrich) (200 mg) in MeOH (60 mL) for 45 minutes, filtered and dried. Was evaporated to chromatography on silica (92: 8 DCM / methanol) to afford the desired Cbz protected lincosamide (185 mg, 61%).

To a stirred suspension of 10% Pd / C (200 mg) in anhydrous EtOH under nitrogen, 1,4-cyclohexadiene (2 mL) was added and after 10 minutes, the Cbz protected lincosamide in EtOH (6 mL) ( 178 mg, 0.33 mmol) was added. The resulting mixture was stirred and heated at reflux overnight. After cooling, the reaction mixture was filtered through a pad of celite, washed with ethanol, filtered, washed and evaporated to dryness. The obtained crude residue is chromatographed on silica (90: 9: 1 DCM / MeOH / concentrated ammonium hydroxide) to give the title compound which is placed in 1: 1 acetonitrile / water (4 mL) and acidified with 1M HCl. And lyophilized to give HCl salt (35 mg) as a colorless powder: MS (ESPOS): 439.3 [M + H] ⁺ , 461.2 [M + Na] ⁺ .

Example 5

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Using the sodium ethanethioleate in the alternative step shown in Scheme 9, the title compound of Example 5 was prepared according to General Method N. The desired final product was obtained by the coupling and deprotection procedure described in Example 4. MS (ESPOS): 412.6 [M + H] +.

Example 6

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Triphenylphosphonium dibromide was used to install 4- (S) bromide leaving group in compound (9b) (P = Cbz, m = 1, LG = Br) and sodium ethanethiol in the alternative step shown in Scheme 9. Using the rate, the title compound of Example 6 was prepared according to General Method N. The desired final product was obtained by the coupling and deprotection procedure described in Example 4. MS (ESPOS): 411.6 [M] ⁺ .

Example 7

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Triphenylphosphonium dibromide was used to install 4- (S) bromide leaving group in compound (9b) (P = Cbz, m = 1, LG = Br) and sodium ethanethiol in the alternative step shown in Scheme 9. Using the rate, the title compound of Example 7 was prepared according to General Method N. The desired final product was obtained by the coupling and deprotection procedure described in Example 4. MS (ESPOS): 429.1 [M + H] ⁺ ; MS (ESNEG): 427.6 [M ⁻ H] ⁻ , 463.6 [M + HCI] ⁻ .

Example 8

4-Ethylsulfanyl-pyrrolidin-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Using the sodium ethanethioleate in an alternative step shown in Scheme 9, the title compound of Example 8 was prepared according to General Method N. The desired final product was obtained by the coupling and deprotection procedure described in Example 4. MS (ESPOS): 429.1 [M + H] ⁺ .

Example 9

4- (4-Methyl-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Tosylate intermediate 14b (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14 in dry DMF (300 μL) under N ₂ (73.2 mg, 92 μmol) was added 4-methylbenzylthiol (lancaster) (63.0 μL, 0.46 mmol) followed by MTBU (33.6 μL, 0.23 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was placed in MeOH (1.5 mL), 0.5 M NaOMe in MeOH (920 μL, 9.2 mmol) was added and the reaction mixture was stirred at rt for 18 h, followed by a Dowex® resin bed (in water 3.3 mL). The resin was washed with methanol (5 x 10 mL), water (1 x 10 mL) and acetonitrile (2 x 10 mL), then the product was washed with MeOH (5 x 10 mL) and MeCN (1 x 10 mL). Eluted by washing with 5% concentrated NH ₄ OH. The combined washes were evaporated and subjected to preparative TLC (95: 5 MeOH: 0.25M NH ₃ / DCM) to give the title compound (25.0 mg, 56%) as a colorless solid: MS (ESPOS): 487.3 [M + H ] ⁺ ; HPLC: C ₁₈ 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 5 min: R _t = 1.91 min.

Example 10

4- (4-Fluoro-phenylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide

Example 10 by the procedure used in Example 9 from tosylate intermediate (14b) (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was 4-fluorothiophenol (Aldrich). MS (ESPOS): 477.3 [M + H] ⁺ .

Example 11

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

Example 11 by the procedure used in Example 9 from tosylate intermediate (14b) (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was 1,1,1-trifluoropropane thiol (Aldrich).

Example 12

4- (3-Methyl-butylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Example 12 by the procedure used in Example 9 from tosylate intermediate (14b) (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was 3-methylbutanethiol (Aldrich). MS (ESPOS): 453.3 [M + H] ⁺ ; HPLC: C ₁₈ 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 min: R _t = 3.90 min.

Example 13

4- (2,4-Dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide

Example 13 by the procedure used in Example 9 from tosylate intermediate 14b (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was 2,4-dichlorobenzyl thiol (mabridge). MS (ESPOS): 541.2 [M] ⁺ ; HPLC: _{Cl 8} 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 min: Rt = 4.383 min.

Example 14

4- (thiophen-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide

Example 14 by the procedure used in Example 9 from tosylate intermediate 14b (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was thiophen-2-yl methanethiol (Aldrich). MS (ESPOS): 479.2 [M + H] ⁺ ; HPLC: _{Cl 8} 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 min: Rt = 3.656 min.

Example 15

4- (Pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide

Example 14 by the procedure used in Example 9 from tosylate intermediate 14b (P = CF ₃ CO, m = 1, R ₂ = H, R ₃ = OAc) prepared in General Method R, Scheme 14. The title compound was prepared. The nucleophile used in the alternative step was 2-mercaptomethyl pyrazine (pyrazine specialty incorporated). The title compound of Example 15 was purified by preparative TLC (16% methanolic ammonia / dichloromethane) to give the product 4- (pyrazin-2-ylmethylsulfanyl) -pyrrolidine-2-carboxylic acid [2- Hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (9 mg, 15%) was obtained. MS (ESPOS): 475.5 [M + H] ⁺ ; 497.4 [M + Na] ⁺ .

Example 16

4- (2,4-Dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide

To a solution of compound 2b (R2 '= H) (100 mg, 0.40 mmol, 1 equiv) in dry DMF (1 mL) at 0 ° C. was added triethylamine (0.18 mL, 1.27 mmol, 3.2 equiv) , Bis (trimethylsilyl) trifluoroacetamide (0.16 mL, 0.60 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture, Boc protected amino acid (9d) (P = Boc, m = 1, R9 = 2,4-dichlorobenzylsulfide), HATU (302), prepared by the general method N (263 mg, 0.65 mmol, 1.63 equiv) mg, 0.80 mmol, 2 equiv) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness and taken up in ethyl acetate (150 mL) and washed with 10% citric acid (2 × 80 mL), water (80 mL), 50% saturated NaHCO ₃ (80 mL) and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to afford the desired Boc protected lincosamide as a yellow syrup.

To a solution of Boc protected lincosamide and methyl sulfide (0.33 mL) in DCM (15 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 twice with toluene. The residue was purified by chromatography to give a white solid (61 mg). The white solid was purified by preparative thin layer chromatography, and 4- (2,4-dichloro-benzylsulfanyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydr Roxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (47.5 mg, 22%) was obtained as a white solid:

Example 17

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Compound (9c) (P = Boc, m = 1, R ⁹ = n-butylsulfide).

N-butylthiol (1.30 mL) in a solution of tosylate (9b) (P = Boc, m = 1) (1.61 g, 4.03 mmol, 1 equiv) in dry DMF (12 mL) prepared by the general method N under N ₂ , 12.1 mmol, 3 equiv), and then 7-methyl-1,5,7-triazacyclocyclo- [4.4.0] deck-5-ene (MTBU) (0.87 mL, 6.05 mmol, 1.5 equiv) Was added. 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 give a clear oil (1.24 g, 97%):

Compound (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. 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 S0 ₄ and evaporated to give a clear oil (9c) (P = Boc, m = 1, R9 = n-butyl) ( 1.21 g, 100%) was obtained: MS (ESPOS): 204.4 [M-Boc + H] ⁺ , 326.4 [M + Na] ⁺ ; MS (ESNEG): 302.3 [M-H] ^- .

4-Butylsulfanyl-pyrrolidin-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -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 -(Trimethylsilyl) trifluoroacetamide (0.12 mL, 0.45 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture was added Boc protected amino acid 9c (P = Boc, m = 1, R9 = n-butylsulfide) (147 mg, 0.49 mmol, 1.63 equiv), HATU (227 mg, 0.60 mmol, 2 equiv) It was. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate (100 mL) and washed with 10% citric acid (2 × 60 mL), water (60 mL), 50% saturated NaHCO ₃ (60 mL) and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to give a yellow syrup.

To a solution of the syrup and methyl sulfide (0.33 mL) in DCM (15 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 twice with toluene. The residue was purified by chromatography to give 4-butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide (95 mg, 73%) was obtained as a white solid:

Example 18

4-azido-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

N-Boc- (2S, 4R) -4-methanesulfonylproline methyl ester (9b) (P = Boc, m = 1, LG = Ms).

N-Boc- (2S, 4R) -4-hydroxyproline methylester (bachem) (9a) (P = Boc, m = 1) in DCM (10 mL) prepared by the general method N (1 g, 4.0 mmol) Pyridine (1.64 mL, 20.0 mmol), methanesulfonyl chloride (0.631 mL, 5.52 mmol) was added, stirred at 0 ° C. for 2 h, and further stirred at rt overnight. More DCM (100 mL) was added, washed with HCl (IN, 50 mL) and the organic portion was dried over magnesium sulfate. Removal of solvent gave mesylate product (1.30 g, 100%) and used without further purification.

N-Boc- (2S, 4S) -4-azidoproline methyl ester (9c) (P = Boc, m = 1, R9 = azide).

N-Boc- (2S, 4R) -4-methanesulfonylproline methylester was placed in DMF (10 mL) added with sodium azide (1.30 g, 20.0 mmol) and heated at 75-80 ° C. overnight. DMF was removed and the product was extracted with ethyl acetate (100 mL) and washed with water (50 mL). Solvent was removed to give azide product 9c (P = Boc, m = 1, R9 = azide) (0.98 g, 90%).

Compound (9d) (P = Boc, m = 1, R9 = azide).

A stirred solution of compound 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. 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 solvent gave protected amino acid N-Boc- (2S, 4S) -4-azidoproline (9d) (P = Boc, m = 1, R9 = azide) (0.8 g, 88%):

1- (2- (S) -4- (S)-(azido) -N-pyrrolidin-2-yl- {1- (R)-[2- (S), 3- (S), 4- (S), 5- (R) -Trihydroxy-6- (R)-(methylsulfanyl) tetrahydropyran-2-yl] -2-hydroxy-prop-1-yl} aceta Amide.

Triethylamine (0.164 mL, 1.18 mmol) and bis- (trimethylsilyl) trifluoroacetamide (0.93 mL, 3.94 mmol) in compound (2b) (R9 '= H) in DMF (5 mL) at 0 ° C. After addition, it was stirred overnight at room temperature. Thereafter, N-Boc- (2S, 4S) -4-azidoproline (300 mg, 1.18 mmol) and HATU (444 mg, 1.18 mmol) were added at 0 ° C., followed by stirring for 4 hours. Finally, 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 give the crude product which was used in the next deprotection step. 30% trifluoroacetic acid (10 mL) and dimethylsulfide (0.5 mL) were added to the crude product in dichloroethane and the reaction mixture was stirred for 1 hour. The solvent was removed and the crude product obtained was chromatographed on silica gel column with 20% methanol in DCM to afford the title compound as a white solid (278 mg, 90%): TLC: R _f = 0.38 (DCM 40% methanol);

Example 19

4- [3- (Furan-2-ylmethylsulfanyl) -prop-1-yl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

4- (3-hydroxy-propyl) -2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl ] -Piperidine-1-carboxylic acid tert-butyl ester.

To a mixture of (2b) (R ^{2 ′} = H) (532 mg, 1.85 mmol, 1 equiv) in dry DMF (4.5 mL) at 0 ° C. was added triethylamine (1.28 mL, 9.25 mmol, 5 equiv) , Bis- (trimethylsilyl) trifluoroacetamide (0.74 mL, 2.78 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. Boc protected amino acid (11f) (R ^{9 ′} = 3-t-butyldimethylsiloxypropyl, P = Boc) (741 mg, 1.85 mmol, 1.0 equiv) and HATU (886) prepared by the general method P in the reaction mixture. mg, 2.33 mmol, 1.26 equiv) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate and washed with 10% citric acid (1 ×), water (1 ×), saturated NaHCO ₃ (1 ×) and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to give a yellow syrup. The residue was taken up in methanol (20 mL) and then Dox® resin (340 mg) was added. The mixture was stirred at room temperature for 1 hour and the resin was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography to give the product 4- (3-hydroxy-propyl) -2- [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester (694 mg, 72%) was obtained as a white solid:

2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) propylcarbamoyl] -4- [3- (toluene-4- Sulfonyloxy) -propyl] -piperidine-1-carboxylic acid tert-butyl ester.

4- (3-hydroxy-propyl) -2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran in DCM (1.5 mL) at 0 ° C. -2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester (196 mg, 0.38 mmol, 1 equiv) and p-toluenesulfone anhydride (123 mg, 0.38 mmol, 1 equiv) Triethylamine (63 μL, 0.45 mmol, 1.2 equiv) was added dropwise to the solution. The reaction mixture was stirred at 0 ° C. for 5 hours and then diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried and concentrated to give a white solid, which was purified by chromatography to give 11 h (147.5 mg, 58%) as a white solid:

4- [3- (furan-2-ylmethylsulfanyl) -propyl] -2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester.

Boc protected tosylate 2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) in dry DMF (0.42 mL) under N ₂ In a solution of -propylcarbamoyl] -4- [3- (toluene-4-sulfonyloxy) -propyl] -piperidine-1-carboxylic acid tert-butyl ester (91 mg, 0.13 mmol, 1 equiv) After addition of furyl mercaptan (68 μL, 0.67 mmol, 5 equiv), 7-methyl-1,5,7-triazacyclo- [4.4.0] dec-5-ene (MTBU) (48 μL, 0.33 mmol, 2.5 equiv) was added. The reaction mixture was stirred at rt overnight, diluted with DCM, washed with brine (3 ×), dried and concentrated. The residue was purified by preparative TLC (8% MeOH / DCM) to give the desired Boc protected thioether 4- [3- (furan-2-ylmethylsulfanyl) -propyl] -2- [2-methyl- 1- (3,4,5-Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester (63.3 mg, 76%) was obtained as a clear syrup: MS (ESPOS): 617.9 [M + H] ⁺ .

Boc protected thioether 4- [3- (furan-2-ylmethylsulfanyl) -propyl] -2- [2-methyl-1- (3,4,5-trihydroxy) in DCM (9 mL) -6-Methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid (3 mL) in a solution of methyl sulfide (0.2 mL) mL) and water (0.2 mL) were added. The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and co-evaporated twice with toluene. The residue was purified by preparative TLC to give the title lincosamide product (13 mg, 25%) for Example 19 as a white solid:

Example 20

4- (3-Imidazol-1-yl-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl -Tetrahydro-pyran-2-yl) -propyl] -amide

4- (3-imidazol-1-yl-prop-1-yl) -2- [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester.

To a mixture of NaH (60%, 11.9 mg, 0.30 mmol, 2 equiv) in dry DMF (0.2 mL) at 0 ° C. was added dropwise a solution of imidazole (40.4 mg, 0.60 mmol, 4 equiv) in DMF (0.25 mL). . The mixture was stirred at 0 ° C for 10 minutes and then cooled to -78 ° C. To the mixture was added dropwise a solution of Boc protected tosylate (100 mg, 0.15 mmol, 1 equiv) in dry DMF (0.4 mL) prepared in Example 19. The mixture was stirred at 0 ° C. for 2 hours and then at room temperature overnight. The reaction mixture was diluted with DCM, washed with brine (3 x), dried and concentrated. The residue was purified by chromatography to give the title Boc protected imidazole compound (60 mg, 71%) as a white solid. MS (ESPOS): 571.8 [M + H] ⁺ .

To a solution of the Boc protected imidazole and methyl sulfide (0.2 mL) in DCM (9 mL) was 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 twice with toluene. The residue was purified by chromatography to give the title lincosamide compound (10 mg, 20%) in Example 20 as a white solid:

Example 21

4- [3- (thiophen-2-ylsulfanyl) -prop-1-yl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

4- [3- (thiophen-2-ylsulfanyl) -prop-1-yl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.

