TW201350498A - Mannose derivatives for treating bacterial infections - Google Patents

Abstract

The present invention relates to compounds useful for the treatment or prevention of bacteria infections. These compounds have formula I: The invention also provides pharmaceutically acceptable compositions containing the compounds and methods of using the compositions in the treatment of bacteria infections. Finally, the invention provides processes for making compounds of the invention.

Description

Mannose derivative for the treatment of bacterial infections Cross-reference to related applications

The present invention claims the benefit of U.S. Provisional Application No. 61/607,778, filed on March 7, 2012, and the benefit of U.S. Provisional Application No. 61/621,776, filed on Apr. 9, 2012; The entire content of each is incorporated herein by reference.

Inflammatory bowel disease (IBD) is a complex chronic inflammatory condition in which two of the more common forms are ulcerative colitis (UC) and Crohn's disease (CD). IBD is a multifactorial disease that results from a combination of susceptibility genetic factors, environmental triggers, gastrointestinal microbial dysbiosis, and inappropriate inflammatory responses (Man et al., 2011, Nat Rev Gastroenterol Hepatol, Mar, 8(3): 152 -68).

Several studies on fecal and mucosal-associated bacterial communities have shown that microbes in patients with Crohn's disease (CD) differ from microbes in healthy controls, and in patients with ulcerative colitis (UC) The same is true. Despite the reported change does not always consistent, but in general the number of E. coli (Escherichia coli) of the increase, and CD patients of Firmicutes (Firmicute) small (Peterson et al., 2008, Cell Host Microbe, 3 : 17- 27; Frank et al., 2007, Proc. Natl. Acad. Sci., 104: 13780-13785). Whether these changes are pathogenic factors or after inflammation is still controversial. To date, several pathogens have been proposed as pathogenic agents. In particular, it has been reported that CD patients in several countries (UK, France, and the United States) have more adherent invasive E. coli (AIEC) than controls (Darfeuille-Michaud et al., 2004, Gastroenterology, 127: 412-421; Martinez-Medina et al., 2009, Inflamm Bowel Dis., 15: 872-882). The AIEC strain has been isolated from ileal lesions of approximately 35% of CD patients compared to approximately 5% of healthy individuals. One of the characteristics of AIEC is its ability to adhere to and invade epithelial cells. It is known from various models that adhes expressed on bacterial cells bind to a specified glycosylation receptor on the surface of the host tissue as an initial and critical step in the pathogenesis, followed by opening novel therapeutic approaches, such as blocking type 1 bacteria. Interaction between hair and CEACAM6 (known host receptor for FimH) (Barnich et al, 2007, J. Clin. Invest., 117: 1566-1574; Carvalho et al, 2009, JEM, vol. 206, no .10, 2179-2189). Therefore, inhibiting the adhesion of AIEC in epithelial cells and thereby inhibiting intracellular replication can prevent the formation of submucosal infections that cause mucosal inflammation and destruction of the epithelial barrier.

It has also been shown in recent years that FimH antagonists are potentially effective in the treatment of urinary tract infections (J. Med. Chem. 2010, 53, 8627-8641).

The present invention provides a compound or pharmaceutically acceptable salt suitable for use in the treatment or prevention of bacterial infections, such as urinary tract infections (UTI) and inflammatory bowel diseases (IBD).

These compounds have the formula (I):

Wherein: X is -H, halogen, (C ₁ -C ₆ )alkyl, -NR ₅ R ₆ , -SR ₇ or -OR ₇ ; Y is absent or is a C ₁ -C ₁₀ aliphatic group, wherein the C Up to four methylene units of the ₁ -C ₁₀ aliphatic group may be optionally substituted with -NR ₈ , -O-, -S-, -C(O)-, -S(O)- or -SO ₂ -; Y is optionally substituted 1-2 times with halogen, OH, C _3-6 cycloalkyl or C _1-6 aliphatic; R ₁ is cycloalkyl, heterocyclyl, aryl or heteroaryl; Substituted by one or more R ₃ or R _3A groups; and R ₂ is -H or alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl; each optionally by one or more Substituting R ₃ or R _3B groups; R ₃ is halogen, -CN, NO ₂ , cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl or C ₁ -C ₁₀ aliphatic, wherein Up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be via -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - Or -P(O)-substitution; each R _{3 is} optionally substituted with one or more R ₄ or R _4A groups; R _3A is a C ₁ -C ₁₀ aliphatic group, wherein the C ₁ -C ₁₀ aliphatic group Up to four methylene units may optionally be via -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P ( O)-substituted; alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic; each optionally substituted by one or more R ₄ or R _4A groups; R _3B is aryl, aralkyl or hetero Aryl; R _3B optionally substituted with one or more R ₄ or R _4A groups; R ₄ is -H or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R _4A is halogen, CN, NO ₂ or C ₁ -C ₁₀ aliphatic group, wherein the C ₁ -C ₁₀ aliphatic group Up to four methylene units may be replaced by -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P(O)-; Each R _{4A is} optionally substituted with 0-3 halo; R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl Or a heteroaryl group, -C(O)R ₉ , -C(O)NHR ₉ or -C(O)OR ₉ ; R ₇ is -H, optionally substituted alkyl, alkenyl, alkynyl, ring An alkyl group, a heterocyclic group, a heteroaryl group or an aryl group, -C(O)R ₉ or -C(O)NHR ₉ ; R ₈ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, or _{-C (O) R 9; R} 9 is -H, optionally substituted by the , Cycloalkyl, heterocyclyl, aryl or heteroaryl; R ₁₀ is -H, -OH, halogen, or optionally substituted alkyl of C ₁ -C _6, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4.

The invention also provides a composition comprising a compound described herein and a pharmaceutically acceptable carrier, adjuvant or vehicle.

The invention also provides a method of treating or preventing a bacterial infection in an individual comprising administering to the individual an effective amount of a compound or composition described herein. The invention also provides methods of preparing the compounds of the invention.

Figure 1: X-ray powder diffraction pattern of Compound 48.

Figure 2: Thermogravimetric analysis (TGA) trace of Compound 48.

The present invention relates to compounds suitable for the treatment or prevention of bacterial infections such as urinary tract infections (UTI) and inflammatory bowel diseases (IBD).

One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein: X is -H, halogen, (C ₁ -C ₆ )alkyl, -NR ₅ R ₆ , -SR ₇ or -OR ₇ ; Y is absent or is a C ₁ -C ₁₀ aliphatic group, wherein the C Up to four methylene units of the ₁ -C ₁₀ aliphatic group may be optionally substituted with -NR ₈ , -O-, -S-, -C(O)-, -S(O)- or -SO ₂ -; Y is optionally substituted 1-2 times with halogen, OH, C _3-6 cycloalkyl or C _1-6 aliphatic; R ₁ is cycloalkyl, heterocyclyl, aryl or heteroaryl; Substituted by one or more R ₃ or R _3A groups; and R ₂ is -H or alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl; each optionally by one or more Substituting R ₃ or R _3B groups; R ₃ is halogen, -CN, NO ₂ , cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl or C ₁ -C ₁₀ aliphatic, wherein Up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be via -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - Or -P(O)-substitution; each R _{3 is} optionally substituted with one or more R ₄ or R _4A groups; R _3A is a C ₁ -C ₁₀ aliphatic group, wherein the C ₁ -C ₁₀ aliphatic group Up to four methylene units may optionally be -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P(O a substitution; an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or a heterocyclic group; each optionally substituted with one or more R _4A groups; R _3B is an aryl group, an arylalkyl group or a heteroaryl group; _{3B is} optionally substituted with one or more R _4A groups; R ₄ is -H or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, ring An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group; R _4A is a halogen, CN, NO ₂ or C ₁ -C ₁₀ aliphatic group, wherein at most four methylene groups of the C ₁ -C ₁₀ aliphatic group The unit may be replaced by -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P(O)-; each R _4A may be 0 depending on the situation. -3 halo substituents; R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) R ₉ , -C(O)NHR ₉ or -C(O)OR ₉ ; R ₇ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Heteroaryl or aryl, -C(O)R ₉ or -C(O)NHR ₉ ; R ₈ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , heteroaryl, aryl or -C(O)R ₉ ; R ₉ is -H, optionally substituted alkyl, naphthenic Or a heterocyclic group, an aryl group or a heteroaryl group; R ₁₀ is -H, -OH, halogen or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4.

In some embodiments, R _{1 is} not a hydrazine or a triazole, and the compound of formula (I) cannot have a structure selected from the group consisting of:

Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein: X is -H, halogen, (C ₁ -C ₆ )alkyl, -NR ₅ R ₆ , -SR ₇ or -OR ₇ ; Y is absent or is -NR ₈ , -O-, -S-, -C(O)O-, -C(O)-, -C(O)N(R ₈ )(CH ₂ ) _m -, -N(R ₈ )C(O)O-, -OC(O) NR ₈ -, -NR ₈ SO ₂ -, -NR ₈ -C(O)-, -SO ₂ -, -NR ₈ C(O)NR ₈ -, -S(O)-, -SO ₂ NR ₈ - , -(C ₁ -C ₆ )alkyl or -(O-(C ₁ -C ₆ alkyl)) _n ; R ₁ is cycloalkyl, heterocyclyl, aryl or heteroaryl; Substituted with one or more R ₃ groups; and R ₂ is -H or alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl; each optionally via one or more R ₃ groups Substituted, wherein R ₃ is -OH, -CN, halogen, -C(R ₁₀ ) ₃ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ ,- SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ , -P(O)(R ₄ ) ₂ , -P(R ₄ ) ₂ , -C ₆ H ₄ -R ₄ or alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl; One or more R ₄ groups, wherein R ₄ is -H or optionally substituted alkyl of C ₁ -C _6, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or hetero Aryl, -C(O)R ₉ , -C(O)NHR ₉ or -C(O)OR ₉ ; wherein R ₇ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkane Or a heterocyclic group, a heteroaryl group or an aryl group, -C(O)R ₉ or -C(O)NHR ₉ ; wherein R ₈ is -H, optionally substituted alkyl, alkenyl, alkynyl, Cycloalkyl, heterocyclyl, heteroaryl, aryl or -C(O)R ₉ ; wherein R ₉ is -H, optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl or hetero Aryl; wherein R ₁₀ is -H, -OH, halogen or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, cycloalkyl, heterocyclo Or aryl or heteroaryl; wherein m is 0, 1 or 2; and wherein n is 0, 1, 2, 3 or 4; in some embodiments, R _{1 is} not hydrazine or triazole, and (I) the compound cannot have a group selected from the group consisting of Structure:

In some embodiments, R ₁ is bonded via a carbon atom.

In other embodiments, R ₁ is cycloalkyl, heterocyclic, aryl or heteroaryl; each optionally substituted with one or more R ₃ groups; R ₂ is -H or alkyl, cycloalkyl, Heterocyclic, aryl, aralkyl or heteroaryl; each optionally substituted by one or more R ₃ groups, wherein R ₃ is -OH, -CN, halogen, -C(R ₁₀ ) ₃ , -( CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R _{4 2} , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ , -P(O) (R ₄ ) ₂ , -P(R ₄ ) ₂ , -C ₆ H ₄ -R ₄ or alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl And optionally substituted by one or more R ₄ groups, wherein R ₄ is -H or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl a cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aromatic Base or heteroaryl, -C(O)R ₉ , -C(O)NH R ₉ or -C(O)OR ₉ ; wherein R ₇ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl or aryl, -C(O R ₉ or -C(O)NHR ₉ ; wherein R ₈ is -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl, aryl or -C ( O)R ₉ ; wherein R ₉ is -H, optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein R ₁₀ is -H, -OH, halogen or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl. Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof embodiment, X is -OH, -F, -OCH ₃ or -CH _3.

Another embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein X is -OR ₇ ; Y is absent or is a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be -NR ₈ , -O-, -S-, -C(O)-, -S(O)- or -SO ₂ - substitution; Y optionally substituted by halogen, OH, C _3-6 cycloalkyl or C _1-6 aliphatic 2 times; R ₁ is a C _6-10 aryl group optionally substituted with one or more R _3A groups; and R ₂ is H, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl, (C _6-10 aryl)-(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl; each R ₂ independently and optionally one or more R _3B groups a group substituted and optionally substituted with one R ₃ group; each R _3A and R _{3B is} independently halogen, -CN, NO ₂ , C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic group, (C _{6 -10} aryl)-(C ₁ -C ₆ alkyl)-; or a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may be optionally subjected to -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P(O)-substituted; each R _3A and R _3B independently and optionally Or a plurality of R ₄ or R _4A groups; R ₃ is C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl, (C _6-10 aryl)-(C ₁ -C ₆ alkyl) - 5-10 membered heteroaryl, or Group; each R ₃ is optionally substituted by one or more R ₄ or R _4A group; R ₄ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; each R _{4 is} optionally substituted with one or more R _4B groups; R _4A is a halogen, CN, NO ₂ or C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be -NR ₄ , -O-, -S-, - C(O)-, -S(O)-, -SO ₂ - or -P(O)-substituted; each R _{4A is} optionally substituted with 0-3 halo; R _4B is halogen, CN, NO ₂ or a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group are optionally subjected to -NR, -O-, -S-, -C(O)-, -S (O)-, -SO ₂ - or -P(O)-substituted; each R _{4A is} optionally substituted with 0-3 halo; R ₇ is H or has 1-2 selected from oxygen, nitrogen or sulfur a heterocyclic 5- to 6-membered heterocyclic group; wherein the 5-6 membered heterocyclic group is independently and optionally substituted by C _1-4 alkyl to 1-4 times, wherein the C _1-4 alkyl group is at most one sub The methyl unit is optionally substituted by -O-; R ₈ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 -8 Heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or _{-C (O) R 9; R} 9 and R ₁₀ are each independently C ₁ -C ₆ alkyl or C ₃ -C ₆ Cycloalkyl; R is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4.

In some embodiments, the compound is not one of the following:

In some embodiments, R _{1 is} optionally substituted with 1-4 R _3A groups; or in some embodiments, with 1-2 R _3A groups. In other embodiments, R ₂ is optionally substituted with 1-4 R _3B groups; or, in some embodiments, substituted with 1-2 R _3B groups. In some embodiments, each R _3A and R _{3B is} optionally substituted with 1-4 R _4A groups; or in some embodiments, with 1-2 R _4A groups. In other embodiments, R _{2 is} optionally substituted with one R ₃ group.

In some embodiments, R _{3 is} optionally substituted with 1-4 R ₄ or R _4A groups; or in some embodiments, with 1-2 R ₄ or R _4A groups. In some embodiments, R _{4 is} optionally substituted with 1-4 R _4B groups; or, in some embodiments, R _4B is substituted with 1-2 groups.

According to another embodiment, Y is absent or is -NR ₈ , -O-, -S-, -C(O)-, -C(R ₁₀ )(OH)-, -C(O)N(R ₈ )(CH ₂ ) _m -, -N(R ₈ )C(O)O-, -OC(O)NR ₈ -, -NR ₈ SO ₂ -, -NR ₈ -C(O)-, -SO ₂ -, -NR ₈ C(O)NR ₈ -, -S(O)-, -SO ₂ NR ₈ , -(C ₁ -C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl-, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O-(C _1-6 alkyl)NR ₈ C(O)-, -O -(C _1-6 alkyl)C(O)NR ₈ , -O-(C _1-6 alkyl)-C(O)- or -((C ₁ -C ₆ )alkyl)-O-; Each of R _3A and R _{3B is} independently -OH, -CN, halogen, -C(R ₁₀ ) ₃ , -C(R ₁₀ ) ₂ OH, -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C (O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O)( R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ or -P(O)(R ₄ ) ₂ ; and R _4A is -OH, - CN, halogen, -C(R ₁₀ ) ₃ , -C(R ₁₀ ) ₂ OH, -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N (R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ , -P(O)(R ₄ ) ₂ ; R ₇ is H or a mannose group.

According to another embodiment, X is -OH; Y is absent or is -NR ₈ , -O-, -S-, -C(O)-, -C(R ₁₀ )(OH)-, -SO ₂ - , -S(O)-, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkenyl, -(C ₁ -C ₆ )alkynyl,-(O-(C ₁ -C) ₆ alkyl)) _n -, -O(C _1-6 alkyl)NR ₈ C(O)-, -O-(C _1-6 alkyl)-C(O)NR ₈ , -O-(C _1-6 alkyl)C(O)- or -((C ₁ -C ₆ )alkyl)-O-; R ₂ is C _6-10 aryl, (C _6-10 aryl)-(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl; each R _{2 is} independently and optionally substituted by one or more R _3B and optionally substituted with one R ₃ ; R ₃ is C _6-10 aryl (C _6-10 aryl)-(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl; each R ₃ independently and optionally one or more selected from R ₄ or R _4A The group is substituted; and R ₈ is -H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl.

In the compound of the invention or a pharmaceutically acceptable salt thereof to another embodiment, X is -OH; Y is absent or is -O -, - S -, - OC (O) NR 8 - , or -C ( O) N(R ₄ )(CH ₂ ) _m -; R ₁ is an aryl group optionally substituted with one or more R _3A groups; and R ₂ is -H or alkyl, cycloalkyl, heterocyclic, Aryl, aralkyl or heteroaryl; each optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ ; each R _3A and R _{3B are} independently -OH, -CN, halogen, -C(R ₁₀ ) ₃ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)R ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , C ₁ -C ₆ alkane a aryl group, an aryl group, an arylalkyl group or a heteroaryl group; each optionally substituted with one or more R ₄ groups; wherein each R _{4 is} independently -H or C ₁ -C ₆ alkyl; wherein m is 0, 1 or 2; and wherein n is 0, 1, or 2.

According to another embodiment, X is -OH; Y absent; R ₁ is optionally substituted with one or more halo, -OR ₄ or _{- (CH 2) n C (} O) OR 4 of substituted phenyl; R ₂ a heteroaryl group optionally substituted with one or more R _3B groups; R _3B is C ₁ -C ₆ alkyl or C(R ₁₀ ) ₃ ; and R ₄ is H or C ₁ -C ₆ alkyl.

According to another embodiment, X is -OH; Y absent; R ₁ is optionally substituted with one or more halo, -OR ₄ or _{- (CH 2) n C (} O) OR 4 of substituted phenyl; R ₂ An aryl group substituted by one or more R 3 _B groups as appropriate; R _3B is -OH, halogen, -CN, -OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)NHR ₄ , -NH-C(O)R ₄ , -SO ₂ R ₄ or -C(O)OR ₄ ; R ₄ is H or a C ₁ -C ₆ alkyl group.

Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof in the embodiment, Y is _{-C (O) N (R 4} ) (CH 2) m -, especially -C (O) NH-.

Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof in the embodiment, Y is -OC (O) NR ₈ -, especially -OC (O) NH-.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl or C ₁ -C ₆ alkynyl.

In another embodiment of the compound of the invention or a pharmaceutically acceptable salt thereof, Y is absent.

In another embodiment of the compound of the invention or a pharmaceutically acceptable salt thereof, Y is -O-.

Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof embodiment, R ₁ is optionally substituted phenyl it. In other embodiments, R ₁ is an optionally substituted naphthyl group.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₁ is optionally substituted phenyl, and R _{1 is} especially one or more halogen, -OR ₄ or -(CH ₂ a phenyl group substituted with _n C(O)OR ₄ . In some embodiments, R ₁ is phenyl substituted with one or more halo, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl. In other embodiments, R ₁ is phenyl substituted with one or more R _3A , wherein R _3A is halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl Or a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group are optionally substituted by -NR ₄ , -O- or -C(O)-. In some embodiments, R ₄ is —H or C ₁ -C ₆ alkyl.

In another embodiment, R ₁ is phenyl substituted with one or more R _3A , wherein R _3A is fluoro, bromo, chloro, CH ₃ , CH ₂ CH ₃ , —C≡CH, OH, OCH ₃ , OCF ₃ , -OCH ₂ C(CH ₃ ) ₃ , -O(CH ₂ ) ₄ CF ₃ , -OCH ₂ C(O)NHCH ₃ , -OCH ₂ C(O)OCH ₃ , -OCH ₂ C≡CCH ₂ CH ₃ , -O(CH ₂ ) ₃ CN, -OCH ₂ CH(CH ₃ )CH ₂ CH ₃ , -OCH ₂ CH ₂ CH(CH ₃ ) ₂ , -O(CH ₂ ) ₃ OCH ₃ , -O( CH ₂ ) ₂ F, -O(CH ₂ ) ₃ F or -CH ₂ CH ₂ C(O)OCH ₃ .

Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof embodiment, R ₂ is optionally substituted with one or more substituent groups R _3B and optionally substituted with one of R ₃ heteroaryl ring. In one example, the heteroaryl ring is selected from the group consisting of pyrazole, thiadiazole, quinoline, anthracene, thiazole, pyridine, and benzothiazole; in another example, the heteroaryl ring is selected from the group consisting of A group consisting of pyrimidine, benzodioxole, benzodioxane, benzothiophene, anthracene, pyrazole, and benzimidazole. In another embodiment, the heteroaryl ring is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, thienyl, thiadiazolyl, thiazolyl, oxadiazolyl, pyridyl, pyrimidinyl , benzodioxolyl, fluorenyl, benzimidazolyl, benzothiazolyl, benzooxadiazolyl, imidazopyridyl, quinolinyl, oxetanyl, tetra Hydroperyl and C _3-6 cycloalkyl.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₂ is an aryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ , and R _{2 is} especially A phenyl or naphthalene which is optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ .

In some embodiments, R ₂ is substituted with one R ₃ group. In some embodiments, R ₃ is phenyl as shown in the formula below.

In some embodiments, R ^3A , R ^{3B ,} and R ^{4A are} each independently halo, —O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl, and R ² is 6 member aryl or heteroaryl. Base ring.

In some embodiments, R _3B is halogen, CN, NO ₂ or C _1-6 aliphatic, wherein up to four methylene units of the C _1-6 aliphatic group may optionally be via -NR ₄ , -O -, -C(O)- or -S(O) ₂ -, wherein R _{3B is} optionally substituted with one or more halogens. In some embodiments, R _{3B is} independently halo, —O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl. In other embodiments, R _3B is fluorine, chlorine, CN, NO ₂ , NH ₂ , CH ₃ , CF ₃ , C(O)CH ₃ , C(O)NH(CH ₃ ), CH ₂ OH, OH, Butyl, CH ₂ C(O)NHCH ₃ or S(O) ₂ CH ₃ . In still other embodiments, R _3B is C ₁ -C ₆ alkyl or C(R ₁₀ ) ₃ . In some embodiments, R _3B is fluoro, chloro, CN, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , C(CH ₃ ) ₃ , C(O)CH ₃ , CH ₂ C(O) OCH ₃ , C(O)OH, C(O)OCH ₃ , C(O)NHCH ₃ , NHC(O)CH ₃ , NHC(O)CHC(CH ₃ ) ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ N(CH ₃ ) ₂ , NH ₂ , N(CH ₃ ) ₂ , OH, OCH ₃ , O(CH ₂ ) ₂ CH ₃ , S(O) ₂ NHCH ₃ or S(O) ₂ CH ₃ . In other embodiments, R _3B is -OH, halogen, -CN, -OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n N (R ₄ ) ₂ , -C(O)NHR ₄ , -NH-C(O)R ₄ , -SO ₂ R ₄ or -C(O)OR ₄ .

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₂ is C ₁ -C ₆ alkyl, cycloalkyl or aralkyl optionally substituted with one or more R 3 _B groups. base. In some embodiments, R _{2 is} also substituted with one R ₃ group.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₂ is an aryl, aralkyl or heteroaryl group optionally substituted with one or more R _3B groups, and R _{2 is} especially Phenyl, benzyl or thienyl, each optionally substituted with one or more R 3 _B groups. In some embodiments, R _{2 is} also substituted with one R ₃ group.

According to another embodiment, R ₁ is phenyl and R ₂ is phenyl.

Another embodiment provides a compound represented by the formula:

In some embodiments, each R ^3A and R ^{3B are} independently halo, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl); and R ₃ is optionally one or more R ₄ Or a heteroaryl ring substituted with an R _4A group. In some embodiments, R ₃ is a 5-membered heteroaryl group, especially an oxadiazolyl, pyrazolyl or thiadiazolyl group. In some embodiments, R ₃ is a heteroaryl ring selected from the group consisting of oxadiazolyl.

In another embodiment of the compound of the invention or a pharmaceutically acceptable salt thereof, R ₂ is -H.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently halogen, C ₁ -C ₆ alkyl or benzyl.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently halogen, C ₁ -C ₆ alkyl or -N(R ₄ ) ₂ .

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently C ₁ -C ₆ alkyl or -C(R ₁₀ ) ₃ .

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently halogen, C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl) .

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently -OH, halogen, -CN, -OR ₄ , -(CH ₂ ) _n C(O )OR ₄ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)NHR ₄ , -NH-C(O)R ₄ , -SO ₂ R ₄ or -C(O)OR ₄ .

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, each of R ^3A and R ^{3B is} independently halogen, C ₁ -C ₆ alkyl, -(CH ₂ ) _n C(O)OR ₄ or -C(O)NHR ₄ . In other embodiments, each of R ^3A and R ^{3B is} independently halogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl).

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₃ is a heteroaryl ring optionally substituted with one or more R ₄ or R _4A groups, the heteroaryl ring being especially Oxadiazole. In some embodiments, R ₃ is a heteroaryl ring optionally substituted with one or more R ₄ groups.

In another embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R ₄ is -H or C ₁ -C ₆ alkyl.

According to another embodiment, X is -OR ₇ and R ₇ is H or .

In some embodiments, R _{7 is} bonded as shown by the formula IA, IB, IC or ID:

Wherein R ₁ , Y and R _{2 are} as defined in any one of the technical solutions.

In other embodiments, R ₇ is H. In some embodiments, X is -OH, -F, -OCH ₃ or -CH _3.

According to another embodiment, X is -OR ₇ and R ₇ is H or ; R ₁ is phenyl or naphthyl; Y is absent or is -O-, -C(O)N(R ₈ )(CH ₂ ) _m -, -OC(O)NR ₈ -, -(C ₁ - C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl-, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O (C _1-6 alkyl)NR ₈ C(O)-, -O(C _1-6 alkyl)C(O)NR ₈ , -O(C _1-6 alkyl)C(O)- or- ((C ₁ -C ₆ )alkyl)-O-; R ₂ is C _6-10 aryl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur Or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur; a 3-8 membered monocyclic heterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur a cyclic group; or a C _3-6 cycloalkyl group; and R ³ is a phenyl group or a 5-6 membered monocyclic heteroaryl group having from 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur.

According to another embodiment, X is -OR ₇ and R ₇ is H or ; R ₁ is phenyl or naphthyl; Y is absent or is -O-, -C(O)N(R ₈ )(CH ₂ ) _m -, -OC(O)NR ₈ -, -(C ₁ - C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl-, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O (C _1-6 alkyl)NR ₈ C(O)-, -O(C _1-6 alkyl)C(O)NR ₈ , -O(C _1-6 alkyl)C(O)- or- ((C ₁ -C ₆ )alkyl)-O-; R ₂ is phenyl, naphthyl, imidazolyl, pyrazolyl, triazolyl, thienyl, thiadiazolyl, thiazolyl, oxadiazolyl , pyridyl, pyrimidinyl, benzodioxolyl, fluorenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, quinolinyl, oxa Cyclobutane, tetrahydropentanyl and C _3-6 cycloalkyl; and R ³ is phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl , thiadiazolyl, pyridyl.

In some embodiments, Y is absent or is -O -, - S -, - C (O) O -, - C (O) -, - C (O) N (R 4) -, - N (R ₄ ) C(O)O-, -OC(O)NR ₄ -, -NR ₄ SO ₂ -, -NR ₄ -, -NR ₄ -C(O)-, -SO ₂ -, -NR ₄ C ( O) NR ₄ -, -S(O)-, -SO ₂ NR ₄ -, -(O-(C ₁ -C ₆ alkyl)) _n or optionally substituted alkyl, alkenyl, alkynyl, Cycloalkyl, heterocyclic, aryl or heteroaryl; in some embodiments, R _{4 is} independently -H or optionally substituted C ₁ -C ₆ alkyl, cycloalkyl, heterocyclic, aryl Or a heteroaryl; in some embodiments, R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl , -C(O)R ₉ , -C(O)NHR ₉ , -C(O)OR ₉ , C(O)NR ₉ SO ₂ -R ₉ or S(O) ₂ R ₉ ; and R ₇ is - H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl, aryl, -C(O)R ₉ or -C(O)NHR ₉ .

Without being bound by theory, certain compounds of the invention may be metabolized by mannoside to a compound that is effective as a FimH inhibitor. The compounds have the formula (I), or a pharmaceutically acceptable salt thereof:

Wherein X is -OR ₇ and an R ₇ sugar derivative such as a mannose derivative.

In some embodiments, the compound is represented by one of the following formulas:

Or a pharmaceutically acceptable salt thereof, wherein X, R ₁ , Y and R _{2 are} as defined herein. In some embodiments, X is OH.

In some embodiments, X is -H, halo, (C ₁ -C ₆ )alkyl, -NR ₅ R ₆ , -SR ₇ or -OR ₇ ; Y is absent or is -O-, -S-, -C(O)O-, -C(O)-, -C(O)N(R ₄ )-, -N(R ₄ )C(O)O-, -OC(O)NR ₄ -,- NR ₄ SO ₂ -, -NR ₄ -, -NR ₄ -C(O)-, -SO ₂ - , -NR ₄ C(O)NR ₄ -, -S(O)-, -SO ₂ NR ₄ - , (O-(C ₁ -C ₆ alkyl)) _n or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R ₁ is or alkane a base, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; each optionally substituted with one or more R ₃ groups, R ₂ being -H or alkyl, cycloalkyl, hetero a ring, aryl or heteroaryl; each optionally substituted by one or more R ₃ groups, wherein R ₃ is halogen, -OR ₄ , -C(O)OR ₄ , -C(O)R ₄ ,- C(O)N(R ₄ ) ₂ , -OC(O)N(R ₄ ) ₂ , -NR ₄ C(O)OR ₄ , -NR ₄ SO ₂ R ₄ , -N(R ₄ ) ₂ ,- NR ₄ C(O)R ₄ , -SO ₂ -R ₄ , -NR ₄ C(O)N(R ₄ ) ₂ , -S(O)R ₄ , -SO ₂ N(R ₄ ) ₂ , -SR ₄ , -P(O)(OR ₄ ) ₂ , -P(O)(R ₄ ) ₂ , -P(R ₄ ) ₂ , -C ₆ H ₄ -R ₄ or alkyl, alkenyl, alkynyl, Cycloalkyl, heteroaryl or heterocyclic; each case Substituted by one or more R ₄ groups, wherein each R _{4 is} independently -H or optionally substituted C ₁ -C ₆ alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein R ₅ and R _{6 are} each independently -H, optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, -C(O)R ₈ , -C(O)NR ₈ SO ₂ -R ₈ , -S(O) ₂ R ₈ or -C(O)OR ₈ ; wherein R ₇ is -H, optionally substituted alkyl, cycloalkyl, heterocyclic, heteroaryl or aryl, -C(O)R ₈ or -C(O)NR ₅ R ₆ ; wherein R ₈ is -H, optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; It is 0, 1, 2, 3 or 4.

In another embodiment, the compounds of the invention are represented by the following structural formula: Or a pharmaceutically acceptable salt thereof.

In another embodiment, the compounds of the invention are represented by the following structural formula: Or a pharmaceutically acceptable salt thereof.

Another acceptable in the compound of the invention or a pharmaceutically acceptable salt thereof embodiment, X is -OH, -F, -OCH ₃ or -CH _3.

In another embodiment, the compounds of the invention are represented by the following structural formula: Or a pharmaceutically acceptable salt thereof, wherein: X is -OH; Y is absent or is -O- or -S-; and R ₁ is alkyl, alkenyl or aryl; each optionally one or more Substituting R ₃ groups; R ₂ is -H or alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; each optionally substituted with one or more R ₃ groups; wherein R ₃ is -OH , halogen, -C(O)NHR ₄ , -NHC(O)R ₄ , -OR ₄ , -C(O)OR ₄ , -SO ₂ -R ₄ or, as the case may be, substituted by one or more R ₄ groups An alkyl group, a cycloalkyl group or a heterocyclic ring; each R _{4 is} independently -H or optionally substituted by a C ₁ -C ₆ alkyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, Y is -O-.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, Y is absent.

Another acceptable compound or the pharmaceutically salt thereof embodiment, R ₁ is optionally substituted phenyl it.

Embodiment, R ₁ is a substituted phenyl the hydroxyl group on another compound acceptable salt thereof, or a pharmaceutically embodiment.

Embodiment, R ₁ is a substituted phenyl group of the methoxy group on another compound acceptable salt thereof, or a pharmaceutically embodiment.

Embodiment, R ₁ is an alkenyl group in another acceptable compound or a pharmaceutically acceptable salt of embodiment, in particular a propylene group.

Another acceptable compound or the pharmaceutically salt thereof embodiment, R ₁ is C ₁ -C ₆ alkyl, in particular propyl.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is -H.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is optionally substituted C ₁ -C ₆ alkyl.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is unsubstituted C ₁ -C ₆ alkyl, especially methyl.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is substituted C ₁ -C ₆ alkyl substituted with halogen, especially with -F.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is a C ₁ -C ₆ alkyl group substituted with a cycloalkyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is a C ₁ -C ₆ alkyl group substituted with a cyclopentyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is C ₁ -C ₆ alkyl substituted with -C(O)O-CH ₃ .

Another acceptable compound or the pharmaceutically salt thereof embodiment, R ₂ is the optionally substituted phenyl.

Embodiment, R ₂ is halogen compound in another acceptable salt thereof, or a pharmaceutically embodiment, in particular the phenyl group substituted by -F.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is phenyl substituted with one or more C ₁ -C ₆ alkyl groups, especially methyl.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is phenyl substituted with one or more guanamines, especially -C(O)NHR ₄ wherein R ₄ is C ₁ - C ₆ alkyl, and preferably methyl.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is phenyl substituted with one or more -NHC(O)R ₄ wherein R ₄ is C ₁ -C ₆ alkyl, It is preferably an isopropyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is phenyl substituted with oxadiazole, and the oxadiazole is further substituted with a C ₁ -C ₆ alkyl group, especially oxadiazole It is a 1,3,4-oxadiazole substituted with a methyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is phenyl substituted with -SO ₂ -(C ₁ -C ₆ )alkyl, especially -SO ₂ -CH ₃ .

Another acceptable compound or the pharmaceutically salt thereof embodiment, R ₂ is diazine, especially pyrimidine.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is cycloalkyl, especially cyclohexane.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is a benzimidazole substituted with a C ₁ -C ₆ alkyl group, especially a methyl group.

In another embodiment of the compound or a pharmaceutically acceptable salt thereof, R ₂ is -C(O)O-(C ₁ -C ₆ )alkyl, especially via -C(O)O-CH ₃ Substituted phenyl.

Another embodiment provides a compound as described in Table 1:

Another embodiment provides a compound selected from the group consisting of compounds 48, 104, 105, 106, 107, 108, 111, 112, 120, 121, 125, 126, 127, 128, 131, 133, 136 , 142, 150, 176 or 178. Another embodiment provides a compound selected from the group consisting of Compound 265 to Compound 290. Another embodiment provides a compound selected from the group consisting of Compound 1 to Compound 72 and Compound 291 to Compound 296.

For the sake of clarity, it should be understood that the list of continuous compounds includes all compounds within the range. For example, "Compound 1 to Compound 3" also means Compound 1, Compound 2 and Compound 3.

method

The invention also provides methods of preparing the compounds of the invention.

One embodiment provides a method of preparing compound 48:

It contains one or more of the following steps:

A) Let the compound of formula ia:

Compound with formula ib:

The formula is formed by reaction with a Suzuki coupling condition known to those skilled in the art (e.g., with a suitable palladium coupling agent in a suitable solvent (such as with diethyl p-oxypalladium in acetonitrile)). Compound:

B) reacting a compound of formula ic under suitable conditions for hydroxylation (for example with OsO ₄ and 4-methyl-4-oxo- morpholine-4-indole in tetrahydrofuran) to form a compound of formula id:

C) reacting a compound of formula id under suitable conditions for oximation (for example with acetic anhydride, a suitable base such as dimethylaminopyridine) and a suitable solvent such as pyridine to form a compound of formula:

D) Let the compound of formula IE and the compound of formula:

Under conditions known to those skilled in the art to be suitable for Suzuki coupling (e.g., with a suitable palladium coupling agent and optionally a base, in a suitable solvent (such as with diethyl p-methoxy palladium, in acetonitrile, or with Pd (PPh) ₃ ) ₄ and sodium bicarbonate, reacted in dioxane)) to form a compound of formula ig:

E) The protecting group of the compound of formula i-g is removed under suitable conditions for the removal of ethyl hydrazide (for example, with a strong base in a suitable solvent (such as with MeONa in methanol) to form compound 48.

The invention also provides a composition comprising a compound described herein and pharmaceutically An acceptable carrier, adjuvant or vehicle.

The invention also provides a method of treating or preventing a bacterial infection in an individual comprising administering to the individual an effective amount of a compound or composition described herein.

In one embodiment of the method, the bacterial infection is a urinary tract infection or an inflammatory bowel disease.

As described herein, a specified number of atoms ranges from any integer therein. For example, a group having 1-4 atoms may have 1, 2, 3 or 4 atoms. The term "stable" as used herein refers to a compound that does not substantially change upon being subjected to conditions that permit its production, detection, recovery, storage, purification, and for one or more of the purposes disclosed herein. In some embodiments, the stabilizing compound or chemically feasible compound is a compound that does not substantially change when maintained at a temperature of 40 ° C or less at a temperature of 40 ° C or less in the absence of moisture or other chemical reaction conditions.

The term "aliphatic" or "aliphatic" as used herein, means a straight (ie unbranched) or branched hydrocarbon chain which is fully saturated or contains one or more unsaturated units but is non-aromatic. base.

Unless otherwise specified, the aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 8 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. The aliphatic group may be a linear or branched substituted or unsubstituted alkyl, alkenyl or alkynyl group. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, t-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

The term "alkyl" as used herein means a saturated straight or branched chain hydrocarbon. The term "alkenyl" as used herein means a straight or branched chain hydrocarbon containing one or more double bonds. The term "alkynyl" as used herein means a straight or branched chain hydrocarbon containing one or more reference bonds.

The term "cycloaliphatic" (or "carbocyclic" or "carbocyclic" or "carbon cyclic") A ring containing a non-aromatic monocyclic carbon having from three to fourteen ring carbon atoms which may be saturated or contain one or more units of unsaturation. In some embodiments, the ring has from three to ten ring carbon atoms; in other embodiments, the ring has three to six carbon atoms. The term includes polycyclic fused, spiro or bridged carbocyclic systems. The term also encompasses polycyclic ring systems wherein the carbocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the linking group or point of attachment is in the carbon On the ring. A fused bicyclic system comprises two rings sharing two adjacent ring atoms, the bridged bicyclic group comprising two rings sharing three or four adjacent ring atoms, the spiro double ring system sharing one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term "heterocycle" (or "heterocyclyl" or "heterocyclic" as used herein) is intended to mean a non-aromatic monocyclic ring having from three to fourteen ring atoms, wherein one or more ring carbons Substituted by a hetero atom such as N, S or O, the non-aromatic monocyclic ring may be saturated or contain one or more units of unsaturation. In some embodiments, the ring has from three to ten ring atoms; in other embodiments, the ring has three to six ring atoms. In still other embodiments, the ring has five to six ring atoms. The term includes polycyclic fused, spiro or bridged heterocyclic systems. The term also encompasses polycyclic ring systems wherein the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the linking group or point of attachment is heterozygous On the ring.

Examples of heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, imidazolidinyl, azepanyl, diazepanyl, triazacyclocycle Heptyl, azacyclooctyl, diazacyclooctyl, triazacycloalkyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazepine Cyclooctyl, oxazepine, thiazepine, thiazepine, benzimidazolone, tetrahydrofuranyl, tetrahydropentanyl, tetrahydrothiophenyl, A phenyl group (including, for example, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrole Pyridyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl , 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidin Pyridyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, porphyrin Tetrahydroquinolinyl, tetrahydro- isoquinolinyl, thieno thienyl, thiophenyl and thiazolyl, benzothiazepin A benzodithiazyl group, a 3-(1-alkyl)-benzimidazol-2-one group, and a 1,3-dihydro-imidazol-2-one group.

Cyclic groups such as cycloaliphatic and heterocyclic rings can be linearly fused, bridged or spirocyclic.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or hydrazine (including any oxidized form of nitrogen, sulfur, phosphorus or hydrazine; any quaternized form of a basic nitrogen; or a heterocyclic ring) It can be substituted for nitrogen, such as N (as in 3,4-dihydro-2 H -pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in pyrrolidinyl substituted on N) ).

The term "unsaturated" as used herein means a portion having one or more units of unsaturation. As is known to those skilled in the art, the unsaturated group can be a partially unsaturated or fully unsaturated group. Examples of partially unsaturated groups include, but are not limited to, butene, cyclohexene, and tetrahydropyridine. The fully unsaturated group can be an aromatic, anti-aromatic or non-aromatic group. Examples of fully unsaturated groups include, but are not limited to, phenyl, cyclooctatetraene, pyridyl, thienyl, and 1-methylpyridine-2(1H)-one.

The term "alkoxy" or "thioalkyl" as used herein, means oxygen ("alkoxy", eg, -O-alkyl) or sulfur ("thioalkyl", eg, -S-alkane. An atom is attached to a molecule of an alkyl group as defined previously.

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" mean an alkyl, alkenyl or alkoxy group optionally substituted by one or more halogen atoms. This term includes perfluorinated alkyl groups, such as -CF ₃ and -CF ₂ CF _3.

The terms "halogen", "halo" and "halo" mean F, Cl, Br or I.

The term "aryl" as used alone or as part of a larger part (as in "aralkyl", "aralkyloxy" or "aryloxyalkyl") refers to a carbocyclic aromatic ring system. System. The term "aryl" is used interchangeably with the term "aromatic ring".

Carbocyclic aromatic ring groups have only carbon ring atoms (usually six to fourteen) and include monocyclic aromatic rings (such as phenyl) and fused polycyclic aromatic ring systems (two or more of which are carbon rings) The aromatic rings are fused to each other). Examples include 1-naphthyl, 2-naphthyl, 1-indenyl and 2-indenyl. a group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic) (such as indoline, phthalimido, naphthylimine, phenidine) The base or tetrahydronaphthyl group, wherein the linking group or point of attachment is on the aromatic ring, is also included within the scope of the term "carbocyclic aromatic ring" as used herein.

The terms "heteroaryl", "heteroaromatic", "heteroaryl ring" used alone or as part of a larger part (as in "heteroarylalkyl" or "heteroarylalkoxy"). , "heteroaryl" and "heteroaromatic" refer to a heteroaromatic ring group having five to fourteen members, including a monocyclic heteroaromatic ring and a polycyclic aromatic ring (wherein a single ring aromatic ring and One or more other aromatic rings are fused). Heteroaryl groups have one or more ring heteroatoms. A group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic) wherein the linking group or point of attachment is on the aromatic ring is also included in the term "heteroaryl" as used herein. Within the scope of this. A bicyclic 6,5 heteroaromatic ring as used herein is, for example, a six member heteroaromatic ring fused to a second five membered ring wherein the linking group or point of attachment is on a six membered ring.

It will be appreciated that the 5-10 membered heteroaryl group includes both monocyclic and bicyclic rings. For example, it may include a 5-6 membered monocyclic ring having 1-4 hetero atoms selected from oxygen, nitrogen or sulfur and a 8- to 6 hetero atom selected from oxygen, nitrogen or sulfur. 10 members double looped ring.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazole A thiazolyl, isothiazolyl or thiadiazolyl group (including, for example, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxanyl) Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3 -pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 -triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl), oxazolyl, benzimidazolyl, benzothienyl, benzofuranyl, fluorenyl, benzene And triazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isodecyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thia Diazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, fluorenyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (eg 2- Quinolinyl, 3-quinolyl, 4-quinolinyl) and isoquinolinyl (eg 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolinyl).

The terms "protecting group" and "protecting group" as used herein are interchangeable and refer to an agent used to temporarily block one or more suitable functional groups of a compound having multiple reactive sites. In certain embodiments, the protecting group has one or more of the following features or preferably all of the following features: a) selective addition to the functional group in a good yield to give a protected substrate, b) the substrate for one or more The reactions occurring at other reactive sites are stable; and c) can be selectively removed in good yield by reagents that do not attack the functional groups that are regenerated and that remove the protecting groups. As will be appreciated by those skilled in the art, in some cases, such agents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are described in detail in "Protective Groups in Organic Synthesis" by Greene, TW, Wuts, PG, Third Edition, John Wiley & Sons, New York: 1999 (and other versions of the book), the entire contents of which are The manner of reference is incorporated herein. The term "nitrogen protecting group" as used herein refers to an agent used to temporarily block one or more suitable nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen protecting groups also have the features exemplified above for the protecting groups and certain exemplary nitrogen protecting groups are also described in detail in Greene, Tw, Wuts, PG "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: Chapter 7 of 1999, the entire contents of which are incorporated herein by reference.

In some embodiments, when indicated, the methylene unit of the aliphatic chain is optionally replaced with another atom or group. Examples of such atoms or groups include, but are not limited to, -NR-, -O-, -C(O)-, -C(=N-CN)-, -C(=NR)-, -C( =NOR)-, -S-, -S(O)-, and -S(O) ₂ -. These atoms or groups can be combined to form larger groups. Examples of such larger groups include (but are not limited to) -OC (O) -, - C (O) CO -, - CO 2 -, - C (O) NR -, - C (= N-CN) , -NRC(O)-, -NRC(O)O-, -S(O) ₂ NR-, -NRSO ₂ -, -NRC(O)NR-, -OC(O)NR-, and -NRSO ₂ NR - wherein R is, for example, an H or C _1-6 aliphatic group or other group as defined herein.

It will be appreciated that such groups may be bonded to the methylene unit of the aliphatic chain via a single bond, a double bond or a para-bond. An example of a substitution (in this case, a nitrogen atom) which is optionally bonded via a double bond to an aliphatic chain is -CH ₂ CH=N-CH ₃ . In some cases, especially at the end, displacements, as the case may be, may be bonded to the aliphatic group via a bond. An example of such a substitution is CH ₂ CH ₂ CH ₂ C≡N. It should be understood that in this case, the terminal nitrogen is not bonded to another atom.

It should also be understood that the term "methylene unit" may also refer to a branched or substituted methylene unit. For example, in the isopropyl moiety [-CH(CH ₃ ) ₂ ], the replacement of the aforementioned "methylene unit" by a nitrogen atom (eg, NR) will yield dimethylamine [-N(CH ₃ ) ₂ ]. In the case of such a person, those skilled in the art should understand that the nitrogen atom is not bonded to any other atom, and in this case, the "R" of "NR" does not exist.

Only such substitutions and combinations of groups that result in a stable structure are contemplated. Substitutions that may be present as appropriate may occur at either end of the chain and/or chain; that is, at the point of attachment and/or also at the end. Two alternatives that are optionally present may also be adjacent to each other within the chain as long as they produce a chemically stable compound. Displacement, as the case may be, also completely replaces all carbon atoms in the chain. For example, C ₃ aliphatic group optionally substituted with -NR -, - C (O) - , and -NR- to form a substituted -NRC (O) NR- (urea).

Unless otherwise indicated, if a substitution occurs at the end, the replacement atom binds to the terminal H. For example, if -CH ₂ CH ₂ CH _{3 is} optionally replaced by -O-, the resulting compound can be -OCH ₂ CH ₃ , -CH ₂ OCH ₃ or -CH ₂ CH ₂ OH. It will be appreciated that if the terminal atom does not contain any free valence electrons, no hydrogen atom is required at the end (e.g., -CH ₂ CH ₂ CH=O or -CH ₂ CH ₂ C≡N).

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformal, and rotational) forms of the structure. For example, the invention includes the R and S configurations of the asymmetric centers, the (Z) and (E) double bond isomers, and the (Z) and (E) configuration isomers. As will be appreciated by those skilled in the art, the substituents are free to rotate about any rotatable key. For example, draw Substituent .

Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational, and rotational mixtures of the present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In the compounds of the invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a location is specifically designated as "H" or "hydrogen", it should be understood that the location has a natural abundance of isotopic composition of hydrogen. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "氘", the position shall be deemed to have a natural abundance (which is 0.015%) of at least 3340 times abundance (ie, incorporated) At least 50.1% 氘).

Both "D" and "d" refer to 氘.

In addition, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, a compound having the structure of the present invention other than replacing hydrogen with hydrazine or hydrazine or replacing carbon with ¹³ C or ¹⁴ C concentrated carbon is within the scope of the present invention. Such compounds are useful in biological assays as, for example, analytical tools or probes.

As indicated herein, upon indication, the compounds of the invention may be taken by one or more conditions as appropriate Substituent substitutions, such as generally described herein or as exemplified by particular classes, subclasses, and materials of the invention. It should be understood that the phrase "replaced as appropriate" and the phrase "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" whether or not preceded by the term "optionally" refers to the replacement of a hydrogen group in a given structure with a group of a given substituent. Unless otherwise indicated, optionally substituted groups may have substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified group, The substituents at each position may be the same or different.

Only such selections and combinations of substituents that result in a stable structure are contemplated. These selections and combinations are apparent to the general practitioner and can be determined without experimentation.

The term "ring atom" is an atom (such as C, N, O or S) in the ring of an aromatic group, a cycloalkyl group or a non-aromatic heterocyclic ring.

The "substitutable ring atom" in the aromatic group is a ring carbon or a nitrogen atom bonded to a hydrogen atom. Hydrogen may be replaced by a suitable substituent as appropriate. Thus, the term "substitutable ring atom" does not include a ring nitrogen or carbon atom that is shared when the two rings are fused. Further, the "substitutable ring atom" does not include a ring carbon or a nitrogen atom, wherein the structure depicts that the ring carbon or nitrogen atom has been attached to a portion other than hydrogen.

An aryl group, as defined herein, may contain one or more substitutable ring atoms which may be bonded to a suitable substituent. Examples of suitable substituents on the substitutable ring carbon atom of the aryl group include R'. R' is -Ra, -Br, -Cl, -I, -F, -ORa, -SRa, -O-CORa, -CORa, -CSRa, -CN, -NO ₂ , -NCS, -SO ₃ H, -N(RaRb), -COORa, -NRcNRcCORa, -NRcNRcCO ₂ Ra, -CHO, -CON(RaRb), -OC(O)N(RaRb), -CSN(RaRb), -NRcCORa, -NRcCOORa, -NRcCSRa , -NRcCON(RaRb), -NRcNRcC(O)N(RaRb), -NRcCSN(RaRb), -C(=NRc)-N(RaRb), -C(=S)N(RaRb), -NRd-C (=NRc)-N(RaRb), -NRcNRaRb, -S(O) _p NRaRb, -NRcSO ₂ N(RaRb), -NRcS(O) _p Ra, -S(O) _p Ra, -OS(O) _p NRaRb or -OS(O) _p Ra; wherein p is 1 or 2.

Ra-Rd are each independently -H, an aliphatic group, an aromatic group, a non-aromatic carbocyclic or heterocyclic group or -N(RaRb) which together form a non-aromatic heterocyclic group. The aliphatic, aromatic and non-aromatic heterocyclic groups represented by Ra-Rd and the non-aromatic heterocyclic group represented by -N(RaRb) are each optionally and independently represented by one or more groups represented by R ^# Replaced by the regiment. Ra-Rd is preferably unsubstituted.

R ^# is halogen, R ⁺ , -OR ⁺ , -SR ⁺ , -NO ₂ , -CN, -N(R ⁺ ) ₂ , -COR ⁺ , -COOR ⁺ , -NHCO ₂ R ⁺ , -NHC(O) R ⁺ , -NHNHC(O)R ⁺ , -NHC(O)N(R ⁺ ) ₂ , -NHNHC(O)N(R ⁺ ) ₂ , -NHNHCO ₂ R ⁺ , -C(O)N(R ⁺ ₂ , -OC(O)R ⁺ , -OC(O)N(R ⁺ ) ₂ , -S(O) ₂ R ⁺ , -SO ₂ N(R ⁺ ) ₂ , -S(O)R ⁺ , -NHSO ₂ N(R ⁺ ) ₂ , -NHSO ₂ R ⁺ , -C(=S)N(R ⁺ ) ₂ or -C(=NH)-N(R ⁺ ) ₂ .

R ⁺ is -H, C1-C4 alkyl, monocyclic aryl, non-aromatic carbocyclic or heterocyclic, each optionally substituted by alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NO ₂ , amine, alkylamine or dialkylamine substitution. R ^{+ is} preferably unsubstituted.

An aliphatic or non-aromatic heterocyclic or carbocyclic group as used herein may contain one or more substituents. An example of a suitable substituent for a ring carbon of an aliphatic or non-aromatic heterocyclic group is R". R" includes the substituents listed above for R' and =O, =S, =NNHR**, = NN(R**)2, =NNHC(O)R**, =NNHCO ₂ (alkyl), =NNHSO ₂ (alkyl), =NR**, spirocycloalkyl or fused cycloalkyl. Each R** is independently selected from hydrogen, unsubstituted alkyl or substituted alkyl. Examples of the substituent on the alkyl group represented by R** include an amine group, an alkylamino group, a dialkylamino group, an aminocarbonyl group, a halogen, an alkyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group. Alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.

When a heterocyclic group, a heteroaryl group or a heteroarylalkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When the nitrogen atom in the aromatic ring of the heteroaryl group has a substituent, the nitrogen may be a quaternary nitrogen.

A preferred substitution position of the non-aromatic nitrogen-containing heterocyclic group is a nitrogen ring atom. Suitable substituents on the nitrogen of the non-aromatic heterocyclic or heteroaryl group include -R^, -N(R^) ₂ , C(O)R^, CO ₂ R^, -C(O)C(O R^, -SO ₂ R^, SO ₂ N(R^) ₂ , C(=S)N(R^) ₂ , C(=NH)-N(R^) ₂ and -NR^SO ₂ R Wherein R^ is hydrogen, an aliphatic group, a substituted aliphatic group, an aryl group, a substituted aryl group, a heterocyclic ring or a carbocyclic ring or a substituted heterocyclic ring or carbocyclic ring. Examples of the substituent on the group represented by R^ include an alkyl group, a haloalkoxy group, a haloalkyl group, an alkoxyalkyl group, a sulfonyl group, an alkylsulfonyl group, a halogen, a nitro group, a cyano group, Hydroxy, aryl, carbocyclic or heterocyclic, pendant oxy, amine, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy a group, a carboxyl group, an alkoxycarbonyl group or an alkylcarbonyl group. R^ is preferably unsubstituted.

Non-aromatic nitrogen-containing heterocycles substituted on the ring nitrogen and attached to the remainder of the molecule at the ring carbon atom are referred to as N-substituted. For example, an N-alkylpiperidinyl group is attached to the remainder of the molecule at two, three or four positions of the piperidinyl ring and is substituted with an alkyl group at the ring nitrogen. A non-aromatic nitrogen-containing heterocycle (such as pyrazinyl) substituted on the ring nitrogen and attached to the remainder of the molecule at the second ring nitrogen atom is referred to as a substituted N-heterocycle on N'. For example, the N'-fluorenyl N-pyrazinyl group is attached to the remainder of the molecule at one ring nitrogen atom and is substituted with a thiol group at the second ring nitrogen atom.

As used herein, an optionally substituted aralkyl group can be substituted on the alkyl and aryl moieties. Unless otherwise indicated, an optionally substituted aralkyl group as used herein is optionally substituted on the aryl moiety.

The terms "one button" and "absent" are used interchangeably to indicate that a group does not exist.

The compounds of the invention are defined herein by their chemical structure and/or chemical name. When a compound is referred to by chemical structure and chemical name and the chemical structure is inconsistent with the chemical name, the chemical structure determines the identity of the compound.

The compounds of the invention may be presented in free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt.

Solid form

Another aspect of the invention provides a solid form of a compound of the invention. One embodiment provides a solid form of Compound 48, wherein the form is selected from the group consisting of Compound 48 free base.

In some embodiments, Compound 48 free base is characterized by a weight reduction from about XX over a temperature range of from about 25 °C to about 350 °C. In other embodiments, Compound 48 free base is characterized by one or more peaks of 4°-45° at 2-theta ± 0.2 in an X-ray powder diffraction pattern obtained using Cu K α-radiation. In still other embodiments, the crystalline Compound 48 free base is characterized by a peak that exhibits one or more of the values recited in the peak maps herein at 2-theta ± 0.2. In some embodiments, crystalline Compound 48 free base is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1.

Pharmaceutically acceptable salt

The term "pharmaceutically acceptable salt" as used herein means that it is suitable for contact with tissues of humans and lower animals in the context of sound medical judgment without undue side effects (such as toxicity, irritation, allergic reactions and the like). And a salt of a compound commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 1977 , 66 , 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared on the spot during the final isolation and purification of the compound. The acid addition salt can be prepared by the following steps: 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the salt thus formed.

Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amine groups with inorganic acids or with organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, such organic acids Such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, butyl Diacid or malonic acid; or a salt formed by the use of other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptane Saccharate, glycerol phosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyl -ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate , nicotinic acid salt, nitrate, oleate, oxalate, palmitate, pamoate, pectate, peroxysulfate, 3-phenylpropionate, phosphate, picric acid Salt, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, pentane Acid salts and the like.

The base addition salt can be prepared by the following steps: 1) reacting the purified compound in acid form with a suitable organic or inorganic base, and 2) isolating the salt thus formed. Salts derived from appropriate bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, and N ⁺ (C _1-4 alkyl) ₄ salts. The invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by this quaternization.

Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and the use of relative ions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aromatics). Amine cation formed by sulfonate. Other acids and bases, although not pharmaceutically acceptable per se, may also be employed in the preparation of salts suitable for use in obtaining intermediates of the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.

It will be understood that the invention encompasses mixtures/combinations of different pharmaceutically acceptable salts as well as mixtures/combinations of the compounds in free form and pharmaceutically acceptable salts.

Pharmaceutically acceptable derivatives of the compounds of the invention in addition to the compounds of the invention The prodrugs or prodrugs can also be used in the compositions to treat or prevent the conditions identified herein.

As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that hydrolyzes, oxidizes, or otherwise reacts under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs may become effective after the reaction under biological conditions or may be active in an unreacted form. Examples of prodrugs encompassed by the invention include, but are not limited to, analogs or derivatives comprising a biohydrolyzable moiety of a compound of the invention (such as biohydrolyzable guanamine, biohydrolyzable ester, biohydrolyzable urethane, Biohydrolyzable carbonate, biohydrolyzable guanidine urea and biohydrolyzable phosphate analog). Other examples of prodrugs include derivatives of the compounds of the invention comprising an OH moiety. Prodrugs can generally be prepared using well known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff, ed., fifth edition).

A "pharmaceutically acceptable derivative" is an adduct or derivative capable of providing, directly or indirectly, a compound, or a metabolite or residue thereof, as otherwise described herein, after administration to a patient in need thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

"Pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable ester, ester or other derivative of a compound of the invention or a salt thereof, which can be provided directly or indirectly after administration to a recipient A compound of the invention or its inhibitory effective metabolite or residue. Particularly advantageous derivatives or prodrugs are derivatives or prodrugs which, when administered to a patient (for example, by allowing the orally administered compound to be more readily absorbed into the blood), enhance the compounds of the present invention Availability or its relative parent material promotes delivery of the parent compound to the biological metabolic zone (eg, the brain or lymphatic system).

Pharmaceutically acceptable prodrugs of the compounds of the invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts, and sulfonates.

As used herein, the phrase "side effects" encompasses the treatment (eg, prophylactic or therapeutic agents). Required effects and side effects. Side effects are always undesirable, but undesired effects are not necessarily unfavorable. Side effects of therapies (eg, prophylactic or therapeutic agents) can be harmful or uncomfortable or dangerous. Side effects include (but are not limited to) fever, chills, lethargy, gastrointestinal toxicity (including stomach and intestinal ulcers and erosion), nausea, vomiting, neurotoxicity, nephrotoxicity, renal toxicity (including diseases such as papillary necrosis and chronic interstitial nephritis) Hepatic toxicity (including increased serum liver enzymes), bone marrow toxicity (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, delayed pregnancy, weakness, somnolence, pain (including muscle pain) , bone pain and headache), hair loss, fatigue, dizziness, extrapyramidal symptoms, sedation, cardiovascular disorders and sexual dysfunction.

In one embodiment, the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers which are suitably selected for the desired form of administration and which are in accordance with conventional pharmaceutical practice.

A pharmaceutically acceptable carrier can contain inert ingredients which do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, for example non-toxic, non-inflammatory, non-immunogenic or free of other undesirable reactions or side effects after administration to an individual. Standard pharmaceutical blending techniques can be used.

A pharmaceutically acceptable carrier, adjuvant or vehicle as used herein includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, which are suitable for the particular dosage form desired. Agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for preparing the same. Unless any conventional carrier medium is incompatible with the compounds of the invention (such as by creating any It is biologically or in an unfavorable manner to interact with any other component of the pharmaceutically acceptable composition, or its use is intended to be within the scope of the invention.

Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; Phosphate, glycine, sorbic acid or potassium sorbate; a mixture of partial glycerides of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal cerium oxide, magnesium tricaprate; polyvinylpyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-block polymer; lanolin; sugar, such as lactose, glucose and sucrose; Such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered scutellaria; malt; gelatin; talc; excipients, such as cocoa butter And suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; Joan Lipids; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic compatible lubricants , such as sodium lauryl sulfate and magnesium stearate; and coloring agents; release agents; coating agents; sweeteners; flavoring agents and fragrances, according to the judgment of the formulator, preservatives and antioxidants may also be present in the composition in.

The compounds of the invention or their pharmaceutically acceptable salts can be formulated into pharmaceutical compositions for administration to an individual as defined herein. Such pharmaceutical compositions comprising a compound effective to treat or prevent a bacterial infection, such as IBD, are another embodiment of the invention.

In one embodiment, the invention is a method of treating or preventing a bacterial infection (such as IBD) in an individual in need thereof, comprising administering to the individual an effective amount of a compound or composition of the invention.

The terms "individual", "patient" and "mammal" as used herein are used interchangeably. The terms "individual" and "patient" mean an animal (eg a bird (such as a chicken, donkey or turkey). Or mammals, mammals preferably include non-primates (eg, cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (eg, monkeys, chimpanzees) And humans), and better for humans. In one embodiment, the individual is a non-human animal, such as an agricultural animal (eg, a horse, cow, pig, or sheep) or a pet (eg, a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the individual is a human.

"Effective amount" as used herein refers to an amount sufficient to elicit a suitable biological response. In the present invention, a suitable biological response is to reduce or improve the severity, duration, progression or onset of bacterial infection; to prevent the progression of bacterial infection; to ablate bacterial infection; to prevent recurrence, progression, onset or progression of symptoms associated with bacterial infection. Or improve or improve the prophylactic or therapeutic effect of another therapy. The precise amount of the compound administered to the individual will depend on the mode of administration, the type and severity of the disease or condition, and the characteristics of the individual (such as general health, age, sex, weight, and tolerance to the drug). It also depends on the extent, severity and type of bacterial infection and the mode of administration. Those skilled in the art should be able to determine the appropriate dosage based on these and other factors. When co-administered with other agents (eg, when co-administered with a bacterial infectious agent), the "effective amount" of the second agent will depend on the type of drug employed. Suitable dosages of the approved agents are known and can be adjusted by those skilled in the art depending on the condition of the individual, the type of condition being treated, and the amount of the compound of the invention employed. If the amount is not explicitly stated, an effective amount should be used.

The term "treating" as used herein refers to reducing or improving the progression, severity and/or duration of bacterial infection or improving bacteria by administering one or more therapies (eg, one or more therapeutic agents (such as a compound of the invention)). Infection with one or more symptoms (preferably one or more discernible symptoms). In a particular embodiment, the term "treatment" refers to at least one measurable body parameter that improves bacterial infection. In other embodiments, the term "treatment" refers to the progression of inhibition of bacterial infection either physically (by, for example, stabilizing a discernible symptom), physiologically (by, for example, stabilizing a body parameter), or both. In other embodiments, the term "treatment" refers to reducing or stabilizing a bacterial infection.

The term "prevention" as used herein refers to reducing the risk of acquiring or producing a given bacterial infection or reducing or inhibiting the recurrence of a bacterial infection. In one embodiment, a compound of the invention is administered as a prophylactic means to a patient, preferably a human, having a genetic predisposition to any of the conditions, diseases or conditions described herein.

The pharmaceutically acceptable composition of the present invention can be orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in powder, ointment or drip) depending on the severity of the infection to be treated. In human form, buccal, orally or nasally, in the form of a human or other animal.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzoyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrogen Fatty acid esters of sterols, polyethylene glycols and sorbitans, and mixtures thereof. Besides the inert diluent, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be employed in accordance with known techniques using dispersible or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-septically acceptable non-toxic diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are often employed as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Injectable formulations can be filtered, for example, by filtration through a bacteria-retaining filter Sterilize the sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

In order to prolong the action of the compounds of the invention, it is generally desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of a compound will depend on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, absorption of the parenterally administered compound is delayed by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations can also be prepared by embedding the compound in liposomes or microemulsions that are compatible with body tissues.

The composition for rectal or vaginal administration is preferably a suppository which can be mixed with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax. Alternatively, the excipients or carriers are solid at ambient temperature but are liquid at body temperature to melt and release the active compound in the rectum or vaginal cavity.

Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and/or a) filler or extender Such as starch, lactose, sucrose, glucose, mannitol and citric acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants , such as glycerin, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate, e) solvents, such as paraffin, f) absorption enhancers, such as four Ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solids Polyethylene glycol, sodium lauryl sulfate And mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose/milk sugar and high molecular weight polyethylene glycols and the like. . The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings and other coatings well known in the art of pharmaceutical formulation). It may optionally contain an opacifying agent and may also be of a composition such that it will release the active ingredient in a delayed manner only, or preferably, in certain portions of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like.

The active compound can also be in microencapsulated form with one or more of the above-described excipients. The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings, controlled release coatings, and other coatings well known in the art of pharmaceutical formulation). In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is customary practice, materials other than inert diluents, such as a tableting lubricant and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer. It may optionally contain an opacifying agent and may also be of a composition such that it will release the active ingredient in a delayed manner only, or preferably, in certain portions of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes.

Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with apharmaceutically acceptable carrier and any necessary preservative or buffer. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the invention. Additionally, the present invention contemplates the use of transdermal patches that have the added advantage of controlled delivery of a compound to the body. Such dosage forms may be prepared by dissolving or dispensing the compound Prepared in the medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

The sterile injectable form of the compositions of the invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-septically acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are often employed as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, and their glyceride derivatives, such as pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions, are suitable for the preparation of injectables. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent (such as carboxymethylcellulose) or a similar dispersing agent which is conventionally used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tweens, Spans) and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, troches, aqueous suspensions or solutions. In the case of tablets for oral use, conventional carriers include, but are not limited to, lactose and corn starch. Lubricants (such as magnesium stearate) are also usually added. For oral administration in capsule form, suitable diluents include Lactose and dried cornstarch. When it is desired to use an aqueous suspension orally, the active ingredient is combined with emulsifying and suspending agents. If necessary, some sweeteners, flavorings or coloring agents may also be added.

Alternatively, the pharmaceutical composition of the present invention can be administered in the form of a suppository for rectal administration. It can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and thus melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutical compositions of this invention may also be administered topically, especially when the therapeutic target includes areas or organs readily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. For each of these regions or organs, it is easy to prepare suitable topical formulations.

Topical application to the lower intestinal tract can be effected with a rectal suppository formulation (see above) or in a suitable enema formulation. Local transdermal patches can also be used.

For topical administration, the pharmaceutical compositions may be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol And water.

For ophthalmic use, the pharmaceutical composition may be formulated as a micron-sized suspension in a pH-adjusted isotonic sterile saline solution or a solution in a pH-adjusted isotonic sterile saline solution, which may contain Or no preservatives (such as benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated into an ointment (such as in paraffin).

The pharmaceutical compositions of the invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be employed with benzyl alcohol or other suitable Preservatives, absorption enhancers that enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents are prepared as solutions in physiological saline.

The dosage regimen using the compounds of the invention can be selected according to a variety of factors, including the severity of the condition or disorder being treated; the activity of the particular compound employed; the age, weight, general health, sex and diet of the particular composition employed; , the route of administration and the rate of excretion of the particular compound employed; the kidney and liver function of the individual; and the particular compound or salt thereof employed, the duration of treatment; similar factors well known in the pharmaceutical and medical arts in combination or concurrent use with the particular compound employed. An effective amount of a compound of the invention required to treat a disease (e.g., prevent disease, inhibit (complete or partial) disease, or prevent disease progression) can be readily determined and specified by those skilled in the art.

The dose of the compound of the invention may range from about 0.01 to about 100 mg/kg body weight per day, from about 0.01 to about 50 mg/kg body weight per day, from about 0.1 to about 50 mg/kg body weight per day, or from about 1 to about 25 mg per day. Within kilograms of body weight/day. It will be appreciated that the total amount per day may be administered in a single dose or may be administered in multiple doses (such as twice, three times or four times per day).

Compounds suitable for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for a single dose of the individual to be treated, wherein each unit contains a predetermined amount of active material which is intended to produce the desired therapeutic effect and, where appropriate, a suitable pharmaceutical carrier. The unit dosage form can be used in a single daily dose or multiple daily doses (e.g., about one to four or more times per day). When multiple daily doses are used, the unit dosage form can be the same for each dose.

An effective amount can be obtained by using the compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with another suitable therapeutic agent (e.g., a cancer therapeutic agent) in the method or pharmaceutical composition of the present invention. When a combination therapy is used, an effective amount can be obtained using a first amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a second amount of another suitable therapeutic agent.

In one embodiment, the compound of the invention and the additional therapeutic agent are each administered in an effective amount (i.e., each in a therapeutically effective amount when administered separately). In another embodiment, the invention combines Each of the therapeutic agents and the other therapeutic agent are administered in an amount (secondary therapeutic dose) that does not provide a therapeutic effect alone. In another embodiment, a compound of the invention can be administered in an effective amount, while another therapeutic agent is administered in a sub-therapeutic dose. In another embodiment, a compound of the invention can be administered in a subtherapeutic dose, while another therapeutic agent (e.g., a therapeutic agent suitable for cancer) is administered in an effective amount.

The terms "combination" or "co-administration" as used herein are used interchangeably to mean the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). The use of such terms does not limit the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to an individual.

Co-administration encompasses administering a first and second amount of a co-administered compound in a substantially simultaneous manner, such as in a single pharmaceutical composition (eg, a capsule or lozenge having a fixed first and second ratio) or Each is administered in a plurality of individual capsules or lozenges. In addition, the co-administration also encompasses the use of each compound in any order in a continuous manner.

When co-administered involves administration of a first amount of a compound of the invention and a second amount of another therapeutic agent, the administration time of such compounds should be sufficiently close to have the desired therapeutic effect. For example, the period of time between administrations that produce the desired therapeutic effect can range from a few minutes to several hours and can be determined by considering the characteristics of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. . For example, the compound of the present invention and the second therapeutic agent can be spaced apart from each other within about 24 hours, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 4 hours of each other. It is administered in any order within an hour or within about 30 minutes of each other.

More specifically, the first therapy (eg, a prophylactic or therapeutic agent, such as a compound of the invention) can be administered prior to administration of the subject's second therapy (eg, a prophylactic or therapeutic agent, such as an anticancer agent) (eg, 5 minutes, 15 minutes prior) 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 Week, 8 weeks or 12 weeks), simultaneous or after (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours) , 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) to vote.

It will be appreciated that a method of co-administering a first amount of a compound of the invention and a second amount of another therapeutic agent can result in an enhanced therapeutic or synergistic therapeutic effect, wherein the combined effect is greater than the administration of the first amount of the compound of the invention separately And the additive effect produced by the second amount of another therapeutic agent.

The term "synergistic" as used herein refers to a combination of a compound of the invention with another therapy (eg, a prophylactic or therapeutic agent) that is more effective than the additive effect of such therapies. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may result in the use of lower doses of one or more therapies and/or may reduce the frequency of such therapies administered to the individual. The ability to use a lower dose of therapy (eg, a prophylactic or therapeutic agent) and/or to administer the therapy at a lower frequency may reduce the toxicity associated with administering the therapy to the individual without reducing the therapy in prevention, control or treatment. The effect of the disease. In addition, synergy can improve the efficacy of the agent in preventing, controlling or treating a condition. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce the adverse or undesirable side effects associated with either therapy alone.

The presence of synergy can be determined using suitable methods for assessing drug interactions. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6: 429-453 (1981)), Loewe's cumulative equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol). Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). The above-mentioned various formulas can be used together with the experimental data to generate a corresponding schema to assist in assessing the role of the drug combination. Corresponding figures relating to the equations mentioned above are concentration-action curves, equivalent line graph curves and combined exponential curves, respectively.

The activity of the compound as an inhibitor of bacterial infection can be assayed in vitro or in vivo. In vitro analysis included an assay to determine inhibition of FimH activity. Another in vitro assay quantifies the ability of the inhibitor to bind to FimH and can be used to inhibit the inhibitor prior to binding. Radiolabeling, isolation of inhibitor complexes, and determination of the amount of bound radiolabels or by competition experiments in which novel inhibitors were incubated with FimH bound to known radioligands were performed. Detailed conditions for analyzing the compounds used in the present invention are set forth in the following examples.

Experiment details

The following abbreviations are used in the following examples:

The compounds of the present invention can be prepared according to the present specification using procedures generally known to those of ordinary skill. Such compounds can be analyzed by known methods including, but not limited to, LC-MS (liquid chromatography mass spectrometry), HPLC (high performance liquid chromatography), and NMR (nuclear magnetic resonance). It should be understood that the following The specific conditions shown are merely examples and are not meant to limit the scope of the conditions that can be used to prepare the compounds of the invention. In fact, the present invention also encompasses the conditions apparent to those skilled in the art in the preparation of the compounds of the present invention in light of the present specification. All variables in the following schemes are as defined herein unless otherwise indicated.

Mass spectrometry samples were analyzed on a Waters UPLC Acquity mass spectrometer operating in electrospray ionization in a single MS mode. The sample was introduced into the mass spectrometer using chromatography. The mobile phase of mass spectrometry consisted of a mixture of 0.1% formic acid and acetonitrile-water. The column gradient conditions were 6 minutes of operation time, 5%-85% acetonitrile-water, Acquity HSS T3 1.8 μm 2.1 mm ID x 50 mm. The flow rate was 1.0 mL/min. The term "Rt (minutes)" as used herein refers to the LC-MS residence time (in minutes) associated with a compound. Unless otherwise indicated, the LC-MS method used to obtain the reported residence time is as detailed above.

Purification by reverse phase HPLC was carried out under standard conditions using a Phenomenex Gemini 21.2 mm ID x 250 mm column, 5 μm, 110 Å. Using a linear gradient of CH ₃ CN-H ₂ O (0.01% TFA with or without buffer) as the mobile phase eluting executed. The solvent system was set according to the polarity of the compound, flow rate, 20 mL/min. Compounds were collected by UV or Waters 3100 mass detector (ESI positive ion mode). The fractions containing the desired compound fractions were concentrated (rotary evaporator) to remove excess CH ₃ CN, and the resulting aqueous solution lyophilized to afford a white foam of the desired material in most cases.

Different combinations of CH ₃ CN-H ₂ O (0.01% TFA as buffer) were used as mobile phase on Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID×250 mm, Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID×50 mm, The flow rate was 1 mL/min, and the HPLC analysis method was performed at PDA 210 nm. Method A: Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID x 250 mm; (10-50% acetonitrile-water 40 min, 0.01% TFA). Method B: Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID x 250 mm; (50-90% acetonitrile-water 40 min, 0.01% TFA). Method C: Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID x 50 mm; (20-60% acetonitrile-water 10 min, 0.01% TFA). Method D: Phenomenex Gemini C18 3 μm 110Å 4.6 mm ID x 50 mm; (10-50% acetonitrile-water 10 min, 0.01% TFA).

Preparation of compounds

The compounds of the invention can be prepared according to Scheme 1 below. These compounds can also be made according to the preparations described in the experiments herein.

PG is a protecting group (such as a pentylene group, an ethenyl group or other protecting groups known to those skilled in the art for protecting a hydroxyl group). CP is used for known metal-mediated reactions (such as, but not limited to, Sonagashira reaction, Negishi reaction, Suzuki reaction, Stille coupling reaction) Suitable coupling partners in the Goldberg reaction.

The initial dihydropyran i is coupled to the appropriate coupling partner R ¹ -CP under suitable coupling conditions (eg CP is Acid), II is formed, and then subjected to a suitable hydroxylation conditions (e.g. OsO _4), form a tetrahydropyran iii. The tetrahydropyran iii can be functionalized with various groups using, for example, metal-mediated coupling reactions and other reactions known to those skilled in the art to form iv , which can then be removed under conditions known to remove protecting groups. Base to form a compound of formula I.

Alternatively, a protected tetrahydropyran v, it can be carried out under suitable coupling conditions similar to the coupling of the coupling with a suitable coupling thereof R ¹ -CP (e.g. CP is Acid), forming vi . The tetrahydropyran vi can be functionalized with various groups using, for example, metal-mediated coupling reactions and other reactions known to those skilled in the art to form vii , which can then be removed under conditions known to remove protecting groups. Base to form a compound of formula I.

The following is a list of key intermediates used to prepare the compounds.

Preparation of intermediate A:

Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3-hydroxyphenyl)tetrahydro-2H-piperidin-2-yl) ester

Step I: Acetic acid [(2R,3S,6S)-3-ethoxycarbonyl-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-3,6-dihydro -2H-piperidin-2-yl]methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (1.100 g, 4.040 mmol) in 10 mL of acetonitrile [3-(Third butyl-dimethyl-decyl)oxyphenyl] is added to the solution Acid (2.038 g, 8.080 mmol) and Pd(OAc) ₂ (136.1 mg, 0.6060 mmol). The mixture was stirred at room temperature for 5 hours, and then another batch of Pd(OAc) ₂ (136 mg, 0.606 mmol) and [3-(t-butyl-dimethyl-decyl)oxyphenyl] was added thereto. Acid (2.038 g, 8.080 mmol). It was then stirred overnight at room temperature. And filtered through a pad of diatomaceous earth with 20 mL CH ₂ Cl ₂ was diluted mixture. The filtrate was concentrated and 20 column volumes using Hex / EtOAc gradient of (0-20%) in the residue was separated Biotage ^TM SNAP 100 g silica gel column, to give the title compound as an oil (805 mg, 1.91 mmol, 47 %), It solidifies after standing.

¹ H NMR (CDCl ₃ , 400 MHz): 7.06 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 6.60 (m, 1H), 5.97 (m, 1H), 5.71 (m, 1H), 5.09 (m, 2H), 4.08 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 1.88 and 1.87 (2s, 6H), 0.78 (m, 9H), 0.00 (m) , 6H).

Step II: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-4, 5-dihydroxy-tetrahydropyran-2-yl]methyl ester

To acetic acid [(2R,3S,6S)-3-acetoxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-3,6-dihydro-2H Add methanesulfonamide (848.0 mg, 8.92 mmol), 2.5% to a solution of p-pyran-2-yl]methyl ester (2.500 g, 5.944 mmol) in water (10 mL) /t-BuOH (10 mL) OsO _{4 /} t-BuOH (1.87 mL, 0.149 mmol), NMO (1.393 g, 11.89 mmol) and dimethylpyridine (689 μL, 5.94 mmol). The mixture was stirred overnight at room temperature. It was then quenched with EtOAc (40 mL) The aqueous phase was then separated, washed with water (20 mL) and washed successively with brine (20 mL), dried over Na ₂ SO _4. After removal of the solvent under reduced pressure, using Biotage ^TM SNAP 100 g column of silica gel 20 column volume of CH ₂ Cl ₂ / MeOH gradient of (0-6%) to give the residue, to give the title compound as an oil (2.200 g, 81%).

¹ H NMR (CD ₃ OD, 400 MHz): 7.06 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 6.58 (m, 1H), 4.85 (m, 1H), 4.64 (m) , 1H), 4.46 (m, 1H), 3.96 (m, 1H), 3.85 (m, 1H), 3.62 (m, 2H), 1.86 and 1.83 (2s, 6H), 0.78 (m, 9H), 0.00 ( m, 6H).

Step III: Intermediate A

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-4,5- Add acetic acid (11 μL, 0.19 mmol) and 1 M TBAF/THF (380 μL, 0.38 mmol) to a solution of dihydroxy-tetrahydropyran-2-yl]methyl ester (85 mg, 0.19 mmol) in 2 mL THF. ). After stirring for 1 hour, the solvent was removed under reduced pressure and 20 column volumes using CH ₂ CL ₂ / MeOH gradient of (0-7%) in the residue was purified Biotage ^TM SNAP 25 g silica gel column, to give an oil of Intermediate A (50 mg, 77%).

¹ H NMR (CD ₃ OD, 400 MHz): 7.18 (m, 1H), 6.86 (m, 2H), 6.70 (m, 1H), 5.07 (m, 1H), 4.86 (m, 1H), 4.60 (m) , 1H), 4.21 (m, 1H), 4.08 (m, 1H), 3.80 (m, 2H), 2.05 and 2.03 (2s, 6H).

Preparation of intermediate B:

Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3-(trifluoromethylsulfonyloxy)phenyl)tetrahydro-2H -piperidin-2-yl)methyl ester

Add 1,1,1-trifluoro-N-phenyl-N(trifluoromethylsulfonyl)methanesulfonate to a solution of Intermediate A (204 mg, 0.599 mmol) in 5 mL CH ₂ Cl ₂ Amine (278 mg, 0.779 mmol) and TEA (167 μL, 1.20 mmol). The mixture was stirred overnight at room temperature. After removal of solvent, 20 column volumes using Hex / EtOAc gradient of (0-50%) in the residue was separated Biotage ^TM SNAP 25 g silica gel column under reduced pressure to give the intermediate as a solid B (242 mg, 85%).

¹ H NMR (CD ₃ OD, 400 MHz): 7.52 (m, 1H), 7.42 (m, 1H), 7.29 (m, 1H), 5.07 (m, 1H), 4.92 (m, 1H), 4.08 (m) , 1H), 3.95 (m, 2H), 3.86 (m, 1H), 2.08 and 2.00 (2s, 6H).

Preparation of intermediate C:

(2R,3S,4R,5S,6R)-2-(3-bromophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step I: Acetic acid ((2R,3S,6S)-3-ethoxycarbonyl-6-(3-bromophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl ester

[[2R,3S,4R)-3,4-Diethoxymethoxy-3,4-dihydro-2H-piperidin-2-yl]methyl acetate was bubbled through nitrogen for 3 minutes. 3.00 g, 11.02 mmol) and (3-bromophenyl) The acid (4.426 g, 22.04 mmol) was degassed in acetonitrile (22 mL). Palladium(II) acetate (371 mg, 1.65 mmol) was added and the reaction mixture was stirred at room temperature for 5 hr then a portion of <RTI ID=0.0>> The solvent was evaporated and the mixture was diluted with dichloromethane (10 mL) and saturated aqueous NaHCO ₃ (20 mL). The mixture was filtered through a phase separation cartridge, and the filtrate was evaporated by Biotage ^TM chromatography using a 50 g silica gel column using 5% -10% EtOAc over 30 min at a flow rate of 40 mL / min of / Hex gradient eluting the purified, to give an oil The title product (1.61 g, 4.36 mmol, 40%).

LC-MS: m/z = 391.1, 393.1 (M+Na ⁺ )

Step II: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-bromophenyl)-4,5-dihydroxytetrahydro-2H-pentan-2- Methyl ester

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-(3-bromophenyl)-3,6-dihydro-2H-pyran-2-yl]methyl ester (1.60 g, 4.33 mmol) methanesulfonamide (618 mg, 6.50 mmol), osmium tetroxide (1.32 mL 2.5 w/v% t-BuOH solution, 0.130 mmol) in water (3.1 mL) and THF (19 mL) And N-methylmorpholine-N-oxide (2.030 g, 17.33 mmol) and the reaction mixture was stirred at room temperature for 2 days. Add another osmium tetroxide (1.32 mL 2.5 w/v% t-BuOH solution, 0.130 mmol), methanesulfonamide (618 mg, 6.50 mmol) and N-methylmorpholine-N-oxide (2.030 g) , 17.33 mmol) and the mixture was stirred for a further 24 hours. The solvent was evaporated, the~~~~~~~~~ Dried over Na ₂ SO ₄ the combined organic extracts were the solvent and evaporated. The resulting gum-like material was dissolved in a minimum amount of MeOH, diluted with diethyl ether and placed in a refrigerator for 2 hours. The mixture was filtered, washed with EtOAc EtOAcqqqq

LC-MS: m/z = 425.1, 427.1 (M+Na ⁺ )

Step III: Intermediate C

Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-bromophenyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yl) The methyl ester (1.48 g) was dissolved in MeOH (20 mL). EtOAc EtOAc (EtOAc (EtOAc) The reaction mixture was neutralized by the addition of Amberlite IR 120H resin until the pH became neutral. The reaction mixture was filtered, and the filtrate was evaporated and washed with _{Et 2 O (2 × 10 mL} ) triturated solid to give the title product as a solid (1.08 g, 3.046 mmol, 70.3 %).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.45 (dd, J = 10.6, 4.1 Hz, 2H), 7.29 (t, J = 7.9 Hz, 1H), 4.91 (d, J) =4.7 Hz,1H), 4.29 (dd, J=4.6, 3.2 Hz, 1H), 3.95-3.71 (m, 3H), 3.61 (dd, J=7.4, 3.1 Hz, 1H), 3.55-3.47 (m, 1H). LC-MS: m/z = 341.1, 343.1 (M+Na ⁺ )

Preparation of intermediate D:

3-((2R,3S,4R,5S,6R)-5-ethoxycarbonyl-6-(ethyloxymethyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl )benzoic acid

Step I: 3-[(2R,3S,6S)-3-Ethyloxy-2-(ethyloxymethyl)-3,6-dihydro-2H-pyran-6-yl]benzoic acid Methyl ester

The title compound of this step was prepared using the same procedure as described in Step 1 for the preparation of Intermediate C, but using (3-methoxycarbonylphenyl). Acid is used as the starting material.

LC-MS: m/z = 371.2 (M + Na ⁺ )

Step II: 3-[(2R,3S,4R,5S,6R)-5-Ethyloxy-6-(ethyloxymethyl)-3,4-dihydroxy-tetrahydropyran-2- Methyl benzoate.

The title compound was prepared using the same procedure as described in Step II of Intermediate C.

LC-MS: m/z = 383.3 (M+H ⁺ )

Step III: Intermediate D

Treatment of 3-[(2R,3S,4R,5S,6R)-5-ethyloxy-6-(ethenyloxymethyl) with MeONa in MeOH (341 μL 25 w/v%, 1.58 mmol) A mixture of methyl 3,4-dihydroxy-tetrahydropyran-2-yl]benzoate (2.20 g, 5.75 mmol) in MeOH (30 mL). The volatiles were evaporated, the mixture was crystalljjjjjjjjjjjjjjj The mixture was neutralized by the addition of Amberlite IR 120H resin until the pH became neutral. The reaction mixture was filtered and EtOAcjjjjjjjjj

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.99 (d, J = 4.4 Hz, 1H), 4.42-4.36 (m, 1H), 3.93 - 3.74 (m, 3H), 3.63 (dd, J = 7.5, 3.1 Hz, 1H), 3.54 -3.49 (m, 1H). LC-MS: m/z = 285.2 (M+H ⁺ )

Preparation of intermediate E:

Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(2-(trifluoromethylsulfonyloxy)phenyl)tetrahydro-2H -piperidin-2-yl)methyl ester

The title compound was prepared according to the procedure described for Intermediates A and B, but [2-(t-butyl-dimethyl-decyl)oxybenzene was used in Step I of the synthetic procedure described for Intermediate A. base] acid.

Preparation of intermediate F:

(Triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(4-ethynylphenyl)tetrahydro-2H-pyran-3,4,5- Triester)

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-(trifluoromethylsulfonyloxy)phenyl]tetrahydroperoxide Methyl-2-yl]methyl ester

To acetic acid (2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-[4-(trifluoromethylsulfonyloxy)phenyl]tetrahydropyran Pyridine (132 μL, 1.63 mmol), Ac ₂ O (128 μL, 1.36 mmol) and DMAP were added sequentially to a solution of -2-yl]methyl ester (256 mg, 0.542 mmol) in 2.6 mL CH ₂ Cl ₂ 6.6 mg, 0.054 mmol). The reaction mixture was stirred for 2 hours at room temperature, washed with water (1 mL) was diluted and the organic layer was dried over Na ₂ SO _4, filtered and concentrated to dryness. The residue was purified by EtOAc EtOAc EtOAc EtOAc (232 mg, 77%).

Step II: Triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(4-((trimethyldecyl)ethynyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triester

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-(trifluoromethylsulfonyloxy)phenyl]tetrahydropyran- a mixture of 2-methyl]methyl ester (1217 mg, 2.187 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (178.6 mg, 0.219 mmol) and CuI (83.3 mg, 0.437 mmol) in 12 mL of DMF Et ₃ N (1.5 mL, 11 mmol) and ethynyl (trimethyl)decane (1.54 mL, 10.9 mmol) were added. The reaction mixture was heated in a sealed tube at 70 ° C for 21 h, cooled to room temperature and diluted with water (40 mL). By EtOAc (5 × 20 mL) and the reaction mixture was extracted with water (3 × 10 mL), washed with brine and the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated to dryness. The residue was purified by EtOAc EtOAcjjjjjjj

Step III. Intermediate F

To triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(4-((trimethyldecyl)ethynyl)phenyl) AcOH (150.6 mg, 143 μL, 2.507 mmol) and 1 M TBAF were added sequentially to a solution of hydrogen-2H-pyran-3,4,5-triester (1.054 g, 2.089 mmol) in THF (21 mL). THF solution (2.298 mL, 1 M, 2.298 mmol). The reaction mixture was stirred at room temperature for 2 hr and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate (10 to 80%) to give triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl) 6-(4-ethynylphenyl)tetrahydro-2H-pyran-3,4,5-triester (892 mg, 99%).

Preparation of intermediate G:

2,2-Dimethylpropionic acid [(2R,3R,4R,5R,6R)-6-(3-bromo-2-methyl-phenyl)-3,4,5-para (2,2- Dimethylpropoxy)tetrahydropyran-2-yl]methyl

Add a solution of n-Bu ₃ MgLi in hexane-heptane-dibutyl ether (8:20:3) (6.6 mL 0.66 M, 4.35 mmol) to 1-bromo-3-iodo-2 at 0 °C Methyl-benzene (3.69 g, 12.42 mmol) in a solution of toluene (6.0 mL) and dibutyl ether (3.6 mL). A solution of ZnBr ₂ -LiBr in dibutyl ether (6.51 mL 1.05 M, 6.83 mmol) was added dropwise, the cooling bath was removed and stirred at room temperature for 1 hour. Add 2,2-dimethylpropionic acid [(2R,3R,4S,5S,6R)-6-bromo-3,4,5-parade (2,2-dimethylpropoxy)tetrahydropyridyl Methyl-2-methyl]methyl ester (6 g, 10.35 mmol, see Sebastien Lemaire et al, Org. Letts . 2012, 14 , 1480-1483) in toluene (10.8 mL), placed at 90 ° C Preheated on an oil bath and stirred for 24 hours. The reaction mixture was cooled to room temperature and poured into 1 N aqueous HCl (80 mL) in, (3 × 50 mL) and extracted with ethyl acetate, washed with brine the combined extracts were dried (Na ₂ SO ₄₎ and concentrated. 300 g of silica gel column using ethyl acetate and the like in hexane degree ^{Biotage SNAP TM (10%, 4} CV) as the eluting agent and the residue was purified to give a light yellow solid of the title compound (4.5 g, 64.9%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.55 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 5.71-5.65 ( m,1H), 5.43 (dd, J=6.9, 2.8 Hz, 1H), 5.30-5.23 (m, 1H), 5.20 (d, J = 6.0 Hz, 1H), 4.68-4.58 (m, 1H), 4.07 (dd, J = 12.0, 3.1 Hz, 1H), 3.87-3.79 (m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.22 (s, 9H), 1.18 (s, 9H), 1.10(s, 9H).

Preparation of intermediate H

(Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(3-bromophenyl)tetrahydropyran-2-yl]methyl ester)

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-bromophenyl)-4,5-dihydroxy-tetrahydropyran-2- at 0 °C DIPEA (969.3 mg, 1.31 mL, 7.50 mmol), DMAP (18.3 mg, 0.150 mmol) was added to a solution of EtOAc (EtOAc (EtOAc) And Ac ₂ O (536.0 mg, 495 μL, 5.25 mmol). The mixture was stirred overnight at room temperature. It was then quenched with saturated sodium bicarbonate solution. With _{CH 2 Cl 2 (3 × 15} mL) the mixture was extracted. The combined organic extracts were washed with EtOAc EtOAc m. The residue was purified using EtOAc EtOAc EtOAcjjjjj

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.55-7.45 (m, 1H), 7.41 (dd, 1H), 7.29 (t, 1H), 5.87 (t, 1H), 5.28 ( t,1H),5.10(dd,1H),5.04(d,1H), 4.36(dd,1H), 4.14(dd,1H),3.86-3.66(m,1H),2.13(2s,6H),2.05 (s, 3H), 2.02 (s, 3H)

Preparation of intermediate I:

[(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(3-allylphenyl)tetrahydropyran-2-yl]methyl acetate

Degassing (indoor vacuum/nitrogen) solution to intermediate H (320 mg, 0.657 mmol) and allyl-tributyl-stannane (261 mg, 244.0 μL, 0.788 mmol) in benzene (10 mL) Pd(PPh ₃ ) ₄ (75.9 mg, 0.066 mmol) was added portionwise, and the reaction mixture was heated at 100 ° C for 48 hours to concentrate. Purification on a 50 g silica gel SNAP column using a gradient of ethyl acetate in hexanes (15% to 40%, 8 CV; 40% 4 CV) as a dissolving solvent to afford a pale yellow oil. Compound (300 mg, quantitative).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.31 (m, 3H), 7.21-7.15 (m, 1H), 6.04-5.93 (m, 2H), 5.35 (t, J = 9.0 Hz, 1H), 5.16 (dd, J=9.2, 3.2 Hz, 1H), 5.13-5.04 (m, 3H), 4.37 (dt, J = 12.1, 7.7 Hz, 1H), 4.14 (dd, J = 12.1, 2.7 Hz, 1H) , 3.81-3.74 (m, 1H), 3.43 (d, J = 6.7 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H).