To a solution of protected tosylate (97 mg, 0.14 mmol, 1 equiv) in dry DMF (0.42 mL) prepared in Example 19 under N ₂ , 2-thienyl mercaptan (across) (68 μL, 0.72 mmol, 5 7-methyl-1,5,7-triazacyclocyclo- [4.4.0] dec-5-ene (MTBU) (51.3 μL, 0.36 mmol, 2.5 equiv) was added. The reaction mixture was stirred at rt overnight, diluted with DCM, washed with brine (3 ×), dried and concentrated. The residue was purified by preparative TLC (8% MeOH / DCM) to give a clear syrup (65.5 mg, 74%): MS (ESPOS): 619.8 [M + H] ⁺ .

To a solution of the syrup and methyl sulfide (0.2 mL) in DCM (9 mL) was 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 twice with toluene. The residue was purified by preparative TLC to give the title lincosamide compound (16 mg, 29%) in Example 21 as a white solid;

Example 22

4- (3-Ethylsulfanyl-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide

The title compound of Example 22 was prepared from the protected tosylate intermediate prepared in Example 19 according to the procedure used in Examples 19-21 using sodium ethanethioleate in an alternative step: MS (ESPOS): 465.3 [M + H] ⁺ .

Example 23

4- (3-Cyano-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide

The title compound of Example 23 was prepared from the protected tosylate intermediate (11h) prepared in Example 19 according to the procedure used in Examples 19-21 using sodium cyanide nucleophile in an alternative step; MS (ESPOS): 430.3 [M + H] +.

Example 24

4- (3-Difluoromethylsulfanyl-prop-1-yl) piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyltetra Hydro-pyran-2-yl) -propyl] -amide

Compound (11c) (R ^{9 ′} = 3-hydroxy-propine).

4-iodopicolinate methyl ester (11b) (4.36 g, 16.5 mmol, 1 equiv), triphenylphosphine (346 mg, 1.32 mmol, 0.08 equiv), copper iodide in triethylamine (60 mL) at 23 ° C (251 mg, 1.32 mmol, 0.08 equiv), to a mixture of palladium acetate (148 mg, 0.66 mmol, 0.04 equiv) was added propargyl alcohol (1.92 mL, 33.0 mmol, 2 equiv) and the reaction mixture at 23 ° C. Stir overnight. The reaction mixture was concentrated under high vacuum and the black residue was purified by column chromatography (2% MeOH in methylene chloride) to give a brown oil. The brown oil was purified again by column chromatography to give the desired product 11c (R ^{9 ′} = 3-hydroxy-1-propane) as a yellow oil (3.0 g, 95%):

HPLC: (Symmetry C ₁₈ 3.5 μm, 4.6 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): Rt = 1.42 min.

Compound (11c) (R ^{9 '} = 3-hydroxy-propyl).

Pd (OH) on 20 wt% carbon in a solution of compound 11c (R ^{9 ′} = 3-hydroxy-1-propine) (2.0 g, 10.5 mmol, 1.0 equiv) in MeOH (120 mL) at 23 ° C. ₂ (1.0 g) was added and the reaction mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated to give the desired product 4- (3-hydroxy-propyl) -pyridine-2-carboxylic acid methyl ester (11c) (R ^{9 '} = 3-hydroxy-propyl) ( 2.03 g, 99%) was obtained as a yellow oil:

HPLC: (Symmetry C ₁₈ 3.5 μm, 4.6 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): Rt = 1.46 min.

Compound (11d) (R ^{9 '} = 3-hydroxy-propyl).

4- (3-hydroxy-propyl) -pyridine-2-carboxylic acid methyl ester (11c) (R ^{9 '} = 1-hydroxypropyl) in MeOH (30 mL) and H ₂ 0 (20 mL) at 23 ° C. To a solution of 1.81 g, 9.28 mmol, 1.0 equiv) was added concentrated HCl (412 L, 11.1 mmol, 1.2 equiv), followed by platinum (IV) oxide (600 mg, 0.33 wt%) and the reaction mixture was hydrogen Stirring vigorously for 48 hours at 1 atmosphere under atmospheric pressure. The reaction mixture was filtered through celite and washed with methanol (200 mL). The combined filtrates were concentrated under reduced pressure to afford the desired product 11d (R ^{9 ′} = 3-hydroxy-propyl) as an HCl salt (2.02 g, 8. 52 mmol, 91%): MS (ESPOS): 202.2 [M + H] ⁺ .

Compound (11e) (R ^{9 '} = 3-hydroxy-propyl, P = Cbz).

Triethylamine (1.54 mL, 11.07 mmol, in a solution of (11d) (R ^{9 ′} = 3-hydroxy-propyl) (2.02 g, 8.52 mmol, 1 equiv) in dichloromethane (50 mL) at 5 ° C. 1.3 equiv) was added and the reaction mixture was stirred for 10 min. Benzylchloroformate (1.55 mL, 11.07 mmol, 1.3 equiv) was added to this solution, and the reaction mixture was stirred at 5 ° C. for 1 hour, 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 ₄ and concentrated. The residue was purified by column chromatography (50% to 75% EtOAc / hexanes gradient) to give the desired product (11e) (R ^{9 '} = 3-hydroxy-propyl, P = Cbz) (2.28 g, 6.80 mmol, 80%) was obtained as a yellow oil:

HPLC: (Symmetry C ₁₈ 3.5 μm, 4.6 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): Rt = 2.50 min.

Compound (11e) (R ^{9 '} = 3-methanesulfonylpropyl, P = Cbz)

Alcohol Intermediate (11e) (R ^{9 '} = 3-hydroxy-propyl, P = Cbz) (2.0 g, 5.97 mmol, 1 equiv) prepared by General Method P in dichloromethane (15 mL) at 0 ° C. To the solution of triethylamine (1.0 mL 7.2 mmol, 1.2 equiv) was added and the reaction mixture was stirred for 15 minutes. To this solution methanesulfone anhydride (1.04 g, 5.97 mmol, 1 equiv) was added and the reaction mixture was stirred at 0 ° C. for an additional 30 minutes. The reaction mixture was partitioned between dichloromethane (250 mL) and saturated aqueous NaHCO ₃ (100 mL). The organic layer was collected, dried over Na ₂ S0 ₄ and concentrated to give the desired mesylate product 11e (R ^{9 '} = 3-methanesulfonylpropyl, P = Cbz) (2.25 g, 5.45 mmol, 91% ) Was obtained as a clear oil:

HPLC (Symmetry® _{Cl 8} 3.5 μm, 4.6 × 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): Rt = 2.86 min.

Compound (11e) (R ^{9 '} = 3-acetylsulfanyl-propyl, P = Cbz)

Potassium thioacetate (3.11 g, in a solution of mesylate (11e) (R ^{9 ′} = 3-methanesulfonylpropyl, P = Cbz) (2.25 g, 5.45 mmol, 1 equiv) in DMF (30 mL) at 5 ° C. 27.3 mmol, 5 equiv) was added and the reaction mixture was stirred at 5 ° C. overnight. The reaction mixture was partitioned between EtOAc (250 mL) and saturated aqueous NaHCO ₃ (100 mL). The organic layer was collected, dried over Na ₂ SO ₄ and concentrated. The crude product obtained was purified by column chromatography (25% EtOAc in hexanes). The desired thioester product 11e (R ^{9 '} = 3-acetylsulfanyl-propyl, P = Cbz) (1.90 g, 4.83 mmol, 89%) was obtained as a yellow oil:

HPLC (Symmetry® C ₁₈ 3.5 μm, 4.6 × 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): retention time = 3.28 min.

Compound (11f) (R ^{9 '} = 3-difluoromethylsulfanyl-propyl, P = Cbz).

To a solution of compound 11e (R ^{9 ′} = 3-acetylsulfanyl-propyl, P = Cbz) (1.90 g, 4.83 mmol, 1 equiv) in ethanol (8 mL) was added 3N NaOH (4.5 mL). The reaction mixture was stirred at room temperature for 45 minutes and then concentrated to give a clear oil. The resulting oil is dissolved in ethanol (20 mL), the reaction mixture is de-oxygenated via evacuation of the reaction flask, and then the reaction mixture is saturated with chlorodifluoromethane gas (Aldrich) at 1 atmosphere pressure. I was. The reaction mixture was stirred at 5 ° C. for 16 h, then neutralized with 1N HCl at 0 ° C. and concentrated under reduced pressure. The residue was made basic with 0.5N aqueous NaOH and washed with ether. The aqueous layer was acidified to pH 2.0 with 1N HCl and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (2 x 100 mL), dried (MgSO ₄ ) and concentrated. The crude residue obtained was purified by column chromatography (50% EtOAc / 49% hexane / 1% AcOH) to give the desired difluoromethyl sulfide product (11f) (R ^{9 ′} = 3-difluoromethylsulfan). Yl-propyl, P = Cbz) (0.75 g, 1.94 mmol, 40%) was obtained as a clear oil:

HPLC (Symmetry® C ₁₈ 3.5 μm, 4.6 × 30 mm column; gradient eluent 2% -98% MeCN 5 min; 1.5 mL / min): Rt = 2.85 min.

Compound (11f) (R ^{9 '} = 3-difluoromethylsulfanyl-propyl, P = Boc).

To the solution (750 mg, 1.94 mmol, 1 equiv) in acetonitrile (100 mL) at 23 ° C. is added iodotrimethylsilane (0.8 mL, 5.81 mmol, 3 equiv) and the reaction mixture is stirred for 30 minutes It was. The reaction mixture was concentrated to give deprotected crude product (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 (Na ₂ SO ₄ ) and concentrated. The crude residue obtained was purified by column chromatography (50: 49: 1 EtOAc / hexanes / AcOH) to give the desired product (11f) (R ^{9 ′} = 3-difluoromethylsulfanyl-propyl, P = Boc ) (671 mg, 98%) was obtained as a clear oil:

4- (3-Difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide.

Diisopropylethylamine (0.3) in a stirred solution of 7-Cl-MTL (6b) (R ² = H, R ³ = Cl) (195 mg, 0.68 mmol, 1.2 equiv) in DMF (2.5 mL) at 23 ° C. mL, 1.71 mmol, 3 equiv), followed by Boc protected amino acid (11f) (R ^{9 ′} = 3-difluoromethylsulfanyl-propyl, P = Boc) in DMF (2.5 mL) (200 mg, 0.57 mmol, 1 equiv) of solution and HBTU (324 mg, 0.95 mmol, 1.5 equiv) were added. The resulting solution was stirred at room temperature for 3 hours and 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 (Na ₂ SO ₄ ) and concentrated. To 23 ° C. (60 mg, 0.12 mmol, 1 equiv) was added 1,2-dichloroethane (5 mL) and water (0.2 mL) at 23 ° C., followed by neat TFA (2.0 mL). The reaction mixture was added and stirred at room temperature for 15 minutes, then concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound in Example 24 as white powder:

Example 25

4- (3-Difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide

4- (3-Difluoromethylsulfanyl-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide.

To a stirred solution of (2b) (R ^{2 ′} = H) in DMF (2.5 mL) at 23 ° C. was added diisopropylethylamine (0.3 mL, 1.7 mmol, 3 equiv) and then in DMF (2.5 mL). A solution of Boc protected amino acid (11f) (R ^{9 ′} = 3-difluoromethylsulfanyl-propyl, P = Boc) (200 mg, 0.57 mmol, 1 equiv) and HBTU were added. The resulting solution was stirred at rt for 3 h and concentrated to dryness. The solid residue was partitioned between ethyl acetate (300 mL) and saturated aqueous NaHCO ₃ . The organic layer was collected, dried (Na ₂ SO ₄ ) and concentrated. To 23 parts 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 the addition of neat TFA (2.0 mL), The reaction mixture was stirred at rt for 15 min and then concentrated. The crude product was purified by preparative HPLC to afford the desired title compound in Example 25 as a white powder:

Example 26

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

4- (3,3-Diethoxy-prop-1-ynyl) -pyridine-2-carboxylic acid methyl ester.

Intermediate (11b) (2.98 g, 11.33 mmol, 1 equiv), triphenylphosphine (238 mg, 0.91 mmol, 0.08 equiv), copper (I) iodide (172.6 mg) prepared by the general method P in a dry flask , 0.91 mmol, 0.08 equiv), palladium acetate (101.6 mg, 0.45 mmol, 0.04 equiv) and triethylamine (42 mL) were added. The mixture was degassed with nitrogen and then 3,3-diethoxy-propane (Aldrich) (2.90 g, 22.7 mmol, 2 equiv) was added. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield a dark colored residue. The residue was purified by chromatography to give yellow oil 11e (R ^{9 '} = 3,3-diethoxy-prop-1-ynyl) (3 g, 100%):

4- (3,3-Diethoxy-1-propyl) -piperidine-1,2-dicarboxylic acid 2-methyl ester (11d) (R ^{9 '} = 3,3-diethoxy-1-propyl) .

Oxidized to a mixture of (11c) (R ^{9 ′} = 3,3-diethoxy-prop-1-ynyl) (3 g), acetic acid (15 mL) and water (15 mL) in MeOH (15 mL). Platinum (1.0 g) was added. The mixture was purged, filled with hydrogen (50 psi) and shaken for 5 hours at room temperature. Platinum oxide was removed by filtration and the filtrate was concentrated to give the desired product 11d (R ^{9 ′} = 3,3-diethoxy-1-propyl) (2.45 g, 79%) as an oil: MS (ESPOS): 296.5 [M + Na] ⁺ .

4- (3,3-Diethoxy-1-propyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester 2-methyl ester (11e) (R ^{9 '} = 3,3-diethoxy- 1-propyl, P = Alloc).

(11d) (R ^{9 '} = 3,3-diethoxy-1-propyl) (2.4 g, 8.79 mmol, 1 equiv) and pyridine (1.26 mL, 11.9 mmol, 1.35 equiv) in THF (29 mL) at 0 ° C To a solution of) allyl chloroformate (0.96 mL, 11.9 mmol, 1.4 equiv) was added dropwise. The mixture was slowly warmed up to room temperature and stirred at room temperature for 3 hours. The solution was filtered and the solvent removed in vacuo. The residue was purified by chromatography to give (11e) (R ^{9 '} = 3,3-diethoxy-1-propyl, P = Alloc) (2.1 g, 66%) as a clear oil: MS (ESPOS) : 380.6 [M + Na] ⁺ .

4- (3-Oxo-propyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester 2-methyl ester.

A solution of (11e) (R ^{9 '} = 3,3-diethoxy-1-propyl, P = Alloc) (2.03 g) in acetic acid (32 mL) and water (8 mL) was stirred overnight at room temperature. The solvent was removed under high vacuum. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate (1 x) and brine (1 x). The organic layer was dried and concentrated. The residue was purified by chromatography to give methyl ester 11e (R ^{9 '} = 3-oxo-propyl, P = Alloc) (1.2 g, 75%) as a clear oil:

4- (2- [1,3] dithiolan-2-yl-ethyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester-methyl ester.

Compound of compound 11e (R9 ′ = 3-oxopropyl, P = Alloc) (248 mg, 0.87 mmol, 1 equiv) and 1,2-ethanedithiol (0.147 mL, 1.75 mmol, 2 equiv) under nitrogen Boron trichloride-acetic acid complex (0.122 mL, 0.87 mmol, 1 equiv) was added to the mixture. The mixture was stirred vigorously for 1 hour. The mixture was diluted with hexanes 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 (11e) (R ^{9 '} = 2- [1,3] dithiolan-2-yl-ethyl, P = Alloc) (144 mg, 46%) as an oil: MS (ESPOS): 382.5 [M + Na] ⁺ .

4- (2- [1,3] dithiolan-2-yl-ethyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester (11f) (R ^{9 '} = (2- [1,3] Dithiolan-2-yl-ethyl), P = Alloc).

(11e) (R ^{9 '} = 2- [1,3] dithiolan-2-yl-ethyl, P = Alloc) (144 mg, 0.40 mmol, 1 equiv) in THF (3 mL) and water (1 mL) To the mixture was added lithium hydroxide monohydrate (67 mg, 1.6 mmol, 4 equiv). The mixture was stirred at rt overnight. THF was removed under vacuum. The aqueous layer was placed in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1 ×), brine (1 ×), dried and concentrated to (11f) (R ^{9 ′} = (2- [l, 3] dithiolan-2-yl-ethyl), P = Alloc) (127 mg, 92%) was obtained as a syrup:

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.

To a mixture of (2b) (R ^{2 ′} = H) (95 mg, 0.33 mmol, 1 equiv) in dry DMF (0.8 mL) at 0 ° C. was added triethylamine (0.23 mL, 1.65 mmol, 5 equiv) , Bis (trimethylsilyl) trifluoroacetamide (0.13 mL, 0.49 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture was added acid (11f) (R ^{9 '} = 2- [1,3] dithiolan-2-yl-ethyl, P = Alloc) (115 mg, 0.33 mmol, 1.0 equiv) and HATU (158 mg, 0.42 mmol). , 1.3 equivalents) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate and washed with 10% citric acid (1 ×), water (1 ×), saturated NaHCO ₃ (1 ×) and brine. The organic layer was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by chromatography to give an Alloc protected lincosamide analog (133 mg, 70%) as syrup: MS (ESPOS): 579.8 [M + H] ⁺ .

Dimedone (0.25 g, 1.78 mmol, 10 equiv) and tetrakis- (triphenylphosphine) in a solution of the Alloc protected lincosamide (103 mg, 0.18 mmol, 1 equiv) in THF (2.3 mL) ) Palladium (41.1 mg, 0.036 mmol, 0.2 equiv) was added. 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 (34 mg, 49%) of Example 27 as a light yellow solid:

Example 27

Example 27 none.

Example 28

4- [2- (4-Methyl-thiazol-2-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan Yl-tetrahydro-pyran-2-yl) -propyl] -amide

4- [2- (4-Methyl-thiazol-2-yl) -ethyl] -piperidine-1,2-dicarboxylic acid 1-allyl ester (11f) (R ^{9 '} = 4-methyl-thiazole- 2-day, P = Alloc).

This intermediate was prepared from intermediate (11b) using 4-tert-butoxycarbonylethyne (Aldrich) as the alkane, using the reaction procedure described in General Method P, Scheme 11. The 4-methyl thiazole moiety was attached to the protected dicarboxylic acid 11e (R ^{9 '} = propionic acid tert-butylester, P = Alloc) by methods known to those skilled in the art. Ester deprotection as carried out in general method P afforded the desired carboxylate intermediate 11f (R ^{9 ′} = 4-methyl-thiazol-2-yl, P = Alloc).

4- [2- (4-Methyl-thiazol-2-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfan Yl-tetrahydro-pyran-2-yl) -propyl] -amide.

Couple of Compound (2b) (R ^{2 ′} = H) with protected amino acid (11f) (R ^{9 ′} = 4-methyl-thiazol-2-yl, P = Alloc) by the procedure described in Example 26. Ring and deprotection were performed to give the title lincosamide of Example 28:

Example 29

4- (3-methoxyimino-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide

Compound 11e (R ^{9 '} = 3-methoxyimino-propyl, P = Alloc).

To a solution of compound 11e (R ^{9 ′} = 3-oxopropyl, P = Alloc) (129 mg, 0.45 mmol) prepared in Example 26 in ethanol (1.3 mL) was added methoxylamine hydrochloride and pyridine. . The reaction mixture was refluxed for 2 hours. Solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with 10% citric acid and brine, dried and concentrated to give compound 11e (R ^{9 '} = 3-methoxyimino-propyl, P = Alloc) (129 mg, 91%). Was obtained as a clear oil: MS (ESPOS): 334.5 [M + Na] ⁺ .

4- (3-methoxyimino-propyl) -piperidine-1,2-dicarboxylic acid 1-allyl ester (11f) (R ^{9 ′} = 3-methoxyimino-propyl, P = Alloc).

Lithium hydroxide monohydrate in a mixture of ester (11e) (R ^{9 '} = 3-methoxyimino-propyl, P = Alloc) (129 mg, 0.41 mmol, 1 equiv) in THF (1.5 mL) and water (0.5 mL) (69 mg, 1.6 mmol, 4 equiv) was added. The mixture was stirred at rt overnight. THF was removed under vacuum. The aqueous layer was placed in ethyl acetate and partitioned with 10% citric acid. The organic layer was washed with water (1 x), brine (1 x), dried and concentrated to (11f) (R ^{9 '} = 3-methoxyimino-propyl, P = Alloc) (114 mg, 93%). Was obtained as a clear oil:

4- (3-methoxyimino-propyl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2- Yl) -propyl] -amide.

To a mixture of (2b) (R ^{2 ′} = H) (109.8 mg, 0.38 mmol, 1 equiv) in dry DMF (0.9 mL) at 0 ° C. was added triethylamine (0.26 mL, 1.91 mmol, 5 equiv) , Bis (trimethylsilyl) trifluoroacetamide (0.15 mL, 0.57 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture was added protected amino acid (11f) (R ^{9 '} = 3-methoxyimino-propyl, P = Alloc) (113.6 mg, 0.38 mmol, 1.0 equiv) and HATU (182 mg, 0.48 mmol, 1.26 equiv) It was. The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate and washed with 10% citric acid (1 x), water (1 x), saturated 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 give the Alloc protected lincosamide product (107 mg, 53%): MS (ESPOS): 532.4 [M + H] ⁺ .

To a mixture of the Alloc protected lincosamide (107 mg, 0.20 mmol, 1 equiv) in THF (2.6 mL) dimethone (282 mg, 2.01 mmol, 10 equiv) and tetrakis (triphenylphosphine) palladium ( 46.5 mg, 0.04 mmol, 0.2 equiv.) Was added. 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 (28 mg, 31%) of Example 29 as a white solid:

Example 30

4- (3-Ethoxyimino-prop-1-yl) -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro -Pyran-2-yl) -propyl] -amide

Substituted ethoxylamine hydrochloride in the imine formation step to synthesize the title compound of Example 30 from intermediate (11e) (R ^{9 ′} = 3-oxopropyl, P = Alloc) as described in Example 29: MS (ESPOS): 462.4 [M + H] ⁺ .

Example 31

4- [2- (5-ethyl-isoxazol-3-yl) -ethyl] -piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.

Substituting hydroxylamine hydrochloride in the imine formation step synthesized the title compound of Example 31 from intermediate (11e) (R ^{9 '} = 3-oxopropyl, P = Alloc) as described in Example 29 (11e) (R ^{9 '} = 3-hydroxyimino-propyl, P = Alloc) was obtained. Ixoxazole heterocycle was attached to intermediate (11e) (R ^{9 ′} = 3-hydroxyimino-propyl, P = Alloc) by ring addition of 1-butane in the presence of N-chlorosuccinimide and TEA. . Coupling and deprotection was performed as described in Example 29: MS (ESPOS): 486.3 [M + H] ⁺ .

Example 32

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile] -amides:

4-position stereoisomer I and 4-position stereoisomer II

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide (stereoisomer 4 (high Rf) and stereoisomer II (low Rf)).

Boc protected amino acid (12d) (P = Boc, R ⁹ = propyl, m = 1) (310 mg, 1. 15, in DMF (3 mL) prepared by General Method Q in the synthetic sequence shown in Scheme 12 at 0 ° C. To a solution of mmol) add 7-Cl MTL (6b) (R ² = H, R ³ = Cl) (306 mg, 1.15 mmol), HBTU (469 mg, 1.3 mmol) and DIEA (290 μL, 2.3 mmol), Stir overnight at room temperature. The DMF was removed by rotary evaporation under high vacuum. The residue obtained was purified on silica gel column chromatography (3% MeOH in DCM) to afford the desired Boc protected 4-F lincosamide (451 mg, 75%) as light brown oil:

To a solution of the Boc protected 4-fluoro lincosamide (451 mg, 0.85 mmol) in DCE (6 mL) was added triethylsilane (0.16 mL), TFA (2 mL) and water and for 1.5 hours at room temperature. Stirred. The reaction solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography using 10% MeOH in DCM as eluent to give the title compound of Example 32, Stereoisomer I (high TLC Rf):

 And stereoisomer II (low TLC Rf)

Obtained.

Example 33

4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile]-amide

4-Fluoro-4-propyl-piperidine-1,2-dicarboxylic acid tert-butyl ester (12d) (P = Boc, R ⁹ = n-propyl, m = 2).

4-fluoro amino acid (12d) Boc protected from starting material (2S) -4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester using general method Q shown in Scheme 12 Was synthesized. The preparation of starting material (2S) -4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester is described in Bousquet, Y .; Anderson, P. C .; Bogri, T .; Duceppe J .; Grenier, L .; Guse, I .; Tetrahedron, 1997, 53 15671-15680.

4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester (12a) (m = 2, P = H, P ₂ = Boc) in DMF (200 mL) (16.0 g, 0.066 mol) ) (Prepared by the method described by Bousquet et al. Tetrahedron, 1997, 53, 15671) was prepared using 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 hours, diluted with EtOAc, extracted with saturated aqueous sodium bicarbonate, 10% aqueous citric acid and brine, the organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. . The product obtained by removing the solvent was azeotropically dried by evaporation from dry benzene to give 14.8 g (98%) of the desired product 4-oxo-piperidine-1,2-dicarboxylic acid 1- Tert-Butyl ester 2-methyl ester 12a (m = 2, P = Me, P ₂ = Boc) was obtained as an oil: TLC R _f 0.53 (hexane / EtOAc, 1: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 5. 33 (broad m, 0.5) rotamers, 5.06 (broad m, 0.5) rotamers, 4.31-4.19 (m, 1), 3.95 (s, 3), 3.95-3.70 (m, 1), 3.16-2.97 (m , 2), 2.71 (m, 2), 1.68 (broad s, 9).

4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester 2-methyl ester (12a) in DCM (60 mL) (m = 2, P = Me, P ₂ = Boc) (5.17 g, 0.02 mol) of a 0 ° C. stirred solution was treated with tetraallyltin (Aldrich) (5.3 mL, 0.022 mol) followed by the dropwise addition of BF ₃ · OEt ₂ (2.5 mL, 0.02 mol). The reaction mixture was stirred for 1 hour, then aqueous 1M potassium fluoride (38.0 mL) and celite (5 g) were added and the reaction mixture was stirred for 3 hours. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM, washed with water and brine, dried over MgSO ₄ and evaporated to dryness. The residue obtained was purified by silica gel column chromatography (DCM 100% to DCM: Acetone 9: 1) to give 3.85 g (64%) of the desired product 4-allyl-4-hydroxy-piperidine-1. , 2-Dicarboxylic acid 1-3-butyl ester 2-methyl ester (12b) (m = 2, P = Me, P ₂ = Boc, R ^{9 '} = allyl) was obtained as an oil.

1 H NMR (300 MHz, CDCl ₃ ) δ 6.11-5.97 (m, 1), 5.42-5.32 (m, 2), 5.06 (broad d, J = 6.0, 0.5) rotamers, 4.87 (broad d, J = 6.0 , 0.5) rotamers, 4.18-4.03 (m, 1), 3.93 (s, 3), 2.48-2.37 (m, 2), 1.98-1.43 (m, 11); MS (ESPOS) 322.0 [M + Na] ⁺ .

Compound 12b (m-2, P-Me, P ₂ -Boc, R ^{9 ′} = allyl) (3. 80 mL, 1.27 mmol) and 10% Pd / C in MeOH (80 mL) under 1 atmosphere of hydrogen A stirred suspension of (Degussa wet form 50% w / w) (1.35 g, 1.3 mmol) was stirred for 6 hours. The reaction mixture was filtered through celite, evaporated to dryness, azeotropically dried by evaporation from toluene and the residue obtained (3.15 g) was used in the next step without further purification.

To a stirred -78 ° C solution of DAST (1.7 mL, 1.3 mmol) in DCM (50 mL) 4-hydroxy-4-propyl-piperidine-1,2-dicarboxylic acid 1-3 in DCM (30 mL) Quat-butyl ester 2-methyl ester was added. The reaction mixture was then stirred for 1 hour and then warmed at -40 ° C for 5 hours. Additional DAST (0.4 mL) was added and the reaction mixture was stirred for an additional 2 hours, saturated aqueous K ₂ CO ₃ (20 mL) and water (60 mL) were added followed by diethyl ether (500 mL) The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting fluorinated crude product was purified by silica gel column chromatography (hexane-EtOAc 9: 1). The residue obtained by chromatography purification was dissolved in dioxane (65 mL) and water (26 mL), cooled to 0 ° C., Os0 ₄ (0.65 mL, 4% aqueous solution) and 30% H ₂ 0 ₂ (10 mL). The reaction mixture is stirred, concentrated to dry overnight, the residue is dissolved in DCM and the organic layer is washed with water (100 mL), 25% aqueous Na ₂ SO ₃ (2x100 mL) and brine (100 mL). Dried over Na ₂ SO ₄ and evaporated to dryness. The obtained residue was purified by silica gel column chromatography (hexane-EtOAc 9: 1) to give the desired product 4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid 1-3- Butyl ester 2-methyl ester (12c) (m = 2, P = Me, P ₂ = Boc, R ⁹ = n-propyl) (1.08 g, 34%) was obtained as an oil.

The synthesis of the title compound of Example 33 from compound 12d (P = Boc, R ⁹ = n-propyl, m = 2) can be readily carried out using the coupling and deprotection conditions in Example 32. have.

MS (ESPOS): 443.1 [M + H] ⁺ ; HPLC: C ₁₈ 3.5 μm, 4.6 × 30 mm column; Gradient eluent 2% -98% MeCN for 10 minutes; 1.5 mL / min): R _t = 3.738 min.

Example 34

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide.

A stirred suspension of compound 12d (P = Boc, R ⁹ = C ₃ H ₇ , m = 1) (164 mg, 0.57 mmol) prepared by General Method Q shown in Scheme 12 was dried with acetonitrile ( 4 mL). Triethylamine (332 μL, 3.02 mmol) was added and the reaction mixture was cooled to 0 ° C. Isobutylchloroformate (78 μL, 0.57 mmol) was added and after 10 minutes the reaction was warmed to 4 ° C. After 1.5 h, a solution of MTL (1a) (151 mg, 0.57 mmol) in 1: 1 acetone: water (4 mL) was added and the reaction mixture was stirred at rt for 10 h. The reaction mixture was evaporated to dryness and chromatographed on silica (95: 5 dichloromethane / MeOH to 95: 8 dichloromethane / MeOH) to give the product as a colorless oil (137 mg, 45%). Was: TLC R _f = 0.32 (9: 1 dichloromethane / MeOH); MS (ESPOS): 411 [M + H-Boc] &lt; ⁺ &gt;, 511 [M + H] ⁺ .

To a solution of the Boc protected lincosamide (125 mg) in DCM (2.0 mL) was added DCE (10.0 mL), trifluoroacetic acid (5 mL), methyl sulfide (0.3 mL), and water (0.3 mL). Added. The reaction mixture was stirred for 40 minutes at room temperature and 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 0.25M NH ₃ / DCM) to give the title compound as a colorless solid (30.0 mg, 30%): MS (ESPOS): 411.6 [M + H ] +.

Example 35

4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile] -amides:

4-position stereoisomer I and 4-position stereoisomer II

4-hydroxy-4-butylproline methylester (12b) (P = Boc, m = 1, R ⁹ = n-butyl).

To a stirred solution of n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78 ° C. compound 12a (P = Boc, P ₂ = Me, m = 1) in THF (5 mL) ( 570 mg, 2.3 mmol) was added. The reaction mixture was stirred at -78 ° C for 2 hours and then at -40 ° C for an additional 1 hour. 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 residue obtained was purified by silica gel column chromatography using 50% EtOAc in hexane as eluent to give 4-hydroxy-4-butylproline methylester (12b) (P = Boc, m = 1, R ⁹ = n-butyl) was obtained as a colorless oil (0.52 g, 73%):

4-fluoro-4-butylproline methyl ester (12c) (P = Boc, m = 1, R ⁹ = n-butyl).