Preparation of intermediate J:

Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-(4,4,5,5-tetramethyl- 1,3,2- Dioxon -2-yl)phenyl]tetrahydropyran-2-yl]methyl

Add 4,4,5,5-tetramethyl-2-(4,4,5,5) to a solution of intermediate H (6.64 g, 13.63 mmol) in DMF (99.6 mL) under nitrogen atmosphere. -tetramethyl-1,3,2-dioxaboron -2-yl)-1,3,2-dioxaboron (5.191 g, 20.44 mmol), KOAc (5.351 g, 54.52 mmol), PdCl ₂ (dppf) (1.113 g, 1.363 mmol) and the mixture was heated to 60 ° C for 22 hours. The mixture was then filtered through celite, and the filtrate was washed with 3 portions of 100 mL hexanes, diluted with 300 mL EtOAc and washed with 20% NH ₄ Cl (100 mL), water (2×100 mL), brine (100 mL) It was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by EtOAc EtOAcjjjjjjj

Preparation of intermediate K:

2,2-Dimethylpropionic acid [(2R,3R,4R,5R,6R)-3,4,5-parade (2,2-dimethylpropenyloxy)-6-[2-methyl -3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)phenyl]tetrahydropyran-2-yl]methyl

Intermediate K (637 mg) was prepared using Intermediate G as starting material as described for the preparation of Intermediate J.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.24 (t, 1H), 5.80-5.73 (m, 1H) , 5.46 (dd, J = 7.2, 2.9 Hz, 1H), 5.31 (t, J = 6.6 Hz, 1H), 5.23 (d, J = 5.3 Hz, 1H), 4.51 (dd, J = 11.7, 6.8 Hz, 1H), 4.12 (dd, J = 12.0, 3.3 Hz, 1H), 3.84 - 3.74 (m, 1H), 2.62 (s, 3H), 1.34 (s, 12H), 1.24 (s, 9H), 1.21 (s , 9H), 1.19 (s, 9H), 1.12 (s, 9H).

Preparation of intermediate L:

Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(4-(((trifluoromethyl))sulfonyl)oxy)phenyl) Tetrahydro-2H-piperidin-2-yl)methyl ester

Step I: Acetic acid [(2R,3S,6S)-3-ethenyloxy-6-(4-hydroxyphenyl)-3,6-dihydro-2H-pyran-2-yl]methyl ester

Acetonitrile (50.00 mL) was added to [[2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl acetate (9.869 g, 36.25 mmol), (4-hydroxyphenyl) A mixture of the acid (5 g, 36.25 mmol) and Pd(OAc) ₂ (1.221 g, 5.438 mmol) was stirred at room temperature overnight. Add an extra amount of (4-hydroxyphenyl) Acid (1 g), the reaction mixture was stirred further for 2 h and filtered over Celite. The filtrate was evaporated and using 340 g silica gel column with a gradient of hexane crude product was purified of 5% -80% EtOAc solution was chromatographed on Biotage ^TM system, to give the title product.

Step II: Acetic Acid [(2R,3S,4R,5S,6R)-3-Ethyloxy-4,5-dihydroxy-6-(4-hydroxyphenyl)tetrahydropyran-2-yl]A ester

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-(4-hydroxyphenyl)-3,6-dihydro-2H-pyran-2-yl]methyl ester (6.03 g, 19.69 mmol) methanesulfonamide (2.810 g, 29.54 mmol), OsO ₄ (6.007 g, 7.4 mL 2.5 w/w% t-BuOH solution) in a suspension of THF (36 mL) / water (24 mL) , 0.5907 mmol) and NMO (4.613 g, 39.38 mmol). The reaction mixture was stirred at room temperature overnight. 1 M Na ₂ S ₂ O ₃ (40 mL) was added and EtOAc (3×40 mL) With brine (15 mL) The washed organic extracts were combined and dried over Na ₂ SO _4. The mixture was filtered, and the solvent was evaporated using 220 g silica gel column chromatography on Biotage ^TM systems CH 0% -20% MeOH gradient of the crude product was purified ₂ Cl ₂ solution to give the title product.

LC-MS: m/z = 329.3 (M+Na+)

Step III: Intermediate L

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(4-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester ( 872 mg, 2.562 mmol) of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide in a solution of CH ₂ Cl ₂ (22 mL) 1.190 g, 3.331 mmol), NEt ₃ (518.5 mg, 714 uL, 5.124 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and using 100 g silica gel column chromatography on Biotage ^TM system 15 column volumes with _{0% -20% MeOH / CH 2} Cl ₂ gradient of the crude product was purified to give the title product.

Preparation of intermediate M:

Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-methoxy-3-(trifluoromethylsulfonyloxy)phenyl] Tetrahydropyran-2-yl]methyl ester

Step I: Acetic acid [(2R,3S,6S)-3-acetoxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-phenyl] -3,6-dihydro-2H-piperidin-2-yl]methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (2 g, 7.346 mmol) in 35 mL ACN [3-[Third butyl(dimethyl)decyl]oxy-4-methoxy-phenyl] is added to the solution Acid (2.073 g, 7.346 mmol) and Pd(OAc) ₂ (247.4 mg, 1.102 mmol). The mixture was stirred overnight at room temperature, and then another batch of Pd(OAc) ₂ (247.4 mg, 1.102 mmol) and [3-[t-butyl(dimethyl)decyl]oxy-4-methyl were added thereto. Oxy-phenyl] Acid (2.073 g, 7.346 mmol). It was then stirred overnight at room temperature. And filtered through a pad of diatomaceous earth with 30 mL of the mixture was diluted with CH ₂ Cl _2. The filtrate was concentrated and the residue was crystallisjjjjjjjjjj

Step II: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-((t-butyldimethylmethyl)alkyl)oxy)-4-methoxy Phenyl)-4,5-dihydroxytetrahydro-2H-piperidin-2-yl)methyl ester

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-phenyl]-3 ,6-Dihydro-2H-piperidin-2-yl]methyl ester (1.85 g, 4.106 mmol) methanesulfonamide (585.9 mg) in water (7.400 mL) / t-BuOH (7.400 mL) , 6.159 mmol), 2.5% OsO _{4 /} t-BuOH (1.044 g, 1.289 mL, 0.1027 mmol), NMO (962.0 mg, 8.212 mmol) and dimethylpyridine (440.0 mg, 475.7 μL, 4.106 mmol). The mixture was stirred at room temperature for 24 hours. It was then quenched with 15% sodium bisulfite (15 mL) and diluted withEtOAc. The aqueous phase was separated, washed with water and brine and dried over sodium sulfate. After removal of the solvent under reduced pressure, using a Biotage SNAP (silica gel column) 50 g 20 column volumes 0-8% MeOH / CH ₂ Cl ₂ gradient to the residue, the title compound was obtained.

Step III: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3-hydroxy-4-methoxy-phenyl)tetrahydroperphenone Methyl-2-yl]methyl ester

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-benzene Add 1 M TBAF/THF (1.651 mL) to a solution of 4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (400 mg, 0.8254 mmol) in CH ₂ Cl ₂ (16.00 mL) 1 M, 1.651 mmol) and AcOH (49.57 mg, 46.94 μL, 0.8254 mmol). The reaction mixture was stirred at room temperature for 2 hours, H ₂ O, brine, dried over Na ₂ SO _4, filtered and dried. Using 0 to 5% (20 cv) on biotage SP (25 g column) MeOH solution of CH ₂ Cl ₂ as the eluting agent and the residue was purified to give the title compound.

Step IV: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-[4-methoxy-3-(trifluoromethylsulfonyloxy) Phenyl]tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3-hydroxy-4-methoxy-phenyl)tetrahydropyran- Add N-[di- oxo-(trifluoro-$1^{4}-thio)methyl group to a solution of 2-methyl]methyl ester (230 mg, 0.6210 mmol) in CH ₂ Cl ₂ (5.750 mL) -1,1,1-Trifluoro-N-phenyl-methanesulfonamide (288.4 mg, 0.8073 mmol) and TEA (125.7 mg, 173.1 μL, 1.242 mmol), not completely dissolved, added CH ₂ Cl ₂ ( 3.450 mL). The mixture was stirred at room temperature for 2 days. After removal of the solvent under reduced pressure, using 20 cv (column _{volumes) 0-5% CH 2 Cl 2 /} MeOH gradient The residue was purified on a Biotage SNAP (25 g column) gave the title compound.

Step V: Intermediate M

To the stirred acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy-6-[4-methoxy-3-(trifluoromethylsulfonate) Pyridine (100.8 mg, 103.1 μL, 1.274 mmol) was added sequentially to a solution of oxy)phenyl]tetrahydropyran-2-yl]methyl ester (200 mg, 0.3981 mmol) in CH ₂ Cl ₂ (3 mL) , acetic anhydride (121.9 mg, 112.7 μL, 1.194 mmol) and DMAP (4.863 mg, 0.03981 mmol), stirred for 16 hours, diluted with water, separated organic solution with a phase separator, washed with aqueous solution of methylene chloride, concentrated The combined organics were purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc

Preparation of intermediate N: ((2R,3S,4R,5S,6R)-2-(3-ethynylphenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol)

Step I: ginseng (2,2-dimethylpropionic acid)(2R,3R,4R,5R,6R)-2-((pentamethyleneoxy)methyl)-6-(3-((trimethyl) (Alkyl)ethynyl)phenyl)tetrahydro-2H-pyran-3,4,5-triester

Add a solution of n-Bu ₃ MgLi in hexane-heptane-dibutyl ether (8:20:3) (2.65 mL 0.65 M, 1.725 mmol) to 2-(3-bromophenyl) at 0 °C A solution of ethynyl-trimethyl-decane (1.248 g, 1.05 mL, 4.928 mmol) in toluene (2.4 mL) and dibutyl ether (1.4 mL) was stirred for 25 hr. A solution of ZnBr ₂ -LiBr in dibutyl ether (2.6 mL 1.05 M, 2.711 mmol) was added dropwise, the cooling bath was removed and stirred at room temperature for 1 hour. Add 2,2-dimethylpropionic acid [(2R,3R,4S,5S,6R)-6-bromo-3,4,5-parade (2,2-dimethylpropoxy)tetrahydropyridyl A solution of methyl-2-yl)methyl ester (2.38 g, 4.107 mmol) in toluene (4.3 mL) was placed in a preheated oil bath at 90 ° C and stirred over the weekend. The reaction mixture was cooled to EtOAc EtOAc (EtOAc) Washed with brine the combined extracts were dried (Na ₂ SO _4), concentrated, hexane-ethyl acetate solution of Biotage ^TM 100 g SNAP column silica gel (0% to 10%, 12 CV, 10% , 5 CV) was purified as a dissolving agent to give the title compound.

Step II: (2R,3S,4R,5S,6R)-2-(3-ethynylphenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

To the stirred 2,2-dimethylpropionic acid [(2R,3R,4R,5R,6R)-3,4,5-paran (2,2-dimethylpropoxy)-6-[ Methanolate was added to a light suspension of 3-(2-trimethyldecylethynyl)phenyl]tetrahydropyran-2-yl]methyl ester (765 mg, 1.137 mmol) in methanol (15 mL) (Sodium ion (1)) (4.6 mL 0.5 M, 2.274 mmol) and stirred at room temperature for 24 hours. To the resulting solution was added DOWEX 50WX4-400 until pH 4-5, filtered and dissolved in methanol. The filtrate was concentrated, using EtOAc-MeOH-H ₂ O in the SNAP Biotage ^TM 40 g silica gel column (47.5: 1.5: 1 to 10: 1.5: 1) was purified from the agent as a solvent, to give the title compound. LC-MS: m/z = 265.28 (M+H ⁺ ).

Preparation of intermediate O: acetic acid [(2R, 3R, 4R, 5R, 6R)-3,4,5-triethoxycarbonyl-6-[4-(trifluoromethylsulfonyloxy)phenyl]tetra Hydroperyl-2-yl]methyl ester

Intermediate F (16.54 g, 29.7 mmol), bis(pinacolyl)diboron (11.36 g, 44.7 mmol) and KOAc (11.77 g, 119.9 mmol) were combined in DMF (250 mL). The resulting mixture was degassed (vacuum, subsequently N _2, 3 ×), followed by addition of _{Pd (DPPF) (Cl) 2} .CH 2 Cl 2 (2.48 g, 3.04 mmol), and the mixture was degassed and stirred at 60 deg.] C 3.5 hours. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and rinsed with several portions of DMF (50 mL). The resulting DMF solution was washed with hexane (3 x 250 mL). Diluted with DMF _{layer, H 2 O (2 × 250} mL) and brine (250 mL) and washed with saturated NH ₄ Cl solution (250 mL),, dried over Na ₂ SO _4, filtered and concentrated to give with EtOAc (750 mL) the crude product was purified by flash gradient (30-40%) of EtOAc in hexanes chromatography using a silicon dioxide in a Biotage ^TM snap 340 g column. The mixed fractions were concentrated and purified using a gradient of ₂ Cl ₂ solution of CH EtOAc (0 to 30%) in silicon dioxide Biotage ^TM snap 340 g column. The title compound (12.94 g, 81% yield) was obtained as a white solid.

Example 1: Preparation of Compound 1

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-hydroxyphenyl)tetrahydropyran-3,4,5-triol

Sodium methoxide (2.9 μL, 0.013 mmol) was added to a solution of Intermediate A (45 mg, 0.132 mmol) in 3 mL MeOH. The mixture was stirred at room temperature for 30 minutes and then neutralized with a resin Amberlite IR 120 (H). After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by EtOAc (EtOAc)

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.18 (m, 1H), 6.90 (m, 2H), 6.66 (m, 1H), 4.91 (m, 1H), 4.40 (m, 1H), 3.80 ( m, 3H), 3.55 (m, 1H), 3.44 (m, 1H). LC-MS: m/z = 257.3 (M+H ⁺ ).

Example 2: Preparation of Compound 2

N-methyl-4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl Benzylamine

Step I: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(4'-(A Hydrazinyl)biphenyl-3-yl)tetrahydro-2H-piperidin-2-yl)methyl ester

Add [4-(methylaminomethylmethyl)phenyl] to a solution of Intermediate B (30 mg, 0.0635 mmol) in 3 mL of dioxane Acid (17.1 mg, 0.0953 mmol), 1 M sodium bicarbonate (254 μL, 0.254 mmol) and Pd(PPh ₃ ) ₄ (7 mg, 0.0064 mmol). The mixture was stirred overnight at 90 ° C under nitrogen. After removal of the solvent under reduced pressure, using 25 column volumes on a Biotage ^TM SNAP 10 g silica gel column) CH ₂ Cl ₂ / MeOH gradient of (0-8%) to give the residue to obtain a mixture of three compounds (20 Mg). The mixture was used directly in the next step without further purification.

Step II: Compound 2

To the solution of the mixture (20 mg) mentioned above in methanol (3 mL) was added a drop of 25% sodium methoxide/methanol. After stirring for 20 minutes, it was neutralized with Amberlite IR 120 (H). After filtration, the solvent was evaporated.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.80 (m, 2H), 7.74 (s, 1H), 7.67 (m, 2H), 7.51 (m, 1H), 7.40 (m, 2H), 4.94 ( d, 1H), 4.38 (m, 1H), 3.77 (m, 2H), 3.66 (m, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 2.84 (s, 3H). LC-MS: m/z = 374.2 (M+H ⁺ ).

Example 3: Preparation of Compound 3

N-methyl-4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy Benzoylamine

Step I: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3-(4-(methylaminomethyl) phenoxy) Phenyl)tetrahydro-2H-piperidin-2-yl)methyl ester

Add 4-(methylamine-mercapto)phenyl to a solution of Intermediate A (50 mg, 0.147 mmol) in 5 mL CH ₂ Cl ₂ Acid (53 mg, 0.296 mmol), molecular sieve (300 mg) and Cu(OAc) ₂ (37 mg, 0.206 mmol). After stirring for 10 minutes, lutidine (85 μL, 0.735 mmol) was added to the mixture. The reaction mixture was then stirred at room temperature for 2 days. After removal of the solvent under reduced pressure using Biotage ^TM SNAP 25 g column of silica gel 20 column volumes CH ₂ Cl ₂ / MeOH gradient of (0-8%) separating the residue to obtain a mixture, which was found based on LC-MS The desired material was obtained and used in the next step without further purification.

LC-MS: m/z = 474.3 (M+H ⁺ ).

Step II: Compound 3

To the solution of the mixture (50 mg) mentioned above in methanol (3 mL) was added a drop of 25% MeONa/MeOH. After stirring for 20 minutes, it was neutralized with Amberlite IR 120 (H). After filtration, the solvent was evaporated.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.79 (m, 2H), 7.42 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 6.98 (m, 3H), 4.94 ( d, 1H), 4.32 (m, 1H), 3.74 (m, 3H), 3.60 (m, 1H), 3.47 (m, 1H), 2.84 (s, 3H). LC-MS: m/z = 390.3 (M+H ⁺ ).

Example 4: Preparation of Compound 4

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(3-methylbenzimidazol-5-yl)phenyl]tetrahydropyran-3,4, 5-triol (trifluoroacetate)

The title compound was prepared using a procedure similar to that described for compound 2, but using 1-methyl-1H-benzo[d]imidazole-6-yl. Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 9.21 (s, 1H), 8.07 (s, 1H), 7.86 (m, 2H), 7.78 (m, 1H), 7.66 (m, 1H), 7.44 ( m, 2H), 4.94 (d, 1H), 4.38 (m, 1H), 4.07 (s, 3H), 3.77 (m, 2H), 3.66 (m, 1H), 3.55 (m, 1H), 3.51 (m) , 1H). LC-MS: m/z = 371.3 (M+H ⁺ ).

Example 5: Preparation of Compound 5

N-methyl-3-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy Benzoylamine

The title compound was prepared using a procedure similar to that described in compound 3, but using 3-(methylamine-methyl)phenyl. acid.

¹ H NMR (CD ₃ OD, 400 MHz): 7.53 (m, 1H), 7.40 (m, 3H), 7.24 (m, 1H), 7.15 (m, 2H), 7.92 (m, 1H), 4.94 (d) , 1H), 4.38 (m, 1H), 3.77 (m, 3H), 3.59 (m, 1H), 3.47 (m, 1H), 2.81 (s, 3H). LC-MS: m/z = 390.3 (M+H ⁺ ).

Example 6: Preparation of Compound 6

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(4'-methyl-[1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran -3,4,5-triol

Intermediate C (126 μL 0.5 M, 0.063 mmol), p-tolyl was heated in a 4 mL sealed vial at 90 °C Acid N-methylpyrrolidine solution (189 μL 0.5 M, 0.095 mmol), PdCl ₂ (dppf) ₂ .CH ₂ Cl ₂ (3.8 mg, 0.0063 mmol) and aqueous Na ₂ CO ₃ (63 μL 2 M, 0.126) Mixture of mmol) for 15 hours. The mixture was filtered through a pad of celite and purified by reverse phase HPLC to give the title compound.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.75 (s, 1H), 7.58-7.49 (m, 3H), 7.44 (dd, J = 9.1, 4.4 Hz, 2H), 7.25 (d, J = 8.0 Hz , 2H), 5.04 (d, J = 3.6 Hz, 1H), 4.50 (t, J = 3.4 Hz, 1H), 3.85 (d, J = 5.0 Hz, 2H), 3.76 (t, J = 7.9 Hz, 1H) ), 3.64 (dd, J = 8.0, 3.1 Hz, 1H), 3.54 (dt, J = 7.9, 4.8 Hz, 1H), 2.37 (s, 3H). LC-MS: m/z = 353.2 (M+Na ⁺ )

Compounds 7 to 22 listed in Table 1 below were prepared using procedures similar to those described for Compound 6:

Example 7: Preparation of Compound 23:

N-phenyl-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzamide

Addition of aniline to NMP solution of intermediate D (88 μL 1 M, 0.088 mmol) NMP solution (194 μL 0.5 M, 0.097 mmol), HATU in NMP (114 μL 1 M, 0.114 mmol) and triethylamine (25 μL, 0.18 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)

¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (d, J = 14.9 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.76-7.65 (m, 3H), 7.53 (t, J) = 7.7 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 5.01 (d, J = 7.3 Hz, 1H), 4.42 (dd, J = 4.5) , 3.2 Hz, 1H), 3.92 (dd, J = 11.9, 7.0 Hz, 1H), 3.86-3.73 (m, 2H), 3.67 (dd, J = 7.4, 3.1 Hz, 1H), 3.57 (td, J = 7.0, 3.0 Hz, 1H). LC-MS: m/z = 360.0 (M+H ⁺ )

Compounds 24 to 38 listed in Table 2 below were prepared using procedures similar to those described in Compound 7:

Example 8. Preparation of Compound 39

N-methyl-2'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- [1,1'-biphenyl]-3-carboxamide

Step I: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3'-(methylaminemethanyl)-[1,1 '-Biphenyl]-2-yl)tetrahydro-2H-piperidin-2-yl)methyl ester.

Intermediate E (50 mg, 0.106 mmol), [3-(methylamine-methyl)phenyl] by bubbling nitrogen through for 2 minutes The mixture of acid (38 mg, 0.21 mmol) and potassium phosphate (43 mg, 0.32 mmol) in dioxane (530 uL) was degassed. PdCl ₂ (dppf) ₂ .CH ₂ CL ₂ (7 mg, 0.011 mmol) was added and the mixture was heated in a 4 mL sealed vial at 90 ° C for 8 hours. The mixture was filtered through EtOAc (EtOAc) elute

LC-MS: m/z = 458.3 (M+H ⁺ )

Step II: Compound 39: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(3'-(methylamine-mercapto)- [1,1'-Biphenyl]-2-yl)tetrahydro-2H-piperidin-2-yl)methyl ester (21 mg, 0.046 mmol) was dissolved in MeOH (0.5 mL). μL 25 w/v%, 0.021 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The reaction was neutralized by adding Amberlite IR 120H resin until the pH became neutral. The reaction mixture was filtered.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 5.02 (d, J = 8.6 Hz, 1H), 4.20 (dd, J = 8.6, 3.2 Hz, 1H), 3.97-3.92 (m, 1H), 3.83-3.73 (m, 3H), 3.55 (q) , J = 9.5 Hz, 1H), 2.92 (s, 3H). LC-MS: m/z = 374.2 (M+H ⁺ )

Example 9: Preparation of Compound 40

N ³ ,N ⁵ -dimethyl-2'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran- 2-yl)-[1,1'-biphenyl]-3,5-dimethylguanamine

The title compound was prepared according to the procedure described for compound 39, but in step 1, N1,N3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-di-boron was used. -2-yl)benzene-1,3-dimethylguanamine (prepared according to the literature procedure Corinne K. Cusumano et al, Sci. Transl. Med. 3, 109ra115 (2011) ).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.27 (t, J = 1.4 Hz, 1H), 8.08 (d, J = 1.3 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.48 ( t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 6.5 Hz, 1H), 4.99 (d, J = 8.6 Hz, 1H), 4.21 (dd, J = 8.6, 3.1 Hz, 1H), 4.01-3.93 (m, 1H), 3.86-3.72 (m, 3H), 3.58-3.46 (m, 1H), 2.94 (s, 6H). LC-MS: m/z = 431.2 (M+H ⁺ )

Example 10: Preparation of Compound 41

(2R,3S,4R,5S,6R)-2-(5-bromo-2-methoxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-tri alcohol

To acetic acid [(2R,3R,4S,5S,6R)-3,4,5,6-tetraethoxymethoxytetrahydropyran-2-yl]methyl ester (40 mg, 0.103 mmol) at 0 °C , 1-Bromo-4-methoxy-benzene (38 mg, 0.21 mmol) and (2,2,2-trifluoroethenyl)oxysilica (34 mg, 0.16 mmol) in dichloromethane (500 μL A solution of tetrachlorostannane in CH ₂ Cl ₂ (308 μL 1 M, 0.308 mmol) was added and the mixture was warmed to room temperature and stirred for 15 hours. The mixture was diluted with saturated aqueous NaHCO ₃ (1 mL), filtered using a phase separation column and washed with _{CH 2 Cl 2 (1 mL)} . Evaporation of the filtrate gave the crude product triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(5-bromo-2-methoxyphenyl)tetrahydro-2H - Piperan-3,4,5-triester, which was dissolved in MeOH (0.5 mL), EtOAc (EtOAc) (EtOAc (EtOAc) The reaction mixture was washed with EtOAc (EtOAc)EtOAc.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.67 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 8.8, 2.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.20 (d, J = 6.9 Hz, 1H), 4.19 (dd, J = 6.9, 3.0 Hz, 1H), 4.09-3.99 (m, 1H), 3.86-3.72 (m, 6H). LC-MS: m/z = 371.1, 373.1 (M+Na ⁺ )

Example 11: Preparation of Compound 42

3-(4-methoxy-3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pentan-2- Methyl phenyl) propionate

The title compound was prepared according to the procedure described for compound 41, using methyl 3-(3-bromo-4-methoxyphenyl)propanoate as starting material.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.39 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.4, 2.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.19 (d, J = 5.8 Hz, 1H), 4.34 (dd, J = 5.8, 3.1 Hz, 1H), 3.98 (dd, J = 11.4, 6.5 Hz, 2H), 3.87-3.76 (m, 5H), 3.74 (dd, J = 6.3, 3.1 Hz, 1H), 3.64 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H). LC-MS: m/z = 357.2 (M+H ⁺ )

Example 12: Preparation of Compound 43-47

Compounds 43-47 were prepared using procedures similar to those described for Intermediate A, but were used appropriately Acid is used as the starting material.

Compound 43:

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-phenylphenyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.76 (s, 1H), 7.63 (dd, 1H), 7.61 (dd, 1H), 7.53 (m, 1H), 7.44-7.39 (m, 2H), 7.33 -7.29(m,1H),5.02(d,1H),4.47(t,1H),3.95-3.83(m,2H),3.73(t,1H0,3.63-3.61(dd,1H),3.54-3.51( m, 1H) .LC-MS: m / z = 339.2 (m + Na +).

Compound 44:

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-methoxyphenyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (t, 1H), 7.07 (s, 1H), 7.00 (d, 1H), 6.82 (dd, 1H), 4.92 (d, 1H), 4.41 (m) , 1H), 3.83-3.80 (m, 2H), 3.77 (s, 3H), 3.69 (t, 1H), 3.54 (dd, 1H), 3.46 (m, 1H). LC-MS: m / z = 293.2 (M + Na +).

Compound 45:

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(2-hydroxyphenyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.32 (d, 1H), 7.14 (t, 1H), 6.85-6.78 (m, 2H), 5.12 (d, 1H), 4.44 (m, 1H), 3.94 (dd, 1H), 3.80-3.73 (m, 3H), 3.62 (m, 1H). LC-MS: m/z =279.2 (M+Na ⁺ ).

Compound 46:

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(4-hydroxyphenyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 (d, 2H), 6.77 (d, 2H), 4.88 (m, 2H), 4.38 (t, 1H), 3.78 (m, 1H), 3.72-3.68 (t, 1H), 3.6-3.57 (dd, 1H), 3.43-3.39 (m, 1H). LC-MS: m/z =279.2 (M+Na ⁺ ).

Compound 47:

(2R,3S,4R,5S,6R)-2-(3-fluorophenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) δ 7.37 (td, 1H), 7.30-7.19 (m, 2H), 6.99 (tt, 1H), 4.92 (t, 1H), 4.39 - 4.28 (m, 1H) , 3.90-3.76 (m, 2H), 3.76-3.65 (m, 1H), 3.56 (dd, 1H), 3.48 (td, 1H). LC-MS: m/z =281.2 (M+Na ⁺ ).

Compound 48:

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl Phenyl]tetrahydropyran-3,4,5-triol

Step I: Acetic acid ((2R,3S,6S)-3-ethoxycarbonyl-6-(3-bromophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (34 g, 124.9 mmol) and (3- Bromophenyl) Add acid (55.19 g, 274.8 mmol) to a solution of pre-degassed (N ₂ /vacuum alternately bubbling × 4 times) in acetonitrile (340.0 mL). The reaction mixture was stirred under an inert (N ₂ ) atmosphere for a period of 65 hours. After 23 hours, additional diethyl p-methoxy palladium (2.804 g, 12.49 mmol) was added. The suspension was filtered through celite and washed with EtOAc. The filtrate was concentrated to dryness to give a brown oil.

The residue was filtered through a pad of EtOAc (EtOAc (EtOAc):

6 minutes in batches by 100 mL / min or 50 mL / flow rate (dry loading crude material on a per gram to about 1.5 g silicon dioxide) is Biotage ^TM column chromatography using a 340 g Snap or 100 g Snap Ultra min and the column The product was purified using EtOAc / EtOAc (EtOAc: EtOAc) Parts of mixed solution were combined (2.66 g crude) and by Biotage ^TM chromatography (dry load) Snap Ultra 50 g silica gel column and using a gradient of EtOAc 14 CV 5% -30% at a flow rate of 50 mL / min of / from hexyl The alkane was repurified as a dissolving agent to give another desired material (1.04 g, 2.2%).

¹ H NMR (400 MHz, methanol-d4) δ 7.61 (dd, J=2.1, 1.3 Hz, 1H), 7.52-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H), 6.26 (ddd, J = 10.4, 3.1, 1.6 Hz, 1H), 5.99 (ddd, J = 10.4, 2.9, 2.1 Hz, 1H), 5.36-5.28 (m, 1H), 5.22 (dddd) , J=6.8, 2.8, 2.1, 1.5 Hz, 1H), 4.24 (dd, J=12.0, 6.9 Hz, 1H), 4.14 (dd, J=12.0, 3.1 Hz, 1H), 3.79 (td, J=7.0) , 3.1 Hz, 1H), 2.08 (s, 3H), 2.06 (s, 3H). LCMS: mass of (M+Na).

Step II: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-bromophenyl)-4,5-dihydroxytetrahydro-2H-pentan-2- Methyl ester

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-(3-bromophenyl)-3,6-dihydro-2H-pyran-2-yl]methyl ester (20.6 g, Addition of OsO ₄ (2.5 Wt.% t-BuOH solution) (23.84 g, 29.40 mL, 2.344 mmol) and 4-methyl-4- in THF (618.0 mL) / water (412.0 mL) Oxy-ion-morpholine-4-indole (19.61 g, 17.35 mL, 167.4 mmol). The mixture was stirred at room temperature for 6 days. The resulting mixture was poured onto 2-Me-THF (500 mL) and 25 mL brine. The layers were separated and the aqueous layer was back extracted with 1×500 mL 2-Me-THF. With brine (200 mL) the combined organic layers were washed once with _{15% Na 2 SO 3 (200} mL) and then washed twice with brine (200 mL) and washed once. Concentrate the solution to a minimum volume. After concentration, the residue turned into a pale yellow gelatinous solid. CH ₂ Cl ₂ (about 250 mL) was added to crystallize the product from the solution. The suspension was stirred at room temperature for 2 hours, sonicated for 5 minutes and stirred at room temperature for an additional 1 hour. The mixture is then filtered and the solid was rinsed with cold _{CH 2 Cl 2 (2 × 50} mL), to give 7.21 g off-white solid.

The filtered mother liquor was concentrated to dryness and the residue was purified by flash chromatography to give the desired material. A total of 12.1 g (54%) of the title compound was obtained.

Step III: Triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-bromophenyl)tetrahydro-2H-pyran-3,4,5 -Triester

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-(3-bromophenyl)-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (12.1 g, 30.01 mmol) 4-(dimethylamino)pyridine (366.6 mg, 3.001 mmol) was added to a solution of pyridine (28.48 g, 29.12 mL, 360.1 mmol). The reaction mixture was then cooled in an ice bath and acetic anhydride (24.51 g, 22.65 mL, 240.1 mmol) was added dropwise while keeping the temperature below 10 °C. The resulting mixture was stirred at room temperature for 20 hours. 100 ml of water was poured into the reaction mixture and stirred for 5 minutes. Then 100 ml of CH ₂ Cl _{2 was added} and stirred for 5 minutes. 200 ml of 1 N HCl (pH = 4-5) was added, transferred to a separatory funnel and the phases were separated. With _{CH 2 Cl 2 (2 × 50} ml) The aqueous phase was back extracted and the combined organic phases. The organic phase was back washed with 200 ml of 1 N HCl (pH = 1) and stirred for 10 minutes, then the phases were separated. The organic phase was then dried over a sodium sulphate filter and evaporated to dryness and then evaporated with Heptane (3.times.ss.sssssssssssssssssssssssssssssssssssssssssss , 5R,6R)-3,4,5-triethoxycarbonyl-6-(3-bromophenyl)tetrahydropyran-2-yl]methyl ester (13.04 g, 26.76 mmol, 89.19%).

¹ H NMR (400 MHz, chloroform-d) δ 7.67 (d, J = 1.4 Hz, 1H), 7.52-7.46 (m, 1H), 7.45-7.39 (m, 1H), 7.30 (t, J = 7.9 Hz , 1H), 5.88 (t, J = 3.3 Hz, 1H), 5.30 (t, J = 8.6 Hz, 1H), 5.11 (dd, J = 8.8, 3.1 Hz, 1H), 5.06 (d, J = 3.5 Hz) , 1H), 4.38 (dd, J = 12.1, 6.9 Hz, 1H), 4.16 (dd, J = 12.1, 2.8 Hz, 1H), 3.82-3.72 (m, 1H), 2.15 (d, J = 1.4 Hz, 6H), 2.07 (s, 3H), 2.04 (s, 3H).

Step IV: Triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethyloxymethyl)-6-(4'-(5-methyl-1,3,4-oxadiazole- 2-yl)-[1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran-3,4,5-triester

Dissolve acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxy) in a 1 L 3-neck round bottom flask equipped with a condenser, heating mantle, magnetic stirrer and N ₂ inlet 5-(3-bromophenyl)tetrahydropyran-2-yl]methyl ester (18.1 g, 37.14 mmol), [4-(5-methyl-1,3,4-oxadiazole-2) -yl)phenyl] A solution of the acid (12.50 g, 61.28 mmol) and sodium bicarbonate (132.6 mL 1.4 M, 185.7 mmol) in dioxane (543.0 mL). Then Pd(PPh ₃ ) ₄ (4.292 g, 3.714 mmol) was added and the mixture was stirred at 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite to remove inorganic salts and filtrate was concentrated. The residue was taken up in EtOAc EtOAc (EtOAc)EtOAc. The title compound (11.74 g, 56%) was obtained.

¹ H NMR (400 MHz, chloroform-d) δ 8.13 (d, J = 8.4 Hz, 2H), 7.84 - 7.76 (m, 3H), 7.63 (dd, J = 5.8, 2.0 Hz, 1H), 7. , J=4.9, 1.7 Hz, 2H), 6.08 (t, J=3.1 Hz, 1H), 5.37 (t, J=9.0 Hz, 1H), 5.20 (dd, J=9.2, 3.0 Hz, 2H), 4.38 (dd, J = 12.1, 6.6 Hz, 1H), 4.19 - 4.06 (m, 1H), 3.83 (ddd, J = 9.0, 6.6, 2.6 Hz, 1H), 2.64 (s, 3H), 2.19 (s, 3H) ), 2.09 (s, 3H), 2.08 (s, 3H), 2.04 (s, 1H), 2.02 (s, 3H), 1.59 (s, 2H), 1.26 (t, J = 7.2 Hz, 1H).

Step V: Compound 48

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[4-(5-methyl-1,3,4-oxadiazole) MeONa (2.239 g, 2.308 mL 25 w/) was added to a solution of 2-yl)phenyl]phenyl]tetrahydropyran-2-yl]methyl ester (11.74 g, 20.72 mmol) in methanol (293.5 mL) w%, 10.36 mmol). The mixture (yellow solution) was stirred at room temperature under nitrogen for 1.5 hours. It was neutralized (pH 8-9 to 4-5) via an amberlist resin IR-120 (x g) column, followed by treatment with 130 mg (4 equivalents, load 1.2 mmol/g, assumed 500 ppm residual Pd) SiliaMetS mercaptan. The mixture was stirred at room temperature (1 h) then filtered on a pad of celite and evaporated to dryness to afford a yellow solid. The residue was adsorbed onto silica gel, then purified on a 100 g snap HP column eluting with a gradient of 0-25% MeOH in dichloromethane. The appropriate fractions were then combined and evaporated to dryness to give 2. The solid was suspended in MeOH (93 mL, 65 vol). The mixture was then stirred at 65 ° C until the product was completely dissolved (45 min). The solution was cooled to room temperature and then evaporated on a rotary evaporator (bath temperature: 40 ° C) under low vacuum until the product was completely crayed out (15-20 ml of MeOH remaining). 30 mL of MTBE (20 vol) was added to the mixture and stirred at room temperature for 1 hour. The white solid was then filtered on Buchner, washed with EtOAc EtOAc EtOAc The solid was then dried in a vacuum oven at 45 °C for 4 days to give the title compound (1, 299 g).

¹ H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.66 (dt, J = 6.7 , 2.1 Hz, 1H), 7.53-7.45 (m, 2H), 4.86 (d, J = 4.7 Hz, 1H), 4.80 (dd, J = 11.9, 5.5 Hz, 2H), 4.72-4.63 (m, 2H) , 4.11 (td, J = 6.0, 3.1 Hz, 1H), 3.68 (td, J = 6.7, 4.9 Hz, 2H), 3.58 (q, J = 5.7 Hz, 1H), 3.50 (ddt, J = 6.3, 5.1 , 2.3 Hz, 2H), 3.16 (d, J = 5.3 Hz, 0H), 3.07 (s, 0H), 2.60 (s, 3H), 1.10 (s, 0H).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (d, 2H), 7.86 (d, 3H), 7.64 - 7.61 (m, 1H), 7.520-7.47 (m, 2H), 5.03 (d, 1H) , 4.59-4.36 (m, 1H), 3.89-3.81 (m, 2H), 3.74 (t, 1H), 3.63 (dd, 1H), 3.55 (td, 1H), 2.62 (s, 3H). LC-MS: m/z = 399.2 (M+H ⁺ ).

Example 13: Preparation of Compound 49-50

Compounds 48-50 were prepared using procedures similar to those described for Compound 2, but were used appropriately in Step I. acid.

Compound 49:

2-methyl-N-[4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl Phenyl]phenyl]propanamide

¹ H NMR (400 MHz, CD ₃ OD) δ 9.70 (s, 1H), 7.67 (s, 1H), 7.63-7.41 (m, 5H), 7.41-7.22 (m, 2H), 4.93 (d, 1H) , 4.39 (t, 1H), 3.75 (d, 2H), 3.68-3.40 (m, 3H), 2.55 (m, 1H), 1.14 (d, 6H). LC-MS: m/z = 402.3 (M+H ⁺ ).

Compound 50:

N-methyl-3-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl Phenylsulfonamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (t, 1H), 7.91 (d, 1H), 7.84-7.75 (m, 2H), 7.70-7.46 (m, 4H), 5.02 (d, 1H) , 4.47-4.40 (m, 1H), 3.85 (qd, 2H), 3.74 (t, 1H), 3.63 (dd, 1H), 3.55 (td, 1H), 2.52 (d, 3H). LC-MS: m/z = 410.1 (M+H ⁺ ).

Compounds belonging to the class of Formula X below are prepared via two different routes. In Route A, Compound X is prepared in two steps from the monomannosidic intermediate Z. In Route B, Compound X is obtained as a by-product in the final step of removing the protecting group from the preparation of the dimannose type compound from the dimannosidic intermediate Y.

Example 14: Preparation of Compound 51 via Route A:

5-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)phenoxy) Dimethyl isophthalate

Step I: 5-(3-((2R,3S,4R,5S,6R)-5-Ethyloxy-6-(ethyloxymethyl)-3,4-dihydroxytetrahydro-2H- Dimethyl piperidin-2-yl)phenoxy)isophthalate

To intermediate A (215 mg, 0.632 mmol) and [3,5-bis(methoxycarbonyl)phenyl] Cu(OAc) ₂ (161 mg, 0.884 mmol) and molecular sieves (4 Å, 800 mg) were added sequentially to a suspension of the acid (301 mg, 1.26 mmol) in 6.4 mL CH ₂ Cl ₂ . The suspension was stirred at room temperature for 15 minutes and 2,6-lutidine (366 μL, 3.16 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and filtered over celite. And purified by flash column chromatography on silica gel (0 to 20% MeOH solution of CH ₂ Cl ₂₎ and the filtrate was evaporated to dryness. The main product was recovered and purified again by reverse phase HPLC to afford the title compound (81 mg, 24%).

Step II: Compound 51: 5-(3-((2R,3S,4R,5S,6R)-5-ethoxycarbonyl-6-(ethyloxymethyl)-3,4 under nitrogen atmosphere Add NaOMe (25% (w/w) to a solution of dimethyl dihydroxytetrahydro-2H-piperidin-2-yl)phenoxy)isophthalate (77 mg, 0.145 mmol) in 4 mL MeOH ) 8.3 μL, 0.036 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered over EtOAc EtOAc EtOAc. The column was washed with methanol and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcqqqq

¹ H NMR (400 MHz, DMSO) δ 8.19 (t, J = 1.5 Hz, 1H), 7.69 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 7.00 (dd, J = 7.9, 2.3 Hz, 1H), 4.67 (d, J = 5.7 Hz, 1H), 3.97 (dd, J = 5.7, 3.0 Hz, 1H), 3.84 (s, 6H), 3.66-3.49 (m, 3H), 3.41 (m, 2H).

Example 15: Preparation of Compound 52

4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy]benzoic acid ester

Compound 52 was prepared using the procedure described for compound 3, but using 4-(methoxycarbonyl)phenyl in the first step] acid.

¹ H NMR (400 MHz, DMSO) δ 7.94 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.14 (s, 1H), 7.02 ( m, 3H), 4.66 (d, J = 5.7 Hz, 1H), 3.95 (dd, J = 5.7, 3.0 Hz, 1H), 3.80 (s, 3H), 3.57 (m, 3H), 3.41 (m, 2H) ). LC-MS: m/z = 391.2 (M+H ⁺ )

Example 16. Preparation of Compound 53

5-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)phenoxy) Dimethyl isophthalate

Compound 53 was prepared using procedures similar to those described for compound 3, but using acetic acid [(2R,3S,4R,5S,6R)-3-ethoxycarbonyl-4,5-dihydroxy-6 in the first step. -(4-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester (Intermediate L, Step II) and 3,5-bis(methoxycarbonyl)phenyl acid.

¹ H NMR (400 MHz, DMSO) δ 8.15 (t, J = 1.5 Hz, 1H), 7.65 (dd, J = 6.5, 1.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.06 ( t, J = 8.5 Hz, 2H), 4.64 (d, J = 6.0 Hz, 1H), 3.94 (dd, J = 6.0, 3.0 Hz, 1H), 3.80 (s, 6H), 3.70-3.49 (m, 3H) ), 3.49-3.33 (m, 2H). LCMS (M+1): 449.3

Example 17. Preparation of Compound 54

4-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)phenoxy) Methyl benzoate

Compound 54 was prepared using procedures similar to those described for compound 3, but using acetic acid [(2R,3S,4R,5S,6R)-3-ethyloxy-4,5-dihydroxy-6 in the first step. -(4-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester (Intermediate L, Step II) and 4-(methoxycarbonyl)phenyl acid.

¹ H NMR (400 MHz, DMSO) δ 7.94 (m, 1 H), 7.46 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.02 (m, 1H), 4.81 ( m, 2H), 4.67 (d, J = 5.8 Hz, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.56 (m, 1H), 3.99 (m, 1H), 3.80 (s, 3H), 3.61 (m, 3H), 3.44 (m, 2H), 3.31 (s, 1H). LCMS (M+1): 391.3

Example 18. Preparation of Compound 55

2-(4-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)benzene Methyl oxy)phenyl)acetate

Compound 55 was prepared using the procedure described for compound 3, but using acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6- (in the first step) 4-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester (Intermediate L, Step II) and 4-(2-methoxy-2-oxoethyl)phenyl acid.

¹ H NMR (400 MHz, DMSO) δ 7.38 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.93 (m, 4H), 4.65 (d, J = 5.6 Hz, 1H), 3.99 (dd, J=5.6, 3.0 Hz, 1H), 3.64 (s, 2H), 3.60 (m, 2H), 3.59 (s, 3H), 3.53 (m, 1H), 3.44 (m, 1H) ), 3.39 (m, 1H). LCMS (M+1): 405.2

Example 19: Preparation of Compound 56

3-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)phenoxy) Methyl benzoate

Step I: Acetic acid ((2R,3S,6S)-3-ethoxycarbonyl-6-(4-hydroxyphenyl)-3,6-dihydro-2H-pyran-2-yl)methyl ester

Stir diacetic acid (2R,3S,4R)-2-(ethyloxymethyl)-3,4-dihydro-2H-pyran-3,4-diester (9.869 g, 36.25 mmol) at room temperature ), 4-hydroxyphenyl Acid (5.00 g, 36.3 mmol) and palladium acetate (1.221 g, 5.438 mol) solution in 50 mL CH ₃ CN in the two days. The mixture was filtered on celite and the filtrate was concentrated to dry. The residue was purified by EtOAc EtOAcjjjjjj

Step II: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(4-hydroxyphenyl)tetrahydro-2H-pentan-2- Methyl ester

To acetic acid ((2R,3S,6S)-3-ethenyloxy-6-(4-hydroxyphenyl)-3,6-dihydro-2H-pyran-2-yl)methyl ester (6.01 g, 0.591 mmol) methanesulfonamide (2.81 g, 29.5 mmol), OsO ₄ (7.4 mL 2.5% (w/w) t-BuOH solution was added to a suspension of THF (36 mL) and water (24 mL). 0.591 mmol) and NMO (4.613 g, 39.4 mmol). The mixture was stirred at room temperature for 24 hours. And the mixture was treated with EtOAc (3 × 40 mL) the product was extracted with 40 mL ₂ S ₂ O ₃ (aq 1 M) Na. With brine (15 mL) was washed and the combined organic layers were dried over Na ₂ SO _4. The resulting solution was evaporated to dryness and by chromatography on silica gel (0% to 20% MeOH solution of CH ₂ Cl ₂₎ to give the residue, to give the title compound (4.447 g, 66%).

Step III: Compound 56: To acetic acid ((2R,3S,4R,5S,6R)-3-ethoxycarbonyl-4,5-dihydroxy-6-(4-hydroxyphenyl)tetrahydro-2H-peri Methyl-2-yl)methyl ester (100 mg, 0.294 mmol) and (3-(methoxycarbonyl)phenyl) Cu(OAc) ₂ (74 mg, 0.411 mmol) and molecular sieves (4 Å, 400 mg) were added sequentially to a suspension of the acid (106 mg, 0.588 mmol) in 6 mL CH ₂ Cl ₂ . The suspension was stirred at room temperature for 15 minutes and 2,6-lutidine (170 μL, 1.47 mmol) was added. The reaction mixture was stirred at room temperature for 2 days and filtered on a SPE column (isolute SCX-2, 1 g). The filtrate was evaporated to dryness. NaOMe (17 μL 25% (w/w) solution, 0.073 mmol) was added to the residue dissolved in methanol (3 mL). The reaction mixture was stirred at room temperature for 18 h and filtered over EtOAc EtOAc EtOAc. The column was washed with MeOH and the filtrate was evaporated to dry. The residue was purified by EtOAc EtOAcqqqq

¹ H NMR (400 MHz, DMSO) δ 7.69 (m, 1 H), 7.52 (t, J = 8.0 Hz, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 7.00 (m, 2H), 4.80 (dd, J=9.8, 4.9 Hz, 2H), 4.66 (d, J = 5.8 Hz, 1H), 4.61 (d, J = 6.2 Hz, 1H), 4.56 (t, J = 5.8 Hz, 1H), 3.99 (m, 1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.56 (m, 1H), 3.44 (m, 2H). LC-MS: m/z = 391.2 (M+H ⁺ )

Example 20: Preparation of Compound 57 via Route B

(2R,3S,4R,5S,6R)-2-[3-(4-fluorophenoxy)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R)-3-ethoxycarbonyl-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-5-hydroxy- 4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetra Hydroperyl-2-yl]methyl ester

To the stirred acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethoxycarbonyl-6-(2,2,2-trichloroacetamimidinyl)oxy -tetrahydropiperidin-2-yl]methyl ester (300 mg, 0.518 mmol) and acetic acid [(2R,3S,4R,5S)-3-acetoxy-6-[3-[t-butyl ( a solution of dimethyl)nonanyloxyphenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (259 mg, 0.569 mmol) in CH ₂ Cl ₂ (10 mL) 4A MS (1.00 g) was added and stirred at room temperature for 30 minutes. After cooling to -40 ° C, freshly opened trimethylmethane trifluoromethanesulfonate (9.4 μL, 0.052 mmol) was added dropwise. The mixture was stirred at -40 ° C and slowly warmed to -10 ° C over 2 hours. Et ₃ N (72 μL, 0.52 mmol) was then added. After removing the cooling bath, the mixture was allowed to warm to room temperature, filtered to remove molecular sieves and concentrated to dryness. Using Biotage ^TM SNAP 50 g silica gel column MeOH / CH ₂ Cl ₂ (0 to 5%, 20 CV) The residue was purified to give an inseparable mixture containing the title compound (375 mg), which was used without further purification directly In the next step.