To a stirred solution of DAST (0.55 g, 3.4 mmol) in DCM (5 mL) at −78 ° C. 4-hydroxyproline (12b) in dry DCM (5 mL) (P = Boc, m = 1, R ⁹ = n-butyl) (520 mg, 1.7 milmol) was added slowly. The mixture was stirred at -78 ° C for 1 hour and then at -10 ° C for an additional 1 hour. DCM (50 mL) was added followed by aqueous NH ₄ Cl (10%, 30 mL). 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 give 4-fluoro-4-butylproline methyl ester (12c) (P = Boc, m = 1, R9 = n-butyl) ( 270 mg, 52%) was obtained as a colorless oil:

4-fluoro-4-butylproline (12d) (P = Boc, m = 1, R 9 = 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 overnight at room temperature. THF was removed and the residue was purified by column chromatography using 10% MeOH in DCM as eluent to give 4-fluoro-4-butylproline (12d) (P = Boc, m = 1, R 9 = n-butyl). ) (0.26 g, 100%) was obtained as a colorless oil:

4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide: stereoisomer I 4 and stereoisomer II 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-Cl MTL, (6b) (R2 = H, R3 = Cl) (117 mg, 0.43 mmol), HBTU (180 mg, 0.47 mmol) and DIEA (111 mg, 0.86 mmol) were added and stirred overnight at room temperature. The solvent was removed and the residue was purified by silica gel column chromatography using 2% MeOH in DCM to afford the desired Boc protected lincosamide intermediate (170 mg, 72%) as a light brown liquid:

To a solution of 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 rt for 1 h. The solvent was removed and the residue was purified by silica gel column chromatography using 10% MeOH in DCM to afford 4-fluoro-4-butyl-pyrrolidine-2-carboxylic acid [2-chloro-1- (3, 4,5-Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (stereoisomer 4) (14 mg, 10%);

¹ H NMR (300 MHz, CD ₃ 0D) δ 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-butyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Propyl] -amide (stereoisomer No. 4) (3 mg, 2%); ¹ H NMR (300 MHz, CD ₃ 0D) δ 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); (ESPOS): 443 [M + H] ⁺ .

Example 36

4-Fluoro-4-ethyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile]-amide

4-Fluoro-4-ethyl-piperidine-1,2-dicarboxylic acid 1-3-butyl ester (12d) (P = Boc, m = 2, R ⁹ = n-ethyl).

Starting material (2S) -4-oxo-piperidine-1,2-di using trimethylsilylacetylene anion as a 2 carbon synthesizing unit in the 4-ketone alkylation step, using the general method Q shown in Scheme 12 Boc-protected 4-fluoro amino acid (12d) was synthesized from carboxylic acid tert-butyl ester. Starting Materials 4-Oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl esters are prepared by Bosquet, Y .; Anderson, PC; Bogri, T .; Duceppe J .; Grenier, L .; Guse, I .; Tetrahedron, 1997, 53 15671-15680. The synthesis of the title compound of Example 36 from compound 12d (P = Boc, m = 2, R ⁹ = ethyl) is readily accomplished using the coupling and deprotection conditions in Example 34. MS (ESPOS): 429.1 [M + H] ⁺ .

Example 37

4-propylidene-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester 2-methyl ester.

TMS-diazomethane (2) in hexane to (2S) -4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester (0.52 g, 2.15 mmol) in methanol (10 mL) mL, 4 mmol) 2M solution was added and stirred at room temperature for 15 minutes. The reaction solvent was removed and the resulting methyl ester product (4-oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl ester 2-methyl ester) was used as such in the next reaction (0.55 g, 100 %):

4-propylidene-piperidine-1,2-dicarboxylic acid 1-3-butyl ester 2-methyl ester.

Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol) in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22 mmol) in THF (10 mL) and stirred at room temperature for 3 hours. . Methyl ester (12a) (P = Boc, m = 2, P2 = Me) (0.55 g, 2.15 mmol) in THF (5 mL) was added slowly to the reaction mixture and then stirred for an additional 2 hours. Then poured into water and extracted with ethyl acetate (30 mL). The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness and the resulting residue is chromatographed with 20% EtOAc in hexane to give the product 4-propylidene-piperidine-1,2- Dicarboxylic acid 1-3-butyl ester 2-methyl ester (0.100 g, 16%) was obtained:

4-propylidene-piperidine-1,2-dicarboxylic acid 1-3-butyl ester.

4-hydroxyl-piperidine-1,2-dicarboxylic acid 1-3-butyl ester 2-methyl ester (0.100 g, 0.353 mmol) in THF (10 mL) lithium hydroxide (0.50) in water (2 mL) g, 11.6 mmol), and the reaction mixture was stirred at rt for 16 h. Then it was poured into water and extracted with ether (20 mL). The aqueous layer was then acidified with 10% HCl (5 mL) and extracted with ethyl acetate (30 mL). The product carboxylic acid 4-propylidene-piperidine-1,2-dicarboxylic acid 1-3-butyl ester obtained after drying and solvent removal was used as such in the next step.

4-propylidene-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide .

Compound (2b) (R2 '= H) (32 mg, 0.12 mmol) in DMF (5 mL), DIEA (0.2 mL, 1.20 mmol), and 4-propylidene-piperidine-1,2-dicarboxylic acid 1 To a stirred solution of -tert-butyl ester (37 mg, 0.14 mmol) HBTU (57 mg, 0.16 mmol) was added and the mixture was stirred at rt for 2 h. Most of the DMF was removed under high vacuum and the crude was taken up in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (10 mL). The solvent was removed in vacuo and the product was purified by silica gel column chromatography using ethyl acetate as eluent to afford the desired Boc protected lincosamide (50 mg, 83%):

To the Boc protected lincosamide (50 mg, 0.10 millimoles) in dichloroethane (6 mL) was added triethylsilane (0.15 mL) followed by 93% aqueous trifluoroacetic acid (2.15 mL). It was. After stirring for 1 hour at room temperature, the solvent was removed at 45 ° C. under reduced pressure. The crude product obtained was purified by silica gel column chromatography using 10% MeOH in DCM as eluent to afford the title compound (5 mg, 12%):

Example 38

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Coupling of Boc-Protected Amino Acid with Compound (2b) (R ^{2 ′} = H).

Boc amino acid (21k) (R ⁹ = n-propyl, R ^9b = H, m = 1) (69 mg, 0.26 mmol, in DMF (2.5 mL) prepared by General Method S shown at Scheme 21 at 23 ° C. 1 equivalent), (2b) (R ^{2 '} = H) (74 mg, 0.26 mmol, 1 equivalent) and HBTU (107 mg, 0.28, 1.1 equivalent) in a solution of N, N-diisopropylethylamine (89 μL, 0.51 mmol, 2 equivalents) was added. The reaction was stirred at 23 ° C. for 2.5 h and then concentrated in vacuo to remove DMF. The resulting residue was dissolved in EtOAc (70 mL), then washed with 1: 1 brine: 10% aqueous citric acid (50 mL), saturated aqueous NaHC0 ₃ (50 mL), brine (30 mL), dried ( MgSO ₄ ), filtered and concentrated to yield 107 mg of the desired coupled product. This material was used in the final deprotection step without further purification:

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid with Boc-deprotection [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl- Obtaining tetrahydro-pyran-2-yl) -propyl] -amide.

To a solution of Boc-carbamate lincosamide (35 mg, 0.070 mmol, 1 equiv) in DCE (5.0 mL) at 23 ° C. was added H ₂ 0 (0.20 mL) followed by TFA (2.0 mL). . The reaction was stirred at 23 ° C. for 30 minutes, then treated with toluene (40 mL), then concentrated to a volume of 10 mL, then treated with a second aliquot of toluene (40 mL) and concentrated to dryness. . The crude product was semi-prepared HPLC (Waters Nova-Pak®); HR C ₁₈ , 6 μm particle size, 60 mm pore size, 25 mm diameter x 100 mm length, 5-60% acetonitrile / 0.1 in H ₂ 0 % AcOH over 30 minutes at 20 mL / min flow rate) to 16 mg pure 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3 , 4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide was obtained:

Example 39

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Coupling of Boc-Protected Amino Acid with (6b) (R ^{2 ′} = H, R ^{3 ′} = Cl).

Boc amino acid (21k) (R ⁹ = n-propyl, m = 1) (131 mg, 0.49 mmol, 1 equiv) in DMF (4.0 mL) prepared by General Method S shown at Scheme 21 at 23 ° C., 7 N, N-diisopropylethylamine in a solution of -Cl MTL (6b) (R ² = H, R ³ = Cl) (132 mg, 0.49 mmol, 1 equiv) and HBTU (203 mg, 0.54, 1.1 equiv) (170 μL, 0.97 mmol, 2 equiv) was added. The reaction was stirred at 23 ° C. for 2.5 h and then concentrated in vacuo to remove DMF. The resulting residue was dissolved in EtOAc (70 mL), then washed with 1: 1 brine: 10% aqueous citric acid (50 mL), saturated aqueous NaHC0 ₃ (25 mL), brine (30 mL), dried and (MgSO ₄ ), filtered and concentrated to yield 276 mg of the desired coupled product. This material was used in the final deprotection step without further purification:

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide.

To a solution of the Boc-carbamate protected lincosamide (225 mg, 0.43 mmol, 1 equiv) in DCE (25 mL) at 23 ° C. was added H ₂ 0 (1.0 mL), followed by TFA (10 mL). Added. The reaction was stirred at 23 ° C. for 30 minutes, then treated with toluene (150 mL), then concentrated to a volume of 30 mL, then treated with a second aliquot of toluene (150 mL) and concentrated to dryness. . The crude product was semi-prepared HPLC (Waters Nova-Pak®); HR C ₁₈ , 6 μm particle size, 60 mm pore size, 25 mm diameter x 100 mm length, 5-60% acetonitrile / 0.1 in H ₂ 0 % AcOH over 30 minutes at 20 mL / min flow rate) to yield 90 mg of pure 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3 , 4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide was obtained:

Example 40

1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro) in anhydrous acetonitrile (3 mL) at room temperature under nitrogen atmosphere. Triethylamine (0.2 mL, 1.44 mmol, 3 equiv) was added to a stirred solution of -pyran-2-yl) -propyl] -amide (200 mg, 0.48 mmol, 1 equiv) followed by bromoacetamide (80 mg). , 0.58 mmol, 1.2 equiv) was added. The resulting mixture was stirred at rt for 18 h and evaporated to dryness. The resulting residue was first purified on silica gel using 7% methanolic-ammonia / dichloromethane as eluent. The desired fractions were collected, evaporated to dryness and repurified by HPLC (for removal of byproducts in the reaction of bromoacetamide and base). After lyophilization, the desired title compound in Example 40 was obtained as a white fluffy powder (2.0 mg): HPLC: Rt = 4.11 min (220.0 nm); ¹ H NMR (300 MHz, CD ₃ OD) δ (rotary isomer) 5.46 (d, J = 5.5, 1), 4.47 (dd, J = 3.02, 2.7, 1.1), 4.31-4.25 (m, 3.3), 4.11 (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 [MH] ^- .

Example 41

1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

Crude 4-pentyl-pyrrolidine-2-carboxylic acid in anhydrous acetonitrile (3 mL) [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide (210 mg, 0.50 mmol, 1 equiv) and a stirred solution of triethylamine (0.21 mL, 1.51 mmol, 3 equiv) were bromoacetonitrile (42 μL, 0.60 mmol, 1.2 equiv). The resulting reaction mixture was stirred at rt for 18 h, evaporated to dryness and purified by chromatography on silica gel using 2.5% methanol in dichloromethane as eluent. The desired fractions were pooled, evaporated to dryness and lyophilized to afford the title compound (11.2 mg, 10%) as a fluff white powder: TLC R _f = 0.2 (5 in dichloromethane). % Methanol);

Example 42

1- (1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra Hydro-pyran-2-yl) -propyl] -amide

1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester.

Boc protected amino acid (7d) (R ^{9 '} = 4-pent-2-enyl) (433 mg, 1.16 mmol, 1 equiv) was stirred in 4M HCl in dioxane (5 mL) for 2 h and then dried. Evaporate until. The residue obtained was co-evaporated until dryness from DCM (3 × 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) and then 1-benzyl-2- (chloromethyl-1H-imidazole (mae Bridge) (338 mg, 1.39 mmol, 1.2 equiv) The reaction mixture was stirred for 48 h at room temperature and evaporated to dryness The residue obtained was diluted with EtOAc (200 mL) and continuously Washed with 10% citric acid, brine, dried over Na ₂ S0 ₄ , filtered and evaporated to dryness The crude obtained was taken up with CH ₂ Cl ₂ / hexanes / MeOH (6: 5: 1). Purified by eluting silica gel chromatography to give the desired N-alkylated product: 1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2- Carboxylic acid benzyl ester (257 mg, 50%) was obtained: Rf = 0.7 (7: 2: 1, CH ₂ Cl ₂ / hexane / MeOH); MS (ESPOS): 444.3 [M + H] &lt; + &gt;.

1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid.

1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester in 4: 1 THF / H ₂ 0 (8 mL) at room temperature To a stirred solution of (257.2 mg, 0.6 mmol, 1 equiv) was added lithium hydroxide monohydrate (250 mg, 5.96 mmol, 10 equiv). The resulting reaction mixture was stirred overnight at room temperature and evaporated to dryness. The obtained residue was dissolved in water (10 mL), the pH of the resulting solution was adjusted to 3-4 and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the acid product 1- (1-benzyl-1H-imidazol-2-ylmethyl) -4- Pent-2-enyl-pyrrolidine-2-carboxylic acid (202 mg, 98%): Rf = 0.4 (7: 2: 1 CH ₂ Cl ₂ / hexane / MeOH), KMn0 ₄ visualization stain; MS (ESPOS): 355 [M + H] &lt; + &gt;; MS (ESNEG): 352 [M ⁻ H] ⁻ .

1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide.

Triethylamine (0.4 mL, 2.9 mmol, 8.7 equiv) in a stirred solution of (2b) (R2 '= H) (96.4 mg, 0.33 mmol, 1 equiv) in dry DMF (1.5 mL) at 0 ° C under N ₂ After addition, BSTFA (0.4 mL, 1.51 mmol, 4.6 equiv) was added. The resulting mixture was stirred at 0 ° C. for 10 minutes, then at room temperature for 30 minutes and recooled. To the reaction was added a solution of 1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pent-2-enyl-pyrrolidine-2-carboxylic acid (194 mg, 0.55 mmol, 1.7 equiv) Then, solid HATU (261 mg, 0.69 mmol, 2.1 equiv) was added. The resulting mixture was stirred at rt for 3 h and evaporated to dryness. The resulting residue was dissolved in EtOAc and then washed with 10% aqueous citric acid, saturated aqueous NaHCO ₃ , brine, dried (MgSO ₄ ), filtered and concentrated. The crude over-silylated compound is dissolved in MeOH (60 mL), treated with Dow's H ⁺ form resin (250 mg) for 45 minutes at room temperature, the reaction mixture is filtered and evaporated to dryness to rincosama Ide product 1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide was obtained.

The crude 1- (1-benzyl-1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1 in anhydrous EtOH (5 mL) in an oven dried sealed tube. A solution of-(3,4,5-trihydroxy-6-methyl sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (280 mg, 0.48 mmol), 10% Pd / C (560 mg) ) And 1,4-cyclohexadiene (1.5 mL) were added. The reaction vessel was purged with N ₂ , sealed and stirred at room temperature for 18 hours. The reaction mixture was filtered through celite, washed several times with reagent alcohol and combined washings and the filtrate was evaporated to dryness. The resulting residue was purified by silica gel chromatography (1: 9 methanolic ammonia / CH ₂ Cl ₂ ). The desired fractions were evaporated to dryness and lyophilized to give the title compound (29.3 mg, 18%) in Example 42: TLC Rf = 0.7 (14% methanolic ammonia / CH ₂ Cl ₂ ), KMn0 ₄ visualization staining; MS (ESPOS): 499.4 [M + H] +

Example 43

1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl in dioxane (1 mL) ) -Propyl] -amide (153 mg, 0.34 mmol, 1 equiv) and agitated suspension of ethylformimidate (Aldrich) (44 mg, 0.40 mmol, 1.2 equiv) was added 1M aqueous NaOH (0.74 mL, 0.74 mmol, 2.2 Equivalent weight). After 1 h, additional ethyl formimidate (44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture and stirring continued for 30 minutes. The reaction mixture was frozen and lyophilized. The lyophilized powder was purified by column chromatography to give the title compound (8 mg): TLC Rf = 0.48 CHCl ₃ / MeOH / 32% aqueous AcOH (5: 3: 1); MS (ESPOS): 447.7 [M + H] &lt; + &gt;, 469.7 [M + Na] &lt; + &gt;, MS (ESNEG): 481.6 [M-H + HCl]-.

Example 44

4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Boc amino acid (21k) (R ⁹ = n-butyl, R ^9b = H, m = 1) prepared by the general method S couples with 7-Cl MTL (6b) (R ² = H, R ³ = Cl) Ring and used without further purification in the final deprotection step. Deprotection and purification as performed in Example 38 above gave the title compound.

Example 45

4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Coupling Boc amino acid (21k) (R ⁹ = n-butyl, R ^9b = H, m = 1) prepared by the general method S with lincosamine (2b) (R ^{2 ′} = H) and Used without further purification in the final deprotection step. Deprotection and purification as performed in Example 38 above gave the title compound.

Example 46

5-propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide

To a solution of protected cyclic amino acid (22h) (R ^9b = H, R ⁹ = propyl) (340 mg, 0.88 mmol) in DMF (3 mL) at 0 ° C. (6b) 7-Cl MTL (R ² = H, R ³ = Cl) (367 mg, 0.988 mmol), TEA (332 μL, 1.76 mmol), HBTU (496 mg, 0.97 mmol) were added and stirred at rt overnight. Thereafter, the solvent was removed. Purification by silica gel column chromatography using 50-100% EtOAc / hexanes provided the desired protected lincosamide (13a) (R ⁹ = propyl, R ^9b = H, m = 2, R ² = H, R ³ = Cl, P ¹ = H, P ² = Boc) (575 mg, 90%) was obtained. MS (ESPOS): 537 [M + l] ⁺ .

Boc protected lincosamide (13a) in DCE (15 mL) (R ⁹ = propyl, R ^9b = H, m = 2, R ² = H, R ³ = Cl, P ¹ = H, P ² = Boc) To a solution of (575 mg, 1.07 mmol) triethylsilane (0.5 mL), TFA (5 mL), water (0.5 mL) was added and stirred at room temperature for 1.5 hours. The reaction solvent was removed and the resulting residue was purified by chromatography on silica using 5-10% MeOH / DCM to give the title compound (433 mg, 92%) as a colorless solid.

MS (ESPOS): 437 [M + l] ⁺ .

Example 47

5-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Unsaturated title compound 5-Example-2,3,6,7-tetrahydro-1H-azin-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6] in Example 46 -Methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (433 mg, 0.99 mmol) and 10% Pd / C (80 mg) were added to MeOH (10 mL) and hydrogenated overnight at 50 psi I was. Solvent was removed to afford crude material. Purification by silica gel column chromatography (20% MeOH / DCM), followed by preparative HPLC (general method AC) to give isomer (1) R _t = 18.3 min (10 mg, 2.3%) and isomer (2) R _t = 18.6 min (58 mg, 13.3%) was obtained.

Isomer 1:

Isomer 2:

Example 48

1-Cyclopropyl-5-propyl-azepane-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] -Amide

5-propyl-azepane-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methyl) in MeOH (2 mL) prepared by the method described in Examples 47, 48 Sulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide (68 mg, 0.16 mmol), acetic acid (0.1 mL) was added and then 1-[(ethoxycyclopropyl) oxy] trimethylsilane (0.2 mL, 0.96 mmol), sodium cyanoborohydride (41 mg, 0.64 mmol) and 3 ′ molecular sieve were added and heated to reflux for 3 hours. The molecular sieve was filtered off and the reaction solvent removed to afford the crude material. Purification by silica gel column chromatography (10% MeOH / DCM) and HPLC gave the title compound (44 mg, 59%).

Example 49

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -5-propyl-azepane-2-carboxylic acid [2-chloro-1- (3,4,5-tri Hydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Isomer (1) or isomer (2) of the title compound in Example 46 (1), wherein R ² = H, R ³ = Cl, R ⁶ = H, R ⁹ = 5-n-propyl and m = 3 ) 4-bromomethyl-5-methyl- [1,3] dioxol-2-one (J. Alexander, et. Al. J. Med. Chem, 1996, in the presence of sodium carbonate in DMF). 39, 480-486), to provide the title compound.

Example 50

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] 5-propyl-azane-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Isomer (1) or isomer (2) of the title compound in Example 46 (1), wherein R ² = H, R ³ = Cl, R ⁶ = H, R ⁹ = 5-n-propyl and m = 3 ) Carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester 4-nitro-phenyl ester in the presence of potassium bicarbonate in DMF (F. Sakamoto, et. Al, Prepared as described in Chem. Pharm. Bull. 1984, 32 (6), 2241-2348).

Example 51

5-Methyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl), as shown in general method Z, was used to determine the cyclic amino acid (22f) prepared by general method T (R ⁹ = propyl, R ^9b = H, m = 2) to couple to intermediate carbamate (13a) (R ⁹ = methyl, R ^9b = H, m = 2, R ² = H, R ³ = Cl, P ¹ = H, P ² = Boc ), Which was deprotected under acidic conditions to give crude unsaturated intermediates. The unsaturated compound was hydrogenated with 10% Pd / C in 50 psi H ₂ in MeOH to give a crude mixture of the 5 isomer. Two 5 isomers were separated by preparative HPLC.

Isomer 1 (low R _t ):

Isomer 2 (high R _t ):

Example 52

5-Ethyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl), as shown in general method Z, was used to determine the cyclic amino acid (22f) prepared by general method T (R ⁹ = propyl, R ^9b = H, m = 2) to couple to intermediate carbamate (13a) (R ⁹ = ethyl, R ^9b = H, m = 2, R ² = H, R ³ = Cl, P ¹ = H, P ² = Boc ), Which was deprotected under acidic conditions to give crude unsaturated intermediates. The unsaturated compound was hydrogenated with 10% Pd / C in 50 psi H ₂ in MeOH to give a crude mixture of the 5 isomer. Two 5 isomers were separated by preparative HPLC.

Isomer 1 (low R _t ):

Isomer 2 (high R _t ):

Example 53

5-Cyclopropylmethyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) and cyclic amino acids (22f) (R ⁹ = cyclopropylmethyl, R, prepared by general method T as shown in general method Z). ^The title compound can be prepared by coupling ^9b = H, m = 2). The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to give the title compound as a mixture of the 5 isomers.

Example 54

5-Cyclopropylmethyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) and cyclic amino acids (22f) (R ⁹ = cyclopropyl, R ^9b prepared by General Method T as shown in General Method Z). = H, m = 2) can be coupled to form the title compound. The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to give the title compound as a mixture of the 5 isomers.

Example 55

5-Ethyl-4-methyl-azpan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) as shown in general method Z and the cyclic amino acid (22f) prepared by general method T (R ⁹ = ethyl, R ^9b = The title compound may be prepared by coupling methyl, m = 2). The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to afford the title compound as a mixture of isomers.

Example 56

4-Ethyl-5-methyl-azepan-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) as shown in general method Z and the cyclic amino acid (22f) prepared by general method T (R ⁹ = methyl, R ^9b = The title compound can be prepared by coupling ethyl, m = 2). The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to afford the title compound as a mixture of isomers.

Example 57

5-Ethyl-6-methyl-azepan-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) as shown in general method Z and the cyclic amino acid (22f) prepared by general method T (R ⁹ = methyl, R ^9b = The title compound can be prepared by coupling ethyl, m = 1). The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to afford the title compound as a mixture of isomers.

Example 58

4-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) and cyclic amino acids (22f) prepared by general method T (R ⁹ = H, R ^9b =) as shown in general method Z. Propyl, m = 2) can be coupled to form the title compound. The unsaturated compound was hydrogenated with 10% Pd / C as in Example 47 to give the title compound as a mixture of isomers 4.

Example 59

5-Fluoro-5-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl ] -Amide

Lincosamine (6b) 7-Cl MTL (R ² = H, R ³ = Cl) and cyclic amino acid (12d) (R ⁹ = propyl, m = 2) were coupled as shown in the general method Z to give the title compound. Was prepared.

Example 60

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopropyl, R ¹ = SMe), as shown in general method Z, is described by Hoeksema, H. et. al. The title compound was prepared by coupling with 4-n-propylhyglic acid prepared by the method of Journal of the American Chemical Society, 1967, 89 2448-2452.

Example 61

4-propyl-piperidine-2-carboxylic acid [cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopropyl, R ¹ = SMe) was converted to 4-propyl-piperidine-1,2-dicarboxylic acid-1-tertiary- as shown in general method Z. Coupling with butyl ester 27b (R ⁹ = propyl) afforded the title compound. Intermediate 13a (R ¹ = SMe, R ²⁰ + R ²¹ = cyclopropyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) was deprotected under acidic conditions The title compound was obtained.

Example 62

5-propyl-azepan-2-carboxylic acid [cyclopropyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopropyl, R ¹ = SMe) was replaced with 5-propyl-azine-1,2-dicarboxylic acid-1-tertiary as shown in the general coupling method Z. Coupling with butyl ester to afford the title compound. Intermediate 13a (R ²⁰ + R ²¹ = cyclopropyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) was deprotected under acidic conditions to afford the title compound. .

MS (ESPOS): 451.2 [M + H] ⁺ .

Example 63

4-propyl-piperidine-2-carboxylic acid [phenyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23f) (R ²⁰ + R ²¹ = Ph, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ + R ²¹ = Ph, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ + R ²¹ = Ph, R ¹ = SMe) was converted to 4-propyl-piperidine-1,2-dicarboxylic acid-tert-butyl ester as shown in the general method Z. 27b) (R ⁹ = propyl) to give the title compound. Intermediate 13a (R ²⁰ + R ²¹ = Ph, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) was deprotected under acidic conditions to afford the title compound.

Example 64

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [phenyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23 g) (R ²⁰ + R ²¹ = phenyl, R ¹ = SMe) was coupled with 4-n-propylhygric acid as shown in general method Z to afford the title compound.

Example 65

4-propyl-piperidine-2-carboxylic acid [cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23f) (R ²⁰ + R ²¹ = cyclopentyl, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopentyl, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopentyl, R ¹ = SMe) was converted to 4-propyl-piperidine-1,2-dicarboxylic acid tert-butyl ester as shown in general method Z. Coupling with (27b) (R ⁹ = propyl) afforded the title compound. Intermediate 13a (R ²⁰ + R ²¹ = cyclopentyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) was deprotected under acidic conditions to afford the title compound. .

Example 66

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

The title compound was prepared by coupling lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopentyl, R ¹ = SMe) with 4-n-propylhyglic acid as shown in general method Z.

Example 67

5-propyl-azpan-2-carboxylic acid [cyclopentyl- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Lincosamide (23 g) (R ²⁰ + R ²¹ = cyclopentyl, R ¹ = SMe) was replaced with 5-propyl-azepine-1,2-dicarboxylic acid-1-tert-butyl as shown in the general method Z. Coupling with the ester gave the title compound. Intermediate 13a (R ²⁰ + R ²¹ = cyclopentyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 3) was deprotected under acidic conditions to afford the title compound. .

Example 68

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -but-3-enyl ] -Amide

Lincosamide (23f) (R ²⁰ = vinyl, R ²¹ = H, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ = vinyl, R ²¹ = H, R ¹ = SMe) was prepared as shown in Scheme 23.

The title compound was prepared by coupling lincosamide (23 g) (R ²⁰ = vinyl, R ²¹ = H, R ¹ = SMe) with 4-n-propylhyglic acid as shown in general method Z.

Example 69

4-propyl-piperidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -but-3-enyl] -amide

Lincosamide (23 g) (R ²⁰ = vinyl, R ²¹ = H, R ¹ = SMe) was converted to 4-propyl-piperidine-1,2-dicarboxylic acid-1-tertiary as shown in the general method Z. Coupling with butyl ester (27b) (R ⁹ = propyl) gave the title compound. Deprotection of intermediate (13a) (R ²⁰ = vinyl, R ²¹ = H, R ¹ = SMe, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) under acidic conditions To give the title compound.

Example 70

5-propyl-azepane-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide

As shown in general method Z, the cyclic amino acid (22f) (R ⁹ = propyl, R ^9b = H, m = 2) prepared by general method T was replaced with lincosamine (23 g) (R ²⁰ = ethyl, R ^21). = H, R ¹ = SMe) to give the title compound. The unsaturated intermediate was hydrogenated to afford the title compound.

Example 71

4-propyl-piperidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide

The title compound in Example 69 was hydrogenated to afford the title compound.

Example 72

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -butyl] -amide

The title compound in Example 68 was hydrogenated to afford the title compound.

Example 73

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Methyl] -amide

Lincosamide (23f) (R ²⁰ + R ²¹ = 4-chlorophenyl, R ¹ = SMe) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ + R ²¹ = 4-chlorophenyl, R ¹ = SMe) was prepared as shown in Scheme 23.

The title compound was prepared by coupling lincosamide (23 g) (R ²⁰ + R ²¹ = 4-chlorophenyl, R ¹ = SMe) with 4-n-propylhyglic acid as shown in general method Z.

Example 74

4-propyl-piperidine-2-carboxylic acid [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl]- Amide

The title compound was prepared by coupling lincosamide (23 g) (R ²⁰ + R ²¹ = 4-chlorophenyl, R ¹ = SMe) with (27b) (R ⁹ = propyl) as shown in General Method Z. .

Example 75

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)- Profile]-amide

Lincosamide (23f) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = isopropyl sulfanyl) was prepared as shown in Scheme 23.

MS (ESPOS): 524.0 [M + Na]

MS (ESNEG): 500.0 [M-H]

Lincosamide (23 g) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = isopropyl sulfanyl) was prepared as shown in Scheme 23.

The title compound was prepared by coupling lincosamide (23 g) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = isopropyl sulfanyl) with 4-n-propylhyglic acid as shown in general method Z. .

Example 76

4-propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamide (23 g) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = isopropyl sulfanyl) was converted to 4-propyl-piperidine-1,2-dicarboxylic acid-1 as shown in the general method Z. The title compound was prepared by coupling with -tert-butyl ester (27b) (R ⁹ = propyl). Intermediate 13a (R ¹ = isopropyl sulfanyl, R ²⁰ = methyl, R ²¹ = methyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) in acidic conditions Deprotection under gave the title compound.

Example 77

1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2- Methyl-propyl] -amide

Lincosamide (23f) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = tert-butyl sulfanyl) was prepared as shown in Scheme 23.

Lincosamide (23 g) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = tert-butyl sulfanyl) was prepared as shown in Scheme 23.

The title compound was prepared by coupling lincosamide (23 g) (R ² = isopropyl, R ¹ = tert-butyl sulfanyl) with 4-n-propylhyglic acid as shown in general method Z.

Example 78

4-propyl-piperidine-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] Amide

Lincosamide (23 g) (R ²⁰ = methyl, R ²¹ = methyl, R ¹ = tert-butyl sulfanyl) as shown in general method Z was converted to 4-propyl-piperidine-1,2-dicarboxylic acid. The title compound was prepared by coupling with -l-tert-butyl ester (27b) (R ⁹ = propyl). Intermediate (13a) (R ¹ = tert-butyl sulfanyl, R ²⁰ = methyl, R ²¹ = methyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) Deprotection under acidic conditions gave the title compound.

Example 79

4- (2-Cyclopropyl-ethyl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide

(11b) (0.5 g, 1.9 mmol, 1 equiv), triphenylphosphine (39.9 mg, 0.15 mmol, 0.08 equiv), copper (I) iodide (28.9 mg) in triethylamine (7 mL) under dry nitrogen To a stirred suspension of 0.15 mmol, 0.08 equiv), palladium acetate (17 mg, 0.076 mmol, 0.04 equiv) was added cyclopropyl acetylene (Aldrich) (0.25 g, 3.8 mmol, 2 equiv). The mixture was stirred at rt overnight. The solvent was removed in vacuo to yield a dark colored residue. The residue was purified by column chromatography to give (11c) (R ^{9 '} = 2-cyclopropyl-eth-1--1-ynyl) (0.39 g, 100%) as a yellow oil.