LC-MS: m/z = </RTI> (M+Na ⁺ ).

Step II: Acetic acid [(2R,3R,4R,5R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R,6R) -3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester

To the stirred containing acetic acid [(2R,3R,4R,5R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-5- Hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy Add acetic acid (41 μL, 0.72 mmol) and 1 M TBAF/THF (1.43 mL) to a solution of THF (4 mL) in THF (4 mL). 1.43 mmol). The mixture was stirred at room temperature for 30 minutes. Then diluted with EtOAc (30 mL), washed successively with water (20 mL) and brine (20 mL), dried over Na ₂ SO _4, and concentrated to dryness. 25 g silica gel column using the Biotange ^TM SNAP 20 column volumes _{CH 2 Cl 2 / MeOH (O} -6%) and the residue was purified to give an inseparable mixture containing the title compound (230 mg), which was used without further purification directly i.e. Used in the next step.

Step III: Acetic Acid [(2R,3R,4R,5R,6R)-3-Ethyloxy-6-[3-(4-fluorophenoxy)phenyl]-5-hydroxy-4-[(2R) ,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(acetoxymethyl) Tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R,6R) -3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (68 mg, 0.101 mmol) and (4-fluorophenyl) An aqueous 4A molecular sieve (400 mg) and Cu(OAc) ₂ (26 mg, 0.142 mmol) were added to a solution of the acid (28 mg, 0.203 mmol) in CH ₂ Cl ₂ (3.4 mL). After stirring for 10 minutes, 2,6-lutidine (59 μL, 0.51 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 days. After filtration on diatomaceous molecular sieves, the filtrate was concentrated and purified using _{20 CV CH 2 Cl 2 / MeOH} (0 to 5%) in 10 g SNAP Biotage ^TM, the obtained mixture containing the title compound (33 mg), which was used without Further purification is carried out.

LC-MS: m/z = 788 (M+Na ⁺ ).

Step IV: Compound 57: To acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-6-[3-(4-fluorophenoxy)phenyl]-5-hydroxy-4 -[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydro A solution of 25% sodium methoxide in MeOH (8.6 μL 1 M, 0.0086 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; After 2 h, the reaction mixture was taken thru a Isolute &lt;RTI ID=0.0&gt;&gt; The filtrate was evaporated to dryness crystals crystals crystals

¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 (t, 1H), 7.11 (d, 1H), 7.05-6.96 (m, 3H), 6.91 (ddd, 2H), 6.78 (dd, 1H), 4.82 (m, 1H), 4.24 (t, 1H), 3.77-3.57 (m, 3H), 3.48 (dd, 1H), 3.43 - 3.29 (m, 1H). LC-MS: m / z = 373.2 (M + Na +).

Example 21: Preparation of Compound 58-60

Compounds 58-60 were prepared according to procedures similar to those described for Compound 3, but were used appropriately acid:

Compound 58: (2R,3S,4R,5S,6R)-2-[3-(3,5-Dimethylphenoxy)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5 - Triol.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 (t, 1H), 7.10 (d, 1H), 7.01 (s, 1H), 6.77 (dd, 1H), 6.67 (s, 1H), 6.50 (s) , 2H), 4.79 (m, 1H), 4.33 (dd, 1H), 3.73 (dd, 1H), 3.69-3.60 (m, 2H), 3.48 (dd, 1H), 3.41-3.31 (m, 1H), 2.16 (s, 6H). LC-MS: m/z = 361.3 (M+H ⁺ ).

Compound 59: (2R, 3S, 4R, 5S, 6R)-2-(hydroxymethyl)-6-(3-phenoxyphenyl)tetrahydropyran-3,4,5-triol.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.30-7.19 (m, 3H), 7.13 (d, 1H), 7.02 (dd, 2H), 6.93-6.83 (m, 2H), 6.80 (dd, 1H) , 4.8 (m, 1H), 4.25 (t, 1H), 3.77-3.57 (m, 3H), 3.49 (dd, 1H), 3.43-3.32 (m, 1H). LC-MS: m/z = 333.2 (M+H ⁺ ).

Compound 60: (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy Phenyl]phenyl]tetrahydropyran-3,4,5-triol.

1H NMR (400 MHz, CD ₃ OD) δ 7.90 (m, 2H), 7.35 (t, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 7.08-6.98 (m, 2H), 6.94 ( d, 1H), 4.86 (d, 1H), 4.52 (s, 1H), 4.39-3.97 (m, 1H), 3.79-3.41 (m, 4H), 2.51 (s, 3H). LC-MS: m/z = 415.2 (M+H ⁺ ).

Example 22: Preparation of Compound 61

(2R,3S,4R,5S,6R)-2-(3-hydroxy-4-methoxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3S,6S)-3-acetoxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-phenyl] -3,6-dihydro-2H-piperidin-2-yl]methyl ester

Commercially available [[2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (2.00 g, 7.34 mmol) in 35 [3-[Tervebutyl(dimethyl)decyl]oxy-4-methoxy-phenyl] is added to the solution in mL CH ₃ CN] Acid (2.073 g, 7.34 mmol) and Pd(OAc) ₂ (247 mg, 1.10 mmol). The mixture was stirred overnight at room temperature, and then another batch of Pd(OAc) ₂ (247 mg, 1.10 mmol) and [3-[t-butyl(dimethyl)decyl]oxy-4-yl were added thereto. Oxy-phenyl] Acid (2.073 g, 7.35 mmol). It was then stirred overnight at room temperature. And filtered through a pad of diatomaceous earth with 30 mL of the mixture was diluted with CH ₂ Cl _2. The filtrate was concentrated and 20 column volumes using Hex / EtOAc gradient of (0-15%) The residue was purified on Biotage ^TM (100 g silica gel column) to afford the title compound as a yellow oil (2.00 g, 60% yield) .

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.87-6.72 (m, 2H), 6.67 (d, 1H), 6.05-5.90 (m, 1H), 5.90-5.71 (m, 1H), 5.26-5.02 (m) , 2H), 4.09 (dd, 1H), 4.02-3.81 (m, 2H), 3.67 (s, 3H), 1.92 (m, 6H), 0.84 (d, 9H), 0.00 (d, 6H).

Step II: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy -phenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-phenyl]-3 ,6-Dihydro-2H-piperidin-2-yl]methyl ester (1.85 g, 4.10 mmol) in water (7.4 mL) / t-BuOH (7.4 mL), methanesulfonamide (586 mg) , 6.16 mmol), 2.5% OsO _{4 /} t-BuOH (1.29 mL, 0.10 mmol), NMO (962 mg, 8.21 mmol) and 2,6-dimethylpyridine (476 μL, 4.10 mmol). The mixture was stirred at room temperature for 24 h, quenched with EtOAc EtOAc EtOAc The aqueous phase was separated, washed with water and brine and dried over Na ₂ SO ₄ . After removal of the solvent under reduced pressure, using a Biotage ^TM SNAP (50 g silica gel _{column) 20 CV CH 2 Cl 2 /} MeOH (0-8%) of a gradient residue was purified to give the title compound (1.38 g, 69% Yield).

¹ H NMR (400 MHz, CD ₃ OD) δ 6.97-6.34 (m, 3H), 4.95-4.86 (m, 1H), 4.68 (d, 1H), 4.50 (dd, 1H), 4.03 (dd, 1H) , 3.89 (dd, 1H), 3.68 (dd, 2H), 3.64 (d, 3H), 1.90 (d, 6H), 1.10-0.68 (m, 9H), 0.00 (d, 6H).

Step III: Compound 61: To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4 Add 1 M MeONa MeOH to a solution of methoxy-phenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (50 mg, 0.103 mmol) in MeOH ( 1.5 mL) Solution (2.3 μL, 0.0103 mmol). The mixture was stirred at room temperature for 30 minutes, and then 1 M TBAF/THF (103 μL 1 M, 0.103 mmol) was added thereto. The mixture was stirred overnight at room temperature. It was then passed through an Isolute SCX-2 SPE (15 mL, 2 g) column (pre-wet with MeOH) and washed twice with 5 mL MeOH. The filtrate was evaporated to dryness crystals crystals crystals

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24-6.46 (m, 3H), 4.38 (t, 1H), 3.82 (s, 3H), 3.79 (dd, 2H), 3.76-3.66 (m, 1H) , 3.58 (dd, 1H), 3.47-3.39 (m, 1H). LC-MS: m/z = 573.3 (dimer+H ⁺ ).

Example 23: Preparation of Compound 62

3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-[1,1' -biphenyl]-3,5-dicarboxylic acid dimethyl ester

To (3,5-bis(methoxycarbonyl)phenyl) under a nitrogen atmosphere Add a NaHCO ₃ aqueous solution to a suspension of intermediate B (222 mg, 0.470 mmol) and Pd(PPh ₃ ) ₄ (54 mg, 0.047 mmol) in 2 mL of dioxane. 1.57 mL of 1.2 M solution, 1.88 mmol). The reaction mixture was heated at 95 ° C for 18 hours, cooled to room temperature and filtered over EtOAc. The filter cake was washed with methanol and the filtrate was evaporated. The residue was dissolved in MeOH (2 mL) and EtOAc (EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 18 h and filtered over EtOAc EtOAc EtOAc. The column was washed with methanol and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcqqqq

¹ H NMR (400 MHz, DMSO) δ 8.44 (t, 1.5 Hz, 1H), 8.39 (d, J = 1.6 Hz, 2H), 7.75 (s, 1H), 7.62 (m, 1H), 7.48 (d, J = 4.8 Hz, 2H), 4.87 (d, J = 4.5 Hz, 1H), 4.82 (d, J = 5.1 Hz, 1H), 4.74 (d, J = 6.3 Hz, 1H), 4.66 (d, J = 6.5 Hz, 1H), 4.59 (t, J = 5.7 Hz, 1H), 4.01 (m, 1H), 3.90 (s, 6H), 3.71 (m, 1H), 3.59 (m, 2H), 3.50 (m, 2H). LC-MS: m/z = 433.3 (M+H ⁺ )

Example 24: Preparation of Compound 63

N ³ ,N ⁵ -dimethyl-3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran- 2-yl)-[1,1'-biphenyl]-3,5-dimethylguanamine

Step I: 3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-[1 ,1'-biphenyl]-3,5-dicarboxylic acid

To 3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- under nitrogen atmosphere To a solution of [1,1'-biphenyl]-3,5-dicarboxylic acid dimethyl ester (73 mg, 0.168 mmol) in 1.5 mL of THF and 1.5 mL of water The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAcjjjjj

Step II: Compound 63: 3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran under nitrogen atmosphere 2-Methyl)-[1,1'-biphenyl]-3,5-dicarboxylic acid (50 mg, 0.124 mmol) in 2 mL of DMF was added sequentially with methylamine (2 M in THF, 155 μL, 0.309 mmol), HATU (118 mg, 0.309 mmol) and DIPEA (65 μL, 0.371 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered over EtOAc EtOAc EtOAc. The column was washed with methanol and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcqqqq

¹ H NMR (400 MHz, DMSO) δ 8.60 (m, 2H), 8.21 (m, 1H), 8.15 (m, 2H), 7.73 (s, 1H), 7.62 (m, 1H), 7.43 (m, 2H) ), 4.73 (d, J = 5.8 Hz, 1H), 4.04 (dd, J = 5.8, 3.0 Hz, 1H), 3.62 (m, 2H), 3.52 (m, 1H), 3.43 (m, 2H), 2.76 (d, J = 4.5 Hz, 6H). LC-MS: m/z = 431.3 (M+H ⁺ )

Example 25. Preparation of Compound 64

N1,N3-dimethyl-5-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran- 2-yl)phenoxy)m-xylylenediamine

Compound 64 was prepared according to procedures similar to those described in Steps I and II of Example 24.

¹ H NMR (400 MHz, DMSO) δ 8.51 (m, 2H), 8.00 (t, J = 1.4 Hz, 1H), 7.50 (dd, J = 4.6, 1.4 Hz, 2H), 7.33 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.07 (s, 1H), 6.87 (dd, J = 8.0, 2.3 Hz, 1H), 4.63 (d, J = 5.7 Hz, 1H), 3.92 (dd, J = 5.5, 3.0 Hz, 1H), 3.62-3.32 (m, 5H), 2.70 (d, J = 4.5 Hz, 6H). LCMS (M+1): 447.3

Example 26: Preparation of Compound 65

2-(3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-[1 Methyl 1'-biphenyl]-3-yl)acetate

Intermediate B (100 mg, 0.212 mmol), (3-(2-methoxy-2-oxoethyl)phenyl) under a nitrogen atmosphere An aqueous solution of NaHCO ₃ (0.71 mL of a 1.2 M solution, 0.847 mmol) was added to a suspension of acid (62 mg, 0.317 mmol) and Pd(PPh ₃ ) ₄ (24 mg, 0.021 mmol) in 2 mL of dioxane. The reaction mixture was heated at 95 ° C for 18 hours, cooled to room temperature and filtered over EtOAc. The filter cake was washed with methanol and the filtrate was evaporated. The residue was dissolved in MeOH (2 mL) and &lt;EMI ID&gt;&gt;MeONa (27 [mu]L 25% (w/w) solution, 0.053 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered over EtOAc EtOAc EtOAc. The column was washed with methanol and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjj

¹ H NMR (400 MHz, DMSO) δ 7.67 (s, 1H), 7.52 (m, 3H), 7.40 (m, 3H), 7.24 (d, J = 7.6 Hz, 1H), 4.74 (d, J = 5.5) Hz, 1H), 4.50 (width unimodal, 4H), 4.08 (dd, J=5.5, 3.0 Hz, 1H), 3.74 (s, 2H), 3.64 (m, 2H), 3.60 (s, 3H), 3.54 (m, 1H), 3.44 (m, 2H). LC-MS: m/z = 389.2 (M+H ⁺ )

Example 27: Preparation of Compound 66

2-(3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-[1 Methyl 1'-biphenyl]-2-yl)acetate

Compound 66 was prepared according to a procedure similar to that described for compound 65, but using (2-(2-methoxy-2- </RTI> ethoxyethyl) phenyl) acid.

¹ H NMR (400 MHz, DMSO) δ 7.38 (m, 2H), 7.32 (m, 3H), 7.28 (s, 1H), 7.21 (m, 1H), 7.12 (m, 1H), 4.71 (d, J) = 5.3 Hz, 1H), 4.48 (width unimodal, 4H), 4.05 (dd, J = 5.3, 3.1 Hz, 1H), 3.60 (m, 4H), 3.54 (m, 1H), 3.49 (s, 3H) , 3.43 (m, 1H), 3.39 (m, 1H). LC-MS: m/z = 389.2 (M+H ⁺ )

Example 28: Preparation of Compound 67

(2R,3S,4R,5S,6R)-2-(4-chloro-3-hydroxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step I: Acetic acid ((2R,3S,6S)-3-ethenyloxy-6-(4-chloro-3-hydroxyphenyl)-3,6-dihydro-2H-pyran-2-yl) Methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (0.900 g, 3.31 mmol) in 10 mL CH ₃ (4-chloro-3-hydroxy-phenyl) added to the solution in CN Acid (1.140 g, 6.61 mmol) and Pd(OAc) ₂ (111 mg, 0.496 mmol). The mixture was stirred at room temperature for 23 hours. Another portion of Pd(OAc) ₂ (111 mg, 0.496 mmol) and (4-chloro-3-hydroxy-phenyl) were added to the reaction. Acid (0.350 g, 2.03 mmol). It was then stirred at room temperature for 27 hours at which time complete consumption of starting material was observed. And filtered through a pad of diatomaceous earth with 10 mL CH ₂ Cl ₂ mixture was diluted. The filtrate was concentrated to a black foam (1.50 g). The crude material was purified with EtOAc EtOAcjjjjjjj LC-MS: m/z = 363 (M+Na ⁺ ).

Step II: Acetic acid ((2R,3S,4R,5S,6R)-3-ethenyloxy-6-(4-chloro-3-hydroxyphenyl)-4,5-dihydroxytetrahydro-2H-peri Methyl-2-methyl)methyl ester

To acetic acid [(2R,3S,6S)-3-acetoxy-6-(4-chloro-3-hydroxy-phenyl)-3,6-dihydro-2H-pyran-2-yl]- Add methane sulfonamide (137 mg, 1.44 mmol), 2.5% OsO ₄ /t-BuOH (363 μL) to a solution of the ester (328 mg, 0.963 mmol) in water (5.9 mL) /t-BuOH (5.9 mL) , 1.16 mmol), NMO (226 mg, 1.93 mmol) and the mixture was stirred for 2 days. The reaction was quenched with EtOAc (20 mL)EtOAc. The aqueous phase was separated, washed with water (10 mL) and brine (10 mL) and dried over Na ₂ SO ₄ and washed. The solvent was evaporated to give an white solid (355 mg). The crude material was purified with EtOAc EtOAcjjjjjjj

Step III: Compound 67: to acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-(4-chloro-3-hydroxy-phenyl)-4,5 at room temperature MeONa (46 μL 25 w/v%, 0.213 mmol) was added to a solution of dihydroxy-tetrahydropyran-2-yl]methyl ester (35 mg, 0.0887 mmol) in anhydrous MeOH (998 uL). The reaction was stirred for 45 minutes, then treated with acidic resin and shaken until the pH was no longer basic. The mixture was filtered and evaporated to give a gum. The gum was dissolved in CH ₃ CN / water (1/1) and lyophilized to give a solid (23 mg). The title compound (13 mg, 49%) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.18 (d, 1H), 6.95 (d, 1H), 6.81 (dd, 1H), 4.24 (m, 1H), 3.79 - 3.70 (m, 2H), 3.64 (t, 1H), 3.43 (ddd, 2H). LC-MS: m/z = 313.1 (M+Na ⁺ ).

Example 29: Preparation of Compound 68

(2R, 3S, 4R, 5S, 6R)-2-(2-chloro-5-hydroxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Compound 68 was prepared according to procedures similar to those described for compound 67, but using (2-chloro-3-hydroxy-phenyl) acid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (dd, 2H), 6.68 (dd, 1H), 5.21. (d, 1H), 4.30-3.93 (m, 2H), 3.94-3.55 (m, 4H) ). LC-MS: m/z = 290.1 (M+).

Example 30: Preparation of Compound 69

Thiophen-2-ylaminocarbamate 3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl Phenyl ester

Step I: Triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethyloxymethyl)-6-(3-((t-butyldimethylmethyl)alkyl)phenyl) ) tetrahydro-2H-pyran-3,4,5-triester

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy] at 0 ° C under N ₂ atmosphere a solution of phenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (Intermediate A, Step II) (1.00 g, 2.20 mmol) in CH ₂ Cl ₂ (20 mL) Lysopyridine (872 μL, 6.60 mmol), DMAP (54 mg, 0.440 mmol) and acetic anhydride (623 μL, 6.60 mmol) were added sequentially. The yellow solution was stirred at 0 ° C for 1.5 hours. _{4 (15%, 2 × 6} ml) the reaction mixture was treated with KHSO4, followed by brine, dried and evaporated to give a gum (1.10 g). The crude material was purified using EtOAc EtOAc (EtOAc:EtOAc)

Step II: Triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-hydroxyphenyl)tetrahydro-2H-pyran-3,4,5 -Triester

To the stirred triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-((t-butyldimethylmethyl)alkyl)benzene Add acetic acid (162 μL, 2.841 mmol) and TBAF (5.68 mL 1) to a solution of tetrahydro-2H-pyran-3,4,5-triester (1.02 g, 1.89 mmol) in THF (11 mL) M, 5.68 mmol). The mixture was stirred at room temperature for 30 minutes, then diluted with EtOAc (30 mL), (20 mL) and washed with water (20 mL) and brine, dried over Na ₂ SO ₄ dried and concentrated to give a clear oil which solidified to a wax Shape. The crude material was purified by lyophilization on a SNAP column (25 g) with Hex/EtOAc (5%; 5 CV, 5-30%; 25 CV, 30-40%; 5 CV, 40-50%; 30 CV). The title compound was obtained as a white foam (409 mg, 48%).

Step III: Compound 69: thiophen-2-ylaminocarbamate 3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- Piperidin-2-yl)phenyl ester

To acetic acid [(2R,3R,4R,5R)-3,4,5-triethoxycarbonyl-6-(3-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester under N ₂ atmosphere Molecular sieves (100 mg), triethylamine (49 μL, 0.35 mmol) and isocyanatothiophene (44 mg, 0.35 mmol) were added sequentially to a solution of (50 mg, 0.118 mmol) in CH ₂ Cl ₂ (500 μL) . The reaction was filtered and the filtrate was evaporated to dry. The residual crude material was purified by EtOAc (EtOAc)

LC-MS: m/z = 380.9 (M+H ⁺ ).

Example 31: Preparation of Compound 70-72

Compounds 70-72 listed in Table 3 were prepared according to procedures similar to those described for compound 69, but using the appropriate isocyanate.

Preparation of Compound 73

((2R,3S,4R,5S,6R)-2-(3-ethynylphenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol)

Step I: 2,2-Dimethylpropionic acid [(2R,3R,4R,5R,6R)-3,4,5-e (2,2-dimethylpropenyloxy)-6-[3 -(2-trimethyldecylethynyl)phenyl]tetrahydropyran-2-yl]methyl ester

Add a solution of n-Bu ₃ MgLi (2.65 mL 0.65 M, 1.725 mmol) in hexane-heptane-dibutyl ether (8:20:3) to 2-(3-bromophenyl) at 0 °C A solution of ethynyl-trimethyl-decane (1.248 g, 1.05 mL, 4.928 mmol) in toluene (2.4 mL) and dibutyl ether (1.4 mL) was stirred for 25 hr. A solution of ZnBr ₂ -LiBr in dibutyl ether (2.6 mL 1.05 M, 2.711 mmol) was added dropwise, the cooling bath was removed, and stirred at room temperature for 1 hour. Add 2,2-dimethylpropionic acid [(2R,3R,4S,5S,6R)-6-bromo-3,4,5-parade (2,2-dimethylpropoxy)tetrahydropyridyl A solution of methyl-2-yl)methyl ester (2.38 g, 4.107 mmol) in toluene (4.3 mL) was placed on a preheated oil bath at &lt;RTIgt; The reaction mixture was cooled to EtOAc EtOAc (EtOAc) Washed with brine the combined extracts were dried (Na ₂ SO _4), concentrated, hexane-ethyl acetate solution of Biotage ^TM 100 g SNAP column silica gel (0% to 10%, 12 CV, 10% , 5 The title compound (765 mg) was obtained as an oil.

Step II. Compound 73

To the stirred 2,2-dimethylpropionic acid [(2R,3R,4R,5R,6R)-3,4,5-paran (2,2-dimethylpropoxy)-6-[ Methanolate was added to a light suspension of 3-(2-trimethyldecylethynyl)phenyl]tetrahydropyran-2-yl]methyl ester (765 mg, 1.137 mmol) in methanol (15 mL) (Sodium ion (1)) (4.6 mL 0.5 M, 2.274 mmol) and stirred at room temperature for 24 hours. To the resulting solution was added DOWEX 50WX4-400 until pH 4-5, filtered and dissolved in methanol. The filtrate was concentrated using Biotage ^TM 40 g silica gel SNAP column _{EtOAc-MeOH-H 2 O (} 47.5: 1.5: 1 to 10: 1.5: 1) solvent was purified from the agent as to give a beige solid of title product (170 mg, 55%).

LC-MS: m/z = 265.28 (M+H ⁺ ).

Preparation of Compound 74

(2R,3S,4R,5S,6R)-2-(4-ethynylphenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared from 2-(4-iodophenyl)ethynyl-trimethyl-decane as described in compound 73.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 (s, 4H), 4.93 (d, J=4.1 Hz, 1H), 4.38-4.33 (m, 1H), 3.87-3.76 (m, 2H), 3.72 (t, J = 7.7 Hz, 1H), 3.55 (dd, J = 7.8, 3.1 Hz, 1H), 3.49-3.42 (m, 1H), 3.46 (s, 1H).

Preparation of Compound 75

(2R,3S,4R,5S,6R)-2-(3-ethynyl-4-methoxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-methoxy-3-(2-trimethyldecylalkylethynyl) Phenyl]tetrahydropyran-2-yl]methyl

The title compound was prepared from Intermediate M using a procedure similar to that described for Intermediate F.

Step II: Compound 75

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-methoxy-3-(2-trimethyldecylalkylethynyl)benzene Add a solution of sodium methoxide in methanol (60 μL 25 w/v%, 0.278 mmol) in a solution of tetrahydropyran-2-yl]methyl ester (145 mg, 0.2712 mmol) in methanol (2 mL) The reaction mixture was stirred at room temperature for 18 hours, and the acid tree was ion exchanged. The lipid (DOWEX 50WX4-400) was quenched until pH 5-6, filtered, washed with anhydrous methanol and concentrated organic solvent. Purification on a Isolera system using a gradient of acetonitrile in water (5%, 3 CV; 5% to 15%, 8 CV; 15% 2 CV) as a dissolving agent on a reverse phase 25 g C18 cartridge. The title compound (66 mg, 0.2168 mmol, 80%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.50 (d, J = 2.1 Hz, 1H), 7.44 (dd, J = 8.9, 2.0 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.86-4.84(m,1H),4.34-4.28(m,1H),3.84(s,3H),3.83-3.75(m,2H),3.72(t,J=7.6 Hz,1H), 3.60(dd, J = 7.7, 3.1 Hz, 1H), 3.57 (s, 1H), 3.48-3.40 (m, 1H). LC-MS: m/z =295.32 (M+H ⁺ ).

Preparation of Compound 76

(2R,3S,4R,5S,6R)-2-(3-bromo-2-methyl-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Add a solution of sodium methoxide in methanol (3.5 mL 0.5 M, 1.75 mmol) to a suspension of EtOAc (EtOAc) To the resulting solution, DOWEX 50WX4-400 was added until pH 4-5, filtered, dissolved in methanol, and the filtrate was concentrated. The residue was purified on a 60 g C18 silica gel column using a gradient of acetonitrile (10%, 2 CV; 10% to 45%, 7 CV; 45%, 3 CV) as an eluent on the Isolera system to give a white solid. The title compound (60 mg, 30.1%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.48 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.9 Hz, 1H), 5.13 (d, J = 7.1 Hz, 1H), 4.18- 4.11 (m, 1H), 4.02 (dd, J = 11.9, 7.4 Hz, 1H), 3.98-3.91 (m, 1H), 3.82 (dd, J = 5.4, 4.2 Hz, 1H), 3.71 (dd, J = 12.0, 3.8 Hz, 1H), 3.63-3.55 (m, 1H), 2.51 (s, 3H). LC-MS: m/z = 333.29 (M+H ⁺ ).

Preparation of Compound 77

(2R,3S,4R,5S,6R)-2-(4-bromo-3-methoxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described in 4-bromo-2-methoxy-benzene as starting material.

^{1 H NMR (400 MHz, CDC3OD} ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.89 (d, J = 4.0 Hz, 1H), 4.33 (t, J = 3.5 Hz, 1H), 3.87 (s, 3H), 3.82 (d, J = 4.8 Hz, 2H), 3.69 (t, J = 7.6 Hz, 1H), 3.57 (dd, J = 7.7, 3.0 Hz, 1H), 3.53-3.45 (m, 1H).

Preparation of Compound 78

(2R,3S,4R,5S,6R)-2-(3-chloro-2-fluoro-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title product was prepared from 1-chloro-2-fluoro-3-iodo-benzene as described in compound 77.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.60-7.52 (m, 1H), 7.42-7.35 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H), 5.14 (d, J = 7.4 Hz , 1H), 4.14 - 4.00 (m, 2H), 3.88 - 3.81 (m, 2H), 3.80 - 3.69 (m, 2H).

LC-MS: m/z = 293.14 (M+H ⁺ ).

Preparation of Compound 79

(2R,3S,4R,5S,6R)-2-[3-(3,5-chlorophenyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Intermediate C (40 mg, 0.125 mmol) and (3,5-dichlorophenyl) in a microwave vial (10 mL) Add K ₂ CO ₃ (35 mg, 0.253 mmol) and SiliaCat DPP-Pd (144.6 mg, 0.0376 mmol) in MeOH (2.5 mL) in MeOH (2.5 mL) It was heated for 20 minutes, diluted with methanol-CH ₂ Cl ₂ - water, filtered and evaporated. The residue was dissolved in methanol-water and neutralized with DOWEX 500 until pH 5 and filtered. The filtrate was concentrated and purified with EtOAcqqqqqq

HPLC details: Phenomenex C18 Gemini AXIA 5 μ 110Å 21.2 x 250 mm; using acetonitrile in water (10% to 60%, 40 minutes, containing 0.01% TFA as buffer).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 (brs, 1H), 7.63 (d, J = 1.9 Hz, 2H), 7.58-7.46 (m, 3H), 7.42 (t, J = 1.9 Hz, 1H) ), 5.01 (d, J = 4.4 Hz, 1H), 4.43 (dd, J = 4.4, 3.2 Hz, 1H), 3.93-3.80 (m, 2H), 3.76 (t, J = 7.3 Hz, 1H), 3.66 (dd, J = 7.5, 3.1 Hz, 1H), 3.56 (td, J = 7.1, 3.1 Hz, 1H). LC-MS: m/z = 385.2 (M+H ⁺ ).

Preparation of Compound 80

3-[[4-[4-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl] Methyl triazol-1-yl]methyl]benzoate

To a stirred solution of methyl 3-(azidomethyl)benzoate (26.0 mg, 0.1362 mmol) and compound 74 (30 mg, 0.114 mmol) in EtOH (520 μL) and H ₂ O (173 μL) CuSO ₄ (9.1 mg, 0.057 mmol) was added to the solution. Add (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-carboxylate to the resulting pale blue suspension (562.2) Mg, 2.84 mmol) (sodium ascorbate). The reaction flask was sealed and the resulting suspension was stirred at room temperature over the weekend, diluted with water and washed with methylene chloride. The resulting aqueous suspension was filtered through a 0.4 micron filter, EtOAc (EtOAc) 15 mg, 27.6%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.1 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.56-7.46 (m, 3H), 5.69 (s, 2H), 4.97 (d, J = 3.5 Hz, 1H), 4.42 (t, J = 3.4 Hz, 1H) ), 3.87 (s, 3H), 3.84-3.81 (m, 2H), 3.74 (t, J = 7.9 Hz, 1H), 3.59 (dd, J = 8.0, 3.0 Hz, 1H), 3.52-3.45 (m, 1H). LC-MS: m/z = 456.43 (M+H ⁺ ).

Preparation of Compound 81

(2R,3S,4R,5S,6R)-2-[4-(1-Benzyltriazol-4-yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4, 5-triol

The title compound was prepared from intermediate F and azidomethylbenzene as described for compound 80, followed by standard removal of the protecting of the acetate using NaOMe/MeOH.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.41-7.29 (m, 5H) ), 5.62 (s, 2H), 4.97 (d, J = 3.7 Hz, 1H), 4.42 (t, J = 3.5 Hz, 1H), 3.85-3.79 (m, 2H), 3.73 (t, J = 7.9 Hz) , 1H), 3.58 (dd, J = 8.0, 3.1 Hz, 1H), 3.52-3.44 (m, 1H). LC-MS: m / z = 398.53 (M + H +).

Preparation of Compound 82

5-[2-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2- Dimethyl]phenyl]ethynyl]benzene-1,3-dicarboxylic acid dimethyl ester.

To 5-iodobenzene-1,3-dicarboxylic acid dimethyl ester (18.9 mg, 0.059 m mol), CuI (1.9 mg, 0.01 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (4.0 mg, 0.005 mmol TEA (29.92 mg, 41.0 μL, 0.296 mmol) and Compound 75 (15 mg, 0.0493 mmol) were added to the mixture in degassed (purged with nitrogen for 5 minutes) in DMF (2 mL) at 50 °C The dark brown reaction mixture was heated under 18 hours, filtered through a 0.4 micron filter on preparative HPLC (injected on Phenomenex C18 Gemini AXIA 5 μm 110A 21.2 x 75 mm for 10 min - 10% ACN / H ₂ O + 0.1% formic acid Purification of the title compound (13 mg, 51.3%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (t, J = 1.6 Hz, 1H), 8.21. (d, J = 1.6 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.42 ( Dd, J = 8.7, 2.3 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.84 - 4.80 (m, 1H), 4.30-4.25 (m, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 3.81-3.69 (m, 2H), 3.65 (t, J = 7.5 Hz, 1H), 3.56 (dd, J = 7.7, 3.1 Hz, 1H), 3.44 - 3.36 (m, 1H). LC-MS: m/z = 495.47 (M+H ⁺ ).

Preparation of Compound 83

3-[2-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2- Phenyl]ethynyl] -N -methyl-benzamide

The title compound was prepared as described for compound 82 using commercially available 3-iodo-N-methylbenzamide.

LC-MS: m/z = 422.43 (M+H ⁺ ).

Preparation of Compound 84

5-[2-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2- Phenyl]ethynyl] -N1,N3 -dimethyl-benzene-1,3-dimethylguanamine

The title compound was prepared as described for compound 82 using commercially available 5-iodo-N1,N3-dimethylm-decylamine.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (t, J = 1.6 Hz, 1H), 8.06 (d, J = 1.6 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.51 7.45 (m, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.90-4.86 (m, 1H), 4.38-4.32 (m, 1H), 3.90 (s, 3H), 3.89-3.77 (m, 2H), 3.74 (t, J = 7.5 Hz, 1H), 3.63 (dd, J = 7.7, 3.1 Hz, 1H), 3.52-3.43 (m, 1H), 2.92 (s, 6H). LC-MS: m / z = 485.48 (M + H +).

Preparation of Compound 85

N1,N3 -dimethyl-5-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran- 2-yl]phenyl]ethynyl]benzene-1,3-dimethylguanamine

The title compound was prepared as described for compound 73 using commercially available 5-iodo-N1,N3-dimethylm-decylamine.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (t, J = 1.6 Hz, 1H), 8.00 (d, J = 1.7 Hz, 2H), 7.60 (s, 1H), 7.45 (d, J = 7.7) Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 4.86 (d, J = 4.3 Hz, 1H), 4.32-4.25 (m, 1H), 3.84-3.64 (m, 3H), 3.53 (dd, J = 7.5, 3.1 Hz, 1H), 3.48-3.40 (m, 1H), 2.84 (s, 6H). LC-MS: m / z = 455.41 (M + H +).

Preparation of Compound 86

3-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]acetylene Methyl benzoate

The title compound was prepared as described for compound 82 using compound 73 and commercially available methyl 3-iodobenzoate.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (t, J = 1.5 Hz, 1H), 8.02-7.96 (m, 1H), 7.76-7.71 (m, 1H), 7.69-7.66 (m, 1H) , 7.55-7.36 (m, 4H), 4.94 (d, J = 4.3 Hz, 1H), 4.41-4.34 (m, 1H), 3.91 (s, 3H), 3.89-3.79 (m, 2H), 3.75 (t , J = 7.5 Hz, 1H), 3.62 (dd, J = 7.6, 3.1 Hz, 1H), 3.56-3.47 (m, 1H). LC-MS: m / z = 399.88 (M + H +).

Preparation of Compound 87

4-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]acetylene Methyl benzoate

The title compound was prepared as described for compound 82 using compound 73 and commercially available methyl 4-iodobenzoate.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.06-7.97 (m, 2H), 7.68 (s, 1H), 7.63-7.58 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 4.94 (d, J = 4.3 Hz, 1H), 4.40 - 4.33 (m, 1H), 3.90 (s, 3H) , 3.88-3.78 (m, 2H), 3.75 (t, J = 7.4 Hz, 1H), 3.61 (dd, J = 7.6, 3.1 Hz, 1H), 3.55-3.47 (m, 1H). LC-MS: m/z = 399.38 (M+H ⁺ ).

Preparation of Compound 88

3-[2-[4-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]acetylene Methyl benzoate

The title compound was prepared as described for compound 82 using compound 74 and commercially available methyl 3-iodobenzoate.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (t, J = 1.5 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.76-7.70 (m, 1H), 7.60-7.43 (m, 3H) , 4.96 (d, J = 4.0 Hz, 1H), 4.42-4.33 (m, 1H), 3.91 (s, 3H), 3.88-3.79 (m, 1H), 3.74 (t, J = 7.6 Hz, 1H), 3.58 (dd, J = 7.8, 3.1 Hz, 1H), 3.52-3.44 (m, 1H). LC-MS: m / z = 399.34 (M + H +).

Preparation of Compound 89

4-[2-[4-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]acetylene Methyl benzoate

The title compound was prepared as described for compound 82 using compound 74 and commercially available methyl 4-iodobenzoate.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.57-7.49 (m, 4H), 4.96 (d, J) =4.1 Hz, 1H), 4.40-4.33 (m, 1H), 3.90 (s, 3H), 3.87-3.78 (m, 2H), 3.74 (t, J = 7.6 Hz, 1H), 3.58 (dd, J = 7.7, 3.1 Hz, 1H), 3.53-3.45 (m, 1H). LC-MS: m/z = 399.38 (M+H ⁺ ).

Preparation of compound 90

N1,N3 -dimethyl-5-[2-[2-methyl-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) Tetrahydropyran-2-yl]phenyl]ethynyl]benzene-1,3-dimethylguanamine

Using compound 76 and 5-ethynyl-N1,N3-dimethylm-decylamine according to The title compound was prepared by the procedure described for compound 82.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.53-7.43 (m, 2H), 7.08 (t, J = 7.9 Hz, 1H), 5.13 (d, J = 7.2 Hz, 1H), 4.14 (dd, J = 7.1, 3.2 Hz, 1H), 4.02 (dd, J = 11.9, 7.5 Hz, 1H), 3.95 (dd, J = 5.4, 3.3 Hz, 1H), 3.82 (dd, J = 5.4, 4.1 Hz, 1H) , 3.71 (dd, J = 12.0, 3.8 Hz, 1H), 3.64 - 3.56 (m, 1H), 2.64 (s, 6H), 2.51 (s, 3H). LC-MS: m / z = 469.51 (M + H +).

Preparation of N1,N3 -dimethyl-5-(2-trimethyldecylethynyl)benzene-1,3-dimethylguanamine (XX) and 5-ethynyl- N1,N3 -dimethyl-benzene -1,3-dimethylguanamine (YY)

Degassing to 5-Iodo- N1,N3 -dimethyl-benzene-1,3-dimethylguanamine (600 mg, 1.86 mmol) and CuI (71.8 mg, 0.377 mmol) in DMF (6.0 mL) (purging with nitrogen for 5 minutes) Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (154.0 mg, 0.1886 mmol), TEA (954 mg, 1.3 mL, 9.43 mmol) and ethynyl (trimethyl) were added sequentially to the solution. The decane (926 mg, 1.33 mL, 9.43 mmol) was heated at 50 ° C. The reaction mixture was extracted with ethyl acetate (3×10 mL). EtOAc (EtOAc) %, 8 CV; 4%, 2 CV) was purified as a dissolving agent to give N1,N3 -dimethyl-5-(2-trimethyldecylethynyl)benzene-1,3-dimethylguanamine XX ( 250 mg, 46%) and 5-ethynyl- N1,N3 -dimethyl-benzene-1,3-dimethylguanamine YY (80 mg, 0.2474 mmol, 13.12%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (t, J = 1.7 Hz, 1H), 8.00 (d, J = 1.7 Hz, 2H), 2.92 (s, 6H), 0.25 (s, 9H) and ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (t, J = 1.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 2H), 3.68 (s, 1H), 2.91 (d, J = 3.6 Hz, 7H). LC-MS: m/z =21.21. (M+H ⁺ ).

Preparation of compound 91

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(2-phenylethynyl)phenyl]tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-(2-phenylethynyl)phenyl]tetrahydropyran- 2-methyl]methyl ester

Add PdCl ₂ (dppf) to the degassed (indoor vacuum / nitrogen purge) mixture of intermediate H (55 mg, 0.1129 mmol), cuprous iodide (4.3 mg, 0.0226 mmol) in DMF (2.2 mL) - CH ₂ Cl ₂ (18.4 mg, 0.0226 mmol), Et ₃ N (57.12 mg, 78.7 μL, 0.565 mmol) and ethynylbenzene (34.6 mg, 37.0 μL, 0.338 mmol), heated at 80 ° C for 6 hours, cooled to rt, diluted with water and extracted with ethyl acetate, washed with brine the combined extracts were dried (Na ₂ SO _4), concentrated, such as ethyl acetate in hexanes to 25g SNAP silica gel column (15% to 50 The title compound (25 mg, 43.6%) was obtained as a yellow oil.

Step II: Compound 91

Add NaOMe solution (500 μL 0.5 M, 0.2500 mmol, MeOH) to a stirred solution of EtOAc (MeOH) (EtOAc) elute The title compound (23.6 mg, 61.4%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.45-7.23 (m, 8H), 4.86 (d, J = 4.2 Hz, 1H), 4.35 - 4.25 (m, 1H), 3.82 - 3.70 (m, 2H), 3.67 (t, J = 7.5 Hz, 1H), 3.53 (dd, J = 7.7, 3.1 Hz, 1H), 3.46-3.36 (m, 1H). LC-MS: m/z = 341.31 (M+H ⁺ ).

Preparation of Compound 92

(2R,3S,4R,5S,6R)-2-[3-[2-(3,5-Dichlorophenyl)ethynyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3 ,4,5-triol

2-(3,5-Dichlorophenyl)ethynyl-trimethyl-decane (29.4 mg, 0.121 mmol), intermediate H (49 mg, 0.1006 mmol), PdCl ₂ (dppf) - under nitrogen atmosphere Add DMF (2.0 mL) to a mixture of CH ₂ Cl ₂ (16.4 mg, 0.020 mmol) and cuprous iodide (3.8 mg, 0.020 mmol), degas twice (vacuum and nitrogen) and add DBU (119.0 μL, 0.798) Methyl) and water (10.0 μL), heated at 95 ° C for 5 hours, cooled to 0 ° C, concentrated, dissolved in DMSO (1 mL), loaded on a 3 g C18 tannin sample loader at 25 g Purification on C18 using an aqueous solution of acetonitrile (10% to 50%) as a dissolving agent on the Isolera system gave (2R,3S,4R,5S,6R)-2-[3-[2-(3, 5-Dichlorophenyl)ethynyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (3 mg, 7%).

LC-MS: m / z = 409.35 (M + H +).

Preparation of Compound 93

N -methyl-3-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl ]phenyl]ethynyl]benzamide.

A solution of compound 86 (10 mg, 0.024 mmol) and methylamine in ethanol (1 mL 33 w/w%) was stirred at room temperature for 5 days. Concentrate the reaction mixture and use 12 g on the Isolera system The title compound (7.5 mg, 76.6%) was obtained as a solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (t, J = 1.5 Hz, 1H), 7.74-7.68 (m, 1H), 7.61-7.55 (m, 2H), 7.47-7.28 (m, 4H) , 4.86 (d, J = 4.3 Hz, 1H), 4.32-4.26 (m, 1H), 3.84 - 3.71 (m, 2H), 3.67 (t, J = 7.4 Hz, 1H), 3.53 (dd, J = 7.6 , 3.1 Hz, 1H), 3.47-3.41 (m, 1H), 2.83 (s, 3H). LC-MS: m/z = 398.4 (M+H ⁺ ).

Preparation of compound 94

N1,N3 -dimethyl-5-[(E)-3-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetra Hydropyran-2-yl]phenyl]prop-1-enyl]benzene-1,3-dimethylguanamine

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(E)-3-[3,5-bis(methyl) Aminomethyl)phenyl]allyl]phenyl]tetrahydropyran-2-yl]methyl

Add 5-iodo- N1,N3 -dimethyl-benzene-1,3-dimethylguanamine (66.5 mg, 0.209 mmol) to a solution of Intermediate I (75 mg, 0.1672 mmol) in DMF (1.9 mL) (See recipe below), palladium acetate (6 mg, 0.0267 mmol), tetrabutylammonium bromide (53.9 mg, 0.1672 mmol), and sodium bicarbonate (42.1 mg, 0.5016 mmol). The reaction mixture was heated overnight at 85 ° C under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted with EtOAc (3 × 10 mL), washed with brine the combined extracts were dried (Na ₂ SO _4), concentrated, methanol, methylene SP1 on silica gel in 25 g SNAP column The chlorinated solution (2%, 4 CV; 2% to 4%, 8 CV; 4%, 2 CV) was purified eluting to afford the title compound (60 mg, 56.2%).

Step II: Compound 94

To the stirred step 1 of acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(E)-3-[3,5- Add a solution of NaOMe in methanol (60 mg) in methanol (0.5 mL) in bis(methylamine-mercapto)phenyl]allyl]phenyl]tetrahydropyran-2-yl]methyl ester (60 mg) 500 μL 0.5 M, 0.25 mmol), stirred at room temperature for 20 h, quenched with EtOAc (EtOAc) EtOAc (EtOAc) (27 mg, 34.0%).

LC-MS: m/z = 471.38 (M+H ⁺ ).

Preparation of 5-iodo- N1,N3 -dimethyl-benzene-1,3-dimethylguanamine

A solution of 5-iodobenzene-1,3-dicarboxylic acid dimethyl ester (2000 mg, 6.25 mmol) and methylamine in ethanol (40 mL 33 w/w%) was stirred in a sealed tube at room temperature for 5 days. The plug was removed and the residue was crystallised eluted eluted eluted elute

¹ H NMR (400 MHz, CD ₃ OD) δ 8.27 (d, J = 1.6 Hz, 2H), 8.22 (t, J = 1.6 Hz, 1H), 2.90 (s, 6H).

Preparation of Compound 95

(2R,3S,4R,5S,6R)-2-[3-[(E)-3-(3,5-Dichlorophenyl)allyl]phenyl]-6-(hydroxymethyl)tetra Hydropyran-3,4,5-triol

The title compound was prepared as described for compound 94 using commercially available 1,3-dichloro-5-iodobenzene.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 (s, 1H), 7.31-7.05 (m, 6H), 6.43 (d, J = 15.8 Hz, 1H), 6.35-6.23 (m, 1H), 4.86 (t, J = 4.8 Hz, 1H), 4.35-4.29 (m, 1H), 3.76-3.70 (m, 2H), 3.66-3.60 (m, 1H), 3.53-3.36 (m, 4H). LC-MS: m / z = 425.23 (M + H +).

Preparation of Compound 96

(2R,3S,4R,5S,6R)-2-[3-[(E)-Cinnamyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 94 using commercially available iodobenzene.

LC-MS: m / z = 357.34 (M + H +).

Preparation of Compound 97

N1,N3 -dimethyl-5-[3-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran- 2-yl]phenyl]propyl]benzene-1,3-dimethylguanamine

A mixture of compound 94 (9 mg, 0.0157 mmol) and Pd/C (wet, Degussa, 18 mg, 0.017 mmol) in methanol (3 mL) was hydrogenated at 40 psi for 5 hrs, filtered, concentrated, dissolved in water - acetonitrile and lyophilized to give the title compound (4 mg, 48.6%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.97 (t, 1H), 7.69 (d, J = 1.6 Hz, 2H), 7.26 (brs, 1H), 7.19 (d, J = 4.6 Hz, 2H), 7.06-7.01(m,1H),4.86(d,J=3.4 Hz,1H), 4.35(t,J=3.3 Hz,1H),3.72(d,J=4.5 Hz,2H),3.63(t,J = 8.2 Hz, 1H), 3.48 (dd, J = 8.2, 3.1 Hz, 1H), 3.41-3.32 (m, 1H), 2.83 (s, 3H), 2.71-2.55 (m, 4H), 1.99-1.84 ( m, 2H). LC-MS: m/z = 473.47 (M+H ⁺ ).

Preparation of Compound 98

(2R,3S,4R,5S,6R)-2-[3-[3-(3,5-Dichlorophenyl)propyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3 ,4,5-triol

A mixture of compound 95 (9 mg, 0.0157 mmol) under 1 atm H ₂ and SiliaCat-Pd (43 mg, 0.05 mmol / g) in a mixture of MeOH (3 mL) in the five hours. The catalyst was filtered off, concentrated, taken up in water-EtOAc elute

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27-7.11 (m, 4H), 7.09-6.99 (m, 3H), 4.86 (d, J = 2.9 Hz, 1H), 4.34 (t, 1H), 3.73 (d, J = 4.6 Hz, 2H), 3.64 (t, J = 8.0 Hz, 1H), 3.52-3.46 (m, 1H), 3.41-3.31 (m, 1H), 2.55 (dt, J = 12.3, 7.8 Hz, 4H), 1.91-1.75 (m, 2H).

Preparation of Compound 99

(2R, 3S, 4R, 5S, 6R)-2-(hydroxymethyl)-6-[3-(3-phenylpropyl)phenyl]tetrahydropyran-3,4,5-triol.

The title compound was prepared from compound 96 as described for compound 97.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27-6.96 (m, 9H), 4.86 (d, J = 3.3 Hz, 1H), 4.35 (t, J = 3.2 Hz, 1H), 3.72 (d, J) =4.6 Hz, 2H), 3.64 (t, J = 8.1 Hz, 1H), 3.49 (dd, J = 8.2, 3.0 Hz, 1H), 3.40-3.33 (m, 1H), 2.60-2.48 (m, 4H) , 1.90-1.77 (m, 2H). LC-MS: m / z = 381.21 (M + Na) +.

Preparation of Compound 100

4-[2-[4-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]B Methyl benzoate

The title compound was prepared from compound 89 as described for compound 97.

LC-MS: m/z = 403.44 (M+H ⁺ ).

Preparation of Compound 101

3-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]B Methyl benzoate

The title compound was prepared from compound 86 as described for compound 97.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84-7.76 (m, 2H), 7.42-7.20 (m, 5H), 7.07 (d, J = 6.3 Hz, 1H), 4.92 (d, J = 3.2 Hz) , 1H), 4.41 (t, J = 3.2 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J = 4.6 Hz, 2H), 3.71 (t, J = 8.3 Hz, 1H), 3.52 (dd , J = 8.3, 3.1 Hz, 1H), 3.42-3.34 (m, 1H), 3.02-2.88 (m, 4H). LC-MS: m/z = 403.4 (M+H ⁺ ).

Preparation of Compound 102

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(2-phenylethyl)phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from compound 91 as described for compound 97.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.32-7.03 (m, 9H), 4.93 (d, J = 3.3 Hz, 1H), 4.41 (t, J = 3.2 Hz, 1H), 3.79 (d, J) =4.6 Hz, 2H), 3.72 (t, J = 8.3 Hz, 1H), 3.54 (dd, J = 8.3, 3.1 Hz, 1H), 3.44 - 3.37 (m, 1H), 2.93 - 2.84 (m, 4H) .

Preparation of Compound 103

4-[2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]B Methyl benzoate

The title compound was prepared from compound 100 as described for compound 97.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84-7.75 (m, 2H), 7.23 - 7.13 (m, 5H), 7.02-6.96 (m, 1H), 4.84 (d, J = 3.3 Hz, 1H) , 4.32 (t, J = 3.2 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 4.6 Hz, 2H), 3.62 (t, J = 8.3 Hz, 1H), 3.43 (dd, J = 8.3, 3.1 Hz, 1H), 3.33-3.25 (m, 1H), 2.95-2.80 (m, 4H). LC-MS: m/z = 403.4 (M+H ⁺ ).

Preparation of Compound 104

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-[4-(5-methyl-1,3,4-oxadiazole-2 -yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

In a 10 mL microwave vial, to compound 76 (31.0 mg, 0.09 mmol) and [4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl] Acid (28.5 mg, 0.14 mmol) in toluene (2.5 mL) and methanol (0.5 mL) in the entire solution was added powdered _{K 3 PO 4 (39.5 mg,} 0.186 mmol), degassed (house vacuum / N ₂ flushed , Pd(PPh ₃ ) ₄ (16.1 mg, 0.014 mmol) was added in portions and sealed, and heated at 95 ° C overnight, filtered through a 0.4 micron filter, concentrated and purified by reverse phase HPLC to give a white solid. The title compound (24 mg, 61.4%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.28 ( t, J = 7.7 Hz, 1H), 7.16 (d, J = 6.7 Hz, 1H), 5.20 (d, J = 7.0 Hz, 1H), 4.26 (dd, J = 6.9, 3.3 Hz, 1H), 4.08- 3.97 (m, 2H), 3.88-3.80 (m, 1H), 3.75 (dd, J = 11.9, 3.8 Hz, 1H), 3.68-3.58 (m, 1H), 2.63 (s, 3H), 2.32 (s, 3H). LC-MS: m / z = 413.37 (M + H +).

Preparation of compound 105

(2R,3S,4R,5S,6R)-2-[2-ethyl-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]phenyl ]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: 2,2-Dimethylpropionic acid [(2R,3R,4R,5R,6R)-6-(3-bromo-2-ethyl-phenyl)-3,4,5-para (2 ,2-dimethylpropenyloxy)tetrahydropyran-2-yl]methyl ester

A solution of n-Bu ₃ MgLi (1.633 mL 0.66 M, 1.078 mmol) in hexane-heptane-dibutyl ether (8:20:3) was added to 1-bromo-2-ethyl at 0 °C. 3-iodo-benzene (958 mg, 3.081 mmol) in a solution of toluene (1.5 mL) and dibutyl ether (0.9 mL), stirred at the same temperature for 3.5 hours, dropwise addition of dibutyl ether of ZnBr ₂ -LiBr Solution (1.6 mL 1.05 M, 1.67 mmol), remove the cooling bath, stir at room temperature for 1 hour, add 2,2-dimethylpropionic acid [(2R,3R,4S,5S,6R)-6-bromo a solution of -3,4,5-e (2,2-dimethylpropenyloxy)tetrahydropyran-2-yl]methyl ester (1.49 g, 2.568 mmol) in toluene (2.7 mL) It was placed on a preheated oil bath at 90 ° C for 18 hours. The reaction mixture was cooled to room temperature, poured into 1 N aqueous HCl, and extracted with ethyl acetate, washed with brine the combined extracts were dried (Na ₂ SO _4), and concentrated. Purification of the residue on a 25 g SNAP silica gel using ethyl acetate-hexane (0% to 10%, 20 CV) as a solvent to afford 2,2-dimethylpropanoic acid as a colorless foam. ,3R,4R,5R,6R)-6-(3-bromo-2-ethyl-phenyl)-3,4,5-parade (2,2-dimethylpropoxy)tetrahydropyran A mixture of 2-yl]methyl ester (527 mg, 0.7708 mmol, 30.01%). This material was used as such in the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 5.52 (d) , J=8.0 Hz, 1H), 5.48-5.42 (m, 1H), 5.22 (d, J=8.1 Hz, 1H), 5.16-5.09 (m, 1H), 4.76 (dd, J=11.5, 8.1 Hz, 1H), 4.16-4.04 (m, 2H), 3.05-2.82 (m, 2H), 1.26 (d, J = 2.9 Hz, 18H), 1.15 (s, 12H), 0.96 (s, 9H)

Step II: Compound 105

2,2-Dimethylpropionic acid [(2R,3R,4R,5R,6R)-6-(3-bromo-2-ethyl-phenyl)-3] from step I in microwave at 100 °C ,4,5-gin(2,2-dimethylpropoxy)tetrahydropyran-2-yl]methyl ester and [4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl] The title compound was prepared using the SiliaCat Pd as described for compound 79, followed by hydrolysis of the pivaloyl ester using NaOMe/MeOH at room temperature as described for compound 76.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.27 ( t, J = 7.7 Hz, 1H), 7.08 (dd, J = 7.5, 1.2 Hz, 1H), 5.21 (d, J = 8.5 Hz, 1H), 4.17 (dd, J = 8.4, 3.1 Hz, 1H), 4.12-4.02(m,2H), 3.91 (dd, J=4.2, 2.3 Hz, 1H), 3.84-3.77 (m, 2H), 2.87-2.66 (m, 2H), 2.62 (s, 3H), 1.02 ( t, J = 7.5 Hz, 3H). LC-MS: m/z = 427.24 (M+H ⁺ ).

Preparation of Compound 106

(2R,3S,4R,5S,6R)-2-[2-Fluoro-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]phenyl] -6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

To [3-(2-Dicyclohexylphosphinoalkylphenyl)-2,4-dimethoxy-phenyl]sulfonate sodium (84.3 mg, 0.1644 mmol), compound 78 (50 mg, 0.1644 mmol) , [3-(2-Dicyclohexylphosphinoalkylphenyl)-2,4-dimethoxy-phenyl]sulfonate sodium (84.3 mg, 0.164 mmol), [4-(5-A) Base-1,3,4-oxadiazol-2-yl)phenyl] Add palladium(II) acetate to the degassed mixture of acid (50.30 mg, 0.2466 mmol) and K ₂ CO ₃ (114 mg, 0.82 mmol) in 2-Me THF (1.2 mL) and water (240 μL) (18.5) Mg, 0.082 mmol), the reaction mixture was slowly heated to 90 ° C, stirred for 20 hours, filtered through celite, washed with 10% H ₂ O-methanol, concentrated, and then applied to a 25 g C18 SNAP silica gel column (10%) The title compound (25 mg, 34.7%) was obtained as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11-8.04 (m, 2H), 7.72 (dd, J = 8.3, 1.3 Hz, 2H), 7.70-7.64 (m, 1H), 7.45 (td, J = 7.5, 1.6 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 5.23 (d, J = 7.2 Hz, 1H), 4.19 (dd, J = 7.2, 2.4 Hz, 1H), 4.11-4.01 ( m, 1H), 3.90-3.74 (m, 4H), 2.62 (s, 3H). LC-MS: m/z = 417.19 (M+H ⁺ ).

Preparation of Compound 107

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-methoxy-4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl]-2-methyl-phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from intermediate K and 2-(4-bromo-3-methoxyphenyl)-5-methyl-1,3,4-oxadiazole as described in compound 79.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.68-7.63 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.30-7.20 (m, 2H), 7.06 (d, J = 7.6 Hz) , 1H), 5.18 (d, J = 5.3 Hz, 1H), 4.31-4.20 (m, 1H), 4.07-3.95 (m, 2H), 3.87-3.83 (m, 1H), 3.82 (s, 3H), 3.79-3.71 (m, 1H), 3.65-3.57 (m, 1H), 2.63 (s, 3H), 2.18 and 2.17 (two single peaks, 3H). LC-MS: m/z = 443.24 (M+H ⁺ ).

Preparation of Compound 108

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-[4-(1-methylpyrazol-3-yl)phenyl]phenyl Tetrahydropyran-3,4,5-triol

The title compound was prepared from intermediate K and 3-(4-bromophenyl)-1-methyl-1H-pyrazole as described in compound 79.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.21. d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 5.11 (d, J = 6.8 Hz, 1H), 4.19 (dd, J = 6.7, 3.2 Hz, 1H), 3.98-3.89 (m, 2H), 3.85 (s, 3H), 3.79-3.73 (m, 1H), 3.68 (dd , J = 11.9, 3.8 Hz, 1H), 3.59-3.49 (m, 1H), 2.25 (s, 3H). LC-MS: m/z = 41.42 (M+H ⁺ ).

Preparation of Compound 109

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-(4-methylsulfonylphenyl)phenyl]tetrahydropyran-3 ,4,5-triol

The title compound was prepared from the intermediate K and 1-bromo-4-(methylsulfonyl)benzene as described in compound 79.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.91 (d, J = 8.3 Hz, 2H), 7.52-7.43 (m, 3H), 7.20 (t, J = 7.7 Hz, 1H), 7.06 (d, J) = 7.4 Hz, 1H), 5.11 (d, J = 7.1 Hz, 1H), 4.17 (dd, J = 7.0, 3.2 Hz, 1H), 4.00-3.89 (m, 2H), 3.78-3.74 (m, 1H) , 3.67 (dd, J = 11.9, 3.7 Hz, 1H), 3.61-3.52 (m, 1H), 3.08 (s, 3H), 2.22 (s, 3H).

Preparation of Compound 110

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-(3-methylsulfonylphenyl)phenyl]tetrahydropyran-3 ,4,5-triol

The title compound was prepared from the intermediate K and 1-bromo-3-(methylsulfonyl)benzene as described in compound 79.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.96-7.90 (m, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.63 (dt, J) =7.7, 1.4 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 6.6 Hz, 1H), 5.19 (d, J) = 7.1 Hz, 1H), 4.25 (dd, J = 7.0, 3.2 Hz, 1H), 4.07-3.98 (m, 2H), 3.84 (dd, J = 5.4, 4.2 Hz, 1H), 3.75 (dd, J = 11.9, 3.8 Hz, 1H), 3.68-3.59 (m, 1H), 3.15 (s, 3H), 2.29 (s, 3H). LC-MS: m/z = 409.24 (M+H ⁺ ).

Preparation of compound 111

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-[3-methyl-4-(5-methyl-1,3,4- Oxadiazol-2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from the intermediate K and 2-(4-bromo-2-methylphenyl)-5-methyl-1,3,4-oxadiazole (see below).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.1 Hz, 1H), 7.32 (s, 1H), 7.30-7.23 (m, 2H) ), 7.17-7.12 (m, 1H), 5.19 (d, J = 6.9 Hz, 1H), 4.26 (dd, J = 6.9, 3.3 Hz, 1H), 4.06-3.97 (m, 2H), 3.86-3.81 ( m, 1H), 3.76 (dd, J = 11.9, 3.8 Hz, 1H), 3.67-3.61 (m, 1H), 2.68 (s, 3H), 2.63 (s, 3H), 2.32 (s, 3H). LC-MS: m / z = 426.89 (M + H +).

Preparation of 2-(4-bromo-2-methyl-phenyl)-5-methyl-1,3,4-oxadiazole

As described for the preparation of step 1- 1-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl] -N,N -dimethyl-methylamine (500 mg, 6.749 mmol), 4- bromo-2-methyl - benzoic acid (1.451 g, 6.749 mmol) in _{POCl 3 (5 mL, 53.64 mmol} ) the mixture was refluxed, and then purified to give a white solid of 2-(4-Bromo-2-methyl-phenyl)-5-methyl-1,3,4-oxadiazole (680 mg, 2.687 mmol, 39.81%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.45 (d, J = 8.7 Hz, 1H), 2.68 (s, 3H) , 2.63 (s, 3H).

References: Gaster, L. et al., PCT International Application ( 1996 ), WO 9619477 A119960627.

Preparation of compound 112

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[3-methoxy-4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl]-2-methyl-phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from intermediate K and 2-(4-bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole as described in compound 79.

LC-MS: m/z = 443.3 (M+H ⁺ ).

Preparation of Compound 113

(2R,3S,4R,5S,6R)-2-[3-[4-[5-[(Dimethylamino)methyl]-1,3,4-oxadiazol-2-yl]benzene Phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

From intermediate J and 1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-N,N-dimethylmethylamine (See the scheme below) The title compound was prepared following the procedure described for compound 106, followed by NaOMe/methanol deacetalization.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 8.5 Hz, 2H), 7.84-7.77 (m, 2H), 7.56 (d, J = 6.6 Hz, 1H), 7.47-7.38 (m) , 2H), 4.95 (d, J = 4.0 Hz, 1H), 4.42-4.34 (m, 1H), 3.82 (s, 2H), 3.79-3.75 (m, 2H), 3.66 (t, J = 7.6 Hz, 1H), 3.55 (dd, J = 7.7, 3.1 Hz, 1H), 3.51-3.43 (m, 1H), 2.32 (s, 6H). LC-MS: m/z = 422.26 (M+H ⁺ ).

Preparation of 1-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl] -N,N -dimethyl-methylamine

Step I: 2-(4-Bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole

A mixture of 4-bromophenyl slowly acyl hydrazide (6.451 g, 30 mmol), a mixture of 2- chloroacetic acid (2.835 g, 30.00 mmol) in _{POCl 3 (21 mL, 225.3 mmol} ) to reflux, the suspension became a pale brown transparent The solution was refluxed for 2.5 hours (Padmavathi, V. et al., Eur. J. Med. Chem. 2011 , 46 , 1367), cooled to room temperature, excess POCl ₃ was removed on a rotary evaporator, and the syrup was poured onto crushed ice. Extract with about 20% EtOAC in methylene chloride solution (3 x 60 mL), wash the combined extracts with bicarbonate solution (up to alkaline pH), dry, concentrate, with methylene chloride ( 5 mL) wet-milling twice gave 2-(4-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole as a pale brown solid. The mother liquor was concentrated and purified with EtOAc EtOAc EtOAc (EtOAc) For a stepwise procedure, see Danie et al., PCT International Application, 2005121152 A1, December 22, 2005.

Step II: 1-(5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl)-N,N-dimethylmethylamine (see preparation below)

Heating 2-(4-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole (500 mg, 1.828 mmol) in dimethylammonium ethanol solution at 100 ° C in a microwave vial mixture (5 mL 33 w / v% , 15.26 mmol) in the 20 minutes (TLC shows complete consumption of starting material), filtered through a 0.4 micron filter, concentrated, diluted with methanol and add Et ₃ N (0.5 mL), load The title compound (422 mg, 81.8%) was obtained as a colorless oil.

_{1H NMR (400 MHz, CDCl 3} ) δ 7.99-7.91 (m, 2H), 7.70-7.63 (m, 2H), 3.83 (s, 2H), 2.40 (s, 6H).

Preparation of Compound 114

Trimethyl-[[5-[4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2- Phenyl]phenyl]-1,3,4-oxadiazol-2-yl]methyl]ammonium

Methyl iodide (20 μL, 0.321 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc). (0.4 mL) was diluted, stirred for 15 min, EtOAc (EtOAc)EtOAc

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (d, J = 8.5 Hz, 2H), 7.92-7.85 (m, 3H), 7.64 (d, J = 6.6 Hz, 1H), 7.53-7.47 (m) , 2H), 5.13 (s, 2H), 5.03 (d, J = 3.9 Hz, 1H), 4.47 (t, J = 3.5 Hz, 1H), 3.89-3.80 (m, 2H), 3.75 (t, J = 7.6 Hz, 1H), 3.68-3.61 (m, 1H), 3.59-3.51 (m, 1H), 3.39 (s, 9H). LC-MS: m/z = 456.65 (M+H ⁺ ).

Preparation of Compound 115

N -[[5-[4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl] Phenyl]phenyl]-1,3,4-oxadiazol-2-yl]methyl]aminocarboxylic acid tert-butyl ester

By intermediate J and N -[[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]methyl] -N -t-butoxycarbonyl-aminocarboxylic acid Tributyl ester The title compound was prepared according to the procedure described for compound 106, followed by de-acetylation of NaOMe/methanol.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (d, J = 8.2 Hz, 2H), 7.88-7.81 (m, 3H), 7.61 (d, J = 6.9 Hz, 1H), 7.53-7.45 (m) , 2H), 5.02 (d, J = 3.9 Hz, 1H), 4.54 (s, 2H), 4.46 (t, J = 3.5 Hz, 1H), 3.89-3.83 (m, 2H), 3.75 (t, J = 7.6 Hz, 1H), 3.64 (dd, J = 7.7, 3.0 Hz, 1H), 3.59-3.50 (m, 1H), 1.46 (s, 9H). LC-MS: m/z = 495.32 (M+H ⁺ ).

Preparation of N -[[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]methyl] -N -t-butoxycarbonyl-carbamic acid tert-butyl ester and N -[[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]methyl]carbamic acid tert-butyl ester

Step I: 2-(azidomethyl)-5-(4-bromophenyl)-1,3,4-oxadiazole

Add a stack of stirred 2-(4-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole (1000 mg, 3.656 mmol) in DMSO (10 mL) Sodium nitoxide (713.0 mg, 10.97 mmol), EtOAc (EtOAc) (EtOAc (EtOAc) The extract was dried (Na ₂ SO ₄ ), concentrated, and purified using ethyl acetate-hexane (15% to 40%, 8 CV; followed by 40%) as a dissolving agent on a 50 g SNAP silica gel column. The title compound (900 mg, 87.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99-7.90 (m, 2H), 7.71 - 7.61 (m, 2H), 4.64 (s, 2H).

Step II: N -[[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]methyl]carbamic acid tert-butyl ester

To a stirred solution of 2-(azidomethyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (600 mg, 2.142 mmol) in THF (6.0 mL) PPh ₃ (590 mg, 2.249 mmol) was added to the solution in μL) (nitrogen evolution occurred after a few minutes, exotherm), the reaction mixture was stirred at room temperature for 2.5 hours, concentrated and dissolved in CH ₂ Cl ₂ (6.0 mL) ) was sequentially added _{Et 3 N (542 mg, 746.0} μL, 5.355 mmol), tert-butoxy carbonyl ester third-butyl carbonate (608 mg, 2.785 mmol) and N, N - dimethyl-pyridin-4 -Amine (17 mg, 0.1392 mmol), EtOAc (EtOAc m. m. The title compound (170 mg, 22.4%) was obtained as a white solid. ).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.86 (m, 2H), 7.69-7.62 (m, 2H), 5.33 (s, 1H), 4.64 (d, J = 5.9 Hz, 2H), 1.48 ( s, 9H).

Preparation of Compound 117

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(5-methyloxazol-2-yl)phenyl]phenyl]tetrahydropyran -3,4,5-triol

Feeding triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-(4,4,5,5-tetramethyl-1) into a microwave vial , 3,2-dioxaboron -2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triester (1 equivalent), 2-(4-bromophenyl)-5-methyloxazole (1 equivalent), ^{Siliacat-DPP-Pd TM (0.26} mmol / g, 0.1 equiv), Cs ₂ CO ₃ (2.2 eq) and acetonitrile. The mixture was heated in a microwave at 100 ° C for 30 minutes, filtered over celite and concentrated to dryness. The residue was taken up in MeOH EtOAc (EtOAc)EtOAc. The mixture was concentrated and loaded onto a cation exchange resin (SXC, column, 1 g). Rinse the column with methanol equivalent to 4 CV. The mixture was concentrated to dryness and purified by reverse phase preparative HPLC to give the desired product.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.5 Hz, 2H), 7.84-7.67 (m, 3H), 7.58-7.50 (m, J = 3.7 Hz, 1H), 7.49-7.35 (m, 2H), 6.84 (d, J = 1.2 Hz, 1H), 4.95 (d, J = 3.8 Hz, 1H), 4.39 (t, 1H), 3.80-3.74 (m, 1H), 3.66 (t, J = 7.7 Hz, 1H), 3.55 (dd, J = 7.8, 3.1 Hz, 1H), 3.50-3.41 (m, 1H), 2.34 (d, J = 1.1 Hz, 3H). LC-MS: m/z = 398.33 (M+H+)

Preparation of Compound 118

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzene Phenyl]tetrahydropyran-3,4,5-triol

By intermediate J and 2-(4-bromophenyl)-5-isopropyl-1,3,4-oxadiazole according to the compound The title compound was prepared by the procedure described in 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 8.0 Hz, 2H), 7.91-7.84 (m, J = 7.4 Hz, 3H), 7.51 (s, 3H), 5.03 (s, 1H) ), 4.46(s, 1H), 3.87-3.83 (m, J = 6.2 Hz, 1H), 3.83-3.79 (m, 1H), 3.73 (dd, J = 15.5, 7.8 Hz, 3H), 3.63 (d, J = 5.3 Hz, 1H), 3.61-3.52 (m, 3H), 1.46 (s, 3H), 1.45 (d, 6H). LC-MS: m/z = 427.34 (M+H+)

Preparation of Compound 119

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(4-oxazol-5-ylphenyl)phenyl]tetrahydropyran-3,4,5 -triol

The title compound was prepared from Intermediate J and 5-(4-bromophenyl)oxazole according to the procedure described for Compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (s, 1H), 7.85-7.78 (m, 3H), 7.78-7.73 (m, J = 8.3 Hz, 2H), 7.62-7.52 (m, J = 17.1 Hz, 2H), 7.50-7.44 (m, J = 4.5 Hz, 2H), 5.03 (d, J = 3.5 Hz, 1H), 4.49-4.44 (m, 1H), 3.89-3.81 (m, J = 6.3 Hz, 2H), 3.74 (t, J = 7.6 Hz, 1H), 3.63 (dd, J = 7.8, 2.8 Hz, 1H), 3.59-3.50 (m, J = 6.5 Hz, 1H) LC-MS: m/ z=384.32 (M+H+)

Preparation of compound 120

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-[5-(2-pyridyl)-1,3,4-oxadiazol-2- Phenyl]phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from the intermediate J and 2-(4-bromophenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (d, J = 4.8 Hz, 1H), 8.28-8.15 (m, J = 20.9, 8.2 Hz, 3H), 8.00 (td, J = 7.8, 1.7 Hz , 1H), 7.90-7.77 (m, 3H), 7.62-7.50 (m, J = 9.8, 5.0 Hz, 2H), 7.49-7.36 (m, 2H), 4.96 (d, J = 4.0 Hz, 1H), 4.42-4.35 (m, 1H), 3.85-3.71 (m, 2H), 3.71-3.62 (m, J = 7.6 Hz, 1H), 3.62-3.53 (m, J = 7.7, 3.1 Hz, 1H), 3.52- 3.43 (m, J = 6.9, 3.4 Hz, 1H). LC-MS: m/z =462.42 (M+H+)

Preparation of Compound 121

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-[5-(5-methyl-2-furyl)-1,3,4-oxa Diazol-2-yl]phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from the intermediate J and 2-(4-bromophenyl)-5-(5-methylfuran-2-yl)-1,3,4-oxadiazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (d, J = 8.5 Hz, 2H), 7.93-7.81 (m, 3H), 7.67-7.58 (m, J = 6.6 Hz, 1H), 7.56-7.43 (m, 2H), 7.27 (d, J = 3.4 Hz, 1H), 6.36 (dd, J = 3.4, 0.9 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.48-4.39 (m, 1H), 3.93-3.80 (m, 2H), 3.75 (t, J = 7.6 Hz, 1H), 3.64 (dd, J = 7.7, 3.1 Hz, 1H), 3.56 (td, J = 6.9, 3.4 Hz, 1H) ), 2.45 (s, 3H). LC-MS: m/z = 465.34 (M+H+)

Preparation of Compound 122

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(1-methylpyrazol-3-yl)phenyl]phenyl]tetrahydropyran -3,4,5-triol

The title compound was prepared from the intermediate J and 3-(4-bromophenyl)-1-methyl-1H-pyrazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.86-7.77 (m, J = 6.4 Hz, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.62-7.54 (m, 2H), 7.48-7.40 (m, 2H), 6.64 (d, J = 2.3 Hz, 1H), 5.03 (d, J = 3.7 Hz, 1H), 4.49 (t, J = 3.4 Hz, 1H), 3.93 (s, 3H), 3.85 -3.82 (m, 2H), 3.74 (t, J = 7.9 Hz, 1H), 3.64 (dd, J = 8.0, 3.2 Hz, 1H), 3.59-3.50 (m, 1H). LC-MS: m/z = 397.34 (M+H ⁺ ).

Preparation of compound 123

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl Phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from the intermediate J and 2-(3-bromophenyl)-5-methyl-1,3,4-oxadiazole according to the procedure described for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.31-8.27 (m, J = 1.6 Hz, 1H), 8.04-7.95 (m, 1H), 7.93-7.80 (m, 2H), 7.70-7.57 (m, J = 9.2, 8.3, 6.1 Hz, 2H), 7.55-7.44 (m, 2H), 5.03 (d, J = 4.1 Hz, 1H), 4.51-4.39 (m, 1H), 3.93-3.81 (m, 2H) , 3.75 (t, J = 7.6 Hz, 1H), 3.64 (dd, J = 7.7, 3.1 Hz, 1H), 3.59-3.50 (m, J = 6.9, 3.3 Hz, 1H), 2.63 (d, J = 3.6 Hz, 2H). LC-MS: m / z = 399.34 (M + H +).

Preparation of compound 124

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[4-(2-methylpyrazol-3-yl)phenyl]phenyl]tetrahydropyran -3,4,5-triol

The title compound was prepared from the intermediate J and 5-(4-bromophenyl)-1-methyl-1H-pyrazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.63-7.53 (m, J = 15.7, 6.1 Hz, 3H), 7.51-7.44 (m, J = 8.3, 3.5 Hz, 3H), 6.40 (d, J = 2.0 Hz, 1H), 5.04 (d, J = 3.9 Hz, 1H), 4.60 (s, 1H), 4.48 (t, J = 3.5 Hz, 1H), 3.90 (s, 3H), 3.88-3.81 (m, J = 9.1, 5.9 Hz, 2H), 3.75 (t, J = 7.8 Hz, 1H), 3.63 (dd, J = 7.8, 3.1 Hz, 1H), 3.58-3.48 (m, 1H). LC-MS: m/z = 397.45 (M+H ⁺ ).

Preparation of compound 125

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-methyl-4-(5-methyl-1,3,4-oxadiazole-2 -yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

Step I: N'-Ethyl-4-bromo-3-methyl-benzamide

Add HATU (3.08 g, 8.1 mmol) to a solution of 4-bromo-3-methyl-benzoic acid (1.45 g, 6.75 mmol), acetonitrile (500 mg, 6.75 mmol) in DMF (20 mL) Triethylamine (1.50 g, 2.07 mL, 14.85 mmol) and the mixture was stirred at room temperature overnight. Ethyl acetate (80 mL) and 20 mL of water were added and the phases separated. The aqueous phase was back extracted once with EtOAc. The organic phases were combined and passed through a phase separation column to give the title compound.

Step II: 2-(4-Bromo-3-methyl-phenyl)-5-methyl-1,3,4-oxadiazole

The title compound was prepared according to the procedure described in Org. Biomol. Chem. , 2012 , 10 , 988.

Step III, IV: Compound 125

The title compound was prepared from the intermediate K and 5-(4-bromophenyl)-1-methyl-1H-pyrazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.57-7.43 (m, 3H), 7.39 (d, J = 8.0 Hz, 1H ), 7.28 (d, J = 7.1 Hz, 1H), 5.00 (d, J = 11.4 Hz, 1H), 4.43 (t, J = 3.2 Hz, 1H), 3.94 - 3.79 (m, 2H), 3.74 (t , J = 7.7 Hz, 1H), 3.63 (dd, J = 7.8, 2.8 Hz, 1H), 3.57-3.46 (m, 1H), 2.62 (s, 3H), 2.35 (s, 3H). LC-MS: m/z = 413.22 (M+H+)

Preparation of Compound 126

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-methoxy-4-[5-(2-pyridyl)-1,3,4- Oxadiazol-2-yl]phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title was prepared from the intermediate J and 2-(4-bromo-3-methoxyphenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole according to the procedure described for compound 117. Compound.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (d, J = 4.5 Hz, 1H), 8.44 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.08-7.95 (m, J =7.0 Hz, 1H), 7.86-7.74 (m, 2H), 7.66-7.56 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.45-7.29 (m, J = 13.5, 8.0 Hz, 3H), 4.96 (d, J = 3.2 Hz, 1H), 4.52 (s, 2H), 4.40 (t, J = 3.2 Hz, 1H), 3.88 (s, 3H), 3.76 (d, J = 4.6 Hz, 2H), 3.68 (t, J = 8.1 Hz, 1H), 3.56 (dd, J = 8.1, 3.0 Hz, 1H), 3.51-3.43 (m, J = 8.3, 4.0 Hz, 1H). LC-MS: m/z = 492.91 (M+H+)

Preparation of Compound 127

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[3-methoxy-4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from Intermediate J and 2-(4-bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole according to the procedure described for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94-7.89 (m, 2H), 7.67-7.63 (m, 1H), 7.50 (d, J = 5.9 Hz, 2H), 7.45 (s, 1H), 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 5.04 (d, J = 3.8 Hz, 1H), 4.51-4.43 (m, 1H), 4.03 (s, 3H), 3.87-3.82 (m, 2H), 3.73 (t, J = 7.7 Hz, 1H), 3.66-3.53 (m, 2H), 2.61 (s, 3H). LC-MS: m/z = 429.53 (M+H+)

Preparation of Compound 128

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-methoxy-4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from Intermediate J and 2-(4-bromo-3-methoxyphenyl)-5-methyl-1,3,4-oxadiazole according to the procedure described for Compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.70-7.64 (m, J = 7.7 Hz, 3H), 7.52-7.39 (m, 4H), 5.03 (d, J = 3.5 Hz, 1H), 4.47 (t , J = 3.3 Hz, 1H), 3.90 (s, 3H), 3.84 - 3.80 (m, J = 5.0 Hz, 2H), 3.75 (t, J = 8.1 Hz, 1H), 3.62 (dd, J = 8.2, 3.0 Hz, 1H), 3.56-3.49 (m, 1H), 3.46 (s, 1H), 2.63 (s, 3H). LC-MS: m/z = 429.44 (M+H+)

Preparation of Compound 129

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl Phenyl]tetrahydropyran-3,4,5-triol

Step I: Triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethyloxymethyl)-6-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) ) tetrahydro-2H-pyran-3,4,5-triester

The title compound was prepared from Intermediate L according to the procedure described for Intermediate H.

Step II: (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl) Phenyl]phenyl]tetrahydropyran-3,4,5-triol

By triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(4-(((trifluoromethyl))sulfonyl)oxy)phenyl) Hydrogen-2H-pyran-3,4,5-triester and [4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl] The title compound was prepared according to the procedure described for compound 2 using the acid as starting material.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 ( d, J = 8.1 Hz, 2H), 5.02 (d, J = 3.7 Hz, 1H), 4.45 (t, J = 3.4 Hz, 1H), 3.84 (d, J = 5.3 Hz, 2H), 3.75 (t, J = 7.9 Hz, 1H), 3.64-3.57 (m, J = 8.0, 3.1 Hz, 1H), 3.56-3.41 (m, 1H), 2.62 (s, 3H). LC-MS: m / z = 399.41 (M + H +).

Preparation of Compound 130

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl Phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared from the intermediate J and 2-(3-bromophenyl)-5-methyl-1,3,4-oxadiazole according to the procedure described for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.68-7.49 (m, J =14.8, 8.1 Hz, 5H), 4.94 (d, J = 3.7 Hz, 1H), 4.52 (s, 1H), 4.38 (t, J = 3.4 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.67 (t, J = 7.9 Hz, 1H), 3.53 (dd, J = 8.0, 3.1 Hz, 1H), 3.48-3.34 (m, 1H), 2.54 (s, 3H). LC-MS: m/z = 399.41 (M+H+)

Preparation of Compound 131

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[2-methyl-3-[2-methyl-4-(5-methyl-1,3,4- Oxadiazol-2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

By intermediate H and 2-(4-bromo-3-methyl-phenyl)-5-methyl-1,3,4-oxadiazole according to The title compound was prepared by the procedure described for compound 79.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.26-7.08 (m, J =14.3, 7.7 Hz, 2H), 6.95 (d, J = 7.4 Hz, 1H), 5.10 (d, J = 6.9 Hz, 1H), 4.22-4.15 (m, 1H), 3.99-3.87 (m, 2H) , 3.75 (q, J = 9.7, 4.9 Hz, 1H), 3.66 (dd, J = 11.8, 3.7 Hz, 1H), 3.59-3.46 (m, J = 9.9 Hz, 1H), 2.54 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H). LC-MS: m/z = 427.45 (M+H+)

Preparation of compound 132

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-methoxy-3-[4-(5-methyl-1,3,4-oxadiazole- 2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

From intermediate M and [4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl] The title compound was prepared according to the procedure described for compound 2.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.57-7.43 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 4.98 (s, 1H), 4.62 (s, 1H), 4.43 (s, 1H), 3.84 (s, 4H), 3.79-3.70 (m, 1H), 3.70-3.63 (m, 1H), 3.57-3.50 (m, 1H), 2.64 (s, 3H). LC-MS: m / z = 429.53 (M + H +).

Preparation of Compound 133

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-[4-(5-methyl-1,3,4-oxadiazol-2-yl) Phenyl]ethynyl]phenyl]tetrahydropyran-3,4,5-triol

To intermediate N (27 mg, 0.101 mmol) and 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (28.88 mg, 0.121 mmol), cuprous iodide (4.19) Mg, 0.022 mmol) PdCl ₂ (dppf) ₂ -CH ₂ Cl ₂ (18.44 mg, 0.0226 mmol) and triethylamine (61) in a degassed (indoor vacuum/nitrogen flush) mixture in DMF (2.200 mL) mg, 84 μL, 0.604 mmol) , heated at 95 deg.] C overnight, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with brine the combined extracts were dried (Na ₂ SO _4), concentrated Purification on reverse phase HPLC gave the title compound.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.4 Hz, 2H), 7.68-7.56 (m, J = 8.2 Hz, 3H), 7.53-7.24 (m, 3H), 4.86 (d) , J = 4.1 Hz, 1H), 4.33-4.25 (m, 1H), 3.83 - 3.64 (m, 2H), 3.58-3.52 (m, J = 7.5, 3.0 Hz, 1H), 3.47-3.34 (m, J = 21.1, 10.4, 5.4 Hz, 2H), 2.54 (s, 3H). LC-MS: m / z = 423.39 (M + H +).

Preparation of Compound 134

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-[2-[4-(5-methyl-1,3,4-oxadiazol-2-yl) Phenyl]ethynyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared according to the procedure described for compound 133 using intermediate F and 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.46 (dd, J = 14.8, 8.1 Hz, 4H), 4.91-4.87 (m, 1H), 4.30 (t, 1H), 3.81-3.71 (m, 2H), 3.70-3.62 (m, 1H), 3.55-3.47 (m, J = 5.0 Hz, 2H), 3.44 3.41 (m, 1H), 2.54 (s, 3H). LC-MS: m/z = 423.40 (M+H+)

Preparation of Compounds 135 and 136

(N1,N3-dimethyl-5-[(Z)-2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)) Tetrahydropyran-2-yl]phenyl]vinyl]benzene-1,3-dimethylguanamine (135)

(N1,N3-dimethyl-5-[(E)-2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)) Tetrahydropyran-2-yl]phenyl]vinyl]benzene-1,3-dimethylguanamine (136)

Under air, compound 85 (140.1 mg, 0.2250 mmol), triethyldecane (52.32 mg, 71.87 μL, 0.4500 mmol), Pd(dppf)Cl ₂ -DCM (2.756 mg, 0.003375 mmol) were fed into the reaction tube. , dppf (6.146 mg, 0.01125 mmol) and copper (+2) cation (sulfate ion (1)) (5.387 mg, 0.03375 mmol) in toluene (1.125 mL), water (112.5 μL). The mixture was refluxed for 24 hours. The solvent was evaporated under reduced pressure and MeOH (2 mL). After stirring overnight, the reaction mixture was taken through a SCX-2 column and rinsed with MeOH. The solvent was removed under reduced pressure.

Compound 135: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (s, 1H), 7.97 (t, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.38-7.24 (m, J =15.3) , 7.7 Hz, 2H), 7.20-7.16 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 12.0 Hz, 1H), 6.73 (d, J = 12.1 Hz, 1H ), 4.82 (d, J = 3.3 Hz, 1H), 4.16 (t, J = 3.3 Hz, 1H), 3.74 - 3.58 (m, 3H), 3.48-3.45 (m, 1H), 3.24 - 3.16 (m, 1H), 3.11 (t, 1H), 2.85 (s, 3H). LC-MS: m/z = 457.49 (M+H+)

Compound 136: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.07-8.01 (m, 3H), 7.68 (s, 1H), 7.46-7.39 (m, 1H), 7.36-7.18 (m, 4H), 4.91 (d, J = 3.7 Hz, 1H), 4.37 (t, J = 3.4 Hz, 1H), 3.77 (d, J = 4.9 Hz, 2H), 3.66 (t, J = 7.8 Hz, 1H), 3.52 (dd , J = 8.0, 2.9 Hz, 1H), 3.48-3.41 (m, 1H), 3.40-3.38 (m, 2H), 2.86 (s, 6H). LC-MS: m/z = 457.41 (M+H+)

Preparation of Compounds 137 and 138

(2R,3S,4R,5S,6R)-2-[3-[(Z)-2-(3,5-Dichlorophenyl)vinyl]phenyl]-6-(hydroxymethyl)tetrahydro Piper-3,4,5-triol (137)

(2R,3S,4R,5S,6R)-2-[3-[(E)-2-(3,5-Dichlorophenyl)vinyl]phenyl]-6-(hydroxymethyl)tetrahydrol Piper-3,4,5-triol (138)

The title compound was prepared from the procedure described for compound 135 and 136.

Compound 137: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.33 - 7.14 (m, 4H), 7.08 - 7.01 (m, J = 1.6 Hz, 3H), 6.70 (d, J = 12.1 Hz, 1H), 6.48 (d, J = 12.1 Hz, 1H), 4.53 (s, 1H), 4.24 (t, J = 3.3 Hz, 1H), 3.76-3.58 (m, 3H), 3.45 (dd, J = 8.1, 3.1 Hz) , 2H). LC-MS: m/z = 412.28 (M+H+)

Compound 138: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.65 (s, 1H), 7.45 (d, J = 1.8 Hz, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.34 - 7.27 ( m, 2H), 7.24 - 7.18 (m, 2H), 7.08 (s, 1H), 7.04 (s, 1H), 4.89 (d, J = 3.7 Hz, 1H), 4.36 (t, J = 3.5 Hz, 1H) ), 3.76 (d, J = 4.9 Hz, 2H), 3.65 (t, J = 7.8 Hz, 1H), 3.51 (dd, J = 7.9, 3.1 Hz, 1H), 3.48-3.38 (m, 1H). LC-MS: m/z = 412.28 (M+H+)

Preparation of Compounds 139 and 140

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[(Z)-styryl]phenyl]tetrahydroper Norm-3,4,5-triol (139)

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[(E)-styryl]phenyl]tetrahydropyran-3,4,5-triol (140)

The title compound was prepared from compound 91 according to the procedure for compound 135 and 136.

Compound 139: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.35-7.27 (m, J = 5.1 Hz, 2H), 7.28-7.09 (m, 7H), 6.62 (d, 2H), 4.27 (t, J = 3.2 Hz, 1H), 3.78-3.62 (m, 4H), 3.48 (dd, J = 8.3, 3.1 Hz, 2H), 3.39-3.33 (m, 2H). LC-MS: m/z = 343.39 (M+H+)

Compound ^{140: 1 H NMR (400 MHz} , CD 3 OD) δ 7.70 (s, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.50-7.41 (m, J = 3.7 Hz, 1H), 7.40- 7.27 (m, 4H), 7.26-7.14 (m, 3H), 4.98 (d, J = 3.7 Hz, 1H), 4.46 (t, J = 3.4 Hz, 1H), 3.84 (d, J = 4.9 Hz, 2H ), 3.73 (t, J = 7.9 Hz, 1H), 3.61 (dd, J = 8.0, 3.1 Hz, 1H), 3.56-3.48 (m, J = 7.8, 4.9 Hz, 1H). LC-MS: m/z = 343.29 (M+H+)

Preparation of Compound 141

N-methyl-2-(1,2,4-triazol-1-yl)-4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6 -(hydroxymethyl)tetrahydropyran-2-yl]phenyl]benzamide

Step I: 4-bromo-N-methyl-2-(1,2,4-triazol-1-yl)benzamide

The title intermediate was prepared by the indoleamine coupling of commercially available 4-bromo-2-(1,2,4-triazol-1-yl)benzoic acid and methylamine (ethanol solution).

Step II: Compound 141

The title compound was prepared from the intermediate J and 4-bromo-N-methyl-2-(1,2,4-triazol-1-yl)benzamide (Step I) according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.74 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.86-7.75 (m, J = 10.9 Hz, 2H), 7.66-7.54 (m, 2H), 7.51-7.35 (m, 2H), 4.93 (d, J = 4.1 Hz, 1H), 4.52 (s, 1H), 4.35 (t, 1H), 3.82-3.70 (m, J =14.7) , 11.8 Hz, 2H), 3.69-3.60 (m, 1H), 3.60-3.51 (m, 1H), 3.52-3.43 (m, 1H), 2.71 (s, 1H). LC-MS: m/z =441.52 (M+H ⁺ ).

Preparation of Compound 142

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[3-(methoxymethyl)-4-(5-methyl-1,3,4- Oxadiazol-2-yl)phenyl]phenyl]tetrahydropyran-3,4,5-triol

Step I: Methyl 4-bromo-2-(methoxymethyl)benzoate.

Add sodium methoxide (748.7 mg, 772 μL 25) to a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1 g, 3.25 mmol) in THF (11 mL) w/v%, 3.57 mmol) and the resulting solution was stirred at 23 ° C overnight. CH ₂ Cl ₂ (15 ml) and water (5 ml) were added, the phases were separated and the organic phase was passed through a phase separation column. The solvent was removed to give the title compound.

Step II: 4-Bromo-2-(methoxymethyl)benzoic acid

To a stirred solution of methyl 4-bromo-2-(methoxymethyl)benzoate (841 mg, 3.25 mmol) in MeOH (11 mL) 32.46 mmol) and the resulting solution was stirred overnight. The pH was adjusted to 7, EtOAc and water were added. Extract the aqueous phase. The latter is discarded and the organic phase is passed through a phase separation column. The solvent was removed to give the title compound.

Step III: N'-Ethyl-4-bromo-2-(methoxymethyl)benzamide

The title compound was prepared according to the procedure described in Org. Biomol. Chem. , 2012 , 10 , 988.

Step IV: 2-[4-Bromo-2-(methoxymethyl)phenyl]-5-methyl-1,3,4-oxadiazole

The title compound was prepared according to the procedure described in Org. Biomol. Chem., 2012 , 10 , 988.

Step V: Compound 142

From intermediate J and 2-[4-bromo-2-(methoxymethyl)phenyl]-5-methyl-1,3,4-oxadiazole (step IV) according to compound 117 The program prepares the title compound.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.79 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.47-7.37 (m, 2H), 4.95 (d, J = 4.0 Hz, 1H), 4.84 (s, 2H), 4.37 (t, 1H), 3.84 - 3.71 (m, 2H), 3.67 (t, J = 7.7 Hz, 1H), 3.56 (dd, J = 7.5, 2.9 Hz, 1H), 3.51-3.44 (m, 1H), 3.39 (s, 3H), 2.55 ( s, 3H). LC-MS: m/z = 443.55 (M+H+)

Preparation of Compound 143

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[3-hydroxy-4-(5-methyl-1,3,4-oxadiazol-2- Phenyl]phenyl]tetrahydropyran-3,4,5-triol

Step I: 2-hydroxy-4-iodo-benzidine chloride

2-Hydroxy-4-iodo-benzoic acid (975 mg, 3.69 mmol) was dissolved in toluene under a nitrogen atmosphere and ethyldichlorodichloride (3.693 mL 2 M, 7.39 mmol). The reaction was stirred for 2 min and dimethylformamide (13.5 mg, 15 uL, 0.185 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the title compound. The latter was used as it is in the next step.

Step II: N'-Ethyl-2-hydroxy-4-iodo-benzimidazole.

2-Hydroxy-4-iodo-benzhydryl chloride (1.43 g, 5.06 mmol) and acetamidine (488 mg, 6.58 mmol) were dissolved in CH ₂ Cl ₂ (17 mL) and added three. Ethylamine (1.127 g, 1.55 mL, 11.1 mmol). The reaction was stirred at room temperature overnight. EtOAc and water were added and the phases were separated. The aqueous phase was back extracted once with EtOAc. The organic phases were combined and passed through a phase separation column. The residue was loaded to a snap 10 g column, and eluting (0 to 100% 20% MeOH solution of CH ₂ Cl ₂₎ to give the title compound.

Step III: 5-iodo-2-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

The title compound was prepared according to the procedure described in Org. Biomol. Chem. , 2012 , 10 , 988.

Step IV: Compound 143

Intermediate J (23.6 mg, 0.0442 mmol), 5-iodo-2-(5-methyl-1,3,4-oxadiazol-2-yl)phenol (39.33 mg, 0.130 mmol) was fed into a microwave vial. , a solution of K ₃ PO ₄ (92.12 mg, 0.434 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (8.86 mg, 0.0109 mmol) in DMF (2.2 mL) and heated in a microwave at 120 ° C 15 minutes. The mixture was filtered on a Millipore and concentrated to dryness. The residue was taken up in MeOH (2 mL)EtOAcEtOAcEtOAc. The mixture is then filtered on a SCX-2 SPE column, 2 M NH MeOH ₃ column was washed with the solution. The filtrate was concentrated to dryness and purified by reverse phase preparative HPLC.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84-7.66 (m, J = 26.2, 18.6 Hz, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.47-7.33 (m, 2H), 7.33 -7.15 (m, J = 9.2 Hz, 2H), 4.94 (d, J = 3.2 Hz, 1H), 4.37 (t, 1H), 3.86-3.72 (m, 2H), 3.66 (t, J = 7.5 Hz, 1H), 3.59-3.42 (m, J = 26.2, 10.1 Hz, 2H), 2.56 (s, 3H). LC-MS: m/z = 415.34 (M+H+)

Preparation of compound 144

2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]quinoline-6 - Methyl formate.

The title compound was prepared from Intermediate J and 2-chloroquinoline-6-carboxylic acid methyl ester according to the procedure for compound 117.

^{1 H NMR (400 MHz, CD3OD} ) δ 8.60 (d, 1H), 8.50-8.41 (m, 1H), 8.28 (s, 1H), 8.23 (m, 1H), 8.08 (m, 3H), 7.59 (d , 1H), 7.51 (t, 1H), 5.01 (d, 1H), 4.49-4.40 (m, 1H), 3.92 (s, 3H), 3.87-3.75 (m, 2H), 3.71 (t, 1H), 3.61 (m, 1H), 3.53 (m, 1H).

LC-MS: 426.4 (M+H+).

Preparation of Compound 145

2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]quinoline-6 -carboxylic acid N-methyl ester

Add saturated methylamine/EtOH solution (1 mL) to 2-[3-[(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(B) in the flask Methyloxymethyl)tetrahydropyran-2-yl]phenyl]quinoline-6-carboxylic acid methyl ester (intermediate before removal of the protecting group in the preparation of compound 144) (15 mg, 0.02527 mmol). The reaction mixture was stirred at room temperature overnight. After the volatiles were removed, EtOAc EtOAc m.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (d, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.13 - 7.78 (m, 4H), 7.56 (d, 1H), 7.49 (t, 1H), 4.99 (d, 1H), 4.48-4.31 (m, 1H), 3.89-3.74 (m, 2H), 3.69 (t, 1H), 3.59 (m, 1H), 3.50 (m, 1H) ), 2.90 (s, 3H). LC-MS: 425.4 (M+H ⁺ ).

Preparation of Compound 146

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-(hydroxymethyl)-1H-benzimidazol-5-yl]phenyl]tetrahydroper Norm-3,4,5-triol

From intermediate J and (5-bromo-1H-benzo[d]imidazol-2-yl)methanol according to compound 117 The procedure described provides the title compound.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.73 (s, 1H), 7.70 (d, 1H), 7.49 (m, 3H), 7.42-7.20 (m, 2H), 4.96 (d, 1H), 4.77 (s, 2H), 4.41 (t, 1H), 3.95-3.71 (m, 2H), 3.67 (t, 1H), 3.56 (m, 1H), 3.47 (m, 1H). LC-MS: 387.3 (M+H ⁺ ).

Preparation of Compound 147

(2R,3S,4R,5S,6R)-2-[3-(2-hydroxy-1H-benzimidazol-5-yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3 4,5-triol

The title compound was prepared from the intermediate J and 5-bromo-1H-benzo[d]imidazol-2-ol according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (s, 1H), 7.50 (d, 1H), 7.46-7.37 (m, 2H), 7.32 (m, 2H), 7.09 (d, 1H), 5.02 (d, 1H), 4.47 (t, 1H), 3.84 (d, 2H), 3.74 (t, 1H), 3.62 (m, 1H), 3.58-3.49 (m, 1H). LC-MS: 373.3 (M+H ⁺ ).

Preparation of Compound 148

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[2-(trifluoromethyl)-1H-benzimidazol-5-yl]phenyl]tetrahydro Piper-3,4,5-triol

The title compound was prepared from Intermediate J and 5-bromo-2-(trifluoromethyl)-1H-benzo[d]imidazole according to the procedure described for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.73 (t, 2H), 7.65-7.37 (m, 4H), 5.04 (d, 1H), 4.48 (t, 1H), 3.85 (m, 2H), 3.74 (m, 1H), 3.64 (m, 1H), 3.60-3.48 (m, 1H). LC-MS: 425.3 (M+H ⁺ ).

Preparation of Compound 149

(2R,3S,4R,5S,6R)-2-[3-(3-butylbenzimidazol-5-yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4, 5-triol

The title compound was prepared from Intermediate J and 6-bromo-1-butyl-1H-benzo[d]imidazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.63 (m, 2H), 7.58 (d, 1H), 7.51-7.33 (m, 2H), 5.05 (d, 1H), 4.50 (t, 1H), 4.31 (t, 2H), 3.91-3.80 (m, 2H), 3.75 (t, 1H), 3.65 (m, 1H), 3.60-3.49 (m, 1H), 2.01-1.80 (m, 2H), 1.35 (m, 2H), 0.96 (t, 3H). LC-MS: 413.4 (M+H ⁺ ).

Preparation of Compound 150

(2R,3S,4R,5S,6R)-2-[3-[3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]phenyl] -6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared from Intermediate J and 2-(4-bromo-2-fluorophenyl)-5-methyl-1,3,4-oxadiazole according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.20-8.00 (m, 1H), 7.89 (s, 1H), 7.77-7.60 (m, 3H), 7.51 (m, 2H), 5.02 (d, 1H) , 4.50-4.38 (m, 1H), 3.85 (m, 2H), 3.74 (t, 1H), 3.63 (m, 1H), 3.56 (m, 1H), 2.64 (s, 3H). LC-MS: 417.3 (M+H ⁺ ).

Preparation of Compound 151

5-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]-1H-benzene Methyl imidazole-2-carboxylate

The title compound was prepared from Intermediate J and methyl 5-bromo-1H-benzo[d]imidazole-2-carboxylate according to the procedure for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.92-7.46 (m, 5H), 7.38 (d, 2H), 4.96 (d, 1H), 4.41 (t, 1H), 3.83-3.74 (m, 2H) , 3.67 (t, 1H), 3.56 (m, 1H), 3.50-3.44 (m, 1H), 2.91 (s, 3H). LC-MS: 414.4 (M+H ⁺ ).

Preparation of Compound 152

N-methyl-2-[5-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl Phenyl]benzimidazol-1-yl]acetamide

From the intermediate J and 2-(5-bromo-1H-benzo[d]imidazol-1-yl)-N-methylacetamide according to The title compound was prepared following the procedure described for compound 117.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.48 (s, 1H), 8.07 (d, 1H), 8.81-7.83 (m, 3H), 7.71-7.61 (m, 1H), 7.51 (d, 2H) , 5.34 (d, 2H), 5.03 (d, 1H), 4.45 (m, 1H), 3.95-3.80 (m, 2H), 3.78-3.68 (m, 1H), 3.68-3.62 (m, 1H), 3.60 -3.53 (m, 1H), 2.82 (d, 3H). LC-MS: 428.6 (M+H ⁺ ).

Preparation of Compound 153

5-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]benzene-1, 3-dicarboxylic acid

To a solution of compound 62 (28 mg, 0.065 mmol) in THF (560 <RTI ID=0.0></RTI></RTI><RTIgt_; After stirring overnight, the reaction mixture was passed through a pre-wash (sequent H ₂ O, methanol and H ₂ O) SCX-2 1 g column with H ₂ O/THF mixture (1:1, 3×1 mL) )rinse. The combined filtrates were concentrated and flash chromatographed by reverse phase using a gradient of 0-50% H ₂ O in a Biotage C18 snap 12 g column purified as eluent. The combined aliquots were concentrated and dried to dryness crystals

¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.49 (d, J = 1.2 Hz, 2H), 7.85 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.60-7.45 (m, 2H), 5.05 (d, J = 4.4 Hz, 1H), 4.45 (dd, J = 4.2, 3.3 Hz, 1H), 3.91 (dd, J = 11.9, 6.9 Hz, 1H), 3.83 (dd, J =11.9, 3.0 Hz, 1H), 3.78 (t, J = 7.3 Hz, 1H), 3.69 (dd, J = 7.5, 3.1 Hz, 1H), 3.58 (td, J = 6.9, 3.0 Hz, 1H). ESI-MS m/z calculated value 404.111072, experimental value 405.33 (M+1) ⁺

Preparation of compound 154

N-methyl-3-[6-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]-2 -naphthyl]benzamide

Step I: Acetic Acid [(2R,3S,6S)-3-Ethyloxy-6-(6-hydroxy-2-naphthyl)-3,6-dihydro-2H-pyran-2-yl]A ester

From (2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (1.49 g, 5.47 mmol) and (6-hydroxyl) -2-naphthyl) The acid (1.0 g, 5.32 mmol) was prepared according to the same procedure as Intermediate A Step. By flash chromatography using a gradient (0-50%) of EtOAc in hexanes to purified on Biotage ^TM snap 50 g column, to give the title compound as an off-white solid of foam (935 mg, 49% yield).

Step II: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(6-hydroxy-2-naphthyl)tetrahydropyran-2- Methyl ester

From [(2R,3S,6S)-3-ethoxycarbonyl-6-(6-hydroxy-2-naphthalenyl)-3,6-dihydro-2H-pyran-2-yl]methyl acetate 930 mg, 2.61 mmol) was prepared according to the same procedure as Intermediate A Step II. Purification by flash chromatography using a gradient of ₂ Cl ₂ solution of i PrOH CH (0-10%) in Biotage ^TM snap 50 g column to give an off-white solid of the title compound (281 mg, 28% yield).

Step III: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-[6-(trifluoromethylsulfonyloxy)-2-naphthalene Tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(6-hydroxy-2-naphthyl)tetrahydropyran-2-yl] Add Et ₃ N (168 μL, 1.21 mmol), 1,1,1-trifluoro-N-phenyl-N to a suspension of methyl ester (235 mg, 0.602 mmol) in CH ₂ Cl ₂ (6 mL) - (Trifluoromethylsulfonyl) methanesulfonamide (266 mg, 0.74 mmol) and another CH ₂ Cl ₂ (4 mL). The resulting suspension was stirred for 3 days, then concentrated and purification using a gradient of ₂ Cl MeOH solution of ₂ CH (0-10%) in Biotage ^TM snap 25 g silicon dioxide column, followed by Biotage ^TM snap 25 g silicon dioxide column The title compound (214 mg, 68% yield) eluted elute

Step IV: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[6-(trifluoromethylsulfonyloxy)-2-naphthyl] Tetrahydropyran-2-yl]methyl ester

To [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-[6-(trifluoromethylsulfonyloxy)-2-naphthyl]tetra Pyridine (100 μL, 1.24 mmol), DMAP (2.5 mg, 0.02 mmol) was added sequentially to a mixture of hydrochloropyran-2-yl]methyl (214 mg, 0.41 mmol) in CH ₂ Cl ₂ (2.2 mL) And Ac ₂ O (97 μL, 1.03 mmol). After stirring for 2 hours, the reaction mixture was diluted with CH ₂ Cl ₂ (5 mL) and 1 N aqueous HCI (5 mL). Separate the layers. The aqueous layer was extracted with CH ₂ Cl ₂ (2×5 mL). The combined organic extracts were concentrated, redissolved in CH ₂ Cl _2, the pre-washed Dowex resin was treated with the 50WX4-400, filtered and the number of parts rinsed with CH ₂ Cl _2. The combined filtrate was concentrated to give the title compound mjjjjjj

Step V: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[6-[3-(methylaminocarbamido)phenyl]-2 -naphthyl]tetrahydropyran-2-yl]methyl ester

Feeding acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[6-(trifluoromethylsulfonyloxy)-2-) into a microwave vial Naphthyl]tetrahydropyran-2-yl]methyl ester (21.5 mg, 0.035 mmol), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxo boron 2-yl)benzamide (11.3 mg, 0.043 mmol), Cs ₂ CO ₃ (37.1 mg, 0.11 mmol) and SiliaCat DPP-Pd (15.3 mg, 0.26 mmol/g, 0.0040 mmol). MeCN (500 μL) was added, the vial was degassed (vacuum and N ₂ , 3× in sequence), capped and microwaved at 100 ° C for 10 minutes. The reaction mixture was diluted with EtOAc, EtOAc (EtOAc)EtOAc. The combined filtrate was concentrated and used directly in step VI.

Step VI: Compound 154

The crude material from step V was dissolved in MeOH (500 uL) and was taken eluted with EtOAc EtOAc EtOAc. After stirring overnight, the reaction mixture was taken through a pre-washed 1 g SCX-2 column and rinsed with MeOH (3×1 mL). The combined filtrates were concentrated and purified by HPLC (injected on Phenomenex C18 Gemini AXIA 5 μm 110A 21.2 x 75 mm for 10 minutes - 10% ACN / H ₂ O + 0.01% TFA - 40% ACN + 0.01 in 20 minutes) % TFA) Purified crude material. The combined fractions were concentrated, EtOAc EtOAcjjjjjjjj

¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (t, J = 1.7 Hz, 1H), 8.07 (s, 1H), 7.94-7.81 (m, 4H), 7.79-7.68 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.50 (t, J = 3.4 Hz, 1H), 3.82-3.75 (m, 2H), 3.70 (t, J = 7.8 Hz, 1H), 3.60 (dd, J = 7.9, 3.1 Hz, 1H), 3.50-3.42 (m, 1H), 2.87 (s, 3H). ESI-MSm/z calc. 423.16818, found 424.4 (M+1) ⁺

Preparation of Compound 155

(2R,3S,4R,5S,6R)-2-[6-(3,5-Dichlorophenyl)-2-naphthyl]-6-(hydroxymethyl)tetrahydropyran-3,4, 5-triol

From acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[6-(trifluoromethylsulfonyloxy)-2-naphthyl]tetrahydro Piperidin-2-yl]methyl ester (compound 154, step IV) and (3,5-dichlorophenyl) The title compound was prepared following the same procedure as Compound 154 (Steps V and VI).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 1H), 8.03-7.94 (m, 3H), 7.78-7.69 (m, 4H), 7.44 (t, J = 1.8 Hz, 1H), 5.12 (d, J = 3.9 Hz, 1H), 4.60-4.53 (m, 1H), 3.89-3.84 (m, 2H), 3.77 (t, J = 7.8 Hz, 1H), 3.67 (dd, J = 7.9, 3.1 Hz, 1H), 3.53 (ddd, J = 7.4, 6.2, 3.6 Hz, 1H). ESI-MS m / z calc. 435.30, found (M ⁺ Na) + 457.28,459.30.

Preparation of Compound 156

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(6-hydroxy-2-naphthyl)tetrahydropyran-3,4,5-triol

To the acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-4,5-dihydroxy-6-(6-hydroxy-2-naphthyl)tetrahydroperoxide from Step 154 of Compound 154 A solution of MeONa in MeOH (54 μL 0.5 M, 0.027 mmol) was added to EtOAc (EtOAc) After stirring overnight, neutralized with Dowex 50WX4-400 resin prewashed The resulting suspension was treated with _{THF (2.5 mL), H 2} O (0.5 mL) and MeOH (1.5 mL) is diluted, filtered and washed with several portions of THF and MeOH. The combined filtrate was concentrated. By reverse phase flash chromatography using a gradient (0-50%) of purified MeCN in H ₂ O solution Biotage ^TM C18 snap 12 g column, to give the title compound as an off-white solid of (19.6 mg, 59% yield) .

¹ H NMR (400 MHz, CD ₃ OD δ 9.68 (width unimodal, 1H), 7.76-7.68 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6, 1.4 Hz, 1H), 7.10-7.01 (m, 2H), 4.86-4.70 (m, 2H), 4.60 (2 broad single peaks, 2H), 4.19 (wide single peak, 1H), 3.65 (wide single peak, 2H) ), 3.60-3.52 (m, 1H), 3.48 (dd, J = 6.7, 2.8 Hz, 1H), 3.39 (dd, J = 11.2, 5.4 Hz, 1H). ESI-MS m/z calculated value 306.111035, experiment Value 307.29 (M+1) ⁺

Preparation of Compound 157

N-methyl-3-[[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Methyl]benzamide

Step I: N,3-dimethylbenzamide

Add HATU (4.80 g, 12.6 mmol), DIEA (3.3 mL, 19.1 mmol) and MeNH ₂ in THF to a solution of 3-methylbenzoic acid (1.3 g, 9.55 mmol) in DMF (13 mL). (7.2 mL 2 M, 14.3 mmol). After stirring for 2 hours, diluted with EtOAc (100 mL) the reaction mixture, brine (50 mL) and washed with _{H 2 O (2 × 50 mL} ), 1 N HCl aqueous solution (50 ml),, dried over Na ₂ SO _4, filtered and concentrated, then purified by flash chromatography using ₂ Cl ₂ gradient of MeOH in CH (2-10%) in Biotage ^TM snap 50 g column. The title compound (1.11 g, 78% yield) was obtained.

Step II: 3-(Bromomethyl)-N-methyl-benzamide

To a refluxing solution of N,3-dimethylbenzamide (1.1 g, 7.34 mmol) and NBS (1.60 g, 8.89 mmol) in CCI ₄ (23 mL) was added AIBN (121 mg, 0.74 mmol). The reaction mixture was stirred at reflux overnight and concentrated, followed by flash chromatography using a gradient (0-70%) of EtOAc in hexanes to purified on Biotage ^TM snap 50 g column, to give the title compound as a clear yellow oil of ( 761 mg, 45% yield). ¹ H NMR (CDCl ₃ ) showed that it contained some succinimide. Used directly in the next step.

Step III: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[[3-(methylaminomethyl)phenyl]phenyl] Phenyl]tetrahydropyran-2-yl]methyl

Intermediate J (108 mg, 0.202 mmol) and 3-(bromomethyl)-N-methyl-benzamide (47 mg, 0.206 mmol) in THF (1.3 mL) A solution of Na ₂ CO ₃ (300 μL 1 M, 0.300 mmol) was added to the solution. The reaction mixture was degassed (vacuum and washed sequentially with N _2, 3 ×) and was added _{Pd (PPh 3) 4 (7.9} mg, 0.0068 mmol). The reaction mixture was degassed again, capped and heated to 70 deg.] C overnight, then diluted with EtOAc, dried over Na ₂ SO ₄ and through isolute 500 mg silicon dioxide column, eluting with several portions of EtOAc. The combined filtrates were concentrated and the crude material obtained was used directly in the next step.

Step IV: Compound 157

Crude acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[[3-(methylaminomethyl) phenyl)) ]Methyl]phenyl]tetrahydropyran-2-yl]methyl ester was dissolved in MeOH (2.2 mL), EtOAc (EtOAc (EtOAc) The SCX-2 1 g column was washed and rinsed with MeOH (3 x 1 mL). The combined filtrates were concentrated and purified by preparative HPLC (caper). After concentrating and lyophilization, the title compound (30 mg, 35% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.62 (dt, J = 7.2, 1.6 Hz, 1H), 7.43-7.33 (m, 3H), 7.30 (d, J = 5.1 Hz) , 2H), 7.19-7.11 (m, 1H), 4.95 (d, J = 3.5 Hz, 1H), 4.41 (t, J = 3.3 Hz, 1H), 4.04 (s, 2H), 3.84 - 3.75 (m, 2H), 3.72 (t, J = 8.1 Hz, 1H), 3.55 (dd, J = 8.1, 3.1 Hz, 1H), 3.43 (ddd, J = 8.4, 6.0, 3.5 Hz, 1H), 2.90 (s, 3H) ). ESI-MS m / z calc. 387.43, found 388.39 (M ⁺ H) +.

Preparation of Compound 158

N-methyl-3-[3-methyl-4-[4-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydroperoxide喃-2-yl]phenyl]phenyl]benzamide

Step I: Trifluoromethanesulfonic acid [2-methyl-4-[3-(methylamine-mercapto)phenyl]phenyl]ester

Add 1,1 to a solution of 3-(4-hydroxy-3-methyl-phenyl)-N-methyl-benzamide (500 mg, 2.07 mmol) in CH ₂ Cl ₂ (12.5 mL) , -N- phenyl-1-trifluoromethyl -N- (trifluoromethanesulfonyl acyl) Amides methanesulfonamide (923 mg, 2.58 mmol) and _{Et 3 N (580 μL, 4.16} mmol). After stirring at room temperature overnight, the reaction mixture was concentrated to dryness, then purified by flash chromatography using a gradient of ₂ Cl ₂ solution of CH EtOAc (0-50%) in Biotage ^TM snap 25 g column. The title compound (827 mg, 98% yield).

Step II: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-[2-methyl-4-[3-(methylamine A) Mercapto)phenyl]phenyl]phenyl]tetrahydropyran-2-yl]methyl

Feeding [2-methyl-4-[3-(methylamine-mercapto)phenyl]phenyl]phenyl]trifluoromethanesulfonate (79 mg, 0.194 mmol), acetic acid [(2R, 3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)phenyl]tetrahydropyran-2-yl]methyl ester (Compound x, previously described in the patent) (90 mg, 0.87 mmol), Cs ₂ CO ₃ (180 mg, 0.55 mmol) and SiliaCat DPP-Pd (79 mg, 0.26 mmol/g, 0.021 mmol). MeCN (2 mL) was added and the vial was capped and microwaved for 10 minutes at 100 °C. The reaction mixture was diluted (1: 1) and passed through the column and 500 mg silicon dioxide with several portions of EtOAc-CH ₂ Cl ₂ with EtOAc-CH ₂ Cl ₂ mixture (1: 1) fractions. The combined filtrates were concentrated, then purified by flash chromatography using a gradient of _{2 2} of Cl CH EtOAc solution (0-80%) in Biotage ^TM snap 10 g column, followed again by flash chromatography on a Biotage ^TM snap 10 Purification by gradient (50-80%)EtOAcEtOAc

Step III: Compound 158

Treatment of acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-[2-] with MeONa in MeOH (42 μL, 0.5 M, 0.51 mmol) Methyl-4-[3-(methylamine-mercapto)phenyl]phenyl]phenyl]tetrahydropyran-2-yl]methyl ester (26 mg, 0.041 mmol) in MeOH (1 mL) Solution. After stirring overnight, the reaction mixture was taken through a pre-washed 1 g SCX-2 column and washed with MeOH (3×1 mL). The combined filtrates were concentrated, suspended in MeCN / H ₂ O mixture (20% MeCN) and the freeze-dried, to give the title compound (16.3 mg, 83% yield) of a white fluffy solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (t, J = 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.82-7.77 (m, 1H), 7.66-7.51 (m, 5H) , 7.39 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1H), 5.06 (d, J = 3.6 Hz, 1H), 4.51 (t, J = 3.4 Hz, 1H), 3.87 (d, J = 4.7 Hz, 2H), 3.78 (t, J = 8.0 Hz, 1H), 3.66 (dd, J = 8.1, 3.1 Hz, 1H), 3.60-3.51 (m, 1H), 2.96 (s, 3H), 2.35 (s, 3H). ESI-MS m / z calc. 463.52, found 464.51 (M ⁺ H) +.

Preparation of Compound 159

N,3'-dimethyl-3"-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2 -yl)-[1,1':4',1"-bitriphenyl]-3-carboxamide

The title compound was prepared according to the procedure described for compound 158, but using intermediate J. It is the starting material in step II.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (t, J = 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.82-7.76 (m, 1H), 7.62 (d, J = 1.2 Hz) , 1H), 7.58-7.43 (m, 5H), 7.36-7.26 (m, 2H), 5.05 (d, J = 3.6 Hz, 1H), 4.49 (t, J = 3.4 Hz, 1H), 3.88-3.82 ( m, 2H), 3.77 (t, J = 7.9 Hz, 1H), 3.66 (dd, J = 8.0, 3.1 Hz, 1H), 3.55 (ddd, J = 8.0, 5.7, 3.9 Hz, 1H), 2.96 (s) , 3H), 2.36 (s, 3H). ESI-MS m / z calc. 463.52, found 464.51 (M ⁺ H) +.

Preparation of Compound 160

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[4-[6-(5-methyl-1,3,4-oxadiazol-2-yl)-2 -naphthyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared according to the procedure described in Compound 158, Steps II and III, using Intermediate O and 2-(6-bromo-2-naphthyl)-5-methyl-1,3,4-oxadiazole as appropriate Starting material. Step II was carried out for 15 minutes at 100 ° C on microwave. By reverse phase flash chromatography using a gradient (0-80%) to give the final compound of MeCN in H ₂ O solution Biotage ^TM C18 snap 30 g column, and then re-purified by prep HPLC (caper), obtained as a fluffy The title compound was obtained as a white solid (3.8 mg, 5% yield).

ESI-MS m/z calc. 448.47, 495.32 (M+H) ⁺ .

Preparation of Compound 161

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[6-(5-methyl-1,3,4-oxadiazol-2-yl)-2 -naphthyl]phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared according to the procedure described in Compound 154 Steps II and III using Intermediate J and 2-(6-bromo-2-naphthyl)-5-methyl-1,3,4-oxadiazole as appropriate Starting material. Step II was carried out for 15 minutes at 100 ° C on microwave. By reverse phase flash chromatography on Biotage ^TM C18 snap 12 g column using a gradient (0-80%) MeCN solution of H ₂ O purification of the final compound was obtained as a fluffy white solid of the title compound (20.4 mg, 28% Two-step yield).

¹ H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.08 ( Dd, J = 8.6, 1.6 Hz, 1H), 7.98 (dd, J = 8.6, 1.6 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.54-7.41 (m) , 2H), 4.87-4.76 (m, 3H), 4.70 (dd, J = 5.8, 4.5 Hz, 2H), 4.16 (td, J = 5.6, 3.2 Hz, 1H), 3.68 (t, J = 5.6 Hz, 2H), 3.57 (dd, J = 11.8, 5.9 Hz, 1H), 3.52-3.44 (m, 2H), 2.62 (s, 3H). ESI-MS m/z calc. 448.47, 495.32 (M+H) ⁺ .

Compounds 162 to 171 were prepared according to the following general procedure.

Step I: 3-((2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydro-2H-pyran-2- Benzoic acid

Pyridine (312 μL, 3.86 mmol), DMAP (6.7 mg, 0.055 mmol) and Ac _{2 were} added sequentially to a suspension of intermediate D (165 mg, 0.551 mmol) in 1.6 mL CH ₂ Cl ₂ under nitrogen. O (312 μL, 3.31 mmol). The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to dryness. By flash column chromatography on silica gel (0 to 20% MeOH solution of CH ₂ Cl ₂₎ to give the residue, to give a final raw product. The product was dissolved in 5 mL CH ₂ Cl ₂ and treated with 1 M HCl (1 mL) and washed. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to dryness to give the title compound (242.2 mg, 97%).

Step II

To 3-[(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]benzoic acid ( Step I, 1 eq.) and the corresponding o-phenylenediamine (1 eq.) in THF were added sequentially with HATU (1 eq.) and DIPEA (1 eq.). The mixture was stirred at room temperature under nitrogen until the reaction was complete and the reaction mixture was diluted with saturated NaHCO _3, extracted by EtOAc, washed with H ₂ O and the organic layers were combined and concentrated to dryness. The residue was dissolved in AcOH and heated to 50 ° C overnight. The reaction mixture was then evaporated to dryness crystals crystals crystals crystals

Step III

The compounds in Table 4 were deacetylated using the procedures described above.

Preparation of Compound 172

N-methyl-2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) Phenyl)-1H-benzo[d]imidazole-5-carboxamide

Preparation of triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethenyloxy) using the methyl 3,4-diaminobenzoate as the reagent in Step II according to the procedure described for Compound 162-171 Methyl)-6-(3-(5-(methoxycarbonyl)-1H-benzo[d]imidazol-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-tri ester.

Step I: 2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)benzene Methyl-1H-benzo[d]imidazole-5-carboxylate

To triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-(5-(methoxycarbonyl)-1H-benzo[d]imidazole- Add NaOMe (0.5 M in MeOH, 42.5) to a solution of 2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triester (49.5 mg, 0.0849 mmol) in methanol (2.4 mL) μL, 0.0212 mmol). Stir the mixture overnight at room temperature via 1 g SCX- 2 SPE column was filtered and concentrated to dryness. The obtained title compound was used as it is in the next step.

Step II: 2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzene -1H-benzo[d]imidazol-5-carboxylic acid

To 2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl) Add -1H-benzo[d]imidazole-5-carboxylic acid methyl ester (0.0849 mmol) in THF (1.5 mL) and water (1.5 mL), EtOAc (1. The mixture was stirred overnight under temperature. An additional portion of LiOH (hydrate, 17.8 mg, 0.425 mmol) was added and the mixture was heated to 35 ° C for 1 hour to complete the reaction. The mixture was then cooled to room temperature, EtOAc (EtOAc m.

Step III: Compound 172

To 2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl) -1H-benzo[d]imidazole-5-carboxylic acid (0.0849 mmol) (see procedure above) MeNH ₂ (2 M in THF, 55.2 μL, 0.110 mmol) was added sequentially to a solution in DMF (2 mL) HATU (42 mg, 0.110 mmol) and DIPEA (22.2 μL, 0.1274 mmol). The mixture was stirred at rt EtOAc (EtOAc)

¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (m, 1H), 8.23 (s, 1H), 8.11 (m, 1H), 8.04 (m, 1H), 7.76 (m, 1H), 7.68 (m) , 2H), 7.58 (t, J = 7.8 Hz, 1H), 5.04 (d, J = 4.4 Hz, 1H), 4.46 (dd, J = 4.3, 3.2 Hz, 1H), 3.88 (m, 2H), 3.78 (t, J = 7.3 Hz, 1H), 3.67 (dd, J = 7.5, 3.1 Hz, 1H), 3.57 (td, J = 6.9, 3.1 Hz, 1H), 2.94 (s, 3H). LC/MS: m/z = 414.6 (M+H ⁺ )

Preparation of Compound 173

N-methyl-2-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) Phenyl)-1H-benzo[d]imidazole-4-carboxamide

The title compound was prepared according to the procedure for compound 163 using methyl 2,3-diaminobenzoate as reagent.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 7.9) Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.29 (m, 1H), 5.00 (d, J = 4.3 Hz, 1H), 4.41 ( m,1H), 3.85 (m, 2H), 3.72 (t, J = 7.4 Hz, 1H), 3.60 (m, 1H), 3.54 (td, J = 7.0, 3.1 Hz, 1H), 3.06 (d, J) =3.5 Hz, 3H). LC/MS: m/z = 414.4 (M+H ⁺ ).

Compounds 174 to 178 in Table 5 were prepared according to the following general procedure.

Feeding Intermediate J (1 eq), the appropriate aryl bromide (1 eq.) Was added to a microwave ^{vial, Siliacat-DPP-Pd TM (} 0.26 mmol / g, 0.1 equiv), Cs ₂ CO ₃ (2.2 eq) and acetonitrile. The mixture was heated in a microwave at 100 ° C for 30 minutes, filtered on celite and concentrated to dryness. The residue was taken up in MeOH EtOAc (EtOAc)EtOAc. AcOH (0.5 eq.) was then added, the mixture was concentrated to dryness and purified by reverse phase preparative HPLC to give the desired product.

Preparation of Compound 179

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)tetrahydro- 2H-pyran-3,4,5-triol

The microwave vial was fed with intermediate J, 5-bromo-1-methyl-benzimidazole (12.1 mg, 0.0574 mmol), K ₃ PO ₄ (37.5 mg, 0.177 mmol), PdCl ₂ (dppf) ₂ (3.6 Mg, 0.0044 mmol), DMF (1 mL) and heated in a microwave at 120 °C for 15 min. The mixture was filtered on a Millipore and concentrated to dryness. The residue was taken up in MeOH (2 mL)EtOAcEtOAcEtOAc. The mixture is then filtered on a SCX-2 SPE column, 2 M NH MeOH ₃ column was washed with the solution. The filtrate was concentrated to dryness and purified title crystals crystals

¹ H NMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 7.88 (m, 1H), 7.80 (m, 1H), 7.60 (m, 3H), 7.45 (m, 2H), 5.04 (d) , J = 3.7 Hz, 1H), 4.50 (t, J = 3.5 Hz, 1H), 3.92 (s, 3H), 3.86 (m, 2H), 3.75 (t, J = 7.9 Hz, 1H), 3.65 (dd , J = 8.0, 3.1 Hz, 1H), 3.55 (m, 1H).

Preparation of Compound 180

Step I: 3-[2-(4-Iodobenzoguanidino)indolyl]-3-oxo-propionic acid ethyl ester

Add to the solution of 4-iodobenzoic acid (2.021 g, 8.149 mmol), 3-mercapto-3-oxo-propionic acid ethyl ester (1.191 g, 8.149 mmol) in DMF (20 mL) HATU (3.408 g, 8.964 mmol), DIPEA (1.7 mL, 9.78 mmol) and mixture was stirred at room temperature overnight. 80 mL of water was added to the mixture and the obtained solid (2.617 g, 85%) was collected by filtration to give the title compound, which was used in the next step.

Step II: Ethyl 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)acetate

3-[2-(4-Iodobenzopyridyl)indolyl]-3-oxo-propionic acid ethyl ester (2587 mg, 6.878 mmol) was suspended in POCl ₃ (25.9 mL) and the mixture was heated to reflux after for 1 hour, cooled to room temperature, evaporated to dryness, the residue was diluted with 50 mL DCM and poured onto 100 g of crushed ice, the layers were separated and the aqueous phase was extracted with _{CH 2 Cl 2 (4 × 50} mL). Dried over Na ₂ SO ₄ the combined organic layers were concentrated to dryness and purified by silica gel chromatography (6 to 50% AcOEt of hexane) to give the title compound (1.750 g, 71%).

Step III: Triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethyloxymethyl)-6-(4'-(5-(2-ethoxy-2-oxoxy) -1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran-3,4,5-triester

Ethyl 2-[5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl]acetate (76.0 mg, 0.212 mmol), PdCl ₂ (dppf) (15.7 mg, 0.0193 mmol ) and _{K 3 PO 4 (81.85 mg,} 0.3856 mmol) in DMF (2.1 mL) of the solution to 100 deg.] C overnight. The mixture was cooled to room temperature, water (4 mL) was evaporated. Washed with water (3 × 5 mL), brine (5 mL) the combined organic layers were washed, dried over Na ₂ SO ₄ dried and concentrated to dryness. The residue was purified by EtOAc EtOAc EtOAc EtOAc

Step IV: Compound 180

To triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(4'-(5-(2-ethoxy-2-oxoethyl) -1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran-3,4,5-triester (31 mg, NaOH (2 M, 24.3 μL, 0.0485 mmol) was added to a solution of MeOH (1 mL) and water (0.5 mL) and the mixture was stirred at room temperature for 3 days. The mixture was then filtered on a SCX-2 SPE column and the filtrate was concentrated to dryness by reverse phase. Purification by preparative HPLC gave the title compound (3.6 mg, 17%).

Preparation of Compound 181

N-methyl-2-(5-(3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran -2-yl)-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)acetamide

The intermediate J was prepared according to the procedure described for the compound 180 and 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)-N-methyl prepared as described below. The title compound was prepared from acetamide.

¹ H NMR (400 MHz, methanol-d4) δ 8.53 (single singular, 1H), 8.10 (m, 2H), 7.85 (m, 3H), 7.62 (m, 1H), 7.49 (m, 2H), 5.03 (d, J = 4.0 Hz, 1H), 4.46 (t, J = 3.6 Hz, 1H), 4.01 (s, 2H), 3.85 (m, 2H), 3.75 (t, J = 7.6 Hz, 1H), 3.58 (m, 8H), 3.43 (m, 2H), 3.35 (s, 3H). LC/MS: m/z = 544.36 (M+H ⁺ )

Step I: 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)acetic acid

To a solution of ethyl 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)acetate (411 mg, 1.148 mmol) in dioxane (4.1 mL) NaOH (1 M, 1.148 mmol) was added and the mixture was heated to 100 ° C for 30 minutes. Was added HCl (1 M, 1.72 mL) , the mixture was concentrated to dryness, washed with water (10 mL) The residue was diluted and extracted with EtOAc (3 × 15 mL), over Na ₂ SO ₄ dried and concentrated to dryness to give the title compound (370 Mg, 98%).

Step II: 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)-N-methylacetamide

Adding a solution to a solution of 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)acetic acid (114.8 mg, 0.3478 mmol) in DMF (1.1 mL) Amine (2M in THF, 191.3 μL, 0.3826 mmol), HATU (145.5 mg, 0.3826 mmol), DIPEA (72.7 The mixture was diluted with water (5 mL) andEtOAcEtOAc. Washed with water (3 × 5 mL), brine (5 mL) the combined organic layers were washed, dried over Na ₂ SO ₄ dried and concentrated to dryness. By silica gel chromatography (1 to 10% MeOH solution of CH ₂ Cl ₂₎ to afford the title compound (51 mg, 43%).

Preparation of Compound 182

N-(2-(2-methoxyethoxy)ethyl)-2-(5-(3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-) 6-(Hydroxymethyl)tetrahydro-2H-piperidin-2-yl)-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)B Guanamine.

Intermediate J was used according to the procedure described for compound 181 and 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)-N- from step 172 of compound 172. 2-(5-(4-Iodophenyl)-1,3,4-oxadiazol-2-yl)-N-(2-(2-methoxyethoxy) prepared by methyl acetamide The title compound was prepared from ethyl)acetamide.

Preparation of Compound 183

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine- 2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triol

Step I: Triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-(5-(methoxycarbonyl)pyridin-2-yl)phenyl ) tetrahydro-2H-pyran-3,4,5-triester

Feeding intermediate J To a microwave vial (189 mg, 0.354 mmol), 6- bromo-pyridine-3-carboxylate (76 mg, 0.354 mmol), Siliacat-DPP-Pd TM (0.26 mmol / g, 136 mg, 0.0354 mmol), Cs ₂ CO ₃ (254 mg, 0.7781 mmol) and acetonitrile (3.8 mL). The mixture was heated in a microwave at 100 ° C for 30 minutes, filtered on celite and concentrated to dryness. The residue was purified by EtOAc EtOAcjjjjjj

Step II: 6-(3-((2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydro-2H-pyran -2-yl)phenyl)nicotinic acid

To triacetic acid (2R,3R,4R,5R,6R)-2-(ethyloxymethyl)-6-(3-(5-(methoxycarbonyl)pyridin-2-yl)phenyl)tetra Add NaOH (2 M, 309.0 μL, 0.6180 mmol) to a solution of hydrogen-2H-pyran-3,4,5-triester (84 mg, 0.155 mmol) in MeOH (3 mL) The mixture was overnight. Then HCl (4 M) was added until a pH between 1 and 2 and the mixture was evaporated to dryness. The residue was redissolved in pyridine (3 mL) were added DMAP (1.9 mg, 0.015 mmol) , Ac 2 O (87.5 μL, 0.927 mmol), the mixture was stirred at rt overnight and concentrated to dryness. (1 M, 5 mL) and the residue was treated with HCl, (3 × 10 mL) and extracted with CH ₂ Cl _2, dried over Na ₂ SO ₄ and concentrated to dryness to give the title compound (75.5 mg, 92%).

Steps III and IV were carried out as previously described in Scheme 171, Steps I and II using acetamidine as a reagent.

This procedure was carried out using procedures similar to those previously described for the preparation of 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)-N-methylacetamide.

Step V: Compound 183

By triacetic acid (2R, 3R, 4R, 5R, 6R)-2-(ethyloxymethyl)-6-(3-(5-(5-methyl-1,3,4-oxadiazole- 2-Based)pyridin-2-yl)phenyl)tetrahydro-2H-pyran-3,4,5-triester The title compound was prepared according to the procedure for compound 171 Step IV.

¹ H NMR (400 MHz, methanol-d4) δ 9.22 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 8.4, 2.3 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J) = 8.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 5.04 (d, J = 4.1) Hz, 1H), 4.47 (t, J = 3.7 Hz, 1H), 3.86 (m, 2H), 3.76 (t, J = 7.5 Hz, 1H), 3.65 (dd, J = 7.7, 3.1 Hz, 1H), 3.55 (dt, J = 7.0, 3.5 Hz, 1H), 2.64 (s, 3H).

Preparation of Compound 184

1-(3'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)-[1 ,1'-biphenyl]-4-yl)ethanone

Intermediate J and 1-(4-iodophenyl)ethanone were used according to the procedure described for compound 180. The title compound was prepared.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 1.3 Hz, 0H), 7.71 (d, J = 8.4 Hz, 2H), 7.53 ( m,1H), 7.41 (m, 2H), 4.94 (d, J = 4.0 Hz, 1H), 4.37 (dd, J = 4.1, 3.0 Hz, 1H), 3.77 (m, 2H), 3.66 (t, J) = 7.6 Hz, 1H), 3.55 (dd, J = 7.7, 3.1 Hz, 1H), 3.47 (dt, J = 7.1, 3.5 Hz, 1H), 2.54 (s, 3H).

Preparation of Compound 185

4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy]benzonitrile

The title compound was prepared using a procedure similar to that described for compound 3, but using (4-cyanophenyl) Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.76-7.58 (m, 2H), 7.44 (t, 1H), 7.35 (d, 1H), 7.24 (s, 1H), 7.14-6.91 (m, 3H) ), 4.93 (d, 1H), 4.34 - 4.25 (m, 1H), 3.90 - 3.65 (m, 3H), 3.59 (dd, 1H), 3.54 - 3.39 (m, 1H). LC-MS: m/z = 358.3 (M+H ⁺ ).

Preparation of Compound 186

1-[4-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy] Phenyl]ketone

The title compound was prepared using a procedure similar to that described for compound 3, but using (4-ethyiphenyl) Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 8.04-7.90 (m, 2H), 7.43 (t, 1H), 7.33 (d, 1H), 7.23 (s, 1H), 7.09-6.92 (m, 3H) ), 4.92 (t, 1H), 4.40-4.24 (m, 1H), 3.94-3.65 (m, 3H), 3.59 (dd, 1H), 3.55-3.40 (m, 1H), 2.55 (s, 3H). LC-MS: m/z = 375.4 (M+H ⁺ ).

Preparation of Compound 187

4-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Oxy]-N-methyl-benzamide

Steps I, II: [Acet(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(3-hydroxy-4-methoxy-phenyl)tetrahydroperoxide Methyl-2-yl]methyl ester

To acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-benzene Add Ac ₂ O (194.7 μl, 2.065 mmol) to a solution of 4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (400 mg, 0.826 mmol) in pyridine (8 mL) And catalytic DMAP (10.08 mg, 0.0826 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to dryness, _diluted with CH ₂ Cl, with H ₂ O, washed with brine. Dried over Na ₂ SO ₄ organic phase was filtered and concentrated. TBAF (1.65 ml of a 1 M solution in THF, 1.65 mmol) and AcOH (47 μl, 0.826 mmol) were sequentially added to a solution of the residue in THF (8 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, ₂ Cl ₂ was diluted with CH, with H ₂ O, washed with brine. Dried over Na ₂ SO ₄ organic phase was filtered and concentrated.

LC-MS: m/z = 455.4 (M+H ⁺ ).

Step III: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[4-methoxy-3-[4-(methylaminemethanyl) Phenoxy]phenyl]tetrahydropyran-2-yl]methyl ester

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-(3-hydroxy-4-methoxy-phenyl)tetrayl from step 61 of compound 61 [4-(Methylamine-methyl)phenyl] was added sequentially to a solution of hydroperan-2-yl]methyl ester (80 mg, 0.176 mmol) in CH ₂ Cl ₂ (4.8 mL) Acid (63 mg, 0.352 mmol), powdered 4A molecular sieve (400 mg) and Cu(OAc) ₂ (44.75 mg, 0.247 mmol). After stirring for 10 minutes, 2,6-lutidine (101.9 μl, 0.88 mmol) was added to the mixture. The reaction mixture was stirred for 2 days at room temperature, _diluted with ₂ Cl CH, filtered over diatomaceous earth. After removal of the solvent under reduced pressure, using 10 g SNAP column of silica gel 24 CV MeOH / CH ₂ Cl ₂ gradient of (0-15%) separating the residue to give a colorless oil of the title compound (58 mg, 56 %).

Step IV: Compound 187

To a solution of the above-mentioned mixture (58 mg) in MeOH (1.6 ml) was added 2 drops of NaOMe (25% w/v in MeOH). After stirring at room temperature overnight, the reaction mixture was crystallised eluted eluted elut elut elut elut elut elut elut elut elut elut

¹ H NMR (CD ₃ OD, 400 MHz): δ 8.31 (s, 1H), 7.79-7.60 (m, 2H), 7.32 (dd, 1H), 7.22 (d, 1H), 7.13 (d, 1H), 6.97-6.75 (m, 2H), 4.89 (d, 1H), 4.31 (m, 1H), 3.86-3.66 (m, 6H), 3.61 (dd, 1H), 3.47 (td, 1H), 2.88 (d, 3H). LC-MS: m/z = 420.3 (M+H ⁺ ).

Preparation of Compound 188

3-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Oxy]-N-methyl-benzamide

The title compound was prepared as described for compound 187, but using [3-(methylaminemethanyl)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.48-7.37 (m, 1H), 7.38-7.22 (m, 3H), 7.23-7.14 (m, 1H), 7.12 (d, 1H), 6.99 (ddd , 1H), 4.91-4.87 (m, 1H), 4.38-4.26 (m, 1H), 3.87-3.67 (m, 6H), 3.65-3.56 (m, 1H), 3.46 (td, 1H), 2.86 (s) , 3H). LC-MS: m/z = 420.4 (M+H ⁺ ).

Preparation of Compound 189

4-[2-Methoxy-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Methyl oxy]benzoate

The title compound was prepared as described for compound 187 but using (4-methoxycarbonylphenyl). Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 8.02-7.80 (m, 2H), 7.34 (dd, 1H), 7.23 (d, 1H), 7.14 (d, 1H), 6.95-6.69 (m, 2H) ), 4.93 (m, 1H), 4.39-4.27 (m, 1H), 3.85 (s, 3H), 3.84-3.76 (m, 2H), 3.74 (s, 4H), 3.73-3.66 (m, 1H), 3.62 (dd, 1H), 3.48 (td, 1H). LC-MS: m/z = 421.4 (M+H ⁺ ).

Preparation of Compound 190

(2R,3S,4R,5S,6R)-2-(2-Fluoro-3-hydroxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 67 using (2-fluoro-3-hydroxyphenyl) Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.01-6.83 (m, 2H), 6.76 (td, 1H), 5.05 (d, 1H), 4.16 (dd, 1H), 3.86 (dd, 1H), 3.79-3.65 (m, 3H), 3.65-3.49 (m, 1H).

LC-MS: m/z = 297.2 (M+Na ⁺ )

Preparation of Compound 191

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[5-hydroxy-2-(trifluoromethoxy)phenyl]tetrahydropyran-3,4,5- Triol

The title compound was prepared as described for compound 67 using (5-hydroxy-2-(trifluoromethoxy)phenyl). Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.17-6.97 (m, 2H), 6.73 (dd, 1H), 5.09 (d, 1H), 4.11 (dd, 1H), 4.00 - 3.80 (m, 4H) ), 3.73 (dt, 1H). LC-MS: m/z = 342.3 (M+H ⁺ )

Preparation of Compound 192

(2R,3S,4R,5S,6R)-2-(2-Fluoro-5-hydroxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 67 using (3-hydroxy-6-fluorophenyl) Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 6.89 (dd, 1H), 6.79 (dd, 1H), 6.66-6.50 (m, 1H), 4.98 (d, 1H), 4.15 (dd, 1H), 3.86 (dd, 1H), 3.78-3.49 (m, 4H). LC-MS: m/z =275.2 (M+H ⁺ )

Preparation of Compound 193

(2R,3S,4R,5S,6R)-2-(4-Fluoro-3-hydroxy-phenyl)-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 67 using (3-hydroxy-4-fluorophenyl) Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.12-6.95 (m, 2H), 6.95-6.75 (m, 1H), 4.85 (d, 1H), 4.33 (t, 1H), 3.87-3.77 (m) , 2H), 3.71 (t, 1H), 3.57 (dd, 1H), 3.53-3.33 (m, 1H). LC-MS: m/z =275.2 (M+H ⁺ )

Preparation of Compound 194

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-hydroxy-5-methyl-phenyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 67 using (3-hydroxy-5-methylphenyl). Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 6.74 (s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 4.86-4.86 (m, 1H), 4.39 (t, 1H), 3.86-3.61 (m, 3H), 3.55 (dd, 1H), 3.45 (ddd, 1H), 2.25 (s, 3H). LC-MS: m/z = 271.2 (M+H ⁺ )

Preparation of Compound 195

N-methyl-4-[4-(trifluoromethoxy)-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetra Hydropyran-2-yl]phenoxy]benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 182, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy- 6-[5-[4-(Methylamine-methyl) phenoxy]-2-(trifluoromethoxy)phenyl]tetrahydropyran-2-yl]methyl ester as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.92-7.70 (m, 2H), 7.43 (dd, 1H), 7.32 (d, 1H), 7.13 - 6.93 (m, 3H), 5.15 (dd, 1H) ), 4.13 - 3.57 (m, 6H), 2.89 (s, 3H). LC-MS: m/z = 474.4 (M+H ⁺ ).

Preparation of Compound 196

4-[2-Fluoro-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but used From the intermediate of compound 183, acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-(2-fluoro-5-hydroxy-phenyl)-4,5-dihydroxy-tetra Hydroperper-2-yl]methyl ester is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.87-7.71 (m, 2H), 7.35 (t, 2H), 7.32-7.14 (m, 1H), 6.97 (d, 2H), 4.86-4.85 (m) , 1H), 4.21 (dd, 1H), 3.87 (dd, 1H), 3.81-3.66 (m, 2H), 3.63 (dd, 1H), 3.57-3.38 (m, 1H), 2.88 (s, 3H). LC-MS: m/z = 408.3 (M+H ⁺ ).

Preparation of Compound 197

4-[2-Fluoro-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 184, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-6-[2-fluoro- 3-[4-(Methylaminocarbamido)phenoxy]phenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester was used as the starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 8.01-7.52 (m, 2H), 7.35 (dd, 1H), 7.25-6.44 (m, 4H), 5.12 (d, 1H), 4.05 (ddd, 2H) ), 3.89-3.76 (m, 2H), 3.72 (dd, 2H), 2.88 (s, 3H). LC-MS: m/z = 408.3 (M+H ⁺ ).

Preparation of Compound 198

4-[2-Fluoro-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 181, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-6-(2-fluoro-) 3-Hydroxy-phenyl)-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.97-7.62 (m, 2H), 7.51 (t, 1H), 7.17 (dt, 2H), 6.97 (dd, 2H), 5.16 (d, 1H), 4.30-3.93 (m, 2H), 3.90-3.59 (m, 4H), 2.89 (d, 3H).

LC-MS: m/z = 408.4 (M+H ⁺ )

Preparation of Compound 199

N-methyl-4-[3-methyl-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2 -yl]phenoxy]benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 185, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy- 6-(3-Hydroxy-5-methyl-phenyl)tetrahydropyran-2-yl]methyl ester was used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.73-7.61 (m, 2H), 7.05 (s, 1H), 6.99-6.83 (m, 3H), 6.72 (s, 1H), 5.39 (s, 1H) ), 4.29-4.14 (m, 1H), 3.82-3.56 (m, 3H), 3.50 (dd, 1H), 3.39 (td, 1H), 2.81 (s, 3H), 2.26 (s, 3H). LC-MS: m/z = 404.3 (M+H ⁺ ).

Preparation of compound 200

3-[2-Fluoro-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 181, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-6-(2-fluoro-) 3-hydroxy-phenyl)-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester and [3-(methylamine-mercapto)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.49 (dt, 2H), 7.43 - 7.28 (m, 2H), 7.20 (t, 1H), 7.09 (dd, 2H), 5.16 (d, 1H), 4.14 (dd, 1H), 4.04 (dd, 1H), 3.92-3.60 (m, 4H), 2.86 (s, 3H). LC-MS: m/z = 408.3 (M+H ⁺ ).

Preparation of Compound 201

N-methyl-3-[4-(trifluoromethoxy)-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetra Hydropyran-2-yl]phenoxy]benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 182, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy- 6-[5-Hydroxy-2-(trifluoromethoxy)phenyl]tetrahydropyran-2-yl]methyl ester and [3-(methylamine-mercapto)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.59-7.40 (m, 1H), 7.42-7.27 (m, 3H), 7.22 (dd, 1H), 7.14-7.03 (m, 1H), 6.94 (dd , 1H), 5.07 (d, 1H), 3.98-3.84 (m, 2H), 3.84-3.59 (m, 4H), 2.81 (d, 3H). LC-MS: m/z = 474.3 (M+H ⁺ ).

Preparation of Compound 202

3-[4-Fluoro-3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 183, acetic acid [(2R,3S,4R,5S,6R)-3-ethyloxy-6-(2-fluoro-) 5-hydroxy-phenyl)-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester and [3-(methylamine-mercapto)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.46-7.38 (m, 1H), 7.38-7.27 (m, 2H), 7.23 (dd, 1H), 7.09-6.97 (m, 2H), 6.95-6.82 (m, 1H), 5.04 (d, 1H), 4.03 (dd, 1H), 3.93 (dd, 1H), 3.78-3.68 (m, 2H), 3.68-3.55 (m, 2H), 2.79 (s, 3H) ). LC-MS: m/z = 408.3 (M+H ⁺ ).

Preparation of compound 203

3-[2-Fluoro-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]-N-methyl-benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 184, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-6-(4-fluoro-) 3-hydroxy-phenyl)-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester and [3-(methylamine-mercapto)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.61-7.47 (m, 1H), 7.47-7.35 (m, 2H), 7.36-7.18 (m, 3H), 7.11 (dd, 1H), 4.86-4.85 (m, 1H), 4.22 (dd, 1H), 3.85 (dd, 1H), 3.78-3.69 (m, 2H), 3.62 (dd, 1H), 3.57-3.41 (m, 1H), 2.87 (s, 3H) ). LC-MS: m/z = 408.4 (M+H ⁺ ).

Preparation of compound 204

N-methyl-3-[3-methyl-5-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2 -yl]phenoxy]benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using the intermediate from compound 185, acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy- 6-(3-Hydroxy-5-methyl-phenyl)tetrahydropyran-2-yl]methyl ester and [3-(methylamine-mercapto)phenyl] Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.56-7.41 (m, 1H), 7.36 (dd, 2H), 7.14-6.99 (m, 2H), 6.90 (s, 1H), 6.71 (s, 1H) ), 5.43 (s, 1H), 4.27 (t, 1H), 3.87-3.60 (m, 3H), 3.53 (dd, 1H), 3.41 (td, 1H), 2.82 (s, 3H), 2.28 (s, 3H). LC-MS: m/z = 404.4 (M+H ⁺ ).

Preparation of Compound 205

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(4-phenoxyphenyl)tetrahydropyran-3,4,5-triol

The title compound was prepared using a procedure similar to that described for compound 3, but using acetic acid [(2R,3S,4R,5S,6R)-3-ethyloxy-4-,5-dihydroxyl from intermediate L step II. -6-(4-hydroxyphenyl)tetrahydropyran-2-yl]methyl ester and phenyl Acid is used as a suitable starting material.

¹ H NMR (CD ₃ OD, 400 MHz): δ 7.37 (d, 2H), 7.31 - 7.13 (m, 2H), 7.12 - 6.95 (m, 1H), 6.95 - 6.78 (m, 4H), 4.84 (t) , 1H), 4.30 (t, 1H), 3.78-3.68 (m, 2H), 3.65 (t, 1H), 3.52 (dd, 1H), 3.39 (ddd, 1H). LC-MS: m/z = 355.3 (M+Na ⁺ ).

Preparation of Compound 206

(2R,3S,4R,5S,6R)-2-[3-(2-fluoroethoxy)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Add Cs ₂ CO ₃ (143.6 mg, 0.44 mmol) to a mixture of intermediate A (30 mg, 0.088 mmol) and 1-fluoro-2-iodo-ethane (45.99 mg, 0.265 mmol) in DMF (600 μl) ). The reaction mixture was heated at 70 ° C for 20 hours and concentrated to dryness. The reaction mixture was diluted with MeOH and treated with Na.sub.2 Na.sub.2 (25% w/v MeOH). After 20 hours at room temperature, the reaction mixture was neutralized with Amberlite IR 120 (H). After filtration, washed with CH ₂ Cl ₂ / MeOH 9/1 with, the solvent was removed under reduced pressure and purified by reverse phase preparative HPLC to the residue, to give a white powder of the title compound (5.2 mg, 17%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.19 (t, 1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.78 (dd, 1H), 4.85 (d, 1H), 4.71-4.64 (m, 1H), 4.55 (dd, 1H), 4.33 (t, 1H), 4.21-4.12 (m, 1H), 4.12-4.03 (m, 1H), 3.78-3.67 (m, 2H), 3.62 (t , 1H), 3.47 (dd, 1H), 3.43-3.33 (m, 1H). LC-MS: m/z = 325.3 (M+Na ⁺ ).

Compounds 207 to 226 in Table 6 were prepared.

Compounds 198 to 217 were prepared from Intermediate A according to the procedure described for compound 197, but using a commercially available bromine or iodine alkylating agent. In some cases, NMP was used instead of DMF as a solvent.

Preparation of Compound 227

N-methyl-3-[[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Oxy]methyl]benzamide

Methylamine in THF (17 μl 2 M, 0.0338 mmol), 2,6-lutidine (6.5 μl, was added sequentially to a solution of compound 224 (11.2 mg, 0.0281 mmol) in NMP (220 μl). 0.0563 mmol) and HATU (13.90 mg, 0.0366 mmol). The reaction mixture was stirred at room temperature overnight and directly purified by reverse phase preparative HPLC to give N-methyl-3-[[3-[(2R,3S,4R,5S,6R)-3,4,5- Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy]methyl]benzamide (8.6 mg, 69%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (s, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.46 (t, 1H), 7.27 (t, 1H), 7.17 (s) , 1H), 7.03 (d, 1H), 6.92 (dd, 1H), 5.14 (s, 2H), 4.93 (d, 1H), 4.41 (t, 1H), 3.89-3.74 (m, 2H), 3.75- 3.58 (m, 1H), 3.54 (dd, 1H), 3.44 (dt, 1H), 2.90 (s, 3H). LC-MS: m/z = 404.4 (M+H ⁺ ).

Preparation of compounds 228 to 251 in Table 7

Compounds 219 to 242 were prepared according to the procedure described for compound 197, but using the reagents described in intermediate L, step II, and a commercially available bromine or iodine alkylating agent.

Preparation of Compound 219

Preparation of Compound 252

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(4-pyridyloxy)phenyl]tetrahydropyran-3,4,5-triol

Add 4-chloropyridine (hydrochloride) (21.15 mg, 0.141 mmol) and Cs ₂ CO ₃ (114.9 mg, 0.353) to a solution of intermediate A (40 mg, 0.118 mmol) in DMF (800 μl) Mm). The reaction mixture was stirred at 120 ° C for 48 h, filtered and concentrated. To a solution of the obtained residue in MeOH (EtOAc) (EtOAc) After 1 hour, the reaction mixture was neutralized with Amberlite IR 120 (H). After filtration, the title compound ( EtOAc, m.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 2H), 7.58-7.29 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H), 6.91 (s, 2H), 4.86 (d, 1H), 4.22 (dd, 1H), 3.77 (dd, 1H), 3.74-3.58 (m, 2H), 3.53 (dd, 1H), 3.44 (td, 1H). LC-MS: m/z = 334.3 (M+H ⁺ ).

Preparation of Compound 253

(2R,3S,4R,5S,6R)-2-[3-(1,3-Benzothiazol-2-yloxy)phenyl]-6-(hydroxymethyl)tetrahydropyran-3 4,5-triol

The title compound was prepared according to the procedure described for compound 243, but using Intermediate A and 2-chlorobenzo[d]thiazole.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.72 (d, 1H), 7.59 (d, 1H), 7.54-7.39 (m, 3H), 7.36 (td, 1H), 7.30-7.19 (m, 2H) , 4.93 (d, 1H), 4.32-4.26 (m, 1H), 3.81 (dd, 1H), 3.77-3.64 (m, 2H), 3.58 (dd, 1H), 3.50 (td, 1H). LC-MS: m/z = 390.3 (M+H ⁺ ).

Preparation of Compound 254

[[2R,3S,4R,5S,6R)-3-Ethyloxy-4,5-dihydroxy-6-[3-(4-quinolinyloxy)phenyl]tetrahydropyran-2 Methyl

The title compound was prepared according to the procedure described for compound 243, but using Intermediate A and 4-chloroquinoline.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.32 (d, 1H), 7.93 (d, 1H), 7.84-7.67 (m, 1H), 7.63-7.52 (m, 1H) , 7.38 (ddd, 3H), 7.11 (d, 1H), 6.59 (d, 1H), 4.89 (d, 1H), 4.27-4.19 (m, 1H), 3.77 (dd, 1H), 3.73-3.61 (m) , 2H), 3.56 (dd, 1H), 3.46 (td, 1H). LC-MS: m/z = 384.4 (M+H ⁺ ).

Preparation of Compound 255

N-methyl-2-[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy ]]-1,3-benzothiazole-6-formamide

The title compound was prepared according to the procedure described for compound 243, but using Intermediate A and 2-chloro-N-methyl-1,3-benzothiazole-6-carbamide. The latter was prepared as follows.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (d, 1H), 7.77 (dd, 1H), 7.61 (d, 1H), 7.51-7.38 (m, 3H), 7.24 (d, 1H), 4.90 (d, 1H), 4.31-4.14 (m, 1H), 3.87-3.60 (m, 3H), 3.54 (dd, 1H), 3.52-3.42 (m, 1H), 2.84 (s, 3H). LC-MS: m/z = 447.4 (M+H ⁺ ).

Preparation of 2-chloro-N-methyl-1,3-benzothiazole-6-carboxamide:

To a solution of 2-chloro-1,3-benzothiazol-6-carboxylic acid (300 mg, 1.40 mmol) in DMF (6 mL) EtOAc (EtOAc m. 2,6-lutidine (488 μl, 4.212 mmol) and HATU (640.7 mg, 1.685 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with H ₂ O, extracted with EtOAc. With saturated NaHCO ₃ solution, the organic phase was washed with brine, dried over Na ₂ SO _4, filtered and dried. The residue was purified with EtOAc EtOAc EtOAc (EtOAc (EtOAc) Amine (290 mg, 91%). LC-MS: m/z = 227.1 (M+H ⁺ ).

Preparation of compound 256

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(3-pyrimidin-2-yloxyphenyl)tetrahydropyran-3,4,5-triol

The title compound was prepared according to the procedure described for compound 243, but using Intermediate A and 2-chloropyrimidine.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (d, 2H), 7.50-7.18 (m, 3H), 7.11 (t, 1H), 7.01 (d, 1H), 4.88 (d, 1H), 4.34 - 4.19 (m, 1H), 3.81-3.57 (m, 3H), 3.52 (dd, 1H), 3.44 (td, 1H). LC-MS: m/z = 335.3 (M+H ⁺ ).

Preparation of Compound 257

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-[(6-nitro-3-pyridyl)oxy]phenyl]tetrahydropyran-3 4,5-triol

The title compound was prepared according to the procedure described for compound 243, but using Intermediate A and 5-bromo-2-nitro-pyridine as the appropriate reagent. The reaction was carried out at room temperature for 20 hours.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (dd, 2H), 7.50 (dd, 1H), 7.47-7.38 (m, 1H), 7.34 (d, 1H), 7.27 (s, 1H), 7.04 (d, 1H), 4.85 (d, 1H), 4.27-4.14 (m, 1H), 3.77 (dd, 1H), 3.72-3.58 (m, 2H), 3.53 (dd, 1H), 3.49-3.39 (m , 1H). LC-MS: m/z = 379.3 (M+H ⁺ ).

Preparation of Compound 258

(2R,3S,4R,5S,6R)-2-[3-[(6-Amino-3-pyridyl)oxy]phenyl]-6-(hydroxymethyl)tetrahydropyran-3 4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(6-nitro-3-pyridyl)oxy]benzene Tetrahydropyran-2-yl]methyl

Acetic anhydride (748.2 μl, 7.93 mmol) and DMAP (4.85 mg, 0.04 mmol) were added sequentially to a solution of compound 257 (300 mg, 0.793 mmol) in pyridine (3 ml). The reaction mixture was stirred at rt EtOAc EtOAc. With saturated NaHCO ₃ solution, H ₂ O, brine and the organic phase was washed carefully, then dried over Na ₂ SO _4, filtered and dried. The residue was purified with EtOAc EtOAc EtOAc EtOAc

LC-MS: m/z = 547.4 (M+H ⁺ ).

Step II: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(6-amino-3-pyridyl)oxy]benzene Tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(6-nitro-3-pyridyl)oxy]phenyl] To a solution of tetrahydropyran-2-yl]methyl ester (130 mg, 0.238 mmol) in MeOH (1. Under 1 atm H ₂ in the reaction mixture was hydrogenated overnight. The catalyst was filtered on celite and washed with MeOH. The filtrate was concentrated and the residue was purified using EtOAc EtOAc EtOAc The title compound was used as the main component of this mixture and was used in the next step without further purification.

LC-MS: m/z = 517.5 (M+H ⁺ ).

Step III: Compound 258

To a solution of the above residue (35 mg) in MeOH (650 <RTI ID=0.0> The reaction mixture was stirred at room temperature for 1 hour and neutralized with Amberlite IR 120 (H). After filtration, the solvent was evaporated,jjjjjjjjjj

¹ H NMR (400 MHz, CD ₃ OD) δ 7.60 (s, 1H), 7.32-7.13 (m, 2H), 7.07 (d, 1H), 6.99 (s, 1H), 6.75 (dd, 1H), 6.56 (d, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.24 (t, 1H), 3.78-3.57 (m, 3H), 3.47 (dd, 1H), 3.41-3.29 (m, 1H). LC-MS: m/z = 349.3 (M+H ⁺ ).

Preparation of compound 259

Compound 249, Step II

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-(2-methylimidazo[1,2-a]pyridine- 6-yl)oxyphenyl]tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3R,4R,5R,6R)-3,4,5-triethoxycarbonyl-6-[3-[(6-amino-3-pyridyl)oxy]phenyl] Chloroacetone (11.56 μl, 0.145 mmol) was added to a solution of tetrahydropyran-2-yl]methyl ester (Compound 249, Step II) (50 mg, EtOAc). The reaction mixture was stirred at 70 ° C overnight, then 1.5 EtOAc (1. The reaction mixture was concentrated to dryness crystall LC-MS: m/z = 555.5 (M+H ⁺ ).

Step II: Compound 259

To a solution of the above crude material (53 mg) in MeOH (1 mL), EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 2 hr, diluted with MeOH and neutralized with Amberlite IR 120 (H). After filtration, the title compound (3 mg, EtOAc)

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (s, 1H), 7.39 (s, 2H), 7.29 (t, 1H), 7.22-6.98 (m, 3H), 6.88 (dd, 1H), 4.82 (d, 1H), 4.28-4.08 (m, 1H), 3.83-3.56 (m, 3H), 3.49 (dd, 1H), 3.44-3.25 (m, 1H), 2.30 (s, 3H). LC-MS: m/z = 387.4 (M+H ⁺ ).

Preparation of compound 260

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(hydroxymethyl)phenyl]tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3S,6S)-3-ethenyloxy-6-[3-(hydroxymethyl)phenyl]-3,6-dihydro-2H-pyran-2-yl] Methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (500 mg, 1.837 mmol) and [3- (hydroxymethyl)phenyl] Pd(OAc) ₂ (61.87 mg, 0.276 mmol) was added to a solution of the acid (558.3 mg, 3.674 mmol) in acetonitrile (5 ml). The reaction mixture was stirred at room temperature for 5 hours. Add 1 equivalent of [3-(hydroxymethyl)phenyl] Acid and 0.075 equivalents of Pd(OAc) ₂ and the reaction mixture was stirred at room temperature overnight. And filtered through a pad of diatomaceous earth was diluted with CH ₂ Cl ₂ mixture. The filtrate was concentrated and purified with EtOAc EtOAcjjjjjjj LC-MS: m/z = 343.3 (M+Na ⁺ ).

Step II: Acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy-6-[3-(hydroxymethyl)phenyl]tetrahydropyran-2 Methyl

To acetic acid [(2R,3S,6S)-3-ethenyloxy-6-[3-(hydroxymethyl)phenyl]-3,6-dihydro-2H-pyran-2-yl]methyl ester (135 mg, 0.4214 mmol) methanesulfonamide (60.13 mg, 0.632 mmol), 2.5% OsO ₄ /t-BuOH (214.3 μl) in a mixture of water (540 μl) / t-BuOH (540 μl) 2.5 w/v%, 0.0210 mmol), NMO (98.73 mg, 0.843 mmol) and 2,6-lutidine (48.81 μl, 0.4214 mmol). The mixture was stirred at room temperature overnight, quenched with 15% EtOAc The aqueous phase was separated, washed with water and brine and dried over sodium sulfate. After removal of the solvent under reduced pressure, using MeOH solution of CH ₂ Cl ₂ (0-12%) in the residue was purified by silica gel 25 g SNAP column, to give a white solid of the title compound (48 mg, 32%). LC-MS: m/z = 377.3 (M+Na ⁺ ).

Step III: Compound 260

To a solution of the above residue (48 mg, 0.135 mmol) in MeOH (540 uL) The reaction mixture was stirred at room temperature for 2 hr, diluted with MeOH and neutralized with Amberlite IR 120 (H). After filtration, the title compound (21.5 mg, 18%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 (s, 1H), 7.35 (dt, 2H), 7.26 (d, 1H), 4.96 (d, 1H), 4.60 (s, 2H), 4.44 (t) , 1H), 3.86-3.77 (m, 2H), 3.73 (t, 1H), 3.57 (dd, 1H), 3.51-3.39 (m, 1H). LC-MS: m / z = 293.3 (M + Na +).

Preparation of compound 261

4-[[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]methoxy Methyl benzoate

Step I: 4-[[3-[(2R,3S,4R,5S,6R)-5-Ethyloxy-6-(ethyloxymethyl)-3,4-dihydroxy-tetrahydroper Methyl-2-methyl]phenyl]methoxy]benzoate

To a solution of methyl 4-hydroxybenzoate (34.35 mg, 0.226 mmol) in THF (1.6 ml), acetic acid [(2R,3S,4R,5S,6R)- 3-Ethyloxy-4,5-dihydroxy-6-[3-(hydroxymethyl)phenyl]tetrahydropyran-2-yl]methyl ester (80 mg, 0.226 mmol), PPh ₃ (62.19 Mg, 0.237 mmol) and DIAD (45.92 μl, 0.237 mmol). The reaction mixture was stirred at rt EtOAc EtOAc (EtOAc m. In the next step. LC-MS: m/z = 511.4 (M+Na ⁺ ).

Step II: Compound 261

To a solution of the above residue (70 mg, 0.14 mmol) in MeOH (EtOAc) (EtOAc) The reaction was stirred at room temperature overnight and neutralized with Amberlite IR 120 (H). After filtration, the title compound (20.2 mg, 21.5%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.91-7.70 (m, 2H), 7.50 (s, 1H), 7.42-7.15 (m, 3H), 7.06-6.83 (m, 2H), 5.09 (s, 2H), 4.87 (t, 1H), 4.33 (t, 1H), 3.83-3.73 (m, 3H), 3.72 (t, 2H), 3.69-3.58 (m, 1H), 3.49 (dd, 1H), 3.43 -3.32 (m, 1H). LC-MS: m / z = 427.4 (M + Na +).

Preparation of compound 262

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[3-(phenoxymethyl)phenyl]tetrahydropyran-3,4,5-triol

The title compound was prepared according to the procedure described for compound 261, but using phenol as reagent.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.48 (s, 1H), 7.31 (dq, 3H), 7.16 (dd, 2H), 6.96-6.68 (m, 3H), 5.00 (s, 2H), 4.89 (d, 1H), 4.35 (t, 1H), 3.78-3.60 (m, 3H), 3.49 (dd, 1H), 3.43-3.30 (m, 1H). LC-MS: m/z = 369.3 (M+Na ⁺ ).

Preparation of compound 263

(2R,3S,4R,5S,6R)-2-[3-[(3,5-Dichlorophenoxy)methyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3 4,5-triol

The title compound was prepared according to the procedure described for compound 261, but using 3,5-dichlorophenol as reagent.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.40 (dq, 3H), 6.99 (s, 3H), 5.10 (s, 2H), 4.95 (t, 1H), 4.41 (t) , 1H), 3.90-3.77 (m, 2H), 3.74 (dd, 1H), 3.57 (dd, 1H), 3.46 (td, 1H). LC-MS: m/z = 437.3 (M+Na ⁺ ).

Preparation of Compound 264

N-methyl-4-[[3-[(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzene Methoxy]benzamide

To a solution of the compound 261 in a mixture of 3/2/1 THF (75 μl) / MeOH (50 μl) / H ₂ O (25 μl) was added LiOH (2.7 mg, 0.113 mmol). The reaction mixture was stirred at room temperature overnight, then acidified with EtOAc EtOAc Methylamine (28.33 μL 2 M in MeOH, 0.0566 mmol), 2,6-lutidine (13.12 μl, 0.113 mmol) was added sequentially to the residue (14.7 mg) in DMF (306 μl). And HATU (17.23 mg, 0.0453 mmol). The reaction mixture was stirred with EtOAc EtOAc m.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.72-7.59 (m, 2H), 7.49 (s, 1H), 7.42-7.18 (m, 3H), 6.95 (d, 2H), 5.07 (s, 2H) , 4.87 (t, 1H), 4.33 (t, 1H), 3.79-3.59 (m, 3H), 3.57-3.43 (m, 1H), 3.41-3.30 (m, 1H), 2.76 (d, 3H). LC-MS: m/z = 404.3 (M+H ⁺ ).

Preparation of Compound 265

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(3-hydroxyphenyl Tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3S,6S)-3-ethoxycarbonyl-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-3,6-dihydro -2H-piperidin-2-yl]methyl ester

To acetic acid [(2R,3S,4R)-3,4-diethoxycarbonyl-3,4-dihydro-2H-pyran-2-yl]methyl ester (1100 mg, 4.040 mmol) in 10 mL of acetonitrile [3-(Third butyl-dimethyl-decyl)oxyphenyl] is added to the solution Acid (2.038 g, 8.080 mmol) and Pd(OAc) ₂ (136.1 mg, 0.6060 mmol). The mixture was stirred at room temperature for 5 hours, and then another batch of Pd(OAc) ₂ (136.1 mg, 0.606 mmol) and [3-(t-butyl-dimethyl-decyl)oxyphenyl] was added thereto. Acid (2.038 g, 8.080 mmol). It was then stirred overnight at room temperature. The mixture was diluted with 20 mL of DCM and filtered through a pad of Celite. The filtrate was concentrated and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc (EtOAc Ethyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-3,6-dihydro-2H-pyran-2-yl]methyl ester (805 mg , 47.38%), which solidifies after standing.

¹ H NMR (CDCl ₃ , 400 MHz): 7.06 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 6.60 (m, 1H), 5.97 (m, 1H), 5.71 (m, 1H), 5.09 (m, 2H), 4.08 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 1.88 and 1.87 (2s, 6H), 0.78 (m, 9H), 0.00 (m) , 6H).

Step II: Acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-4, 5-dihydroxy-tetrahydropyran-2-yl]methyl ester

To acetic acid [(2R,3S,6S)-3-acetoxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-3,6-dihydro-2H Methyl sulfonamide (848.1 mg, 8.916 mmol), 2.5% was added to a solution of p-pyran-2-yl)methyl ester (2.5 g, 5.944 mmol) in water (10 mL) / t -BuOH (10 mL) OsO _{4 /} t-BuOH (1.865 mL, 0.1486 mmol), NMO (1.393 g, 11.89 mmol) and 2,6-dimethylpyridine (636.9 mg, 688.5 μL, 5.944 mmol). The mixture was stirred overnight at room temperature. It was then quenched with 15% EtOAc (EtOAc) (EtOAc) The aqueous layer was separated, and the organic layer was washed with water (20 mL) After the solvent was removed under reduced pressure, the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc ( EtOAc 5S,6R)-3-Ethyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-4,5-dihydroxy-tetrahydropyran-2- Methyl ester (2.2 g, 81.42%).

1H NMR (CD ₃ OD, 400 MHz): 7.06 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 6.58 (m, 1H), 4.85 (m, 1H), 4.64 (m, 1H), 4.46 (m, 1H), 3.96 (m, 1H), 3.85 (m, 1H), 3.62 (m, 2H), 1.86 and 1.83 (2s, 6H), 0.78 (m, 9H), 0.00 (m) , 6H).

Step III: Acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxyphenyl]-5- Hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy -tetrahydropyran-2-yl]methyl ester

To the stirred acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethoxycarbonyl-6-(2,2,2-trichloroacetamimidinyl)oxy -tetrahydropyran-2-yl]methyl ester (300 mg, 0.5176 mmol) and acetic acid [(2R,3S,4R,5S,6R)-3-acetoxy-6-[3-[Third a solution of dimethyl (dimethyl)nonanyloxyphenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (258.8 mg, 0.5694 mmol) in DCM (10 mL) 4A MS (1.0 g) was added and stirred at room temperature for 30 min. After cooling to -40 ° C, freshly opened trimethylmethane trifluoromethanesulfonate (9.4 μL, 0.052 mmol) was added dropwise. The mixture was stirred at -40 ° C and slowly warmed to -10 ° C over 2 hours. Et ₃ N (72.2 μL, 0.5180 mmol) was then added. After removing the cooling bath, the mixture was allowed to warm to room temperature, filtered to remove molecular sieves and concentrated to dryness. The residue was purified using MeOH/DCM (0 to 5%, 20 CV) on a Biotage SNAP 50 g silica gel to give [[2R,3R,4R,5R,6R)-3-ethyloxy-6- [3-[T-butyl(dimethyl)decyl]oxyphenyl]-5-hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethylhydrazine An inseparable mixture of oxy-6-(ethoxycarbonylmethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (375 mg), which was purified without further purification That is, it is used directly in the next step.

LC-MS: m/z = 807.5 (M+Na ⁺ ).

Step IV: Acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R, 6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester

To the stirred containing acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-6-[3-[third (Dimethyl)nonanyl]oxyphenyl]-5-hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(B Addition of acetic acid to a solution of a mixture of decyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (375 mg, 0.4778 mmol) in THF (4 mL) (40.8 μL, 0.7174 mmol) and 1 M TBAF/THF (1.433 mL, 1.433 mmol). The mixture was stirred at room temperature for 30 minutes. It was then diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified using MeOH/DCM (0-6%, 20 CV) on a Biotage SNAP 25 g silica gel to afford &lt;[&quot;&quot;&quot;&quot; Hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetra An inseparable mixture of dihydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (230 mg). It was used directly in the next step without further purification.

LC-MS: m/z = 693.3 (M+Na ⁺ ).

Step V: Compound 265

To the stirred containing acetic acid [(2R,3R,4R,5R,6R)-3-ethoxycarbonyl-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S, 5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester A solution of (66 mg, 0.09842 mmol) in MeOH (3 mL)EtOAc. It was then neutralized with Amberlite IR 120 (H) and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified using reverse phase preparative HPLC to give (2,,,,,,,,,,,,,,,,,,,,,,, 2-(Hydroxymethyl)-6-(3-hydroxyphenyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol ( 27 mg).

¹ H NMR (CD ₃ OD, 400 MHz): 7.09 (m, 1H), 6.83 (m, 2H), 6.57 (m, 1H), 5.08 (d, 1H), 5.04 (d, 1H), 4.42 (m) , 1H), 3.90 (m, 1H), 3.58-3.77 (m, 5H), 3.47-3.54 (m, 3H), 3.40 (m, 2H).

LC-MS: m/z = 418.4 (M+H ⁺ ).

Preparation of Compound 266

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-hydroxyphenyl Tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Steps I and II were carried out using a procedure similar to compound 265.

Step III: To a stirred acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethoxycarbonyl-6-(2,2,2-trichloroacetamimine fluorenyl) )oxy-tetrahydropiperidin-2-yl]methyl ester (486.9 mg, 0.8400 mmol) and acetic acid [(2R,3S,4R,5S,6R)-3-ethenyloxy-6-[4-[ Tert-butyl(dimethyl)decyloxy]oxyphenyl]-4,5-dihydroxy-tetrahydropyran-2-yl]methyl ester (381.9 mg, 0.8400 mmol) in DCM (15 mL) 4A MS (1.0 g) was added to the solution and stirred at room temperature for 30 min. After cooling to -40 ° C, trimethylmethane trifluoromethanesulfonate (7.6 μL, 0.04206 mmol) was added dropwise, the mixture was stirred at -40 ° C under nitrogen and slowly warmed to -10 ° C over 1 hour. Et ₃ N (117.1 μL, 0.8400 mmol) was then added and allowed to warm to room temperature. After filtration to remove the molecular sieves, the solvent was evaporated under reduced pressure and the residue was purified using MeOH/DCM (0 to 5%, 20 CV) on a Biotage SNAP 50 g silica gel column to give several fractions with the desired mass. An insoluble mixture (700 mg) was used in the next step without further purification.

LC-MS: m/z = 807.5 (M+Na ⁺ ).

Step IV: Acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(4-hydroxyphenyl)-4-[(2R,3S,4S,5R, 6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester

Acetic acid (47.8 μL, 0.8405 mmol) and 1 M TBAF/THF (1.680 mL, 1.680 mmol) were added to a mixture of the above-mentioned mixture (700 mg) in 10 mL THF. The mixture was stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, EtOAc m. The residue was purified with EtOAc EtOAc EtOAc elut elut elut elut elut elut elut elut .

LC-MS: m/z = 693.3 (M+Na ⁺ ).

Step V: Compound 266

To the solution of the mixture (50 mg) mentioned above in methanol (3 mL) was added a drop of 25% sodium methoxide/methanol. After stirring at room temperature for 20 minutes, it was neutralized with Amberlite IR 120 (H). After filtration, the solvent was evaporated.

1H NMR (400 MHz, CD ₃ OD): δ 7.19 (d, 2H), 6.68 (d, 2H), 5.04 (m, 2H), 4.41 (s, 1H), 3.89 (m, 1H), 3.77-3.57 (m, 6H), 3.56-3.44 (m, 2H), 3.38 (m, 2H). LC-MS: m/z = 441.3 (M+Na ⁺ ).

Preparation of Compound 267:

4-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]-N-methyl-benzamide

To acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R,6R) -3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (236 mg, 0.3519 mmol) (4-N-Methylaminocarbonylphenyl) in a solution of 5 mL DCM Acid (126.6 mg, 0.7034 mmol), molecular sieve 4Å (500 mg) and Cu(OAc) ₂ (89.49 mg, 0.4927 mmol). After stirring for 10 minutes, 2,6-lutidine (203.9 μL, 1.760 mmol) was added to the mixture. Stir at room temperature for 2 days. After removing the solvent under reduced pressure, the residue was purified using MeOH/DCM gradient (0-6%, 20 CV) on a Biotage SNAP 25 g silica gel column to give a mixture containing the desired product (about 240 mg). It was used in the next step after further purification. To the solution of the mixture (240 mg) mentioned above in methanol (3 mL) was added a drop of 25% MeONa/MeOH. After stirring at room temperature for 20 minutes, it was neutralized with Amberlite IR 120 (H). After filtration, the solvent was evaporated.

¹ H NMR (CD ₃ OD, 400 MHz): 7.80 (m, 2H), 7.41 (m, 1H), 7.31 (m, 1H), 7.20 (s, 1H), 7.02 (m, 2H), 6.96 (m) , 1H), 5.18 (d, 1H), 5.09 (d, 1H), 4.42 (m, 1H), 3.95 (m, 1H), 3.64-3.77 (m, 6H), 3.54 (m, 3H), 3.32 ( m, 1H), 2.89 (s, 3H).

LC-MS: m/z = 552.3 (M+H ⁺ );

Preparation of Compound 268:

3-[4-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]-N-methyl-benzamide

The title compound was prepared as described for compound 267, but using (3-N-methylaminocarbonylphenyl) Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.39 (m, 5H), 7.08 (m, 1H), 6.92 (d, 2H), 5.06 (d, 1H), 5.02 (s, 1H), 4.37 ( m, 1H), 3.90-3.84 (m, 1H), 3.83-3.65 (m, 4H), 3.65-3.41 (m, 6H), 2.79 (s, 3H). LC-MS: m / z = 552.3 (M + H +).

Preparation of Compound 269:

3-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]-N-methyl-benzamide.

The title compound was prepared as described for compound 267, but using (3-N-methylaminocarbonylphenyl) Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.45 (d, 1H), 7.33 (m, 3H), 7.18 (m, 1H), 7.08 (m, 2H), 6.83 (d, 1H), 5.25- 4.91 (m, 2H), 4.38 (s, 1H), 3.87 (m, 1H), 3.70 (m, 2H), 3.66-3.53 (m, 4H), 3.54-3.35 (m, 3H), 3.32-3.24 ( m, 1H), 3.03 (d, 3H).

LC-MS: m / z = 552.3 (M + H +).

Preparation of Compound 270:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-[3-(4-fluorophenoxy)phenyl]-3,5-dihydroxy -6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

4.3 mg white powder, 16.7% yield.

The title compound was prepared as described for compound 267, but using 4-fluorophenyl Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.25 (m, 1H), 7.13 (d, 1H), 7.05-6.87 (m, 5H), 6.76 (m, 1H), 5.03 (m, 2H), 4.36 (m, 1H), 3.86 (m, 1H), 3.7-3.4 (m, 9H), 3.21. (m, 1H). LC-MS: m/z = 513.2 (M+H ⁺ ).

Preparation of Compound 271:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(3-phenoxy Phenyl) tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

4.2 mg white powder, 15.5% yield.

The title compound was prepared as described for compound 267, but using phenyl Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.26 (m, 2H), 7.14 (d, 1H), 7.02 (m, 2H), 6.90 (m, 2H), 6.78 (m, 2H), 5.10 ( d, 1H), 5.01 (d, 1H), 4.60-4.16 (m, 1H), 3.87 (dd, 1H), 3.76-3.44 (m, 4H), 3.44-3.35 (m, 2H), 3.49-3.29 ( m, 4H). LC-MS: m / z = 495.2 (M + H +).

Preparation of Compound 272:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-[3-[4- (5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]phenyl]tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran -3,4,5-triol

The title compound was prepared as described for compound 267, but using (4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl) Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.97-7.84 (m, 2H), 7.35 (m, 1H), 7.25 (d, 1H), 7.17 (s, 1H), 7.11-7.00 (m, 2H) ), 6.92 (d, 1H), 5.06 (m, 2H), 4.43 (m, 1H), 3.87 (m, 1H), 3.7-3.22 (m, 10H), 2.51 (s, 3H). LC-MS: m/z = 577.3 (M+H ⁺ ).

Preparation of Compound 273:

N-[4-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R) -3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]phenyl]-2-methyl -propanamide

The title compound was prepared as described for compound 267, but using (4-isobutylaminophenyl) Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 9.63 (s, 1H), 7.44 (m, 2H), 7.24 (m, 1H), 7.12 (d, 1H), 7.03 (s, 1H), 6.94 6.82 (m, 2H), 6.77 (d, 1H), 5.04 (m, 2H), 4.37 (m, 1H), 3.87 (m, 1H), 3.79-3.55 (m, 6H), 3.57-3.44 (m, 2H), 3.40 (dd, 1H), 3.35-3.25 (m, 1H), 2.52 (dt, 1H), 1.10 (d, 6H). LC-MS: m/z = 580.3 (M+H ⁺ ).

Preparation of Compound 274:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-[3-(3,5-Dimethylphenoxy)phenyl]-3, 5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 267, but using 3,5-dimethylphenyl Acid is used as a reagent.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.31 (m, 1H), 7.18 (d, 1H), 7.11 (s, 1H), 6.82 (d, 1H), 6.75 (s, 1H), 6.59 ( s, 2H), 5.19 (d, 1H), 5.10 (d, 1H), 4.48 (m, 1H), 3.96 (m, 1H), 3.80-3.63 (m, 6H), 3.58 (m, 2H), 3.45 (m, 2H), 2.25 (s, 6H). LC-MS: m/z = 523.3 (M+H ⁺ ).

Preparation of Compound 275:

4-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenyl]-N-methyl-benzamide

Step I: Triacetic acid (2R,3S,4S,5R,6R)-2-(((2R,3R,4R,5R,6R)-3-ethoxycarbonyl-2-(ethenyloxymethyl)) -5-hydroxy-6-(3-(((trifluoromethyl))sulfonyl)oxy)phenyl)tetrahydro-2H-piperidin-4-yl)oxy)-6-(ethoxime) Methyl)tetrahydro-2H-pyran-3,4,5-triester

To acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-[(2R,3S,4S,5R,6R) -3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (compound 256, Step IV) (858 mg, 1.279 mmol) of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (594.1) in 10 mL of DCM Mg, 1.663 mmol) and TEA (445.7 μL, 3.198 mmol). The mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, the residue was separated on a Biotage SNAP 100 g silica gel column using ethyl acetate/hexane gradient (0-50%, 20 CV) to give a solvent containing two of the desired masses. An inseparable mixture (800 mg) was used in the next step without further purification.

LC-MS: m/z = 825 (M+Na ⁺ ).

Step II

To triacetic acid (2R,3S,4S,5R,6R)-2-(((2R,3R,4R,5R,6R)-3-ethoxycarbonyl-2-(ethenyloxymethyl)-5 -hydroxy-6-(3-(((trifluoromethyl))sulfonyl)oxy)phenyl)tetrahydro-2H-piperidin-4-yl)oxy)-6-(acetoxymethyl) [4-(Methylamine-methyl)phenyl] was added to a solution of tetrahydro-2H-pyran-3,4,5-triester (60 mg, 0.075 mmol) in 3 mL of dioxane. Acid (20.06 mg, 0.1121 mmol), PdCl ₂ (dppf) ₂ -DCM (6.10 mg, 0.00748 mmol) and sodium carbonate (112.1 μL 2 M, 0.2242 mmol). The mixture was stirred overnight at 90 ° C under nitrogen. After removal of the solvent under reduced pressure, the residue was purified using EtOAc/EtOAc (EtOAc) ), which was used directly in the next step without further purification.

LC-MS: m/z = 788.4 (M+Na ⁺ ).

Step III: Compound 275

To the above mentioned mixture (30 mg) (from step II) was added a solution of 25% sodium methoxide/methanol in methanol (3 mL). After stirring at room temperature for 20 minutes, it was neutralized with Amberlite IR 120 (H). After filtration, the solvent was removed under reduced pressure and purified to purified crystals crystals crystalssssssssssssssssssssss Hydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl] Oxy-tetrahydropiperan-2-yl]phenyl]-N-methyl-benzamide (4.9 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (m, 3H), 7.75 (m, 2H), 7.58 (d, 1H), 7.46 (m, 2H), 5.28 (d, 1H), 5.14 (d) , 1H), 4.59 (d, 1H), 3.97 (m, 1H), 3.87 (m, 2H), 3.68 (m, 3H), 3.60 (m, 3H), 3.40 (m, 2H), 2.92 (s, 3H). LC-MS: m/z = 536.3 (M+H ⁺ ).

Preparation of Compound 276:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-[3-(4- Methylsulfonylphenyl)phenyl]tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 275, but using (4-(methylsulfonyl)phenyl) The acid is used as the reagent in step II.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.93 (d, 2H), 7.84 (d, 2H), 7.79 (s, 1H), 7.54 (d, 1H), 7.50-7.35 (m, 2H), 5.19 (d, 1H), 5.05 (d, 1H), 4.52 (s, 1H), 4.49 (d, 1H), 3.88 (m, 1H), 3.76 (d, 2H), 3.65 (d, 2H), 3.51 (m, 5H), 3.06 (s, 3H). LC-MS: m/z = 557.3 (M+H ⁺ ).

Preparation of Compound 277:

5-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenyl]-N1,N3-dimethyl-benzene-1 3-dimethylguanamine

The title compound was prepared as described for compound 275, but using (3,5-bis(methylaminemethanyl)phenyl) The acid is used as the reagent in step II.

¹ H NMR (400 MHz, CD ₃ OD): δ 8.23 (m, 3H), 7.78 (s, 1H), 7.64 (d, 1H), 7.57-7.42 (m, 2H), 5.24 (d, 1H), 5.14 (s, 1H), 4.61 (s, 1H), 4.56 (d, 1H), 3.96 (m, 1H), 3.86 (m, 2H), 3.76 (m, 2H), 3.69-3.59 (m, 3H) , 3.54 (m, 2H), 2.95 (s, 6H). LC-MS: m/z = 593.3 (M+H ⁺ ).

Preparation of Compound 278:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-(3-cyclohexylphenyl)-3,5-dihydroxy-6-(hydroxyl) Tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I

To acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-5-hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethylhydrazine Oxy-6-(ethoxymethyl)tetrahydropyran-2-yl]oxy-6-[3-(trifluoromethylsulfonyloxy)phenyl]tetrahydropyran-2- Add 1-cyclohexenyl to a solution of methyl ester (80 mg, 0.09967 mmol) in 3 mL of dioxane Acid (18.83 mg, 0.1495 mmol), PdCl ₂ (dppf) ₂ -DCM (8.14 mg, 0.009967 mmol) and sodium carbonate (149.5 μL 2 M, 0.2990 mmol). The mixture was stirred overnight at 90 ° C under nitrogen. After removal of the solvent under reduced pressure, the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc Further purification was used directly in the next step.

Step II

A catalytic amount of 10% Pd/C was added to the methanol solution of the mixture (62 mg) mentioned above. The flask was attached to a hydrogen balloon for hydrogenation. The mixture was stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssss Used in the next step.

Step III: Compound 278

A catalytic amount of 25% sodium methoxide/methanol was added to a solution of the above-mentioned mixture (41 mg) in methanol (3 mL). After stirring for 30 minutes, it was neutralized with a resin Amberlite IR120 (H). After filtration, the solvent was removed under reduced pressure and the residue was purified using EtOAc EtOAc (EtOAc) ,6R)-2-(3-cyclohexylphenyl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydrogen Piperan-3,4,5-triol (2 mg).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.26 (s, 1H), 7.16 (m, 2H), 7.02 (d, 1H), 5.12 (d, 1H), 5.05 (d, 1H), 4.47 ( m, 1H), 3.90 (m, 1H), 3.79-3.54 (m, 6H), 3.53-3.45 (m, 2H), 3.39 (m, 2H), 2.42 (m, 1H), 1.70 (m, 5H) , 1.41-1.14 (m, 5H). LC-MS: m/z = 485.4 (M+H ⁺ ).

Preparation of Compound 279:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(3-pyrimidine-5 -ylphenyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

The title compound was prepared as described for compound 275, but using pyrimidin-5-yl The acid is used as the reagent in step II.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.03 (m, 3H), 7.79 (s, 1H), 7.59-7.40 (m, 3H), 5.17 (d, 1H), 5.03 (d, 1H), 4.46 (d, 1H), 3.87 (m, 1H), 3.81-3.73 (m, 2H), 3.70-3.62 (m, 2H), 3.57-3.33 (m, 6H). LC-MS: m/z = 481.3 (M+H ⁺ ).

Preparation of Compound 280:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-[3-(3- Methylbenzimidazol-5-yl)phenyl]tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (trifluoroacetate) Ion (1))

The title compound was prepared as described for compound 275, but using (1-methyl-1H-benzo[d]imidazole-6-yl) The acid is used as the reagent in step II.

1H NMR (400 MHz, CD ₃ OD) δ 9.01 (s, 1H), 8.02 (s, 1H), 7.79 (m, 3H), 7.58 (d, 1H), 7.46-7.36 (m, 2H), 5.19 ( d, 1H), 5.05 (d, 1H), 4.49 (d, 1H), 4.05 (s, 3H), 3.89 (m, 1H), 3.81-3.76 (m, 2H), 3.71-3.63 (m, 3H) , 3.60-3.50 (m, 3H), 3.45 (m, 2H). LC-MS: m/z = 533.3 (M+H ⁺ ).

Preparation of Compound 281:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-allyl-3,5-dihydroxy-6-(hydroxymethyl)tetrahydroper Butan-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,5-diethoxycarbonyl-6-allyl-4-[(2R,3S,4S,5R,6R)-3, 4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester

Stirred acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethoxycarbonyl-6-[(2R,3S,4S,5R,6R)-2) at 0 °C ,3,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-4-yl]oxy-tetrahydropyran-2-yl]methyl ester (500 mg, 0.7368 mmol And TMS triflate (159.8 μL, 0.8842 mmol) was added to a solution of allyl-trimethyl-decane (351.2 μL, 2.210 mmol) in 10 mL of dry acetonitrile. The mixture was stirred at room temperature overnight and quenched with EtOAc (EtOAc) After removal of the solvent <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>

LC-MS: m/z = 683.3 (M+Na ⁺ ).

Step II: Compound 281

To a stirred solution of the compound (31 mg) (from step I) in methanol (3 mL) was added a drop of 25% sodium methoxide. The mixture was stirred overnight at room temperature. Then use Amberlite IR120 (H) was neutralized and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified using EtOAc EtOAcqqqqq

1H NMR (CD ₃ OD, 400 MHz): 5.79 (m, 1H), 4.96-5.07 (m, 3H), 3.85 (m, 2H), 3.56-3.80 (m, 8H), 3.45 (m, 3H), 2.42 (m, 2H). LC-MS: m/z = 367.2 (M+H ⁺ ).

Preparation of Compound 282:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-[(E)-3-Cyclohexylallyl]-3,5-dihydroxy- 6-(Hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3,5-diethoxycarbonyl-6-[(E)-3-cyclohexylallyl]-4-[(2R,3S) ,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl Methyl ester

To the stirred acetic acid [(2R,3R,4R,5R,6R)-3,5-diethoxycarbonyl-6-allyl-4-[(2R,3S,4S,5R,6R)-3 ,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (Compound 281, Step I (40 mg, 0.06055 mmol) in a solution of DCM (2 mL), EtOAc (EtOAc: EtOAc (EtOAc) The mixture was stirred overnight at 40 ° C under nitrogen. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc

1H NMR (CDCl ₃ , 400 MHz): 5.47 (m, 1H), 5.15-5.31 (m, 5H), 4.96-5.02 (m, 2H), 4.26 (m, 2H), 3.98-4.07 (m, 5H) , 3.78 (m, 1H), 2.38 (m, 1H), 1.90-2.27 (m, 21H), 1.88 (m, 1H), 1.65 (m, 6H), 1.02-1.22 (m, 5H).

Step II: Compound 282

A solution of the compound (30 mg) from MeOH (3 mL) was added EtOAc EtOAc. Neutralized with resin Amberlite IR-120 (H). After filtration, the residue was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H NMR (CD ₃ OD, 400 MHz): 5.43 (m, 1H), 5.33 (m, 1H), 5.02 (s, 1H), 3.85 (m, 2H), 3.48-3.77 (m, 10H), 3.37 ( m, 1H), 2.32 (m, 1H), 2.22 (m, 1H), 1.84 (m, 1H), 1.60 (m, 5H), 0.96-1.18 (m, 5H). LC-MS: m/z = 449.3 (M+H ⁺ ).

Preparation of Compound 283:

4-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, Methyl 4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]propyl]benzoate

Step I: 4-[(E)-3-[(2R,3R,4R,5R,6R)-3,5-Diethoxycarbonyl-6-(ethyloxymethyl)-4-[( 2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran- Methyl 2-yl]prop-1-enyl]benzoate

To the stirred acetic acid [(2R,3R,4R,5R,6R)-3,5-diethyloxy-6-allyl-4- [(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydroper Methyl 4-vinylbenzoate (49.11 mg, 0.3028 mmol) and gem were added to a solution of m--2-yl)methyl ester (Compound 281, Step I) (50 mg, 0.07 569 mmol) in DCM (5 mL) Catalyst II (6.2 mg, 0.0075 mmol). The mixture was stirred overnight at 40 ° C under nitrogen. The residue was purified with EtOAc EtOAc m.

LC-MS: m/z = 817.3 (M+Na ⁺ ).

Step II: 4-[3-[(2R,3R,4R,5R,6R)-3,5-Diethoxycarbonyl-6-(ethyloxymethyl)-4-[(2R,3S, 4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl] Propyl]methyl benzoate

A catalytic amount of 10% Pd/C was added to a solution of the product (50 mg) from MeOH (3 mL). The mixture was then hydrogenated using a hydrogen balloon. After stirring at room temperature for 30 minutes, the mixture was filtered and the solvent was removed under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc.

LC-MS: m/z = 819.4 (M+Na ⁺ ).

Step III: Compound 283

4-[3-[(2R,3R,4R,5R,6R)-3,5-Diethoxycarbonyl-6-(ethyloxymethyl)-4-[(2R,3S) ,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl Add a drop of 25% sodium methoxide/methanol to a solution of methyl benzoate (45 mg, 0.07530 mmol) in 2 mL MeOH. The mixture was stirred at room temperature for 20 minutes. It was then neutralized with Amberlite IR120 (H). After filtration, the solvent was evaporated,jjjjjjjjjj

¹ H NMR (400 MHz, CD ₃ OD): δ 7.91 (d, 2H), 7.32 (d, 2H), 5.10 - 5.03 (m, 1H), 3.97 - 3.89 (m, 2H), 3.86 (s, 3H) ), 3.78 (m, 7H), 3.65 (m, 6.2 Hz, 2H), 3.55 (m, 1H), 3.37 (m, 1H), 2.73 (m, 2H), 1.91-1.60 (m, 3H), 1.57 -1.41 (m, 1H). LC-MS: m/z = 503.3 (M+H ⁺ ).

Preparation of Compound 284:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(3-methoxy Phenyl) tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-methoxyphenyl)-4-[(2R,3S,4S, 5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester

To acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-hydroxyphenyl)-4-I[(2R,3S,4S,5R,6R) -3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (compound 256 Cs ₂ CO ₃ (42.2 mg, 0.13 mmol) and MeI (8.1 μL, 0.130 mmol) were added sequentially to a solution of step IV) (58 mg, 0.086 mmol) in DMF (1.16 mL). Stirring the reaction mixture at 50 deg.] C overnight, then diluted with EtOAC, washed successively with H ₂ O and brine. Dried over Na ₂ SO ₄ organic phase was filtered and concentrated. CH MeOH in using the Biotage SNAP 10 g silica gel column ₂ Cl ₂ solution (0 to 8%, 20 CV) The residue was purified to give the desired compound in the form of a mixture of compounds of the same mass, which was used without any further purification by In the next step.

LC-MS: m/z = 685.3 (M+H ⁺ ).

Step II: Compound 284

To acetic acid [(2R,3R,4R,5R,6R)-3-acetoxy-5-hydroxy-6-(3-methoxyphenyl)-4-[(2R,3S,4S,5R, 6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]methyl ester (47 To a solution of MeOH (940 μL) was added anhydrous K ₂ CO ₃ (9.4 mg, 0.068 mmol). The reaction mixture was stirred at room temperature for 1 hour, then neutralized with a resin Amberlite IR-120 (H), filtered and dried. The residue was purified by preparative HPLC to afford (2,,,,,,,,,,,,,,,,,,,,,,,,,, 6-(3-methoxyphenyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (29.6 mg, 54 %Yield).

1H NMR (400 MHz, CD ₃ OD): δ 7.25 (t, 1H), 7.12-6.96 (m, 2H), 6.81 (m, 1H), 5.19 (d, 1H), 5.12 (d, 1H), 4.52 (t, 1H), 3.97 (m, 1H), 3.85-3.79 (m, 1H), 3.78 (s, 3H), 3.75-3.36 (m, 9H). LC-MS: m/z = 433.2 (M+H ⁺ ).

Preparation of Compounds 285 to 288:

The title compound was prepared as described for compound 284, using the appropriate commercially available alkylation reagent.

Compound 285:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-[3-(cyclopentylmethoxy)phenyl]-3,5-dihydroxy -6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)-tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD): δ 7.15 (t, 1H), 6.99 (s, 1H), 6.91 (d, 1H), 6.71 (d, 1H), 5.10 (d, 1H), 5.04 ( d, 1H), 4.48-4.40 (m, 1H), 3.89 (m, 1H), 3.83-3.29 (m, 12H), 2.35-2.12 (m, 2H), 1.75 (d, 2H), 1.66-1.42 ( m, 3H), 1.30 (m, 2H). LC-MS: m/z = 501.4 (M+H ⁺ )

Compound 286:

2-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, Methyl 4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]acetate

¹ H NMR (400 MHz, CD ₃ OD): δ 7.27 (m, 1H), 7.07 (d, 2H), 6.91-6.69 (m, 1H), 5.15 (m, 2H), 4.71 (s, 2H), 4.51 (t, 1H), 3.96 (m, 1H), 3.90-3.79 (m, 1H), 3.8 (s, 3H), 3.74-3.35 (m, 9H). LC-MS: m/z = 491.3 (M+H ⁺ )

Compound 287:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-2-[3-(2-fluoroethoxy)phenyl]-3,5-dihydroxy -6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD): δ 7.19 (m, 1H), 7.06-6.92 (m, 2H), 6.76 (m, 1H), 5.11 (d, 1H), 5.03 (m, 1H), 4.72-4.63(m,1H),4.62-4.51(m,1H),4.48-4.36(m,1H),4.21-4.13(m,1H),4.13-4.07(m,1H),3.89(m,1H) ), 3.80-3.29 (m, 10H). LC-MS: m/z = 465.3 (M+H ⁺ )

Compound 288:

2-[3-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2R,3S,4S,5S,6R)-3, 4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl]phenoxy]-N-methyl-acetamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.06 (s, 1H), 7.21 (t, 1H), 7.10-6.96 (m, 2H), 6.80 (m, 1H), 5.05 (m, 2H), 4.45 - 4.29 (m, 3H), 3.88 (m, 1H), 3.74 (m, 2H), 3.69-3.53 (m, 5H), 3.53-3.32 (m, 3H), 2.72 (d, 3H). LC-MS: m/z = 490.3 (M+H ⁺ )

Preparation of Compound 289:

(2R,3S,4S,5S,6R)-2-[(2R,3R,4R,5R,6R)-3,5-dihydroxy-2-(3-hydroxy-4-methoxy-phenyl) -6-(hydroxymethyl)tetrahydropyran-4-yl]oxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3-ethoxycarbonyl-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy -phenyl]-5-hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran -2-yl]oxy-tetrahydropyran-2-yl]methyl

To the stirred acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethoxycarbonyl-6-(2,2,2-trichloroacetamimidinyl)oxy -tetrahydropyran-2-yl]methyl ester (Intermediate M, Step II) (500.2 mg, 0.8629 mmol) and acetic acid [(2R,3R,4S,5S,6R)-3,4,5-triethyl醯-ethoxy-6-(2,2,2-trichloroacetamimidino)oxy-tetrahydropyran-2-yl]methyl ester (500.2 mg, 0.8629 mmol) in DCM (18.04 mL) 4A molecular sieve powder (1 g) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. After cooling to -40 ° C, trimethyl decyl trifluoromethanesulfonate (15.6 μL, 0.08629 mmol) was added dropwise to the mixture. Stir at -40 ° C and slowly ramp to -5 ° C over 1 hour. Subsequently, NEt ₃ (120.3 μL, 0.8629 mmol) was added and the mixture was allowed to warm to room temperature, filtered to remove molecular sieves and concentrated to dryness. The residue was purified with EtOAc EtOAc EtOAc.

LC-MS: m/z = 815.5 (M+H ⁺ ).

Step II: Acetic acid [(2R,3R,4R,5R,6R)-3-ethoxycarbonyl-5-hydroxy-6-(3-hydroxy-4-methoxy-phenyl)-4-[(2R ,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethenyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2 Methyl

To acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-6-[3-[t-butyl(dimethyl)decyl]oxy-4-methoxy-benzene 5-hydroxy-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2 Add 1 M TBAF/THF (1.841 mL 1 M, 1.841 mmol) to a solution of methoxy-tetrahydropyran-2-yl]methyl ester (0.75 g, 0.9204 mmol) in THF (22.50 mL) AcOH (52.3 μL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue was dissolved in DCM, washed successively with H ₂ O and brine, dried over Na ₂ SO _4, filtered and dried. 25 g silica gel column using a MeOH solution of CH ₂ Cl ₂ (0-10%, 25 CV) the residue was purified by Biotage SNAP, to give the title compound as a mixture of inseparable.

LC-MS: m/z = 701.4 (M+H ⁺ ).

Step V: Compound 289

To acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-5-hydroxy-6-(3-hydroxy-4-methoxy-phenyl)-4-[(2R,3S) ,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl ] methyl ester (36 mg, 0.05138 mmol) in MeOH was added anhydrous _{K 2 CO 3 (7.1 mg,} 0.051 mmol) (720.0 μL) of the solution. The reaction mixture was stirred at room temperature for 1 hour, then neutralized with a resin Amberlite 120 (H), filtered and dried. The residue was purified by EtOAcqqqqqq

¹ H NMR (400 MHz, CD ₃ OD): δ 6.99-6.79 (m, 3H), 5.10 (d, 2H), 4.46 (s, 1H), 3.96 (m, 1H), 3.87-3.73 (m, 5H) ), 3.75-3.62 (m, 4H), 3.59 (m, 2H), 3.53-3.44 (m, 1H), 3.43-3.34 (m, 1H). LC-MS: m/z = 449.3 (M+H ⁺ ).

Preparation of Compound 290:

Step I: Acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-5-hydroxy-6-[4-methoxy-3-[4-(2-methylpropenyl) Amino)phenoxy]phenyl]-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydrogen Piperidin-2-yl]oxy-tetrahydropyran-2-yl]methyl

To acetic acid [(2R,3R,4R,5R,6R)-3-ethenyloxy-5-hydroxy-6-(3-hydroxy-4-methoxy-phenyl)-4-[(2R,3S) ,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran-2-yl]oxy-tetrahydropyran-2-yl Methyl ester (Compound 289, Step II) (70 mg, 0.10 mmol) and [4-(2-methylpropenylamino)phenyl] 4A molecular sieve powder (400 mg) and Cu(OAc) ₂ (25.41 mg, 0.1399 mmol) were added to a solution of the acid (41.37 mg, 0.20 mmol) in DCM (5 mL). After stirring for 10 minutes, 2,6-lutidine (53.53 mg, 57.9 μL, 0.50 mmol) was added to the mixture and stirred at room temperature for 20 hours. The reaction mixture was filtered to remove the molecular sieves and concentrated to dryness. The residue was purified using MeOH / DCM (EtOAc (EtOAc)

Step II: Compound 290

To acetic acid [(2R,3R,4R,5R,6R)-3-ethoxycarbonyl-5-hydroxy-6-[4-methoxy-3-[4-(2-methylpropenylamino) Phenoxy]phenyl]-4-[(2R,3S,4S,5R,6R)-3,4,5-triethoxycarbonyl-6-(ethyloxymethyl)tetrahydropyran 2-yl] oxy - tetrahydropyran-2-yl] methyl ester (63.5 mg, 0.07368 mmol) in MeOH was added anhydrous _{K 2 CO 3 (10.18 mg,} 0.07368 mmol) (1.270 mL) in the solution. The mixture was stirred at room temperature for 1 hour, neutralized with a resin Amberlite 120 (H), filtered and dried. The residue was purified by EtOAc EtOAcjjjjjj

1H NMR (400 MHz, CD ₃ OD) δ 9.64 (s, 1H), 7.43 (m, 2H), 7.24 (d, 1H), 7.10 (m, 2H), 6.88-6.71 (m, 2H), 5.09 ( m, 2H), 4.42 (s, 1H), 3.94 (m, 1H), 3.83-3.32 (m, 13H), 2.58 (m, 1H), 1.17 (d, 6H). LC-MS: m/z = 610.4 (M+H ⁺ ).

Preparation of Compound 291:

5-(3-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)phenoxy) Interphthalic acid

5-[3-[(2R,3S,4R,5S,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenoxy]benzene- Dimethyl 1,3-dicarboxylate (Compound 51) (26.9 mg, 0.05159 mmol) was dissolved in THF (463 μL) and H ₂ O (463 μL). LiOH (10.8 mg, 0.2580 mmol) was added and the mixture was stirred overnight. The mixture was acidified with EtOAc (EtOAc) (EtOAc)

LC-MS: m/z = 421.25 (M+H ⁺ ).

Preparation of Compound 292:

N-methyl-3-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) Phenoxy)benzamide

The title compound was prepared using a procedure similar to that described for compound 3, but using acetic acid ((2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy-6-(4-hydroxyl) Phenyl)tetrahydro-2H-piperidin-2-yl)methyl ester (Intermediate L, Step II) and (3-(methylamine-methyl)phenyl) Acid is used as a suitable starting material.

¹ H NMR (400 MHz, DMSO-D ₆ ) δ 8.45 (m, 1H), 7.56 (m, 1H), 7.43 (m, 4H), 7.13 (m, 1H), 6.99 (m, 2H), 4.66 ( d, J = 5.6 Hz, 1H), 4.00 (dd, J = 5.6, 3.0 Hz, 1H), 3.69-3.50 (m, 3H), 3.50-3.35 (m, 2H), 2.73 (m, 3H). LC-MS: m/z = 390.25 (M+H ⁺ ).

Preparation of Compound 293:

2-(3-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-piperidin-2-yl)benzene Methyl oxy)phenyl)acetate

The title compound was prepared using a procedure similar to that described for compound 3, but using acetic acid ((2R,3S,4R,5S,6R)-3-acetoxy-4,5-dihydroxy-6-(4-hydroxyl) Phenyl)tetrahydro-2H-piperidin-2-yl)methyl ester (Intermediate L, Step II) and (3-(2-methoxy-2-oxoethyl)phenyl) Acid is used as a suitable starting material.

¹ H NMR (400 MHz, DMSO-D ₆ ) δ 7.38 (m, 2H), 7.31 (m, 1H), 6.95 (m, 4H), 6.86 (m, 1H), 4.64 (d, J = 5.4 Hz, 1H), 3.99 (m, 1H), 3.66 (s, 2H), 3.64-3.51 (m, 6H), 3.47-3.37 (m, 2H). LC-MS: m/z =405.21. (M+H ⁺ ).

Preparation of Compound 294:

4'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-[1,1' -biphenyl]-3-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for compound 158 using EtOAc (EtOAc).

¹ H NMR (400 MHz, DMSO-D ₆ ) δ 8.13 (t, J = 1.6 Hz, 1H), 7.90 (m, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 4.69 (m, 1H), 4.03 (m, 1H), 3.83 (s, 3H), 3.58 (m, 2H), 3.56-3.47 ( m, 2H), 3.43 - 3.34 (m, 1H). LC-MS: m/z = 375.3 (M+H ⁺ ).

Preparation of Compound 295:

N-methyl-4'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- [1,1'-biphenyl]-3-carboxamide

The title compound was prepared using the intermediate O and 3-bromo-N-methylbenzamide as the appropriate starting material.

¹ H NMR (400 MHz, DMSO-D ₆ ) δ 8.53 (d, J = 4.4 Hz, 1H), 8.08 (s, 1H), 7.77 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H) , 7.49 (m, 3H), 4.74 (m, 3H), 4.62 (m, 2H), 4.08 (s, 1H), 3.55 (m, 3H), 3.40 (m, 2H), 2.77 (d, J = 4.5) Hz, 3H). LC-MS: m/z = 374.32 (M+H ⁺ ).

Preparation of Compound 296:

N-methyl-4'-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- [1,1'-biphenyl]-4-carboxamide

The title compound was prepared using the intermediate O and 4-bromo-N-methylbenzamide as the appropriate starting material.

¹ H NMR (400 MHz, DMSO-D ₆ ) δ 8.42 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 9.8 Hz, 2H), 4.77 (d, J = 4.8 Hz, 1H), 4.70 (m, 2H), 4.62 (d, J = 5.9 Hz) , 1H), 4.55 (t, J = 5.8 Hz, 1H), 4.04 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 3.50 (m, 1H), 3.38 (m, 2H), 2.73 (d, J = 4.4 Hz, 3H). LC-MS: m/z = 374.32 (M+H ⁺ ).

Thermal analysis of compound 48

The thermogravimetric analysis of Compound 48 was performed to determine the % weight loss over time using TA Instrument TGA Q5000 (asset number V014258). The sample was added to an aluminum pan pre-weighed to tare and heated from ambient temperature to 350 ° C at 10 ° C / min. The weight loss was about 2.3%, with an increasing and significant weight loss observed at >100 °C. TGA knot It is shown in Figure 2.

Compound 48 (free base) XRPD

The XRPD was recorded in a reflective mode at room temperature using a Bruker D8 Discover system (asset tag number V012842) equipped with a sealed tube light source and a Hi-Star zone detector (Bruker AXS, Madison, WI). Operate the X-ray generator at a voltage of 40 kV and a current of 35 mA. The powder sample was placed on a Si zero background wafer. The two frames were recorded with an exposure time of 120 seconds each. The data was then integrated in a range of 0.02° in the range of 3°-41°2q and combined into one continuous pattern. Figure 1A shows an X-ray powder diffraction pattern of a sample.

Representative XRPD peaks for compound 48:

Competitive combination analysis

The 177 amino acids of the FimH protein are expressed as fusion proteins together with the thrombin of the pET21b plastid in the bacteria. This FimH protein sequence contains a carbohydrate recognition domain (CRD) and should be referred to as FimH-CRD. After the protein is expressed in bacteria, the FimH-CRD protein is purified to homogeneity and the thrombin label is removed by protease cleavage. Use 5 nM Alexa 647 nectar The glycosidic probe and 60 nM FimH-CRD performed a competitive binding assay by fluorescence polarization. Samples were analyzed in a small volume 384-well microtiter plate with a final volume of 20 μl. The final assay buffer conditions were as follows, 50 mM Tris-Cl (ph 7.0), 100 mM NaCl, 1 mM EDTA, 5 mM β-mercaptoethanol, 0.05% BSA, and 2.5% DMSO. Perform two analyses on FimH called Analysis 1 or Analysis 2. The analysis conditions were the same for both analyses except that the compounds of Analysis 1 were prepared by manual dilution in serial dilutions (12-point dose response), while the compounds of Analysis 2 were also serially diluted by the robotic system (12). Point dose reaction) was prepared and first prepared in duplicate in a 384 well Corning polypropylene round pan. The compound of the analysis plate 2 was subsequently frozen and must be thawed prior to use. The Alexa 647 probe and FimH-CRD were first added to the assay buffer followed by 0.5 μl of test compound (analysis 1 or 2) at a final concentration of 0.4 nM to 75 μM (12-point titration, 3-fold serial dilution). Control wells of the Alexa 647 probe were prepared under the same conditions, but the FimH-CRD protein was added. The plates were then incubated for 5 hours at room temperature in the dark and under humid conditions (to prevent drying). Plates were read using a SpectraMax Paradigm multi-mode plate reader and an appropriate fluorescent polarization detection column (Alexa-647).

The Alexa 647 mannoside probe was prepared using a procedure similar to that reported for FAM mannoside (Han, Z. et al., 2010, J. Med. Chem., 53, 4779) and is described in the following scheme.

Stirring (2S,3S,4S,5S,6R)-2-(4-aminobutoxy)-6-(hydroxymethyl)tetrahydropyran-3,4,5- at room temperature Triol (2.21 mg, 0.009 mmol) and (2E)-2-[(2E,4E)-5-[3,3-dimethyl-5-sulfonate-1-(3-sulfonatepropyl)吲哚-1-鎓-2-yl]penta-2,4-dienyl]-3-[6-(2,5-di-oxypyrrolidin-1-yl)oxy-6- Phenoxy-hexyl]-3-methyl-1-(3-sulfonylpropyl)porphyrin-5-sulfonate (potassium (3)) (4.9 mg, 0.0044 mmol) in DMF (44) Et ₃ N (5.4 mg, 7.0 μL, 0.053 mmol) was added to the blue solution in μL). The solution was stirred at room temperature overnight, concentrated, dissolved in water and purified on EtOAc EtOAc EtOAc EtOAc Alexa 647 mannoside probe (3.3 mg, 34%).

Since a dose response of formula K _d values for compounds of the measured curves of each compound in duplicate using twelve concentrations. The curve of the data points was fitted using a fluorescence polarization competitive displacement analysis and the Kd of the resulting curve was interpolated using GraphPad Prism software version 50.4 (GraphPad software Inc., San Diego, CA, USA).

Mouse model of inflammatory bowel disease (IBD): The CEACAM6 mouse model can be humanized using a transgenic gene. (Carvalho FA et al, (2009) J Exp Med. September 28; 206 (10): 2179-89). CEACAM6 mice infected with these transgenic genes as described. Infected mice can then be treated with the compounds of the invention.

Although a plurality of embodiments of the invention have been described, it is obvious that the basic examples of the invention can be changed. Other examples of methods, processes and processes for using the compounds of the invention are obtained. Therefore, it is to be understood that the scope of the invention is defined by the appended claims

Claims (79)

a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein X is -OR ₇ ; Y is absent or is a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be -NR ₈ , -O-, -S-, -C(O)-, -S(O)- or -SO ₂ - substitution; Y optionally substituted by halogen, OH, C _3-6 cycloalkyl or C _1-6 aliphatic 2 times; R ₁ is a C _6-10 aryl group optionally substituted with one or more R _3A groups; and R ₂ is H, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl, (C _6-10 aryl)-(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl; each R ₂ independently and optionally one or more R _3B groups a group substituted and optionally substituted with one R ₃ group; each R _3A and R _{3B is} independently halogen, -CN, NO ₂ , C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic group, (C _{6 a -10} aryl)-(C ₁ -C ₆ alkyl)- or C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be subjected to -NR ₄ , -O-, -S-, -C(O)-, -S(O)-, -SO ₂ - or -P(O)-substitution; each R _3A and R _3B independently and optionally Substituted by a plurality of R ₄ or R _4A groups; R ₃ is C ₃ -C ₆ cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl, (C _6-10 aryl)-(C ₁ -C ₆ alkyl) - 5-10 membered heteroaryl, or ; Each R ₃ is optionally substituted with one or more R ₄ or R _4A substituted; R ₄ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl or 5-10 membered heteroaryl; each R _{4 is} optionally substituted with one or more R _{4 B} groups; R _4A is halogen , CN, NO ₂ or a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may be optionally subjected to -NR ₄ , -O-, -S-, -C (O)-, -S(O)-, -SO ₂ - or -P(O)-substituted; each R _{4A is} optionally substituted with 1-3 halo; R _4B is halogen, CN, NO ₂ or C _{a 1} -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may be optionally subjected to -NR, -O-, -S-, -C(O)-, -S( O)-, -SO ₂ - or -P(O)-substituted; each R _{4B is} optionally substituted with 1-3 halo; R ₇ is H or has 1-2 molybdenum selected from oxygen, nitrogen or sulfur a 5-6 membered heterocyclic group of an atom; wherein the 5-6 membered heterocyclic group is independently and optionally substituted by C _1-4 alkyl, 1-4 times, wherein at most one of the C _1-4 alkyl groups The base unit is optionally substituted by -O-; R ₈ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3- 8 members a cyclic group, a C _6-10 aryl group or a 5-10 membered heteroaryl group; or -C(O)R ₉ ; R ₉ and R _{10 are} each independently a C ₁ -C ₆ alkyl group or a C ₃ -C ₆ ring Alkyl; R is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; The compound is not one of the following: The compound of claim 1, wherein Y is absent or is -NR ₈ , -O-, -S-, -C(O)-, -C(R ₁₀ )(OH)-, -C(O)N( R ₈ )(CH ₂ ) _m -, -N(R ₈ )C(O)O-, -OC(O)NR ₈ -, -NR ₈ SO ₂ -, -NR ₈ -C(O)-, - SO ₂ -, -NR ₈ C(O)NR ₈ -, -S(O)-, -SO ₂ NR ₈ , -(C ₁ -C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl -, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O-(C _1-6 alkyl)NR ₈ C(O)-, -O-(C _1-6 alkyl)C(O)NR ₈ , -O-(C _1-6 alkyl)-C(O)- or -((C ₁ -C ₆ )alkyl)-O -; each R _3A and R _{3B are} independently -OH, -CN, halogen, -C(R ₁₀ ) ₃ , -C(R ₁₀ ) ₂ OH, -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O (R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ or -P(O)(R ₄ ) ₂ ; and R _4A is -OH , -CN, halogen, -C(R ₁₀ ) ₃ , -C(R ₁₀ ) ₂ OH, -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)OR ₄ , -C(O)N(R ₄ ) ₂ , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -N HC(O)OR ₄ , -NHSO ₂ R ₄ , -NH-C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , -P(O)(OR ₄ ) ₂ , -P(O)(R ₄ ) ₂ ; and R ₇ is H or a mannose group. The compound of claim 1 or claim 2, wherein X is -OH; Y is absent or is -NR ₈ , -O-, -S-, -C(O)-, -C(R ₁₀ )(OH) -, -SO ₂ -, -S(O)-, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkenyl, -(C ₁ -C ₆ )alkynyl, -(O -(C ₁ -C ₆ alkyl)) _n -, -O(C _1-6 alkyl)NR ₈ C(O)-, -O-(C _1-6 alkyl)-C(O)NR ₈ , -O-(C _1-6 alkyl)C(O)- or -((C ₁ -C ₆ )alkyl)-O-; R ₂ is C _6-10 aryl, (C _6-10 aryl a group of -(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl; each R ₂ independently and optionally via a C _6-10 aryl group, (C _6-10 aryl)-(C ₁ -C ₆ alkyl)- or 5-10 membered heteroaryl substituted; R ₈ is -H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl. The compound of any one of claims 1 to 3, wherein R ₁ is optionally substituted phenyl. The compound of any one of claims 1 to 3, wherein R ₁ is an optionally substituted naphthyl group. The compound of any one of claims 1 to 5, wherein X is -OR ₇ and R ₇ is H or A compound of claim 6 wherein R _{7 is} as defined by the formula IA, IB, IC or ID: Wherein R ₁ , Y and R _{2 are} as defined in any one of claims 1 to 7. The compound of claim 6, wherein R ₇ is H. The compound of any one of claims 1 to 8, wherein X is -OH, -F, -OCH ₃ or -CH ₃ . The compound of any one of claims 1 to 9, wherein: X is -OR ₇ and R ₇ is H or ; R ₁ is phenyl or naphthyl; Y is absent or is -O-, -C(O)N(R ₈ )(CH ₂ ) _m -, -OC(O)NR ₈ -, -(C ₁ - C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl-, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O (C _1-6 alkyl)NR ₈ C(O)-, -O(C _1-6 alkyl)C(O)NR ₈ , -O(C _1-6 alkyl)C(O)- or- ((C ₁ -C ₆ )alkyl)-O-; R ₂ is C _6-10 aryl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur Or an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur; a 3-8 membered monocyclic heterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur a cyclic group; or a C _3-6 cycloalkyl group; R ₃ is a phenyl group or a 5-6 membered monocyclic heteroaryl group having from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. The compound of any one of claims 1 to 9, wherein: X is -OR ₇ and R ₇ is H or ; R ₁ is phenyl or naphthyl; Y is absent or is -O-, -C(O)N(R ₈ )(CH ₂ ) _m -, -OC(O)NR ₈ -, -(C ₁ - C ₆ )alkyl-, -(C ₁ -C ₆ )alkenyl-, -(C ₁ -C ₆ )alkynyl-,-(O-(C ₁ -C ₆ alkyl)) _n -, -O (C _1-6 alkyl)NR ₈ C(O)-, -O(C _1-6 alkyl)C(O)NR ₈ , -O(C _1-6 alkyl)C(O)- or- ((C ₁ -C ₆ )alkyl)-O-; R ₂ is phenyl, naphthyl, imidazolyl, pyrazolyl, triazolyl, thienyl, thiadiazolyl, thiazolyl, oxadiazolyl , pyridyl, pyrimidinyl, benzodioxolyl, fluorenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, quinolinyl, oxa Cyclobutane, tetrahydropentanyl and C _3-6 cycloalkyl; and R ₃ is phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl , thiadiazolyl, pyridyl. The compound of any one of claims 1 to 9, wherein: X is -OH; Y is absent or is -O-, -S-, -OC(O)NR ₈ - or -C(O)N(R ₄ ) (CH ₂ ) _m -; R ₁ is an aryl group optionally substituted with one or more R _3A groups; and R ₂ is -H or alkyl, cycloalkyl, heterocyclic, aryl, aryl An alkyl or heteroaryl group; each optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ ; wherein each R _3A and R _{3B is} independently -OH, -CN, halogen, -C ( R ₁₀ ) ₃ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)R ₄ , -C (O)N(R ₄ ) ₂ , -N(R ₄ )C(O)(R ₄ ) ₂ , -OC(O)NHR ₄ , -NHC(O)OR ₄ , -NHSO ₂ R ₄ , -NH -C(O)R ₄ , -SO ₂ -R ₄ , -NHC(O)NHR ₄ , -S(O)R ₄ , -SO ₂ NHR ₄ , -SR ₄ , C ₁ -C ₆ alkyl, aryl Or an aryl group or a heteroaryl group; each independently and optionally substituted with one or more R ₄ groups; wherein each R _{4 is} independently -H or C ₁ -C ₆ alkyl; wherein m is 0, 1 or 2; and wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 12, wherein X is -OH; Y is absent; R ₁ is optionally one or more halogens, -OR ₄ or -(CH ₂ ) _n C(O)OR _a substituted phenyl group; R ₂ is a heteroaryl group optionally substituted with one or more R 3 _B groups; R _3B is C ₁ -C ₆ alkyl or C(R ₁₀ ) ₃ ; and R ₄ is H or C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 12, wherein X is -OH; Y is absent; and R ₁ is optionally one or more halogens, -OR ₄ or -(CH ₂ ) _n C(O)OR _a substituted phenyl group; R ₂ is an aryl group optionally substituted with one or more R 3 _B groups; R _3B is -OH, halogen, -CN, -OR ₄ , -(CH ₂ ) _n C(O) OR ₄ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)NHR ₄ , -NH-C(O)R ₄ , -SO ₂ R ₄ or - C(O)OR ₄ ; and R ₄ is H or C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 14, wherein X is -OH. The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)N(R ₄ )(CH ₂ ) _m -. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NH-. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R ₁ is optionally substituted phenyl. The compound of any one of claims 1 to 18, wherein R ₂ is a heteroaryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ , as the compound or a pharmaceutically acceptable salt thereof. ring. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group The ring is selected from the group consisting of pyrazole, thiadiazole, quinoline, indole, thiazole, pyridine, and benzothiazole. The compound of claim 19 or 20, wherein R _3A and R _{3B are} each independently halogen, C ₁ -C ₆ alkyl or benzyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R ₂ is an aryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ . The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R ₂ is phenyl or naphthalene, optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ . The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R ₂ is C ₁ - optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ C ₆ alkyl, cycloalkyl or aralkyl. The compound of any one of claims 1 to 12, 15 and 18 to 24, or a pharmaceutically acceptable salt thereof, wherein Y is -OC(O)NR ₈ -. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein Y is -OC(O)NH-. The compound of claim 25 or 26, wherein R ₁ is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof, wherein R ₂ is an aryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ , Aralkyl or heteroaryl. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R ₂ is phenyl, benzyl or thiophene, optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ base. The compound of claim 28 or 29, wherein R _3B is halogen, C ₁ -C ₆ alkyl or -N(R ₄ ) ₂ , or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 12, 15 and 18 to 24, or a pharmaceutically acceptable salt thereof, wherein Y is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl or C ₁ - C ₆ alkynyl. The compound of any one of claims 1 to 12, 15 and 18 to 24, or a pharmaceutically acceptable salt thereof, wherein Y is absent. The compound of claim 31 or claim 32, wherein R ₁ is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. The compound of claim 33, wherein R ₁ is phenyl substituted with one or more R _3A , wherein R _3A is halogen, C ₁ -C ₆ alkyl, C ₁ -C, or a pharmaceutically acceptable salt thereof _{a 6} alkenyl group, a C ₁ -C ₆ alkynyl group or a C ₁ -C ₁₀ aliphatic group, wherein up to four methylene units of the C ₁ -C ₁₀ aliphatic group may optionally be -NR ₄ , -O- or -C(O)-displacement. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R ₁ is phenyl substituted with one or more halogens, -OR ₄ or -(CH ₂ ) _n C(O)OR ₄ . The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R ₁ is phenyl substituted by one or more halogen, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl . The compound of claim 34 or 35, wherein R ₄ is -H or C ₁ -C ₆ alkyl, or a pharmaceutically acceptable salt thereof. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R ₁ is phenyl substituted with one or more R _3A , wherein R _3A is fluoro, bromo, chloro, CH ₃ , CH ₂ CH ₃ , -C≡CH, OH, OCH ₃ , OCF ₃ , -OCH ₂ C(CH ₃ ) ₃ , -O(CH ₂ ) ₄ CF ₃ , -OCH ₂ C(O)NHCH ₃ , -OCH ₂ C(O) OCH ₃ , -OCH ₂ C≡CCH ₂ CH ₃ , -O(CH ₂ ) ₃ CN, -OCH ₂ CH(CH ₃ )CH ₂ CH ₃ , -OCH ₂ CH ₂ CH(CH ₃ ) ₂ , -O( CH ₂ ) ₃ OCH ₃ , -O(CH ₂ ) ₂ F, -O(CH ₂ ) ₃ F or -CH ₂ CH ₂ C(O)OCH ₃ . The compound of any one of claims 31 to 38, or a pharmaceutically acceptable salt thereof, wherein R ₂ is a heteroaryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ ring. The compound of claim 39 or claim 42, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl ring is imidazolyl, pyrazolyl, triazolyl, thienyl, thiadiazolyl, thiazolyl, cacao Diazolyl, pyridyl, pyrimidinyl, benzodioxolyl, fluorenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, quinolyl , oxetanyl, tetrahydropyranyl and C _3-6 cycloalkyl. The compound of claim 39 or claim 42, wherein the heteroaryl ring is selected from the group consisting of pyrimidinyl, benzodioxolyl, benzodioxane, or a pharmaceutically acceptable salt thereof a group consisting of a benzothiophenyl group, a fluorenyl group, a pyrazolyl group, and a benzimidazolyl group. A compound of claim 39, which is represented by the formula: Wherein R ^3A , R ^3B and R ^{4A are} each independently halogen, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl; and R ² is a 6 membered aryl or heteroaryl ring. The compound of any one of claims 39 to 42 or a pharmaceutically acceptable salt thereof, wherein R _3B is halogen, CN, NO ₂ or C _1-6 aliphatic, wherein the C _1-6 aliphatic group Up to four methylene units may be optionally substituted with -NR ₄ , -O-, -C(O)- or -S(O) ₂ -, wherein R _{3B is} optionally substituted with one or more halogens. The compound of any one of claims 39 to 42 or a pharmaceutically acceptable salt thereof, wherein R _3B is fluorine, chlorine, CN, NO ₂ , NH ₂ , CH ₃ , CF ₃ , C(O)CH ₃ C(O)NH(CH ₃ ), CH ₂ OH, OH, butyl, CH ₂ C(O)NHCH ₃ , S(O) ₂ CH ₃ . The compound of any one of claims 39 to 42 or a pharmaceutically acceptable salt thereof, wherein R _3B is C ₁ -C ₆ alkyl or -C(R ₁₀ ) ₃ . The compound of any one of claims 31 to 38, or a pharmaceutically acceptable salt thereof, wherein R ₂ is an aryl group optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ . The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R ₂ is phenyl or naphthalene, optionally substituted with one or more R 3 _B groups and optionally substituted with one R ₃ . The compound of claim 46 or 47, or a pharmaceutically acceptable salt thereof, wherein R _3B is halogen, CN, NO ₂ or C _1-6 aliphatic, wherein up to four of the C _1-6 aliphatic groups The methylene unit may be optionally substituted with -NR ₄ , -O-, -C(O)- or -S(O) ₂ -, wherein R _{3B is} optionally substituted with one or more halogens. The compound of claim 46 or 47, or a pharmaceutically acceptable salt thereof, wherein R _3B is fluoro, chloro, CN, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , C(CH ₃ ) ₃ , C(O)CH ₃ , CH ₂ C(O)OCH ₃ , C(O)OH, C(O)OCH ₃ , C(O)NHCH ₃ , NHC(O)CH ₃ , NHC(O)CHC(CH ₃ ) ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ N(CH ₃ ) ₂ , NH ₂ , N(CH ₃ ) ₂ , OH, OCH ₃ , O(CH ₂ ) ₂ CH ₃ , S(O) ₂ NHCH ₃ or S(O) ₂ CH ₃ . The compound of claim 46 or 47, or a pharmaceutically acceptable salt thereof, wherein R _3B is -OH, halogen, -CN, -OR ₄ , -(CH ₂ ) _n C(O)OR ₄ , -(CH ₂ ) _n OR ₄ , -(CH ₂ ) _n N(R ₄ ) ₂ , -C(O)NHR ₄ , -NH-C(O)R ₄ , -SO ₂ R ₄ or -C(O)OR ₄ . The compound of claim 46 or 47, or a pharmaceutically acceptable salt thereof, wherein R ₂ is substituted once by R ₃ , wherein R ₃ is a heteroaryl group optionally substituted with one or more R ₄ or R _4A groups; ring. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl ring is an oxadiazolyl group. The compound of any one of claims 48 to 52, wherein R ₄ is -H or C ₁ -C ₆ alkyl, or a pharmaceutically acceptable salt thereof. The compound of claim 52 or claim 53, wherein R ₁ is phenyl and R ₂ is phenyl. The compound of any one of claims 31 to 38, wherein R ₂ is -H, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 13 and 18 to 24, or a pharmaceutically acceptable salt thereof, wherein Y is -O-. The acceptable compound of the requested item 56 or a pharmaceutically acceptable salt thereof, wherein R ₁ is optionally substituted phenyl it. The compound of claim 57, wherein R _3A is halogen, C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl), or a pharmaceutically acceptable salt thereof. The compound of claim 56 or 57, wherein R ₂ is an aryl group optionally substituted with one or more R 3 _B groups, or a pharmaceutically acceptable salt thereof. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein R ₂ is phenyl optionally substituted with one or more R 3 _B groups. The compound of claim 60, wherein R ³ is R ^3A , R ^3B or R ^3C represented by the formula: Wherein R ^3A and R ^{3B are} each independently halogen, C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); and R ₃ is optionally substituted by one or more R ₄ groups; An aryl ring. The compound of claim 61, wherein R ₃ is a 5-membered heteroaryl group. The compound of claim 62, wherein R _{3 is} oxadiazolyl, pyrazolyl or thiadiazolyl. The compound of claim 63, wherein R _{3 is} oxadiazolyl. The compound according to any one of claims 59 to 61, wherein R _3B is halogen, C ₁ -C ₆ alkyl, -(CH ₂ ) _n C(O)OR ₄ or -, or a pharmaceutically acceptable salt thereof C(O)NHR ₄ . The compound of any one of claims 59 to 61, wherein R _3B is halogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 59 to 61, wherein R ₃ is a heteroaryl ring optionally substituted with one or more R _4A or R ₄ groups, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 62 to 67, wherein R _4A is CH ₃ , C(O)CH ₃ , C(O)NHCH ₃ , -CH ₂ N (CH ₃ ), or a pharmaceutically acceptable salt thereof ₂ , CH ₂ C(O)OH, -CH ₂ C(O)NHCH ₃ , NHC(O)O(CH ₃ ) ₃ , CH(CH ₃ ) ₂ or CH ₂ C(O)NH(CH ₂ CH ₂ O) ₂ CH ₃ and R ₄ is pyridyl or furyl. The compound of any one of claims 62 to 67, wherein R _4A is -H or C ₁ -C ₆ alkyl, or a pharmaceutically acceptable salt thereof. A compound of claim 1 which is selected from the group consisting of The compound of claim 69, which is selected from the group consisting of one or more of the following compounds: Compounds 48, 104, 105, 106, 107, 108, 111, 112, 120, 121, 125, 126, 127, 128, 131, 133, 136 , 142, 150, 176 or 178. The compound of claim 71, wherein the compound is selected from the group consisting of Compound 265 to Compound 290. The compound of claim 71, wherein the compound is selected from the group consisting of Compound 1 to Compound 72 and Compound 291 to Compound 296. A composition comprising a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. A method of treating or preventing a bacterial infection in an individual, comprising administering to the individual an effective amount of a compound of any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, or a composition according to claim 74. The method of claim 75, wherein the bacterial infection is a urinary tract infection or an inflammatory bowel disease. The method of claim 75, wherein the bacterial infection is colitis. The method of claim 75, wherein the bacterial infection is Crohn's disease. A method of inhibiting FimH of an individual comprising administering to the individual an effective amount of a compound of any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, or a composition of claim 74.