To a solution of (11c) (R ^{9 ′} = 2-cyclopropyl-eth-1-ynyl) (0.39 g, 1.9 mmol) in methanol (15 mL) was added 10% Pd / C (0.2 g). The mixture was purged, filled with hydrogen (1 atm) and stirred overnight at room temperature. Palladium was removed by filtration and the filtrate was concentrated to give 4- (2-cyclopropylethyl) -pyridine-2-carboxylic acid methyl ester (0.38 g, 97%) as a yellow oil. (Intermediate not shown)

To a mixture of 4- (2-cyclopropylethyl) -pyridine-2-carboxylic acid methyl ester (0.38 g) in MeOH (8 mL) and water (8 mL) concentrated HCl (158 μL) and platinum oxide (0.2 g) ) Was added. The mixture was purged, filled with hydrogen (1 atm) and stirred overnight. Platinum oxide was removed by filtration and the filtrate was evaporated to yield a light yellow solid (11d) (R ⁹ = 2-cyclopropylethyl) which was used without further purification.

To the crude residue 11d (R ⁹ = 2-cyclopropylethyl) 2N NaOH (3.8 mL) and t-butyl alcohol (2 mL) were added. 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 and then washed with ether. The aqueous layer was acidified to pH = 2.0 with 2N HCl and extracted twice with ethyl acetate twice. The combined organic layers were dried over MgSO ₄ and concentrated to 4- (2-cyclopropylethyl) -piperidine-1,2-dicarboxylic acid 1-3-butyl ester (11f) (P = Boc, R ⁹ = 2-cyclopropylethyl) (0.42 g, 77%) was obtained as a clear syrup.

MS (ESPOS): 320.3 [M + Na] ⁺ ; MS (ESNEG): 296.2 [M ⁻ H] ⁻ .

Lincosamide (6b) (R ² = H, R ³ = Cl) was replaced with 4- (2-cyclopropylethyl) -piperidine-1,2-dicarboxylic acid, grade 1-3, as shown in general method Z. Coupling with -butyl ester (11f) (P = Boc, R ⁹ = 2-cyclopropylethyl) gave the title compound. Deprotection of intermediate (13a) (R ²⁰ = methyl, R ²¹ = methyl, R ⁹ = propyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 2) under acidic conditions to give the title compound It was.

MS (ESPOS): 451.3 [M + H] ⁺ .

Example 80

4-cyclopropylmethyl-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Using the starting material 4-cyclopropylmethylpyridine prepared by alkylation of cyclopropylbromide and 4-picolin by the method described in Osuch et al, Journal of the American Chemical Society, 1955, 78, 1723. 4-Cyclopropylmethylpyridine-2-carboxylic acid, compound 10b (R ⁹ = cyclopropylmethyl) was prepared using general method O. A modified method is described below.

To a solution of 4-picoline (1.1 g, 11.8 mmol) in THF (5 mL) at −78 ° C., add a LDA 2M solution in THF / heptane / ethylbenzene (Aldrich) (5.9 mL, 11.8 mmol) and produce The resulting reaction mixture was stirred at -78 ° C for 3 hours and then at -40 ° C for 1 hour. Then cyclopropyl bromide (1.43 g, 11.8 mmol) was added at -78 ° C, warmed to room temperature and stirred at room temperature for 1 hour. Saturated aqueous NH ₄ Cl (10 mL) was added to the reaction mixture, the aqueous phase was extracted with EtOAc (10 × 2 mL) and the combined organic extracts were dried over Na ₂ SO ₄ . The solvent was removed and the product 4-cyclopropylmethylpyridine (0.5 g, 31%) was obtained and used without further purification.

As in the general method AA, lincosamide (6b) (R ² = H, R ³ = Cl) is coupled with 4-cyclopropylmethylpyridine-2-carboxylic acid (10b) (R ⁹ = cyclopropylmethyl) to give an intermediate. (13b) (R ¹ = SMe, R ² = Me, R ³ = H, R ⁹ = cyclobutyl-ethyl, P ¹ = H) was obtained, which was reduced to the title compound by catalytic hydrogenation.

MS (ESPOS): 437.2 [M] ⁺ .

Example 81

4- (2-Cyclobutyl-ethyl) -piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide

4- (Cyclo) using the general method O using starting material 4- (cyclobutyl-ethyl) -pyridine prepared by alkylation of bromomethylcyclobutane and 4-picolin as described in Example 80 Butyl-ethyl) -pyridine-2-carboxylic acid, compound 10b (R ⁹ = cyclobutyl-ethyl) was prepared.

As in the general coupling method AA, lincosamide (6b) (R ² = H, R ³ = Cl) was substituted with 4- (cyclobutyl-ethyl) -pyridine-2-carboxylic acid (10b) (R ⁹ = cyclobutyl- Coupling with ethyl) yields intermediate (13b) (R ¹ = SMe, R ² = Me, R ³ = H, R ⁹ = cyclobutyl-ethyl, P ¹ = H), which is titled by catalytic hydrogenation. Reduced to compound.

MS (ESPOS): 465.2 [M] +.

Example 82

4-Cyclobutylmethyl-piperidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

4-cyclobutylmethylpyridine-pyridine-2- using general method O using the starting material 4-cyclobutylmethylpyridine prepared by alkylation of cyclobutyl bromide and 4-picolin as described in Example 80. Carboxylic acid, compound 10b (R ⁹ = 4-cyclobutylmethyl) was prepared.

Coupling lincosamine (6b) (R ² = H, R ³ = Cl) with 4-cyclobutylmethylpyridine-2-carboxylic acid (10b) (R ⁹ = 4-cyclobutylmethyl) as in the general coupling method AA Ringing gave intermediate 13b (R ¹ = SMe, R ² = Me, R ³ = H, R ⁹ = cyclobutylethyl, P ¹ = H) which was reduced to the title compound by catalytic hydrogenation.

MS (ESPOS): 451.2 [M + H] &lt; + &gt;.

Example 83

4-cyclopropylmethyl-pyrrolidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Protected amino acid intermediate (2S, 4R) -4-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid- using cyclopropylmethyl triphenylphosphonium bromide (Aldrich) as starting material in the Whitig olefination step Class 1-3-butyl esters are described in Goodman et al. Prepared by the synthetic sequence described in Journal of Organic Chemistry, 2003, 68, 3923.

Lincosamine (6b) (R ² = H, R ³ = Cl) was converted to (2S, 4R) -4-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid- as shown in general coupling scheme 11. Intermediate (13b) (R ¹ = SMe, R ² = Me, R ³ = H, R ⁹ = cyclopropylmethyl, P ¹ = H, P ² = carboxylic acid-t- Butyl ester, m = 1) was obtained, which was deprotected under acidic conditions to give the title compound.

MS (ESPOS): 423.2 [M + H] +.

Example 84

4- (2-Cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Amino acid intermediate (2S, 4R) -4- (2-cyclobutylidene-ethyl)-by general method K by alkylation of pyroglutamic acid ester (7a) and (2-bromo-ethylidene) -cyclobutane Pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester was prepared. An allylic halide (2-bromo-ethylidene) -cyclobutane starting material was prepared from cyclobutanone in a two step manner disclosed in US Pat. No. 3,711,555.

Lincosamine (2b) (R ¹ = SMe, R ² = Me) was coupled with protected amino acid (8c) (R ^{9 ′} = 2-cyclobutylidene-ethyl) to give intermediate carbamate (13a) (R ¹ ). = SMe, R ² = Me, R ⁹ = 2-cyclobutylidene-ethyl, P ¹ = H, P ² = Boc, m = 1), which was deprotected under acidic conditions to give the title compound. .

MS (ESPOS): 429.1 [M + H] ⁺ .

Example 85

4- (2-Cyclobutylidene-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Amino acid intermediate (2S, 4R) -4- (2-cyclobutylidene-ethyl)-by general method K by alkylation of pyroglutamic acid ester (7a) and (2-bromo-ethylidene) -cyclobutane Pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester was prepared. An allylic halide (2-bromo-ethylidene) -cyclobutane starting material was prepared from cyclobutanone in a two step manner disclosed in US Pat. No. 3,711,555.

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with protected amino acid (8c) (R ^{9 '} = 2-cyclobutylidene-ethyl) to give intermediate carbamate (13a) (R ¹ ). = SMe, R ² = Me, R ⁹ = 2-cyclobutylidene-ethyl, P ¹ = H, P ² = Boc, m = 1), which was deprotected under acidic conditions to give the title compound. .

MS (ESPOS): 450.1 [M + H] ⁺ .

Example 86

4- (2-Cyclobutyl-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide

Amino acid intermediate (2S, 4R) -4- (2-cyclobutylidene-ethyl)-by general method K by alkylation of pyroglutamic acid ester (7a) and (2-bromo-ethylidene) -cyclobutane Pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester was prepared. An allylic halide (2-bromo-ethylidene) -cyclobutane starting material was prepared from cyclobutanone in a two step manner disclosed in US Pat. No. 3,711,555.

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with protected amino acid (7d) (R ⁹ = 2-cyclobutylidene-ethyl) to give intermediate carbamate (13a) (R ¹ =). SMe, R ² = Me, R ⁹ = 2-cyclobutyl-ethyl, P ¹ = H, P ² = Boc, m = 1)), which was deprotected under acidic conditions to afford the title compound.

MS (ESPOS): 451.2 [M] ⁺ .

Example 87

4- (2-Cyclopropyl-ethyl) -pyrrolidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide

Lincosamine (2b) (R ¹ = SMe, R ² = Me) was coupled with the protected amino acid (8c) (R ^{9 ′} = 2-cyclopropyl-ethyl) prepared by the general method M to yield intermediate carbamate ( 13a) (R ¹ = SMe, R ² = Me, R ⁹ = cyclopropyl-ethyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 1), which is deprotected under acidic conditions To give the title compound.

MS (ESPOS): 437.2 [M + H] ⁺ .

Example 88

4-Fluoro-1- (2-hydroxy-ethyl) -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 18a (Example 32) was treated with ethylene oxide in methanol as detailed above in Scheme 19 to afford the title compound.

MS (ESPOS): 473.3 [M + H] ⁺ .

Example 89

4-Butyl-4-fluoro-piperidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile]-amide

Starting material (2S) -4-oxo-piperidine-1,2-dicarboxylic acid using general method Q shown in Scheme 12 using 1-butyne anion as 4-carbon synthesizing unit in 4-ketone alkylation step 4-Fluoro-4-butyl-piperidine-1,2-dicarboxylic acid 1-3-butyl ester (12d) boc-protected from 1-3-butyl ester (P = Boc, m = 2, R ⁹ = n-butyl). Starting materials 4-Oxo-piperidine-1,2-dicarboxylic acid 1-3-butyl esters are prepared by Bosquet, Y .; Anderson, PC; Bogri, T .; Duceppe J .; Grenier, L .; Guse, I .; Tetrahedron, 1997, 53 15671-15680.

As shown in the general method Z, lincosamide (6b) (R ² = H, R ³ = Cl) is coupled with (12d) (P = Boc, m = 2, R ⁹ = butyl) to form an intermediate (13a). ) (R ² = H, R ³ = Cl, R ⁹ = butyl, P ¹ = H, P ² = Boc, m = 2), which was deprotected under acidic conditions to afford the title compound.

MS (ESPOS): 457.0 [M + H] ⁺ .

Example 90

4-Cyclopropylmethyl-4-fluoro-piperidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide

Lincosamide (6b) (R ² = H, R ³ = Cl) was coupled with (12d) (P = Boc, m = 2, R ⁹ = cyclopropylmethyl) as shown in the general method Z to intermediate (13a) (R ² = H, R ³ = Cl, R ⁹ = cyclopropylmethyl, P ¹ = H, P ² = Boc, m = 2), which is deprotected under acidic conditions to afford the title compound It was.

MS (ESPOS): 455.0 [M + H] ⁺ .

Example 91

3-Butyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Azetedinic acid (25f) (R ⁹ = butyl) (52 mg, 0.20 mmol, 1 equiv), 7-Cl MTL (6b) (R ² = H, R ³ = Cl) in DMF (2.0 mL) at 23 ° C. To a solution of (58 mg, 0.20 mmol, 1 equiv) and HBTU (84 mg, 0.22 mmol, 1.1 equiv) was added DIPEA (88 μL, 0.51 mmol, 2.5 equiv). 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, washed with 1: 1 brine / saturated aqueous NaHC0 ₃ (100 mL), brine (50 mL), dried (MgS0 ₄ ), filtered and concentrated to 82 mg (0.17 mmol, 84%). To obtain (13a) (R ² = H, R ³ = Cl, R ⁹ = butyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0) as a glassy solid, which is the next step Used without purification in.

Carbamate (13a) in 1,2-dichloroethane (10 mL) at 23 ° C. (R ² = H, R ³ = Cl, R ⁹ = Butyl, P ¹ = H, P ² = Boc, m = 0) To a solution of (82 mg, 0.17 mmol, 1 equiv) was added H ₂ 0 (0.40 mL) followed by TFA (4.0 mL). After stirring for 20 minutes at 23 ° C., toluene (50 mL) was added and the resulting solution was concentrated to dryness. The residue was semi-prepared HPLC (Waters Nova-Pak® HR C ₁₈ , 6 μm particle size, 60 μs pore size, 20 mm ID x 100 mm, 5-60% acetonitrile w / 0.1 in H ₂ 0 % HCl for 30 min, 20 mL / min flow rate) to afford 41 mg of the title compound as a white solid.

Example 92

3-cyclopropylmethyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (25f) (R ⁹ = cyclopropylmethyl) as shown in the general method Z to intermediate (13a) (R ² ). = H, R ³ = Cl, R ⁹ = cyclopropylmethyl, P ¹ = H, P ² = Boc, m = 0), which was deprotected under acidic conditions to afford the title compound.

Example 93

3-propyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (25f) (R ⁹ = propyl) to show intermediate (13a) (R ² = H) as shown in the general method Z. , R ³ = Cl, R ⁹ = propyl, P ¹ = H, P ² = Boc, m = 0), which was deprotected under acidic conditions to afford the title compound.

Example 94

3-Butyl-1- (2-hydroxy-ethyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide

3-Butyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy] prepared in Example 91 as shown in Scheme 19 (R ⁶ = 2-hydroxyethyl) A sample of -6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide was alkylated with ethylene oxide to afford the title compound.

Example 95

3-Butyl-1-methyl-azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] Amide

Formic acid (95%, 1.0 mL) was added to a solution of Boc-carbamate (25f) (R ⁹ = butyl) (236 mg, 0.92 mmol, 1 equiv) in aqueous formaldehyde (37%, 2.0 mL) at 23 ° C. It was. The resulting mixture was heated at 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 H ₂ 0 (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 H ₂ O to give a cloudy suspension, which was filtered through a nylon membrane (0.2 μm) and concentrated to give 3-butyl-1-methyl-azetidine-2- as the main component. 186 mg of a white solid which is a carboxylic acid hydrochloride salt was obtained. This material was used without further purification.

MS (ESPOS): 172.3 [M + H].

Coupling lincosamine (6b) (R ² = H, R ³ = Cl) with 3-butyl-1-methyl-azetidine-2-carboxylic acid hydrochloride salt as shown in general method Z to afford the title compound. It was.

Example 96

3-Pentyl-azetidine-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (25f) (R ⁹ = pentyl) to show intermediate (13a) (R ² = H) as shown in the general method Z. , R ³ = Cl, R ⁹ = pentyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which was deprotected under acidic conditions to afford the title compound.

Example 97

3- (3-Methyl-butyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)- Profile]-amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (25f) (R ⁹ = 3-methyl-butyl) as shown in general method Z to obtain intermediate (13a) ( R ² = H, R ³ = Cl, R ⁹ = 3-methyl-butyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is deprotected under acidic conditions to give the title The compound was obtained.

Example 98

3- (3-Cyclopropyl-propyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (26f) (R ⁹ = 3-cyclopropyl-propyl) as shown in the general method Z intermediate (13a). (R ² = H, R ³ = Cl, R ⁹ = butyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is deprotected under acidic conditions to give the title compound. It was.

Example 99

3- (3-Cyclobutyl-propyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (26f) (R ⁹ = 3-cyclopropyl-propyl) as shown in the general method Z intermediate (13a). (R ² = H, R ³ = Cl, R ⁹ = (3-cyclobutyl-propyl), P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is obtained under acidic conditions Deprotection gave the title compound.

MS (ESPOS): 451.2 [M + H]

Example 100

3- (2-Cyclobutyl-ethyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (26f) (R ⁹ = 2-cyclobutyl-ethyl) as shown in the general method Z intermediate (13a). (R ² = H, R ³ = Cl, R ⁹ = 2-cyclobutyl-ethyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is deprotected under acidic conditions To give the title compound.

Example 101

3- (2-Cyclopropyl-ethyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (26f) (R ⁹ = 2-cyclopropyl-ethyl) as shown in the general method Z intermediate (13a). (R ² = H, R ³ = Cl, R ⁹ = 2-cyclopropyl-ethyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is deprotected under acidic conditions To give the title compound.

Example 102

3- (3,3-Difluoropropyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2- Yl) -propyl] -amide

Lincosamine (6b) (R ² = H, R ³ = Cl) was coupled with azetedinic acid (26f) (R ⁹ = 3,3-difluoropropyl) as shown in the general method Z to obtain an intermediate ( 13a) (R ² = H, R ³ = Cl, R ⁹ = 2-cyclopropyl-ethyl, P ¹ = H, P ² = carboxylic acid-t-butyl ester, m = 0), which is obtained under acidic conditions Deprotection gave the title compound.

Example 103

4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide

2-Methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propylcarbamoyl] 4-pentyl-pyrrolidine-1-carboxylic acid tert-butyl ester.

2- (1-amino-2-methyl-propyl) -6-propyl-tetrahydro-pyran-3,4,5-triol (51.9) in dry DMF (4.5 mL) prepared by general method AB at 0 ° C. mg, 0.21 mmol, 1 equiv) was added triethylamine (117 μL, 0.84 mmol, 4 equiv) followed by BSTFA (84 μL, 0.32 mmol, 1.5 equiv). The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 45 minutes. The reaction mixture was prepared with the protected amino acid (7d) (R ⁹ = n-pentyl, P = Boc) (72 mg, 0.25 mmol, 1.2 equiv) and HATU (120 mg, 0.32 mmol, 1.5 equiv) prepared by the general method L. Added. The reaction mixture was stirred at rt for 2 h, evaporated to dryness, placed in Et ₂ O (150 mL) and washed with 10% citric acid (1 ×), saturated NaHCO ₃ (1 ×) and brine. The organic layer was dried over MgSO ₄ and concentrated to give the crude product (190 mg) as a yellow oil. The residue was taken in DCE (6 mL) and trifluoroacetic acid (4 mL) containing water (0.2 mL) was added with stirring. The reaction mixture was stirred at rt for 1 h and then co-evaporated repeatedly from DCE to remove solvent in vacuo. Purification by column chromatography on silica using 10% 0.25M NH ₃ in MeOH / DCM afforded the product (38.4 mg, 43%).

Example 104

4-propyl-piperidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide

The title compound in Example 2 was prepared following the process described in Example 103 using Intermediate 10b prepared with the general method O (R ⁹ = n-propyl).

(ESPOS): 401.7 [M + H] ⁺ .

Example 105

4-propyl-piperidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2,2,2-trifluoro-ethylsulfanyl) -tetrahydro- Pyran-2-yl] -propyl} -amide

The intermediate 27a prepared by the general method * was 4-propyl-piperidine-1,2-dicarboxylic acid 1-3-butyl ester.

MS (ESNEG): 270.2 [M ⁻ H] ⁻ .

The title compound was prepared according to the process described in General Method R and illustrated in Scheme 16 using 1,1,1-trifluoroethanethiol as thiol nucleophile. Coupling and deprotection of the protected amino acid intermediate 4-propyl-piperidine-1,2-dicarboxylic acid 1-3-butyl ester was carried out as in Example 103.

(ESPOS): 473.7 [M + H] ⁺ .

Example 106

4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-ethoxyethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide

2- [1- (6-Allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl) -2-methyl-propylcarbamoyl] -4-pentyl-pyrrolidine-1- Carboxylic acid tert-butyl ester.

Building block (15c) (650 mg, 1.26 mmol, 1 equiv) and protected amino acid (7d) (R ⁹ = pentyl, P = Boc) (395 mg, 1.39 mmol, 1.1 in dry DMF (5.0 mL) at 0 ° C. DIEA (0.88 mL, 5.0 mmol, 4 equiv) was added to the stirred solution of solids, followed by solid HATU (956 mg, 2.52 mmol, 2.0 equiv). The reaction mixture was stirred at rt for 3 h, evaporated to dryness, placed in ethyl acetate and washed with 10% citric acid (1 ×), water (1 ×), saturated NaHCO ₃ (1 ×) and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to give a yellow syrup. The filtrate was concentrated and the residue was purified by column chromatography on silica using 10% EtOAc / hexanes to 20% EtOAc / hexanes to give the product 2- [1- (6-allyl-3,4,5- Tris-benzyloxy-tetrahydro-pyran-2-yl) -2-methyl-propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a colorless oil (897 mg, 89%).

2- {2-Methyl-1- [3,4,5-tris-benzyloxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl -Pyrrolidine-1-carboxylic acid tert-butyl ester.

Sustained light blue color was observed by stirring the stirred solution (634 mg, 0.81 mmol, 1 equiv) in DCM (60 mL) at −78 ° C. with a stream of ozone in oxygen for 20 minutes. After 30 minutes excess ozone was removed with a stream of N ₂ , a solution of DMS (3 mL) in DCM (10 mL) was added and the solution was allowed to warm at room temperature overnight. The solution is evaporated to dryness, the residue is dissolved in EtOH (50 mL), cooled to 0 ° C., treated with NaBH ₄ (300 mg 8.1 mmol, 10 equiv) and after 1 h the reaction mixture is acidified Excess NaBH4 to decompose, remove the solvent and the crude product was purified by column chromatography using 20% EtOAc / hexanes on silica to give the alcohol product (304 mg, 47%).

2- {2-Methyl-1- [3,4,5-tris-benzyloxy-6- (2-ethoxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl -Pyrrolidine-1-carboxylic acid tert-butyl ester.

To a stirred solution of NaH (4.4 mg 0.183 mmol, 1 equiv) washed in THF (0.8 mL) at 0 ° C. alcohol intermediate 2- {2-methyl-1- [3,4,5-tris-benzyloxy-6 -(2-hydroxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid tert-butyl ester (144 mg, 0.183 mmol, 1 equiv. ) Was added and after 10 min EtI (73 μL, 0.92 mmol, 5.0 equiv) was added and the reaction mixture was stirred overnight. The reaction mixture is evaporated to dryness, the filtrate is concentrated and the residue is purified by preparative chromatography with 30% EtOAc / hexanes to give the product 2- {2-methyl-1- [3,4,5 -Tris-benzyloxy-6- (2-ethoxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid tert-butyl ester (33.8 mg 22%) was obtained 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- {2-Methyl-1- [3,4,5-tris-benzyloxy-6- (2-ethoxy-ethyl) -tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl -Degussa 50% w / w wet 10% Pd / C (80 mg) suspended in pyrrolidine-1-carboxylic acid tert-butyl ester (33.8 mg) and MeOH (3 mL) at 20 at 1 atmosphere H ₂ Stir for hours. The reaction mixture was filtered through celite and evaporated to dryness to afford the crude product, which was purified by column chromatography using 3% to 5% MeOH / DCM over silica to give Boc protected ether product (19 mg). ) Was obtained, placed in DCE (1 mL) and trifluoroacetic acid (1 mL) containing water (0.05 mL) was added with stirring. The reaction mixture was stirred at rt for 1 h and then co-evaporated repeatedly from DCE to remove solvent in vacuo. Lyophilization of the TFA salt from 1: 1 MeCN / water containing excess HCl afforded the title compound (13.0 mg 66%).

Example 107

1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

The title compound was prepared according to the process illustrated in Scheme 19. Ethylene oxide was used as the alkylating agent. 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl in MeOH (2 mL) at 0 ° C.) To the stirred solution of) -propyl] -amide (Example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μL) was added condensed ethylene oxide (200 μL) and the reaction mixture was stirred for 48 h. It was. The reaction mixture was evaporated to dryness and the resulting residue was purified by column chromatography using 20% 0.25M NH ₃ in MeOH / DCM on silica to give crude N alkylated product. The crude product is taken up in Et ₂ 0, filtered, the filtrate is treated with 2M HCl in Et ₂ O, the precipitated HCl salt is collected, washed with Et ₂ 0 and lyophilized to give the title compound a colorless powder (4.4 mg). , 34%).

MS (ESPOS): 473.6 [M + H] ⁺ .

Example 108

4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propyl] -amide

2- {2-Methyl-1- [3,4,5-tris-hydroxy-tetrahydro-pyran-2-yl] -propylcarbamoyl} -4-pentyl-pyrrolidine-1-carboxylic acid tertiary- Butyl ester.

To a stirred solution of wet Raney Nickel (R1) (300 mg) suspended in EtOH (5 mL) under N ₂ was l- (2- (S) -4- (R) -n-pentylpy in EtOH (5 mL). Ralidin-2-yl) -N- {1- (R)-[2- (S) -3- (S), 4- (S), 5- (R) -trihydroxy-6- (R )-(Methylthio) tetrahydropyran-2-yl] -2-methylprop-1-yl} acetamide (85.0 mg 0.164 mmol, 1 equiv) was added. The reaction mixture is refluxed for 2 hours, cooled to room temperature, filtered through celite and evaporated to dryness to give crude product (66 mg), which is columned with 3% MeOH / DCM over silica. Purification by chromatography gave N-Boc protected des-thiomethyl product (42.7 mg 55%).

TLC R _f = 0.27 (10% MeOH / DCM); MS (ESPOS): 473.6 [M + H] ⁺ , (ESNEG): 507.5 [M + HCl].

4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propyl] -amide.

N-Boc protected product Des-thiomethyl product was placed in DCE (5 mL) and trifluoroacetic acid (5 mL) containing water (0.1 mL) was added with stirring. The reaction mixture was stirred at room temperature for 40 minutes and then co-evaporated repeatedly from DCE to remove solvent in vacuo. The residue is dissolved in 1: 1 MeCN / water, cooled to 0 ° C., 1M HCl (0.5 mL) is added, the solution is filtered and lyophilized to give the title compound (26 mg, 43%) as a colorless powder. Obtained as

TLC (CHCl ₃ : MeOH: 32% aqueous AcOH) R _f = 0.58; MS (ESPOS) 387.3 [M + H] ⁺ .

Examples 109-127, 142, and 143 can be prepared according to the methods described herein.

Example 109

4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide

Example 110

5-propyl-azepane-2-carboxylic acid [2-chloro-l- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 111

5-propyl-azane-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 112

5-propyl-azane-2-carboxylic acid [1- (6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl]- Amide

Example 113

5-propyl-azane-2-carboxylic acid [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -methyl] -amide

Example 114

4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 115

4-Pentyl-pyrrolidine-2-carboxylic acid [1- (6-Butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide

Example 116

4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl]- Amide

Example 117

Phosphoric Acid Mono- (4,5-Dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} 2-propyl-tetrahydro-pyran -3- days) ester

Example 118

Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran -3- days ester

Example 119

Phosphoric Acid Mono- (4,5-Dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} 2-propyl-tetrahydro-pyran -3- days) ester

Example 120

Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran -3- days ester

Example 121

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 122

2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Example 123

1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 124

2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Example 125

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl]- Profile} -amide

Example 126

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl]- Profile} -amide

Example 127

4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 142

4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-methylsulfanyl-ethyl) -tetrahydro-pyran-2-yl] -Propyl} -amide

Example 143

4-propyl-pyrrolidine-2-carboxylic acid [1- (6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide.

The following specific prodrug examples 128 to 141 are prepared from each of the parent compounds above using the methods described above.

Example 128

Phosphoric Acid Mono- (6- {2-Chloro-1-[(5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro -Pyran-3-yl) ester

Example 129

Hexadecanoic acid 6- {2-chloro-1-[(5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetrahydro- Pyran-3-yl ester

Example 130

Phosphoric Acid Mono- (6- {2-chloro-1-[(5-fluoro-5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2- Methylsulfanyl-tetrahydro-pyran-3-yl) ester

Example 131

Hexadecanoic acid 6- {2-chloro-1-[(5-fluoro-5-propyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfan Yl-tetrahydro-pyran-3-yl ester

Example 132

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -5-fluoro-5-propyl- Azepan-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Example 133

5-Fluoro-1- (5-methyl-2-oxo- [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

Example 134

5-cyclopropylmethyl-1- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -azepane-2-carboxylic acid [2-chloro-1- (3,4,5 -Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example 135

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -5-cyclopropylmethyl-azepan- 1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Example 136

Hexadecanoic acid 6- {2-chloro-1-[(5-cyclopropylmethyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl-tetra Hydro-pyran-3-yl ester

Example 137

Phosphoric acid mono- (6- {2-chloro-1-[(5-cyclopropylmethyl-azpan-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methylsulfanyl- Tetrahydro-pyran-3-yl) ester

Example 138

Hexadecanoic acid 6- {2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl) -amino] -propyl} -4,5-dihydroxy-2-methyl Sulfanyl-tetrahydro-pyran-3-yl ester

Example 139

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

Example 140

2- [2-Chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-fluoro-4-propyl- Piperidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester

Example 141

4-Fluoro-1- (5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-propyl-piperidine-2-carboxylic acid [2-chloro-1- (3 , 4,5-Trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide

Example A

Sensitivity test

Compounds were tested according to the microdilution method of the National Council of Clinical Trials (NCCLS). Dilution antimicrobial sensitivity test method for aerobic growing bacteria; [Approved standard-5 edition. NCCLS Document M7-A5, NCCLS, Wayne, PA. 2000; National Council of Clinical Trials. Methods for testing antimicrobial sensitivity of anaerobic bacteria; [Approved Standard-5 Edition. NCCLS Document M11-A4, NCCLS, Wayne, PA. 2001]. Assays were performed in sterile 96-well microtiter trays (Graner) with round wells.

Compound manufacture

Stock solutions of test compounds and control antibiotics were prepared at 10 mg / ml in DMSO. DMSO was used as solvent to dilute each drug serially 2-fold to 100-fold of the desired final concentration in microtiter plates across each column. The wells of columns # 1-11 contain drug and column # 12 was stored as growth control for microorganisms in the absence of drug. Each well in the parent plate was diluted with sterile deionized water, mixed and dispensed in a volume of 10 μL to each well in the resulting assay plate.

Preparation of Inoculum

Stock cultures were prepared using the MicroBank ^™ method (Pro-Lab Diagotics) and stored at -80 ° C. To propagate aerobic strain, one bead is removed from the frozen vial, aseptically streaked on trypticase soy agar (diffco), chocolate agar (remel) or blood agar (remel), overnight 35 Incubated at ℃. Anaerobic microorganisms were incubated in Brussela agar (Remel) supplemented with hemin and vitamin K at 35 ° C. for 24 to 48 hours using anaerobic jar (Mitsubishi). NCCLS Guidelines (Methods for Diluting Antimicrobial Sensitivity Tests for Bacteria Growing in Aerobic Environments; [Approved standard-5 edition. NCCLS Document M7-A5, NCCLS, Wayne, PA. 2000]; National Clinical Trials Standards Council.Standardized inoculum was prepared using direct colony suspension according to the method for testing antimicrobial susceptibility of anaerobic bacteria; [Approved Standard-5 Edition. NCCLS Document M11-A4, NCCLS, Wayne, PA. 2001]. . Isolated colonies were selected from agar plates from 18 to 24 hours, resuspended in 0.9% sterile saline and matched to 0.5 McFarland turbidity criteria. The suspension was used within 15 minutes of preparation.

Preparation of Assay Plates for MIC

Medium was prepared at a concentration of 1.1. Müller-Hilton Bros MHB (Diffco) supplemented with Ca ++ and Mg ++ as recommended by NCCLS, MHB, HTM bros (Remel) supplemented with 5% horse lysed blood, or hemin and vitamin K Brucella Bros (Remel) supplemented with. In each organism, the standardized suspension was diluted with the appropriate growth medium in a sterile reservoir. After mixing, wells in drug containing assay plates were inoculated in a volume of 90 μl. As such, for each MIC measurement, each well contains a final volume of 100 μl with an inoculation size of about 5 * 105 cfu / ml and a DMSO of 1% or less.

Interpretation of the MIC

The completed microtiter plate was incubated for 16 to 20 hours at 35 ° C. in aerobic organisms for aerobic organisms and 46 to 48 hours at 35 ° C. in anaerobic organisms (Mitsubishi) for anaerobic organisms. The optical density of each well was measured at 600 nm using a Versamax microplate reader (Molecular Devices, Sunnyvale, CA). MIC was defined as the lowest drug concentration resulting in complete inhibition of observable bacterial growth.

Isomer I of Example 47 and Isomer II of Example 47 had an in vitro potency of MIC ≦ 4 μg / mL against Gram-negative microorganisms. In comparison to clindamycin, which showed 8 μg / mL of MIC for strain ATCC 31517 in H. influenza, isomers 1 and 2 of Example 47 also showed MIC of 0.5 μg / mL for strain ATCC 31517 in H. influenza.

Example B

Efficacy of S. aureus Sepsis in Murine

Models known in the art (Goldstein, BP, G. Candiani, TM Arain, G. Romano, I. Ciciliato, M. Berti, M. Abbondi, R. Scotti, M. Mainini, F. Ripamonti, and et al 1995.Antimicrobial activity of MDL 63, 246, a new semisynthetic glycopeptide antibiotic Antimicrob Agents Chemother. 39: 1580-1588 .; Misiek, M., TA Pursiano, F. Leitner, and KE Price 1973. Microbiological properties of a new cephalosporin , BL-S 339: 7- (phenylacetimidoyl-aminoacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) ceph-3-em-4-carboxylic acid Antimicrob Agents Chemother. 3: 40 Efficacy test was performed in the S. arueus murine sepsis model according to

Compound manufacture

Compounds were dissolved in 2% Tween 80 for oral administration or in 0.9% NaCl solution for intravenous administration. Compounds were administered 1 hour after bacterial inoculation. Vancomycin or ampicillin was used as a control.

Efficacy Model

Male or female ICR mice weighing 22 ± 2 g from MDS Pharma Service were used for evaluation. Food and water were provided freely. A group of 6 mice weighing 22 ± 2 g was used in the experiment. Mice were inoculated intraperitoneally with 4 104 CFU Staphylococcus aureus Smith in 0.5 ml Brain Heart Infusion Broth (Diffco) with 5% mucin (Sigma). Death was confirmed once a day for 7 days after bacterial inoculation.

While the invention has been described and illustrated herein with reference to various specific materials, procedures, and examples, it will be understood that the invention is not limited to material combinations of specific materials and procedures selected for this purpose. Those skilled in the art will appreciate that many variations on these details are possible.

Claims (19)

A compound of formula (IA), or a pharmaceutically acceptable salt thereof: <Formula IA>

Where

Is a double bond; R ¹ is C _1-8 alkylsulfanyl; R ² and R ³ are independently selected from the group consisting of hydrogen, hydroxy, halo and C _1-8 alkyl; R ⁶ is hydrogen; C _{1 -8} alkyl; And hydroxy, cyano, already selected from the furnace, carbamoyl or a C _{1 -8} imidazole group consisting of alkyl substituted with imidazolyl; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Halo, cyano, C _{1 -8} alkyl, C _{3 -8} cycloalkyl, C _{3 -8} cycloalkenyl skill fluoride, C _{1 -8} alkoxyimino, C _{1 -8} alkyl substituted with thiazolyl, pyridinyl, already pyridazinyl, tiolran yl, C _1-8 substituted alkyl child rapid fire group, the C _1-8 alkyl ylsulfanyl, halo-substituted C _1-8 alkyl ylsulfanyl, substituted C _1-8 alkyl days furan ylsulfanyl or tea to Using the method of monosubstituted C _{1 -8} alkyl day 0498; C _{2 -8} alkenyl; Substituted C _{2 -8} alkenyl days halo or pyridine; Halo; And -S (O) _q R ¹³ ; q is an integer of 0, 1 or 2; R ¹³ is a C _{1 -8} alkyl; C _{1 -8} alkyl, halo, C _{1 -8-substituted} phenyl, phenyl, thiophenyl or substituted C _1-8 alkyl days pyrazine substituted by halo-alkyl; And phenyl substituted with halo; m ¹ is 0 to 2; t is 0-3. The method of claim 1, The nitrogen-containing ring in formula (IA)

Phosphorus compounds. A compound selected from the group consisting of: 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide; 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-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide; 1- (2-Methoxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide; 1- (1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra Hydro-pyran-2-yl) -propyl] -amide; 1- (2-Formylamino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide; 1- (2-Amino-ethyl) -4-pentyl-pyrrolidine-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-pentyl-pyrrolidine- 1-yl} -acetic acid methyl ester; 1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide; 1-Iminomethyl-4-pentyl-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-chloro-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; 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide; And 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide. A compound of formula (IB), or a pharmaceutically acceptable salt thereof: <Formula IB>

Where R ¹ is hydrogen; C _1-8 alkyl; C _1-8 alkyl substituted with hydroxy, C _1-8 alkoxy, C _3-8 cycloalkyl or C _1-8 alkylsulfanyl; C _1-8 alkoxy; And C _1-8 alkylsulfanyl substituted with halo; R ² and R ³ are independently selected from hydrogen, hydroxy, halo and C _{1 -8} group consisting of alkyl; R ⁶ is hydrogen; C _{1 -8} alkyl; And it is selected from a hydroxy C _{1 -8} alkyl substituted by the group consisting of; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Halo, cyano, C _{1 -8} alkyl, C _{3 -8} cycloalkyl, C _{3 -8} cycloalkyl alkylidene, C _{1 -8} alkoxyimino, C _{1 -8} alkyl substituted with thiazolyl, pyridinyl, imidazolyl , tiolran yl, C _1-8 substituted alkyl child snapshot thiazolyl, C _1-8 alkyl ylsulfanyl, C _1-8 alkyl substituted with halo ylsulfanyl, substituted C _1-8 alkyl days furan or thiophene-ylsulfanyl substituted C _{1 -8} alkyl days 0498 days; C _{3 -8} cycloalkyl; And halo; m is 1; only Compound of formula IB is (Streptococcus ah streptococcus pneumoniae pneumoniae ), Staphylococcus aureus), Staphylococcus epidermidis (Staphylococcus epidermidis), Enterococcus nose kusu par potassium switch (Enterococcus faecalis), Enterobacter nose kusu par when Titanium (Enterococcus faecium ), Haemophilus influenzae ), Moraxella catarrhalis ), Escherichia coli ), Bacteroides fragilis , Bacteroides tetaotaomicron ( Bacteroides thetaiotaomicron ) and Clostridium difficile ) has a minimum inhibitory concentration of 32 μg / mL or less for one or more organisms selected from the group consisting of: A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -propyl] -amide; 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; 1- (2-hydroxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2 -Yl) -propyl] -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]- Amides; Phosphoric acid mono- (4,5-dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro- Pyran-3-yl) ester; Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran 3-yl ester; Phosphoric acid mono- (4,5-dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro- Pyran-3-yl) ester; Hexadecanoic acid 4,5-dihydroxy-6- {2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl) -amino] -propyl} -2-propyl-tetrahydro-pyran 3-yl ester; 1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-pentyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester; 1- (5-Methyl-2-oxo- [1,3] dioxol-4-ylmethyl) -4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5- Trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propyl] -amide; 2- [2-Methyl-1- (3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl) -propylcarbamoyl] -4-propyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester; 4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-hydroxy-ethyl) -tetrahydro-pyran-2-yl]- Propyl} -amide; 4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (3-hydroxy-propyl) -tetrahydro-pyran-2-yl]- Propyl} -amide; 4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -propyl] -amide; 4-propyl-pyrrolidine-2-carboxylic acid {2-methyl-1- [3,4,5-trihydroxy-6- (2-methylsulfanyl-ethyl) -tetrahydro-pyran-2-yl] -Propyl} -amide; And 4-propyl-pyrrolidine-2-carboxylic acid [1- (6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl) -2-methyl-propyl] -amide. A pharmaceutical composition for treating a bacterial infection in a mammal, comprising a therapeutically effective amount of the compound according to claim 1 or 4 and a pharmaceutically acceptable carrier. The method of claim 6, A pharmaceutical composition for administering a compound to a mammal orally, parenterally, transdermally, topically, rectally or intranasally. The method of claim 6, A pharmaceutical composition wherein the compound is administered in an amount of 0.1 to 100 mg / kg body weight / day. A compound of formula (I), or a pharmaceutically acceptable salt thereof: <Formula I>

Where W is a nitrogen-containing ring

ego; m is 0 or 1; Positions in the nitrogen-containing ring are numbered consecutively in a counterclockwise direction starting with 1 in nitrogen; R ¹ is hydrogen; C _{1 -8} alkyl; Hydroxy, C _{1 -8} alkoxy, C _{3 -8} cycloalkyl or C _{1 -8-substituted} C _{1 -8} alkyl days alkylsulfanyl; C _{1 -8} alkoxy; C _{1 -8} alkyl ylsulfanyl; And it is selected from the group consisting of a C _{1 -8} days alkylsulfanyl substituted with halo; R ² and R ³ are independently selected from the group consisting of hydrogen, hydroxy, halo and C _1-8 alkyl; R ⁶ is hydrogen; C _{1 -8} alkyl; Hydroxy, cyano, imino, carbamoyl or substituted C _{1 -8} alkyl-imidazolyl; C _{3 -8} cycloalkyl;

It is selected from the group consisting of; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Haloalkyl, C _{1 -8} alkyl ylsulfanyl, halo-substituted C _{1 -8} alkyl ylsulfanyl, furan days substituted C _{1 -8} alkyl ylsulfanyl or thiophenyl substituted C _{1 -8} alkyl day to 0498; And C _{3 -8} independently selected from the group consisting of cycloalkyl-alkyl; only Excludes compounds in which all R ⁹ are hydrogen. A compound of formula (IA), or a pharmaceutically acceptable salt thereof: <Formula IA>

Where

Is a double bond; R ¹ is C _{1 -8} alkylsulfanyl day and; R ² and R ³ are independently selected from hydrogen, hydroxy, halo and C _{1 -8} group consisting of alkyl; R ⁶ is hydrogen; C _1-8 alkyl; C _1-8 alkyl substituted with hydroxy, cyano, imino, carbamoyl or imidazolyl;

It is selected from the group consisting of; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Halo, cyano, C _{1 -8} alkyl, C _{3 -8} cycloalkyl, C _{3 -8} cycloalkyl alkylidene, C _{1 -8} alkoxyimino, C _{1 -8} alkyl substituted with thiazolyl, pyridinyl, imidazolyl , tiolran yl, C _1-8 substituted alkyl child snapshot thiazolyl, C _1-8 alkyl ylsulfanyl, C _1-8 alkyl substituted with halo ylsulfanyl, substituted C _1-8 alkyl days furan or thiophene-ylsulfanyl substituted C _{1 -8} alkyl days 0498 days; C _{2 -8} alkenyl; Substituted C _{2 -8} alkenyl days halo or pyridine; C _{3 -8} cycloalkyl; Halo; And -S (O) _q R ¹³ ; q is an integer of 0, 1 or 2; R ¹³ is a C _{1 -8} alkyl; C _{1 -8} alkyl, halo, C _{1 -8-substituted} phenyl, phenyl, thiophenyl or substituted C _1-8 alkyl days pyrazine substituted by halo-alkyl; And phenyl substituted with halo; m ¹ is 0 to 2; t is 0-3. The method of claim 10, The nitrogen-containing ring of formula (I)

Phosphorus compounds. A compound of formula (IB), or a pharmaceutically acceptable salt thereof: <Formula IB>

Where R ¹ is hydrogen; C _{1 -8} alkyl; Hydroxy, C _{1 -8} alkoxy, C _{3 -8} cycloalkyl or C _{1 -8-substituted} C _{1 -8} alkyl days alkylsulfanyl; C _{1 -8} alkoxy; And it is selected from the group consisting of a C _{1 -8} days alkylsulfanyl substituted with halo; R ² and R ³ are independently selected from hydrogen, hydroxy, halo and C _{1 -8} group consisting of alkyl; R ⁶ is hydrogen; C _{1 -8} alkyl; And hydroxy is selected from the group consisting of a substituted C _{1 -8} alkyl; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Halo, cyano, C _{1 -8} alkyl, C _{3 -8} cycloalkyl, C _{3 -8} cycloalkyl alkylidene, C _{1 -8} alkoxyimino, C _{1 -8} alkyl substituted with thiazolyl, pyridinyl, imidazolyl , tiolran yl, C _1-8 substituted alkyl child snapshot thiazolyl, C _1-8 alkyl ylsulfanyl, C _1-8 alkyl substituted with halo ylsulfanyl, substituted C _1-8 alkyl days furan or thiophene-ylsulfanyl substituted C _{1 -8} alkyl days 0498 days; C _3-8 cycloalkyl; And halo; m is 1. A compound of formula (II): or a pharmaceutically acceptable salt thereof: <Formula II>

Where W is a nitrogen-containing ring

ego; m is 0 or 1; Positions in the nitrogen-containing ring are numbered consecutively in a counterclockwise direction starting with 1 in nitrogen; R ¹ is hydrogen; C _1-8 alkyl; C _1-8 alkyl substituted with hydroxy, C _1-8 alkoxy, C _3-8 cycloalkyl or C _1-8 alkylsulfanyl; C _1-8 alkoxy; C _1-8 alkylsulfanyl; And C _1-8 alkylsulfanyl substituted with halo; R ²⁰ and R ²¹ are independently hydrogen, hydroxy, halo, C _{1 -8} alkyl or alkenyl or C _{2 -8} alkenyl, or R ²⁰ and R ²¹ are together substituted with C _{3 -8} cycloalkyl, phenyl or halo, Forms phenyl; R ⁶ is hydrogen; C _{1 -8} alkyl; Hydroxy, cyano, imino, carbamoyl or substituted C _{1 -8} alkyl-imidazolyl; C _{3 -8} cycloalkyl;

It is selected from the group consisting of; R ⁹ which may be mono- or polysubstituted in the ring on the same or different carbons is hydrogen; C _1-8 alkyl; Thiazolyl, pyridinyl, imidazolyl substituted with halo, cyano, C _1-8 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkylidene, C _1-8 alkoxyimino, C _1-8 alkyl , tiolran yl, C _1-8 substituted alkyl child snapshot thiazolyl, C _1-8 alkyl ylsulfanyl, C _1-8 alkyl substituted with halo ylsulfanyl, substituted C _1-8 alkyl days furan or thiophene-ylsulfanyl substituted C _{1 -8} alkyl days 0498 days; C _3-8 cycloalkyl; And halo. A compound selected from the group consisting of: 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide; 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-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide; 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; 1- (2-Methoxy-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro- Pyran-2-yl) -propyl] -amide; 1- (1H-imidazol-2-ylmethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetra Hydro-pyran-2-yl) -propyl] -amide; 1- (2-Formylamino-ethyl) -4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran -2-yl) -propyl] -amide; 1- (2-Amino-ethyl) -4-pentyl-pyrrolidine-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-pentyl-pyrrolidine- 1-yl} -acetic acid methyl ester; 1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl ) -Propyl] -amide; 1-Iminomethyl-4-pentyl-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-chloro-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; 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2 -Yl) -propyl] -amide; 4-propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran- 2-yl) -propyl] -amide; And 3- (3-Cyclobutyl-propyl) -azetidine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -Propyl] -amide. A pharmaceutical composition for treating a bacterial infection in a mammal, comprising a therapeutically effective amount of the compound according to any one of claims 10 and 12 to 14 and a pharmaceutically acceptable carrier. The method of claim 15, A pharmaceutical composition for treating a bacterial infection caused by any pathogen of Haemophilus influenzae, Enterococcus paecalis and Enterococcus paesium. The method of claim 15, A pharmaceutical composition for administering a compound to a mammal orally, parenterally, transdermally, topically, rectally or intranasally. The method of claim 15, A pharmaceutical composition wherein the compound is administered in an amount of 0.1 to 100 mg / kg body weight / day. 5-propyl-azepine-2-carboxylic acid [2-chloro-1- (3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide .