UA98123C2 - Inhibitors of sodium glucose co-transporter 2 and methods of their use - Google Patents

Abstract

Compounds and pharmaceutical compositions comprising them are disclosed that may be useful for the treatment of diseases and disorders such as diabetes and obesity.

Description

This application claims priority over U.S. Provisional Patent Application No. 60/848156, filed Sep. 29, 2006, U.S. Provisional Patent Application No. 60/905714, filed Mar. 8, 2007, and U.S. Provisional Patent Application No. 60/948780 , filed July 10, 2007, the disclosures of which are incorporated herein by reference in their entirety.

The present invention relates to methods of treating metabolic diseases and disorders such as diabetes, compounds and pharmaceutical compositions useful in the above methods.

Sodium glucose cotransporter 2 (50112) is a transporter that reabsorbs glucose from the renal filtrate and prevents glucose from being excreted in the urine. Because competitive 501 T2 inhibitors cause the excretion of glucose in the urine, they can be used to normalize high blood glucose levels due to diseases such as diabetes. Napaipop, A.G., Ekhrep Orip. Tpeg. Raiepiv 15(11):1531-1540 (2005).

A number of 5012 inhibitors have been described in the literature. See, for example, the above publication

Napaiope; US patent Mo 6515117; publication of US patent applications MoMo 5 2006/0035841, 05 2004/0138439.

At least one inhibitor is undergoing clinical trials as a drug for the treatment of type 2 diabetes. See, for example, Kotogovki, V.

Spsoze Oriake Tgaperopeg 2 (51 T2), Nedisez Raviipd Zegyt Siisoze apa Siisoze Ehsigwiop ip Toure 2 Oiabeievz

Meiiiiiv Rayepiv Omega 14 OYUOauv" Ategisap Oiareyev Avvp. 67!" Zsiepiis Zevviopv5. Arvigasi 0188-OV (2007).

The first known inhibitor of 50IT2 was the natural product phlorizin //(glucose-1-(2-(p-O-glucopyranosyloxy)-4,6-dihydroxyphenyl|-3-(4-hydroxyphenyl)-1-propanone) and "all subsequent inhibitors 50172 are glycosides isolated from its structure", Napaiop, see above, p. 1533. Phlorizin consists of a glucose moiety and two hydroxylated aromatic rings connected by a propanone spacer. EpgepKkgapl, U.K.S., ei ai., J. Oiareiz Meyar. Nev. Nem. 21:31-38 (2005). A review of the patent literature fails to identify any synthetic inhibitors of 50IT2 that do not contain a glucoside or its derivative. Napaop, see above. Indeed, "due to the relative uniformity of the glycosides , presented in the 50112 patent literature, it is increasingly difficult for inventors of potential drugs to find the unexplored area of chemical synthesis of such compounds." Ibid., p. 1537. But such attempts are nevertheless being made. See, for example, US patent application Mo 11 /168905, filed in the name of Eskpagai ei a/.. and titled "O-HuI orugapozuI-Zycrziyshea RNepui! Oegmaymev, Medisatepiv Sopiaipipu zisp Sotroshpa", Tpeig Oze apa Rgose55 Ttog Tpeig Mapitasitsge"; US patent application Mo 11/182986 filed in the name

EsKpagai ey a). and titled "MeiPpuiidepe-O-HuiorugapozuI-apa Oho-O-HuIorugapozu!-5ЦОзийШшей Оегимаиймев,

Medisatepiv Sopiaipipd Zysp Sotroitspa5, Tpeig Oze apa Rgosez5 Tog Tpeiig Mapitasiige"; and US patent application Me 11199962, filed in the name of EsKpagai ei ai. and entitled "O-HuiorugapozuI-Rpepu!-Z!crziysheya Susiee5, Medisatepiv

Sopiaipipd Bishop Sotroshpav, TNeig Ove apa Rgosev5 og TNeig Mapygasiige".

The present invention relates to novel inhibitors of 50172. One embodiment of the invention relates to compounds of the formula:

Koso H Kg 1 of their pharmaceutically acceptable salts and solvates, where: A means an optionally substituted aryl, cycloalkyl or heterocycle; X means O, 5 or MEz; when X stands for O, Ki is OMKchl, ZNA, ZONA, 5O2Nid or M(Rid)2; when X is 5, Ki is hydrogen, OVld, 5Nil, 5OH A or 5024; when X stands for MEz, Vi is BOTH, FOR, ZONE, 502H or

From; each Cld independently represents hydrogen or optionally substituted alkyl, aryl or heterocycle; K2 means fluorine or OCgd; each Kol, Nov and Kos independently means hydrogen, optionally substituted alkyl, C(O)alkyl,

C(O)aryl or aryl; Kz means hydrogen, C(O)Kza, COgAza, COM(Azv)2 or optionally substituted alkyl, aryl or heterocycle; each Kzd independently represents an optionally substituted alkyl or aryl; and each Kzv independently represents hydrogen or optionally substituted alkyl or aryl.

Another embodiment of the invention relates to compounds of the formula:

ХК, Code

Kov

KosOo N Co

And , their pharmaceutically acceptable salts or solvates, where: A means an optionally substituted aryl, cycloalkyl or heterocycle; X means O or MEz; Ag means fluorine or ORga; each Ega, B2c and Cos independently represents hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl or aryl; Kz means hydrogen or optionally substituted alkyl, aryl or heterocycle; Kv stands for hydrogen or C(O)Kvd; Nad means hydrogen or optionally substituted alkyl, alkoxy or aryl; Ed and Cov independently stand for OKes or 5Kes or taken together represent 0, 5 or

MAvs; and each Cos independently represents an optionally substituted alkyl, aryl, or heterocycle.

The present invention relates to pharmaceutical compositions containing the compounds described herein. The present invention also relates to methods of inhibiting the activity of 501 T2, as well as methods of treatment, prevention and elimination of relapse of various diseases and disorders.

The defined objects of this invention can be understood with reference to figure 1, which shows the effect of various compounds of this invention on urinary glucose excretion in mice. These compounds were administered orally at a dose of 30 mg/kg.

The basis of this invention is partly the discovery that the compounds of the formulas: x В ХЕ Code

Kov

KosO N Ko oso N Kk;

I, p, having the substituents described below, can inhibit sodium glucose cotransporter 2 (501 12).

Unless otherwise specified, the term "alkenyl" means a straight, branched and/or cyclic hydrocarbon containing 2-20 (eg, 2-10 or 2-6) carbon atoms and having at least one carbon-carbon double bond. Specific alkenyl groups include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl.

Unless otherwise specified, the term "Alkoxy" means an -O-alkyl group. Examples of alkoxy groups include, but are not limited to, -OSH3, -"OSNeaCH3, -"F(CHg)25 CH, -"F(CHg)zCH3, -F(CHg)"SnHz, and -F(CHg)zCH.

Unless otherwise specified, the term "alkyl" means a straight, branched and/or cyclic hydrocarbon ("cycloalkyl") containing 1-20 (eg, 1-10 or 1-4) carbon atoms. Alkyl groups containing 1-4 carbon atoms are defined as "lower alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl groups can be monocyclic or polycyclic and examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. Additional examples of alkyl groups include groups with a linear, branched, and/or cyclic structure (eg, 1-ethyl-4-methylcyclohexyl). The definition of the term "alkyl" includes saturated hydrocarbons, as well as alkenyl and alkynyl groups.

Unless otherwise specified, the term "alkylaryl" refers to an alkyl group bonded to an aryl group.

Unless otherwise specified, the term "alkylheteroaryl" refers to an alkyl group bonded to a heteroaryl group.

Unless otherwise specified, the term "alkylheterocycle" means an alkyl group bonded to a heterocycle.

Unless otherwise specified, the term "alkynyl" means a straight, branched, or cyclic hydrocarbon containing 2-20 (eg, 2-20 or 2-6) carbon atoms and having at least one carbon-carbon triple bond. Specific alkynyl groups include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1- heptynyl, 2-heptynyl, b-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-noninyl, 2-noninyl, 8-noninyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise specified, the term "aryl" means an aromatic ring or an aromatic or partially aromatic ring system consisting of carbon and hydrogen atoms. An aryl group may include several rings linked or fused to each other. Examples of aryl groups include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indane, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydronaphthalene, and tolyl.

Unless otherwise specified, the term "arylalkyl" means an aryl group bonded to an alkyl group.

Unless otherwise specified, the term "halogen" means fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the term "heteroalkyl" refers to an alkyl group (eg, linear, branched, or cyclic) in which at least one of the carbon atoms is replaced by a heteroatom (eg, M, O, or 5).

Unless otherwise specified, the term "heteroaryl" refers to an aryl group in which at least one of the carbon atoms is replaced by a heteroatom (eg, M, O, or 5). Examples of such groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl and triazinyl.

Unless otherwise specified, the term "heteroarylalkyl" refers to a heteroaryl group bonded to an alkyl group.

Unless otherwise specified, the term "heterocycle" means an aromatic, partially aromatic, or non-aromatic monocyclic or polycyclic ring or ring system consisting of carbon atoms, hydrogen atoms, and at least one heteroatom (eg, M, O, or 5). A heterocycle may include multiple (ie, two or more) rings fused or bonded to one another. Heterocycles include heteroaryls. Examples of such groups include, but are not limited to, benzo|1,3|dioxolyl, 2,3-dihydrobenzoi|1,4|dioxynyl, cinolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxyranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.

Unless otherwise specified, the term "heterocycloalkyl" means a heterocycle bound to an alkyl group.

Unless otherwise specified, the term "heterocycloalkyl" means a non-aromatic heterocycle.

Unless otherwise specified, the term "heterocycloalkylalkyl" refers to a heterocycloalkyl group bonded to an alkyl group.

Unless otherwise indicated, the term "Inhibits 501 T2 ip mimo" refers to the inhibition of 501 T2 determined when performing the ip mimo assay described in the following examples.

Unless otherwise specified, the terms "eliminate relapse" and "eliminate relapse" mean preventing the recurrence of a specified disease or disorder in a subject previously suffering from said disease or disorder, and/or increasing the duration of remission in a subject suffering from said disease or disorder violation

The specified terms mean a change in the threshold of occurrence, development and/or duration of a disease or disorder or a change in the subject's reaction to a given disease or disorder.

Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts obtained from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Pharmaceutically acceptable base-addition salts include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts derived from lysine, M, M'-dibenzylethylenediamine, chlorprocaine, choline , diethanolamine, ethylenediamine, meglumine (M-methylglucamine) and procaine. Acceptable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzosulfonic, benzoic, camphorsulfonic, citric, ethylenesulfonic, formic, fumaric, furonic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic. , hydrogen chloride, isethiobase, lactic, maleic, malic, almond, methanesulfonic, mucilaginous, nitrogenous, pumamic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric and paratoluenesulfonic acids. Particularly acceptable non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids. Thus, examples of particularly acceptable salts include hydrochloride and mesylate.

Other salts are well known in the art. See, for example, the posts of Betipdiopje Rpaptaseshiis! Zsiepsev, 181" unit. (Mask Rybiizpipd, Eaziop RA: 1990) and VBetipdiop: Tpe BZsiepse apa Rgasiise oi Rpagtasu, 1917 vea. (Mask Rybiivnipo,

Eazyup RA: 1995).

Unless otherwise specified, a "potent 501 T2 inhibitor" is a compound having an IC 501 T2 value of less than about 500 nm.

Unless otherwise specified, the terms "prevent" and "prevention" refer to measures taken before a subject develops a specified disease or disorder that inhibit or reduce the severity of the disease or disorder. In other words, these terms mean prevention.

Unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, one or more symptoms associated with a given disease or condition, or to eliminate recurrence. "Prophylactically effective amount" of a compound means an amount of the drug, used alone or in combination with other agents, that has a prophylactic effect in preventing disease. The term "prophylactically effective amount" can mean an amount that improves the prevention or enhances the prophylactic effectiveness of another prophylactic agent.

Unless otherwise specified, a "selectively acting 5012 inhibitor" is a compound that has an IC 511 value at least 10 times higher than the IC 511 value of BI T2.

Unless otherwise indicated, the term "IC 501 T1" means the IC 501 value of the compound obtained in the human 501 T1 inhibition assay described in the examples below.

Unless otherwise specified, the term "IC 501 T2" means the IC 501 value of the compound obtained in the human ip miigo 501 T2 inhibition assay described in the examples below.

Unless otherwise specified, the term "mixture of stereoisomers" means racemic mixtures, as well as mixtures with an increased content of stereoisomers (for example, K/5-30/70, 35/65, 40/60, 45/55, 55/45, 60/ 40, 65/35 and 70/30).

Unless otherwise specified, the term "stereomerically pure" means a composition that contains one stereoisomer of a compound and is essentially free of other stereoisomers of said compound. For example, a stereomerically pure composition that contains a compound with one stereocenter should essentially not contain the opposite stereoisomer of the given compound. A stereomerically pure composition that contains a compound with two stereocenters should essentially not contain other diastereomers of the given compound. Typically, a stereomerically pure compound includes approximately more than 80 wt. 9 of one stereoisomer of the compound and approximately less than 20 wt. 90 other stereoisomers of this compound, approximately more than 90 wt. 95 of one stereoisomer of the compound and approximately less than 10 wt. of other stereoisomers of this compound, approximately more than 95 wt. of one stereoisomer of the compound and approximately less than 5 mab. 90 other stereoisomers of this compound, approximately more than 97 wt. 95 of one stereoisomer of the compound and approximately less than C wt. 90 other stereoisomers of this compound or approximately more than 99 wt. 95 of one stereoisomer of the compound and approximately less than 1 wt. 95 other stereoisomers of this compound.

Unless otherwise specified, the term "substituted" when used to describe a chemical structure or group means a derivative of that structure or group in which one or more hydrogen atoms have been replaced by a chemical moiety or functional group, including, but not limited to, an alcohol, an aldehyde , alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (eg methyl, ethyl, propyl, tert-butyl), alkynyl, alkylcarbonyloxy (-

OS(O)alkyl), amide (-C(O)MH-alkyl- or -alkylMHC(O)alkyl), amidinyl. (-C(MH)UMN-alkyl- or -C(ME)MH"), amine (primary, secondary or tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (-MNOC( O)O-alkyl- or -OC(O)MH-alkyl), carbamyl (for example, SOMN", as well as SOMN-alkyl, SOMN-aryl and SOMN-arylalkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halogen, haloalkyl (e.g., -C3, -C3, -C(C3)3), heteroalkyl, hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxo, phosphodiester, sulfide, sulfonamido (eg, 5O»MH»g), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl, and arylalkylsulfonyl), sulfoxide, thiol (eg, sulfhydryl, simple thioether) and urea (-CHMNSOMN-alkyl-).

Unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a beneficial therapeutic effect in the treatment or prevention of recurrence of a disease or condition,

to delay or minimize one or more symptoms associated with a given disease or condition. A "therapeutically effective amount" of a compound means an amount of the drug, used alone or in combination with other treatments, that provides a beneficial therapeutic effect in the treatment or prevention of recurrence of a disease or condition. The term "therapeutically effective amount" can mean an amount that improves overall treatment, alleviates or eliminates symptoms or causes of a disease or condition, enhances the therapeutic effectiveness of another drug.

Unless otherwise specified, the terms "treat" and "treatment" refer to measures taken during a subject's illness that reduce the severity of the disease or disorder, or delay or slow the progression of the disease or disorder.

Unless otherwise specified, the term "include" has the same meaning as the term "including but not limited to", and the term "includes" has the same meaning as the term "includes but is not limited to".

Similarly, the term "such as" has the same meaning as the term "such as, but not limited to".

Unless otherwise noted, one or more adjectives immediately preceding several nouns refer to each noun. For example, the phrase "optionally substituted alkyl, aryl, or heteroaryl" has the same meaning as the phrase "optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl."

It should be noted that a chemical group forming part of a larger compound may have in this description a name commonly used to designate a single molecule or a name commonly used to designate a radical. For example, the terms "pyridine" and "pyridyl" have the same meaning when used to refer to a moiety attached to other chemical moieties. Thus, the two phrases "HON, where X is pyridyl" and "HON, where X is pyridine" have the same meaning and mean the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that, if the stereochemistry of a structure or part of a structure is not marked, for example, by bold or dashed lines, such structure or part of a structure approximately includes all stereoisomers.

In addition, any atom shown in the drawing with unsaturated valences is assumed to be attached to a sufficient number of hydrogen atoms to saturate the valences. In addition, chemical bonds depicted as one solid line parallel to one dashed line mean both single and double (for example, aromatic) bonds, if the valences allow such a possibility.

Compounds

One embodiment of the invention relates to compounds of the formula:

Koso H Ko 1 from their pharmaceutically acceptable salts and solvates, where: A means an optionally substituted aryl, cycloalkyl or heterocycle; X means O, 5 or MEz; when X stands for O, Ki is OMKchl, ZNA, ZONA, 5O2Nid or M(Rid)2; when X is 5, Ki is hydrogen, OVld, 5Nil, 5OH A or 5024; when X stands for MEz, Vi is OBBA, ZA, ZONE, 502H or

From; each Cld independently represents hydrogen or optionally substituted alkyl, aryl or heterocycle; K2 means fluorine or OCgd; each Kol, Nov and Kos independently means hydrogen, optionally substituted alkyl, C(O)alkyl,

C(O)aryl or aryl; Kz means hydrogen, C(O)Kza, COgAza, COM(Azv)2 or optionally substituted alkyl, aryl or heterocycle; each Kzd independently represents an optionally substituted alkyl or aryl; and each Kzv independently represents hydrogen or optionally substituted alkyl or aryl.

Individual compounds have the formula:

Koso N go

OKov.

Some compounds have the formula:

And Hu V

OKov.

Some compounds have the formula:

di x Hm

AND,

OV

One embodiment of the invention relates to compounds of the formula:

In x Kk

Kos N Co

Ovov their pharmaceutically acceptable salts and solvates, where: A means an optionally substituted aryl, cycloalkyl or heterocycle; B means optionally substituted aryl, cycloalkyl or heterocycle; X means O, 5 or MEz; U means O, 5, 50, 50", MV, (С(Ав)2г)р, (С(Нв)2иа-С(О)-(С(Ав)2г)а, (С(А5)2 )a-С(О)0-(С(Ав)2); -(С(А5)2)а, (С(А5)2)а-МАС(О)-(С(Ав)г)а or (С(П5)2)а-МАВАС(О)МНАа-(С (A5)2)d; when X means 0, Ki is

ОА, ЗА, ОВ А, 5О2Nid or M(Kid)2; when X means 5, Ki is hydrogen, OKd, ZNA, ONA or 5O»Vid; when X means MEz, Vi is OKll, 5Nllx, ZONE, 502Nd or Ed; each Ed independently represents hydrogen or optionally substituted alkyl, aryl or heterocycle; KE2 means fluorine or ORga; each Kha, Bzv and Kos independently means hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl or aryl; Kz means hydrogen, C(O)Kza, CO2NAz, COM|(Azv)2 or optionally substituted alkyl, aryl or heterocycle; each Kzd independently represents an optionally substituted alkyl or aryl; each Kzv independently represents hydrogen or optionally substituted alkyl or aryl; each B independently means hydrogen or optionally substituted alkyl; each K5 independently represents hydrogen, hydroxyl, halogen, amino, cyano, OB5l, 5P5d or optionally substituted alkyl; each E5d independently means optionally substituted alkyl; p equals 0-3, and each 4 independently equals 0-2.

Individual compounds have the formula:

In oso N Vo

Ov

Some compounds have the formula:

In oso Yi Ko

OVov

Some compounds have the formula:

IN

Koso and Kg

OV

Some compounds have the formula: (Kt

In their Kk

Eoso and v

OBov where each Kye independently means hydrogen, hydroxyl, halogen, amino, cyano, nitro, C-SVva, OVvlh, ZVva, 5OVva, 5ZO»2Ava, C(O)Nvah, COgNAvla, CO2H, COM(Nva)(Nva), SOMN(Nva), SOMN»g, MNO(O)Nvah, MNOO»Nva or optionally substituted alkyl, aryl or heterocycle; each Kvd independently represents an optionally substituted alkyl, aryl, or heterocycle; each K7 independently means hydrogen, hydroxyl, halogen, amino, cyano, nitro, C-SAta, OB, 5NAha,

ZONE, 5O2Ata, C(O)Hta, CO»2Ata, SON, COM(Ata)(Ata), SOMN(Hta), SOMN», MNO(O)Ata, MNOO»Hta or optionally substituted alkyl, aryl or heterocycle; each K7iA independently represents a substituted alkyl, aryl or heterocycle; t is equal to 1-3, and n is equal to 1-3.

Some compounds have the formula: (K)t

In t, Xx Ka no t Ko on

Some compounds have the formula: (Kv)p (Kg)t ro no t Ko on

Some compounds have the formula: (Kv)p (Ktt oi no H Ko on

One embodiment of the invention relates to compounds of the formula:

HKA Code

Kov

KosOo N Co

PP of their pharmaceutically acceptable salts and solvates, where: A means an optionally substituted aryl, cycloalkyl or heterocycle; X means O or MEz; B2 means fluorine or OKgld; each Ega, Hgv and Cos independently represents hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl or aryl; Kz means hydrogen or optionally substituted alkyl, aryl or heterocycle; Kv stands for hydrogen or C(O)Kvd; Nad means hydrogen or optionally substituted alkyl, alkoxy or aryl; Ed and Cov independently stand for OKes or 5Kes or taken together represent 0, 5 or

MAvs; and each Cos independently represents an optionally substituted alkyl, aryl, or heterocycle.

With respect to the various formulas presented herein, in some compounds, whenever possible, A represents an optionally substituted b-membered aryl or heterocycle. In other compounds, A means an optionally substituted 5-membered heterocycle. In some compounds, A means an optionally substituted fused bicyclic heterocycle.

In some compounds, B means an optionally substituted β-ene aryl or heterocycle. In other compounds, B means an optionally substituted 5-membered heterocycle. In other compounds, B means an optionally substituted fused bicyclic heterocycle.

In some compounds, X means 0. In other compounds, X means 5. In other compounds, X means MKz.

In some compounds, U means (С(Ка)г)р, and, for example, р equals 1. In some compounds, У means (С(К5)2)а4-С(О)- (С(БА5)2)а, and, for example, each d is independently 0 or 1.

In some compounds, Ki means OKal. In other compounds, Ki means 5Clal. In other compounds, Ki means ZOK: A. In other compounds, Ki means 5O»2Niia. In other compounds, Ki means M(Kid)". In other compounds, Ki stands for hydrogen. In other compounds, Ki means Cl.

In some compounds, Kid stands for hydrogen. In other compounds, Cd is optionally substituted alkyl (eg, optionally substituted lower alkyl).

In some compounds, K2 means fluorine. In other compounds, K2 means OKha.

In some compounds, Kg means hydrogen.

In some compounds, Kgv means hydrogen.

In some compounds, Kos stands for hydrogen.

In some compounds, Ez stands for hydrogen. In other compounds, Kz means optionally substituted lower alkyl

(eg, optionally substituted methyl).

In some compounds, Ka represents hydrogen or optionally substituted lower alkyl.

In some compounds, each R5 is hydrogen or optionally substituted lower alkyl (eg, methyl, ethyl, C3).

In some compounds, Ke represents hydrogen, hydroxyl, halogen, OCvd, or optionally substituted lower alkyl (eg, optionally halogenated methyl, ethyl, or isopropyl). In some compounds, Keye stands for hydrogen. In some compounds, Keye stands for halogen (e.g., chlorine). In some compounds, Ke stands for hydroxyl. In some compounds, Kw stands for OCwad (for example, methoxy, ethoxy). In some compounds, Ke represents an optionally substituted methyl (for example, CE3).

In some compounds, K7 is hydrogen, C-SVata, OH, or optionally substituted lower alkyl (eg, optionally halogenated methyl, ethyl, or isopropyl). In some compounds, K7 means hydrogen. In some compounds, K7 is C-C6, and E7l is, for example, an optionally substituted (eg, lower alkyl or halogen) monocyclic aryl or heterocycle. In some compounds, K7 stands for OKg?aA (for example, methoxy, ethoxy).

In some compounds, K7 is acetylenyl or optionally substituted methyl or ethyl.

Individual compounds according to this invention have the formula: - lo SI ro no to on on

Ma)

Other compounds have the formula: - lo С

SA, they but N on on

C(b)

Other compounds have the formula: - lo SI o

IM ro no N on on

Co.)

Other compounds have the formula: - lo SI o pp ХК mA

I SHK c) no t on on tsa)

Other compounds have the formula: - lo SI

SA, he drank this dream

Me)

Other compounds have the formula:

- lo SI » pr M MMA oo on

AND; .

In certain compounds of formulas I(a)-(4), X means 0. In other compounds X means 5. In other compounds X means

MA", and Kz means, for example, hydrogen. In individual compounds of formulas I(a)-(i), Vd means hydrogen. In other compounds

From means optionally substituted methyl or ethyl.

Preferred compounds are potent inhibitors of 50172. Individual compounds have IC 512 values of less than about 500, 400, 300, 250, 200, 150, 100, 75, 50, or 25 nM.

Certain compounds are selective 501 T2 inhibitors. For example, the specified compounds have a value of ISvzo 56 T1, which is at least 10, 15, 20, 25, 50, 75 or 100 times higher than the value of ISvzo Ba T2.

Methods of synthesis

The compounds of this invention can be prepared by methods known in the art and by methods discussed herein. For example, the compounds may be prepared by the methods shown in Scheme 1 below.

Scheme 1

Hg

Zno no N N va (SISOU, DMSO, ME o onsie ve v; o pl tt A ce)

N nn A-z tv8b. i vach SN» tveb i ik You, tF

Cha) c) on

In A takes 0000 pON , Se) b) I Ovid in; in tvBo no AsonN. but about that Ton a) Not he

In the implementation of this method, the known alcohol 1(a) (see, for example, Mysioide5, 20:649-6523 (2001)) is oxidized under acceptable conditions (for example, with the help of an oxidant such as oxalyl chloride in DMSO) with the formation of aldehyde 1(65 ). The bromide of formula 1(c) is treated with an agent such as butyllithium or magnesium bromide, followed by the addition of aldehyde 1(b), obtaining alcohol 1(4). The resulting compound is treated with alcohol or water under acidic conditions to form compound 1(e). If it is desired to convert compound 1(e) into various other compounds included in the scope of this invention (for example, compounds of formula I, where one or more elements Ega, B2v and Kos are not hydrogen, and/or Ki means 5Kld or МНЕ 4 ), methods well known in the art can be used.

With reference to scheme 1 and other methods of synthesis described in this description, it can be noted that well-known methods of obtaining fragments A and A-U-B, as well as methods of their use for obtaining 501 T2 inhibitors.

For example, the synthesis of bound diaryl derivatives in the preparation of 501 T2 inhibitors is described in US patents MoMo 7045665 and 7053060; in US patent applications MeMo 10/735179, 10/745075, 11/080150 and 11/182986 and in international patent applications MeoMeo UMO 2006/006496 and UMO 2006/089872.

The synthesis of 501 T2 inhibitors, which contain linked phenylcarbocyclic fragments, is described, for example, in US patent applications MeMo 11/190315 and 11/199962.

The synthesis of linked heterocycles and their use in the preparation of inhibitors 5012 is described, for example, in US patent applications MoMe 10/540519, 10/734573, 11/247216, 11/247356 and international patent applications MoMo

MO 03/020737, MO 2004/058790, MO 2004/080990, MO 2004/089967, UMO 2005/011592, Mo 2005/012242, MO 2005/012243, UMO 2005/012318, UUOO 2005/0215

Piperidine-based compounds can be prepared by the methods shown in Scheme 2 below.

Scheme 2 on Ma o. he

In Ya-o in her-o

Bra Ho vnvsho riv in tvvbo to in tvvb No 7 Re ORRA 7 No 2(a) 2(B)

Mz

ХХ ю n У Нз 1. Assi, meon Ya-on N". РЮ?2 in МОН 2. ASON, BUT in wo no don AsOonN, MeOnN know on z(s) shcha) 00 N

When implementing this method, compound 2(a), which can be obtained by the method shown in scheme 1,

contacts with azide (for example, diphenylphosphoryl azide) under conditions that provide azide 2(b).

The azide is then treated under acidic conditions to give the unprotected furan 2(c), which is then treated with a reducing agent (eg, hydrogen in the presence of platinum oxide) under acidic conditions to give compound 2(4). If desired to convert compound 2(4) into various other compounds that are included in the scope of this invention (for example, compounds of formula I, where one or more elements Ega, Bgv and Kos are not hydrogen, and/or Ki means ZKl1d or MNE) , methods well known in the art can be used.

Compounds based on tetrahydrothiopyran can be obtained according to scheme 3.

Scheme Z on ZAS not o see SNUSOZN, OEAO sv u o

N g V rch N SIV r:e

В в: your but В; in your but

З(а) З(Б) и Н -- - и- in miy A i / и в д-- ry ra, KN AS or not XX century; tvo no DREAM, BUT nob tu ton ze) zvu he

In the implementation of this method, compound C(a), which can be obtained according to scheme 1, is contacted with an acceptable sulfur-containing compound (for example, thioacetate) under acceptable conditions (for example, in the presence of diethylazodicarboxylate) with the formation of thioacetate 3(B). The thioacetate is then treated with an acceptable base (for example, cesium hydroxide) to form a thiol of formula C(c), which is then treated with alcohol or water under acidic conditions to give compound C(4). If it is desired to convert compound C(4) into various other compounds that are included in the scope of this invention (for example, compounds of formula I, where one or more elements Kga, Nzv and Kos are not hydrogen, and/or Ki means Э or МНЕ: A), methods well known in the field can be used.

Compounds containing a fluorinated sugar or sugar analog (compounds of formula I, where Kg is E) can be prepared from the corresponding substituted starting substances by methods known in the art. See, for example, US patent application Me 10/735179.

Compounds with an open structure (eg, compounds of formula II) can be readily prepared by methods known in the art. For example, these compounds can be prepared by the methods shown in Scheme 4 below.

Scheme 4 on osSOoyusn»z and? With (o; SNSOSI? and (o

IN; в твво Но в в: твзО НО

Aa) 4(c) heh o

IN

NSYI, VoSON 3. tin yo Ke D Seke no N on (s) on

In the implementation of this method, the compound 4(a), which can be obtained according to scheme 1, contacts a reactive compound (for example, methyl chloroformate) under acceptable conditions to form methyl carbonate 4(B). Then methyl carbonate is treated with alcohol under acidic conditions to form compound 4(c).

If desired, for the conversion of compound 4(c) into various other compounds that are included in the scope of this invention (for example, compounds of formula III, where one or more elements Ea, H2c and Es are not hydrogen), methods well known in the art can be used this industry.

Using methods known in this field, it is easy to modify the synthesis methods presented above to obtain a number of compounds. Stereomerically pure compounds can be obtained using chiral chromatography and other well-known methods. See, for example, uasdtsev, 5., ei aI.,, Epapiotegv5,

Vasetaiyez apa Nezoishiope5 (UMieu Ipiegzsiepse, Mem Hoik, 1981); UMiep, 5.N., and AI., Techzganedgop 33:2725 (1977); Hey

E.S, iegeospetivighu oi Sagrop Sotrotspav5 (Meogamu NIIII, MU, 1962); and U/iep, 5.N., Tarieez oi Kezoimipd Adepiv apa

Oriyas! Nezoiishiopv, p. 268 (E.I... Eiei, Ed., Opim. oi Moigte Sate Rgezv, Moigte Yuate, IM, 1972).

In addition, when performing synthesis methods, chiral starting substances can be used to obtain products with an increased content of stereomers or pure products.

Methods of application

The present invention relates to a method of inhibiting 501 T2 activity, which comprises contacting 501712 with an effective amount of a compound of the present invention (ie, a novel compound disclosed herein). In one variant of the implementation of the invention, the protein is used by IP. In another embodiment of the invention, the protein is used ex mimo.

The present invention also relates to a method of reducing blood glucose levels in a subject (eg, a mammal such as a human, dog, or cat), which comprises administering to the subject an effective amount of a compound of the present invention.

The present invention also relates to a method of increasing urinary glucose excretion in a subject, which includes administering to the subject an effective amount of a compound of the present invention.

The present invention also relates to a method of restoring or increasing insulin sensitivity in a subject, which comprises administering to the subject an effective amount of a compound of the present invention.

The present invention also relates to a method of treating, eliminating relapse, or preventing a disease or disorder in a subject, which includes administering to the subject a therapeutically or prophylactically effective amount of a compound of the present invention. Examples of diseases and disorders include atherosclerosis, cardiovascular disease, diabetes (types 1 and 2), hyperglycemia, hypertension, lipid disorders, obesity, and syndrome X.

Type 2 diabetes is a particularly prevalent disease.

The amount of compound administered, the method of administration, and the dosage regimen of the compound may depend on factors such as the specific disease to be treated, relapse prevention, or elimination, as well as the subject's age, sex, and health. The significance of such factors is well known in the art, and treatment conditions can be adjusted to these factors by routine experimentation.

Pharmaceutical drugs

The present invention relates to pharmaceutical compositions containing one or more compounds according to the present invention. Some pharmaceutical compositions are single-dose unit dosage forms intended for oral administration, mucosal administration (for example, for nasal, sublingual, vaginal, transbuccal or rectal administration), parenteral administration (for example, for subcutaneous administration, intravenous administration, etc. injection of a shock dose, intramuscular or intra-arterial administration) or percutaneous administration to a subject. Examples of dosage forms include, but are not limited to, tablets; dragee; capsules, such as soft elastic gelatin capsules; starch capsules; pastilles; cakes; dispersions; suppositories; ointments; poultices; pasta; powders; bandages; creams; plasters; solutions; stickers; aerosols (for example, nasal sprays or inhalers); gels; liquid dosage forms for oral and transmucosal administration, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or liquid water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to form liquid dosage forms suitable for parenteral administration to a subject.

The drug must correspond to the method of administration. For example, drugs intended for oral administration must be protected by an enteric coating from degradation in the gastrointestinal tract.

Similarly, the preparation may contain ingredients that facilitate the delivery of the active ingredients to the site of exposure. For example, compounds can be introduced in liposomal preparations to protect them from the effects of cleaving enzymes, facilitate transfer into the circulatory system and penetration through cell membranes into the intracellular space.

The composition, form and type of dosage form may vary depending on the application. For example, a dosage form used for the immediate treatment of a disease may contain greater amounts of one or more active ingredients compared to a dosage form used for the long-term treatment of the same disease. Similarly, a dosage form for parenteral administration may contain smaller amounts of one or more active ingredients compared to a dosage form for oral administration in the treatment of the same disease. Those skilled in the art are aware of the above and other factors that determine the difference between specific dosage forms of the present invention. See, for example, the post

Vetipdyup'z Rnagtaseciis! Zsiepsev, 18!" vd. (Mask Rybiizpipou, Eaviop RA: 1990).

Pharmaceutical compositions according to the present invention are preferably administered orally. Discrete dosage forms intended for oral administration include tablets (eg, chewable tablets), dragees, capsules, and liquids (eg, flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art. See, for example, the publication of Vetipdiopye Rpagtaseshiis! Zsiepsev, 18!" unit. (Mask Rybiyenipo, Eaviop RA: 1990).

Specific dosage forms for oral administration are prepared by combining the active ingredients in a thoroughly mixed mixture with at least one excipient according to standard pharmaceutical mixing methods. Excipients can have different forms depending on the form of the drug required for administration.

Because of their ease of administration, tablets and capsules are the most preferred dosage forms for oral administration. If desired, tablets can be coated using standard aqueous or non-aqueous methods. Such dosage forms can be obtained by standard methods used in pharmacy. As a rule, pharmaceutical compositions and dosage forms are obtained as a result of homogeneous and thorough mixing of active ingredients with liquid carriers, finely divided solid carriers or both together, with the subsequent, if necessary, providing the product with the appropriate form. Disintegrants can be introduced into solid dosage forms for rapid dissolution. Lubricants can also be added to the dosage forms, which facilitate the manufacture of dosage forms (for example, tablets).

Examples

The following non-limiting examples may assist in understanding aspects of the present invention.

Example 1. Synthesis of (25, ZK, AK, 55)-2-|I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

The title compound was obtained in several stages.

A. Preparation of |((Zab5, 55, 6, bak)-6-(tert-butyldimethylsilaniloxy)-2,2-dimethyltetrahydrofuro|2,3- 4|11,3|dioxol-5-yl|methanol

The specified compound was synthesized by methods known in this field. See, for example, Mysieozides Mysieoideev, 20:649-652 (2001) and references therein.

B. Preparation of (Za5, 5, 6K, bab)-6-(tert-butyldimethylsilaniloxy)-2,2-dimethyltetrahydrofuro|2,3-a)|1,3|dioxol-5-carbaldehyde

A solution of DMSO (0.84 ml, 11.8 mmol) in CHe2Si (5 ml) was added dropwise to a solution of oxalyl chloride (0.76 ml, 8.7 mmol) in CH2Cl (55 ml) in an M atmosphere at -782С . After 15 minutes, alcohol from stage A (2.40 g, 7.9 mmol) was added dropwise in SNeSi" (20 ml). After 15 minutes, MEIiz was slowly added. The reaction mixture was allowed to slowly warm to room temperature for 105 minutes, then quenched with H2O, diluted with ESO, and washed with H2O, a saturated aqueous solution of MnSOO, and a saturated salt solution. The combined organic phases were subjected to reverse extraction with ESO, which was washed in the specified sequence. The combined organic phases were dried

M9Bo", was filtered and concentrated in a vacuum, obtaining (Zav, 5K, 6K, base)-6-(tert-butyldimethylsilanyloxy)-2,2-dimethyltetrahydrofuro(2,3-4|11,3|dioxol-5-carbaldehyde ( 2.4 g, purity about 64 95 according to NMR results).

The product was used in the next step without further purification.

C. Production of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene

The specified compound was prepared as described in US patent application Me 10/745075, filed in the name of Oezprapaye eig a. December 23, 2003

O. Preparation of (5)-(Za5, 55, 6B8, bab)-6-(tert-butyldimethylsilanyloxy)-2,2-dimethyltetrahydrofuro|2,3-a)|11,3|dioxol-5-yl|-( 4-chloro-3-(4-ethoxybenzyl)phenyl|methanol

To a solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene from stage C (3.6 g, 11.1 mmol) in THF (60 mL) under atmosphere

M2 at -782C was added dropwise Vig and (2.5M solution in hexanes, 4.4 ml, 11.1 mmol). After 30 minutes, the aldehyde from stage B (2.4 g, purity 64 95, 5.1 mmol) in THF (20 ml) was added dropwise, the reaction mixture was stirred for 30 minutes at -782C, allowed to warm to room temperature and stirred for 60 minutes, extinguished with a saturated aqueous solution of MNACI, diluted with ESO and washed with HO and a saturated salt solution.

The combined washing waters were subjected to reverse extraction of Ei2O, which was washed in the specified sequence.

The combined organic extracts were dried over Md5O»4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (120 g 5iO", 0-20 95 EOAc:hexanes, 75 minutes, 85 ml/min.), obtaining pure (5)-M(Zab, 55, 68, bab)-6-(tert -butyldimethylsilanyloxy)-2,2-dimethyltetrahydrofuroic|2,3-4|11,3|dioxol-5-yl|-I(4-chloro-3-(4-ethoxybenzyl)phenyl|methanol (0.84 g, 1 .5 mmol, 30 95), C5 epimer (0.83 g) and several mixed fractions (0.51 g).

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.37 (d, U-8.34 Hz, 1H), 7.18-7.23 (m, 1H), 7.15 (d , 9-2.02 Hz, 1H), 7.06-7.11 (m, 2H), 6.80-6.84 (m, 2H), 5.99 (d, U-3.79 Hz, 1H), 5.21 (d, U-2.78 Hz, 1H), 5.11 (d, 9U-2.53 Hz, 1H), 4.46 (d, 9U-3.54

Hz, 1TN), 3.97-4.10 (m, 5Н), 3.95 (t, 9U-2.65 Hz, 1Н), 1.38-1.44 (m, 6Н), 1.30 (с, ЗН), 0.84 (с, 9Н), 0.10 (с, ЗН), -0.08 (с,

ZN).

E. Preparation of (25, ZK, AK, 55)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

A solution of 0.35 M HCI in MeOnH was prepared by adding AsciI (0.25 mL, 3.5 mmol) to Meon (10 mL) and stirring for 15 minutes. Alcohol from stage O (0.84 g, 1.5 mmol) was treated with the resulting solution for 16 hours at room temperature and for 2 hours at 802C in a sealed ampoule. The reaction mixture was cooled to room temperature, quenched with Kg2СО3, brought to the ground state, diluted with СНеССи, filtered and concentrated in a vacuum. The product was purified by flash chromatography (40 g 5iO, 0-1095 Meon:CH2Cl, 60 min, 35 mL/min), suspended in H2O and lyophilized to give (25, ZE, 4K, 55)-2-(4 -chloro-3-(4-ethoxybenzyl)phenyl|-6-methoxytetrahydropyran-3,4,5-triol (0.46 g, 1.1 mmol, 75 95) as a white solid.

C:- and D-anomers were detected by NMR at a ratio of 1.2:1.

IN YAMRE (400 MHz, chloroform-a) 6 m.h.: 7.38-7.42 (m, 1H), 7.22-7.26 (m, 2H), 7.11 (d, 9- 8.34 Hz, 2H), 6.81-6.85 (m, 2H), 4.86 (d, 9U-3.79 Hz, 1H o), 4.43 (d, 9U-9.85 Hz , 1H o), 4.34 (d, 9-7.58 Hz, 1H p), 4.16 (d, U-9.35 Hz, 1H p), 3.99- 4.12 (m, 4H ), 3.80-3.86 (m, 1H o), 3.64-3.72 (m, 1H), 3.54 (s, ЗН p), 3.46-3.54 (m, 1 .5H), 3.45 (s, ЗН s), 2.69 (d, 9-2.53

Hz, 1H V), 2.62 (d, U-2.27 Hz, 1H direct), 2.50 (d, U-2.27 Hz, 1H DV), 2.12 (d, U-9, 85 Hz, 1H s), 2.00 (d, 9U-3.03 Hz, 1H r), 1.98 (d, U-2.78 Hz, 1H so), 1.41 (t, U-6 .95 Hz, ZN). MS (EbBu (MeAMNA|-426.

Example 2. Synthesis of (35, AK, 5, 65)-6-I4-chloro-3-(4-ethoxybenzyl)phenyl|tetrahydropyran-2,3,4,5-tetraol

NUS lo SI vo

He

The alcohol of example 1, stage O (51 mg, 0.093 mmol) was treated with ASON':H2O at a ratio of 1:1 (1 mL) at 802 in a sealed ampoule for 18 hours. The reaction mixture was cooled to room temperature and diluted

EtOAc, transferred to a flask and concentrated in vacuo. The residue was dissolved in CH2Cl3, treated with MnSO2 and Ma5Ox for 30 minutes, filtered and concentrated in vacuo. The product was purified by flash chromatography (4 g of 5iO", 0-

12 96 Meon:SnNesi", 30 minutes, 10 ml/min), suspended in Neo and lyophilized to give (35, 4K, 5, 65)-6-|4-chloro-3-(4-ethoxybenzyl)phenyl| tetrahydropyran-2,3,4,5-tetraol (31 mg, 0.079 mmol, 85 95) as a white solid. NMR revealed C:- and D-anomers at a ratio of 11.

IN YAMRE (400 MGu, methanol-d) 6 m.ch. 7.34 (dd, 9U-8.08, 4.04 Hz, 1H), 7.22-7.30 (m, 2H), 7.09 (d, 9-8.34 Hz, 2H), 6 .80 (d, U-8.08 Hz, 2H), 5.16 (d, 9U-3.79 Hz, 1H o), 4.65 (d, 9U-9.60 Hz, 1H s or D) , 4.59 (d, 9-7.58 Hz, 1H s or p), 4.14 (d, 9-9.60 Hz, 1H sabo p), 3.96-4.07 (m, 4H) , 3.76 (t, U-9.35 Hz, 1H sabo p), 3.50 (dd, U-9.60, 3.79 Hz, 1H o or

P), 3.43 (t, --9.09 Hz, 1H sabo p), 3.23-3.29 (m, 1.5H), 1.36 (t, 9-7.07 Hz, ZN ). MS (Eb.-u) (MAMNAaH -412.

Example 3. Synthesis of (25, ZK, AK, 55)-2-|I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-ethoxytetrahydropyran-3,4,5-triol

Nzs o SI

MA, ot no N on on

A solution of 0.35 M NCI in EUN was prepared by adding AsciI (0.025 mL, 0.35 mmol) to EUN (1 mL) and stirring for 15 minutes. The alcohol of example 1, stage O (61 mg, 0.11 mmol) was treated with the resulting solution for 2 hours at 809C in a sealed ampoule. The reaction mixture was cooled to room temperature, quenched with concentrated MNAOH, brought to the ground state, treated with ManCO3 for 30 minutes, diluted

SneosiI", was filtered and concentrated in a vacuum. The product was purified by flash chromatography (4 g BO", 0-10 95

Meon:snesi", 40 minutes, 10 ml/min), suspended in Neo and lyophilized to give (25, ZK, 4K, 55)-2-|I4-chloro-3-(4-ethoxybenzyl)phenyl|-6 -ethoxytetrahydropyran-3,4,5-triol (40 mg, 0.095 mmol, 85 95) as a white solid. NMR revealed C:- and D-anomers in a ratio of 1.75:1.

IN NMR (400 MHz, chloroform-4) 5 ppm: 7.28-7.32 (m, 1H), 7.14 (m, 2H), 7.02 (d, 9U-8.84 Hz , 2H), 6.72-6.76 (m, 2H), 4.88 (d, 9U-4.04 Hz, 1H axis), 4.37 (d, U-9.60 Hz, 1H axis) , 4.33 (d, 9-7.83 Hz, 1H p), 4.06 (d, 9U-9.35 Hz, 1H p), 3.89-4.02 (m, 4H), 3, 36-3.87 (m, 5H), 2.62 (s, 1H VD), 2.54 (s, 1H oso), 2.41 (d, 9U-1.52 Hz, 1H D), 2, 02 (d, 9-10.936 Gu, 1Н s), 1.92 (d, у-2.53 Hz, 1Н), 1.32 (t, У-6.95 Hz, ЗН), 1.13-1 ,19 (m, ZN). MS (Ebu) (MAMNA) -440.

Example 4. Synthesis of (25, ZK, 4, 55, 65)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-isopropoxytetrahydropyran-3,4,5-triol and (25, ZK , AK, 55, 6K)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-6-isopropoxytetrahydropyran-3,4,5-triol

NzS about SI Nzb. 0 СНз НзС. about si NzS. And SNZ

ХК ХХ no otu son noi su son he he

A solution of 0.35 M CARRIER in I-RHON was prepared by adding AscIi (0.025 mL, 0.35 mmol) to i-RHON (1 mL) and stirring for 15 minutes. The alcohol of example 1, stage O (68 mg, 0.12 mmol) was treated with the resulting solution for 2 hours at 809C in a sealed ampoule. The reaction mixture was cooled to room temperature, quenched with concentrated MNAOH, brought to the ground state, treated with MansSoOz for 30 minutes, diluted

СНосиИ", was filtered and concentrated in a vacuum. The residue was purified by flash chromatography (4 g of 5iO", 0-10 95

Meon:snNegsi", 40 minutes, 10 ml/min.), obtaining 50 mg of the substance, which was then purified by preparative HPLC (column C18 19x50 mm, 20-70 96 Mesm:nHgo (10 mM MNaAOAc), 14 minutes, 30 ml/ min.), obtaining (25, ZK, 4, 55, 65)-2-|(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-isopropoxytetrahydropyran-3,4,5-triol (D-anomer , 7 mg, 0.016 mmol) and (25, ZB, 48, 55, 68)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-isopropoxytetrahydropyran-3,4,5-triol ( sx-anomer, 25 mg, 0.057 mmol). -triol

IN NMR (400 MHz, chloroform-4) 5 ppm: 7.37-7.40 (m, 1H), 7.26 (m, 2H), 7.12 (d, 928.59 Hz, 2H ), 6.80-6.84 (m, 2H), 4.48 (d, 9-7.83 Hz, 1H), 4.15 (d, U-9.35 Hz, 1H), 3.95 -4.10 (m, 5H), 3.69 (t, 9U-9.09 Hz, 1H), 3.46-3.52 (m, 2H), 2.69 (width, 1H), 2.43 (width s, 1H), 2.05 (width s, 1H), 1.41 (t, 9-7.07 Hz, ZN), 1.22 (t, 9-6.57 Hz , 6H). MS (EbBzh)

IMAMNA|-454. (25, ZA, 48, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-isopropoxytetrahydropyran-3,4,5-triol

IN NMR (400 MHz, chloroform-4) 6 m.h.: 7.39 (d, 928.84 Hz, 1H), 7.22 (m, 2H), 7.11 (d, 9-8.59 Hz, 2H), 6.80-6.85 (m, 2H), 5.04 (d, U-4.04 Gu, 1H), 4.51 (d, U-9.60 Hz, 1H), 3.98-4.10 (m, 4H), 3.93 (ddd, U-12.25, 6.32, 6.19 Hz, 1H), 3.82 (t, 9U-9.22 Hz, 1H), 3.62 (dd, 929.47, 3.66 Hz, 1H), 3.49 (t, 9U-9.22 Hz, 1H), 2.03 (width, ЗН), 1, 41 (t, 9U-6.95 Hz, ZN), 1.23 (d, U-6.32 Hz, ZN), 1.19 (d, U-6.06 Hz, ZN). MS (Eb-u) (MAMNAG -454.

Example 5. Synthesis of (25, ZK, AK, 55, 6)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol and (25, ZE , AG, 55, 65)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

NS about SI dream of the National Academy of Sciences. lo SI sne yan, (c) ko t, IF) o

AH AH no n on no N on on on

A sample of the compound of example 1, stage E (80 mg) was dissolved in 4 ml of a mixture of 30 95 ethanol/hexanes and injected in the form of 400 μl portions into a SpigaiRak AO-N column (20x250 mm, 5.5 ml/min., a mixture of 31.55 95 ethanol/hexane as eluent at the same ratio, room temperature, process duration 30 minutes) to separate the two isomers from each other. The first isomer (room temperature, 23 minutes) was identified as the alpha isomer (6E, mg), and the second isomer (room temperature, 26 minutes, 21 mg) was identified as the beta isomer (65). (25, ZA, 48, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.39 (d, 9U-8.84 Hz, 1H), 7.22-7.25 (m, 2H), 7.11 (d , 98.59 Hz, 2H), 6.83 (d, -8.59 Hz, 2H), 4.85 (d, 9U-4.04 Hz, 1H), 4.42 (d, 9U-9, 60 Hz, 1H), 3.99-4.11 (m, 4H), 3.82 (t, 9U-9.22 Hz, 1H), 3.66 (width, 1H), 3.42- 3.48 (m, 4H), 2.79 (width s, 1H), 2.23 (d, 9-1.26 Hz, 1H), 2.12 (width s, 1H), 1.40 (t, 9U-6.95 Hz, ZN).

MS (E5-y (MAMNa) -426. (25, ZA, 48, 55, 65)-2-I(I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5 -triol

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.39 (d, 9U-8.59 Hz, 1H), 7.23-7.26 (m, 2H), 7.11 (d , 9-8.84 Hz, 2H), 6.80- 6.84 (m, 2H), 4.33 (d, 9-7.58 Hz, 1H), 4.07-4.17 (m, 2H), 3.98-4.04 (m, ЗН), 3.68 (t, 9U-9.09 Hz, 1H), 3.46-3.55 (m, 5H), 2.89 (width .с, 1Н), 2.64 (width с, 1Н), 2.16 (width с, 1Н), 1.40 (t, 9-7.07 Hz, ЗН). MS (Eb"u (MAMNAa | -426.

(25, ZK, AK, 55, 65)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol) was also synthesized separately using the following method.

A. Preparation of (35, AK, 55, 65)-2,4,5-triacetoxy-6-|14-chloro-3-(4-ethoxybenzyl)phenyltetrahydropyran-3-yl acetic acid ester

The alcohol of example 1, stage O (6.80 g, 12.4 mmol) was treated with ASON/HgO at a ratio of 3:2 (62 mL) at 10022 for 22 hours. The reaction mixture was concentrated in a vacuum, subjected to vortex mixing with toluene three times and placed in a high vacuum. The residue was treated with acetic anhydride (9.4 mL, 99.2 mmol) in pyridine (25 mL) for 16 h. The reaction mixture was quenched with H2O, stirred for 1 hour, diluted with E2O, washed with 1 M aqueous solution of Manzoh, HgO, saturated aqueous solution of Manzoh and saturated salt solution (with reverse extraction), dried over Ma5O, filtered and concentrated in vacuo. The residue was purified by flash chromatography (120 g 5i0, 0-50 95 EIAs/hexanes), obtaining (35, 4, 55, 65)-2,4,5-triacetoxy-6-14-chloro-3-(4- ethoxybenzyl)phenyl|tetrahydropyran-3-yl acetic acid (6.10 g, 10.9 mmol, 87 95).

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.36 (dd, 9U-8.08, 2.02 Hz, 1H), 7.19 (dt, U-8.34, 2, 02 Hz, 1H), 7.07-7.09 (m, 1H), 7.06 (dd, U-8.72, 1.64 Hz, 2H), 6.83 (d, U-8.59 Hz, 2H), 6.44 (d, U-3.54 Hz, 0.5H o), 5.84 (d, U-8.08 Hz, 0.5H p), 5.55 (t, U -9.98 Hz, 0.5Н o), 5.33 (t, 9U-9.71 Hz, 0.5Н D), 5.20-5.27 (m, 1Н), 5.09 (t, U-9.60 Hz, 0.5 N VD), 5.03 (t, 9-9.73

Hz, 0.5N os), 4.78 (d, 910.11 Hz, 0.5N os), 4.47 (d, 9U-9.85 Hz, 0.5N dD), 3.94-4, 09 (m, 4H), 2.20 (s, 1.5H oso), 2.11 (s, 1.5H

Р), 2.06 (s, 1.5Н D), 2.05 (s, 1.5Н о), 2.02 (s, 1.5Н о), 2.01 (s, 1.5Н ВД) , 1.74 (s, 1.5Н s), 1.72 (s, 1.5Н D), 1.41 (t, U-6.95

Hz, ZN). MS (E5.u (Me-MNa)"-580.

B. Preparation of (25, 35, 4K, 55, 65)-4,5-diacetoxy-2-bromo-6-|14-chloro-3-(4-ethoxybenzyl)phenyl|hetrahydropyran-

Z-yl ester of acetic acid

Tetraacetate from stage A (8.08 g, 14.4 mmol) was treated with 33 95 Ng in ASON (30 mL) for 1 hour. The reaction mixture was diluted with СНоСі» (60 ml), stirred for 30 minutes, diluted with OSM, washed three times with ice-cooled Neo and a saturated aqueous solution of Manso»z (with reverse extraction), dried over Ma5O», filtered and concentrated in vacuo to give (25 , 35, 4, 55, 65)-4,5-diacetoxy-2-bromo-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|tetrahydropyran-3-yl ester of acetic acid.

IN YAMRE (400 MHz, chloroform-4) b m.h.: 7.37 (d, 9U-8.34 Hz, 1H), 7.17 (dd, 958.21, 2.15 Hz, 1H), 7.12 (d, 952.27

Hz, 1), 7.06 (d, 9U-8.59 Hz, 2H), 6.83 (d, 9U-8.59 Hz, 2H), 6.71 (d, 9U-4.04 Hz, 1H), 5.64 (t, 9U-9.73 Hz, 1H), 5.10 (t, 9-9.73 Hz, 1H), 4.92-4.98 (m, 2H), 3, 94-4.11 (m, 4H), 2.13 (s, ЗН), 2.03 (s, ЗН), 1.74 (s, ЗН), 1.41 (t, 9-7.07 Hz , ZN). MS (E5A) (MAMNA) -602. b. Preparation of (25, 35, Ak, 55, 65)-4,5-diacetoxy-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-2-methoxytetrahydropyran-3-yl acetic acid ester

Crude bromide from stage B (8.4 g, 14.4 mmol) and 2n0 (1.2 g, 14.4 mmol) were dissolved in Meon (144 mL) and heated at 702C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite with EtOAc and concentrated in vacuo. The residue was recrystallized from Meon in two portions to give (25, 35, 4, 55, 65)-4,5-diacetoxy-6-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-2-methoxytetrahydropyran- Acetic acid 3-yl ester (5.98 g, 11.2 mmol, 78 95) in the form of pure p-anomer.

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.37 (d, U-8.08 Hz, 1H), 7.22 (dd, 9U-8.21, 2.15 Hz, 1H ), 7.05-7.10 (m, ЗН), 6b.80-6.85 (m, 2H), 5.29 (t, 59.47 Hz, 1H), 5.11 (dd, 9U- 9.73, 7.96 Gu, 1H), 5.02 (t, 929.73 Hz, 1H), 4.54 (d, U-8.08 Hz, 1H), 4.33 (d, U- 9.85 Hz, 1H), 3.96-4.09 (m, 4H), 3.49 (s, ЗН), 2.08 (s, ЗН), 1.99 (s, ЗН), 1, 71 (s, ZN), 1.41 (t, U-6.95 Hz,

ZN). MO (EBBU) (MAMNA)!-552.

O. Preparation of (25, ZE, AK, 55, 65)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

Recrystallized triacetate from step C (5.98 g, 11.2 mmol) was treated with KCO3 (7.7 g, 56 mmol) in MEOH (112 mL) with vigorous stirring for 1 h. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in OSM, washed with H2O and saturated salt solution, dried over

M95Bo", was filtered and concentrated in a vacuum. The residue was passed through a layer of silica gel with 5 95 Meon:CN, concentrated in vacuo, suspended in H2O and lyophilized to give (25, ZK, AK, 55, 65)-2-|14-chloro-3-(4-ethoxybenzyl) phenyl|-b-methoxytetrahydropyran-3,4,5-triol (4.37 g, 10.7 mmol, 96 95) as a white solid.

IN NMR (400 MHz, chloroform-4) 6 m.h.: 7.39 (d, 928.59 Hz, 1H), 7.23-7.27 (m, 2H), 7.11 (d, 9U -8.59 Hz, 2H), 6.82 (d, U-8.59 Hz, 2H), 4.33 (d, U9-7.83 Hz, 1H), 4.15 (d, 9U-9 ,35 Hz, 1H), 3.98-4.12 (m, 4H), 3.68 (t, U-9.09 Gu, 1H), 3.53 (s,

ЗН), 3.46-3.53 (m, 2H), 2.80 (width s, 1H), 2.58 (width s, 1H), 2.09 (width s, 1H), 1 .40 (t, 9-7.07 Hz, ZN). MS (Ebu

IM-AAMNA)-426.

Example 6. Synthesis of M-(е25, 35, а4в, 5, 65)-6-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxytetrahydropyran-2-ylyl M-propylacetamide seam po. - powder: but N on on

The bromide of Example 5, stage B (58 mg, 0.1 mmol) was treated with propylamine (0.1 mL) in CH 2 ocSi (0.5 mL) at 402C for 1.5 h. The reaction mixture was purged with M", then purged twice with SNeoSi". The residue was treated with acetic anhydride (78 μL, 0.82 mmol) in pyridine (1 mL) overnight. The reaction mixture was quenched with MeOnH, stirred for 30 minutes, diluted with ETO, washed with 1 M aqueous solution of Manzoch, HgO, saturated aqueous solution of MansoOz and saturated salt solution (with reverse extraction), dried over MdzoO", filtered and concentrated in vacuum. The intermediate was treated with K2CO3 (14 mg, 0.10 mmol) in MeOH (1 mL) for 1.5 h. The reaction mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (12 g

BIO", 0-10 95 Meon:SNe2), obtaining a substance with a purity of 90 95. The product was further purified by HPLC (column C18 19x50 mm, 20-70 95 Mesm:Nho (10 mM MNaAOAc), 14 minutes, 30 ml/min. ), suspended in HgO and lyophilized, obtaining M-(25, 35, 48, 58, 65)-6-I(4-chloro-3-(4-ethoxybenzyl)phenyl/|-3,4,5-trihydroxytetrahydropyran- 2-yl)-M-propylacetamide (3 mg, 0.0063 mmol, 15 95) in the form of rotamers at a ratio of 2:1.

IN NMR (400 MHz, Meob) 5 m.h.: 7.29-7.40 (m, 1H), 7.16-7.26 (m, 2H), 7.08 (d, 9-86 Hz , 2H), 6.81 (d, U-8.6 Hz, 2H), 5.59 (d, U-8.6 Hz, 0.33H), 4.98 (d, 9-11.9 Hz , 0.67N), 4.25 (d, 9U-9.3 Hz, 0.67N), 4.17 (d, 9U-9.9 Hz, 0.33N), 3.92- 4.06 ( m, 4H), 3.46-3.64 (m, ZN), 3.06-3.28 (m, 2H), 2.16 (s, ZN), 1.49-1.68 (m, 2H), 1.36 (t, U-6.9 Hz, ZN), 0.93 (t, 9-7.5

Hz, 1H), 0.87 (t, 9-7.5 Hz, 2H). MS (Ebzu) (MANI -478.

Example 7. Synthesis of oxime (2E, 35, 45, 55)-5-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-2,3,4,5- tetrahydroxypentanal

Nzb. o SI on «ONA nob U tone on

The compound of example 2 (50 mg, 0.13 mmol) and hydroxyamine hydrochloride (26 mg, 0.38 mmol) were dissolved in pyridine (0.65 ml) and stirred for 3 hours. The reaction mixture was diluted with EIHUACs, washed with 1 M aqueous solution

Manzoh, NgO, a saturated aqueous solution of MansSOOz and a saturated salt solution (with reverse extraction), dried over Ma»5Ox4, filtered and concentrated in a vacuum. The residue was suspended in Neo and lyophilized to give (2K, 35, 45, 55)-5-|14-chloro-3-(4-ethoxybenzyl)phenyl|-2,3,4,5-tetrahydroxypentanal oxime (46 mg, 0 ,11 mmol, 88,905) in the form of a mixture of oxime isomers at a ratio of 5:1.

Major isomer

IN NMR (400 MHz, Meob) 5 m.h.: 7.31-7.36 (m, 2H), 7.23-7.30 (m, 2H), 7.10 (d, 9-8, 8 Hz, 2H), 6.80 (d, 9U-8.6 Hz, 2H), 4.63 (d, 9-81 Hz, 1H), 4.28 (t, 9U-6.8 Hz, 1H ), 3.96-4.03 (m, 4H), 3.90-3.94 (m, 1H), 3.59 (dd, 9U-8.0, 1.6 Hz, 1H), 1, 36 (t, U-6.9 Hz, ZN); MS (EbZ-) (MANI -410.

Example 8. Synthesis of oxime (35, Ak, 5E, 65)-6-|14-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxytetrahydropyran-2-one

NzS mo SI i pr, IF) r: oo

He

A. Preparation of (35, AK, 55, 65)-4,5-diacetoxy-6-14-chloro-3-(4-ethoxybenzyl)phenyl|-2-hydroxytetrahydropyran-3-yl ester of acetic acid

The tetraacetate of Example 5, Step A (200 mg, 0.36 mmol) was treated with benzylamine (39 μL, 0.36 mmol) in DMF (1.8 mL) for 2 hours. The reaction mixture was diluted with EC2O, washed with a 1M aqueous solution of Manzosia, Ngo, a saturated aqueous solution of ManHsSOOz and a saturated salt solution, dried over MudbBO»4, filtered and concentrated in a vacuum. The residue was purified by flash chromatography (12 g 5i0", 0-50 95 EOAc:hexanes), obtaining (35, 48, 55, 65)-4,5-diacetoxy-6-14-chloro-3-(4-ethoxybenzyl) phenyl|-2-hydroxytetrahydropyran-3-yl acetic acid ester (142 mg, 0.27 mmol, 77,905) as anomers in a 3:1 ratio.

IN NMR (400 MHz, chloroform-a) 5 ppm: 7.33-7.40 (m, 1H), 7.18-7.23 (m, 1H), 7.09-7.14 ( m, 1H), 7.06 (d, U-8.6 Hz, 2H), 6.82 (d, 9U-8.6 Hz, 2H), 5.59-5.66 (m, 0.75H ), 5.56 (t, 9U-3.7 Hz, 0.75N), 5.34 (t, 9U-9.6 Hz, 0.25N), 4.90-5.11 (m, 2, 75Н), 4.86 (t, U-8.2 Hz, 0.25Н), 4.39 (d, U-9.9 Hz, 0.25Н), 3.93-4.10 (m, 4Н ), 3.36 (d, 9U-8.6 Hz, 0.25Н), 2.81 (dd, 93.8, 1.3 Hz, 0.75Н), 2.12 (s, 0.75Н) , 2.12 (s, 2.25N), 2.02 (s, 0.75N), 2.01 (s, 2.25N), 1.73 (s, 2.25N), 1.72 (s , 0.75Н), 1.А1 (t, 9-71 Hz, ЗН); MS (Eb.-y) (MAMNAG -538.

B. Preparation of (35, Ak, 55, 65)-4,5-diacetoxy-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-2-(2)-hydroxyimino|tetrahydropyran-3-yl ether acetic acid

The compound from stage A (142 mg, 0.27 mmol) and hydroxyamine hydrochloride (57 mg, 0.82 mmol) were dissolved in pyridine (1.4 mL). The reaction mixture was stirred for 6 hours, diluted with EtOAc, washed with 1M aqueous solution

Manzo», NgO, a saturated aqueous solution of MansoOz and a saturated salt solution (with reverse extraction), dried over Ma»5O»x, filtered and concentrated in a vacuum. The residue was dissolved in SNeosCl, cooled to -

782C, was treated with OB (49 μl, 0.33 mmol) and then with M-chlorosuccinimide (44 mg, 0.33 mmol). The reaction mixture was stirred for 20 minutes at -782C and allowed to warm to room temperature for 15 minutes. The reaction mixture was diluted with EtOAc, washed with H2O and saturated salt solution (with reverse extraction), dried over Ma953O», filtered and concentrated in vacuo. The residue was purified by flash chromatography (12 g 5iO", 0-50 90 EOAc:hexanes), obtaining (35, 4K, 55, 65)-4,5-diacetoxy-6-14-chloro-3-(4-ethoxybenzyl) phenyl|-2-|(2)-hydroxyimino|hetrahydropyran-3-yl acetic acid ester (97 mg, 0.18 mmol, 67 Vol).

IN NMR (400 MHz, chloroform-4a) 5 m.h.: 7.42 (d, 98.1 Hz, 1H), 7.30 (dd, 9U-8.2, 2.1 Hz, 1H), 7.18 (d, 9U-2.3 Hz, 1H), 7.07 (d, U-8.6 Hz, 2H), 6.83 (d, 9U-8.6 Hz, 2H), 6, 64 (s, 1H), 5.53 (d, 9U-4.5 Hz, 1H), 5.28 (dd, 9U-5.8, 4.5 Hz, 1H), 5.16-5.22 (m, 1H), 5.10-5.15 (m, 1H), 3.98-4.10 (m, 4H), 2.19 (s, ЗН), 2.07 (s, ЗН), 1.78 (s, ZN), 1.41 (t, 9-71 Hz, ZN);

MO (E5-5 (MANI -534.

C. Preparation of oxime (35, 48, 5B, 65)-6-I(4-chloro-3-(4-ethoxybenzyl)phenyl/|-3,4,5-trihydroxytetrahydropyran-2-one

The compound from step B (97 mg, 0.18 mmol) was treated with a 7.0 M solution of Mn in MeOH (1.8 mL) for 1 hour.

The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (12 g 51iO»2, 0-12 95

Meon:cH»cSiI»), suspended in HgO and lyophilized, obtaining oxime (35, 4K, 5K, 65)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxytetrahydropyran -2-one (57 mg, 0.14 mmol, 77 95) as a white solid.

IN NMR (400 MHz, Meob) 5 m.h.: 7.36-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.12 (d, 98.8 Hz , 2H), 6.80 (d, 9U-8.8 Hz, 2H), 4.91-4.95 (m, 1H), 4.14 (d, 9U-5.6 Hz, 1H), 4 .03-4.10 (m, 2H), 3.99 (sq, 9-7.1 Hz, 2H), 3.73-3.78 (m, 1H), 3.55 (dd, 929.9 , 6.6 Hz, 1H), 1.36 (t, 9-71 Hz, ЗН); MS (EvBu) (MANI -408.

Example 9. Synthesis of (25, ZE, AK, 5K)-2-|(4-chloro-3-(4-ethoxybenzyl)phenyl|-5-fluoro-6-methoxytetrahydropyran-3,4-diol

NS io SI du po a:

He

A. Preparation of (25, ZK, 45)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydro-2H-pyran-3,4-diyldiacetate

In a flask containing 282 mg of tetraacetate of example 5, stage A (0.5 mmol), 1.25 ml of HBg (33 95 in

NOAc). The reaction mixture was stirred for one hour, diluted with 50 ml of dichloromethane and quenched by pouring ice water into the mixture. The organic layer was separated and washed with a saturated aqueous solution

Mansoz and saturated salt solution. The mixture was dried over magnesium sulfate and the solvents were concentrated in vacuo.

The crude residue was taken up in 0.5 mL of dichloromethane and added to a suspension of copper(II) sulfate (20 mg, 0.125 mmol), powdered 2n (82 mg, 1.25 mmol), and sodium acetate (984 mg, 12 mmol) in 2.5 ml of a mixture of acetic acid/water (3:2, vol.:06.). The resulting mixture was stirred at room temperature for 4 hours, then another 20 mg of copper(II) sulfate and 82 mg of powdered 2p were added to the reaction mixture and stirred for 18 hours. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and removed in vacuo. Flash chromatography gave (25, ZK, 45)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydro-2H-pyran -3,4-diyldiacetate (32 mg, yield 16 9).

IN YAMRE (400 MHz, chloroform-4) b m.h.: 7.36 (d, U-8.08 Hz, 1H), 7.20 (dd, 98.08, 2.27 Hz, 1H), 7.16 (d, 952.27

Hz, 1H), 7.08 (d, 9U-8.59 Hz, 2H), 6.82 (d, 9U-8.59 Hz, 2H), 6.57 (dd, U-6.06, 1 ,52 Hz, 1H), 5.54 (ddd, 9U-7.07, 2.53, 1.52

Hz, 1), 5.32 (dd, uU-9.60, 7.07 Hz, 1H), 4.83-4.88 (m, 1H), 4.01 (kv, U-6.82 Hz , 2H), 3.96-4.10 (m, 2H), 1.96 (s, ЗН), 1.77 (s, ЗН), 1.40 (t, 9U-6.82 Hz, ЗН) . MS (Eb.-u) (MAMNA)-462.

B. Preparation of (25, ZK, 48, 58, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5-fluoro-6-methoxytetrahydro-2H-pyran-3,4-diol

Selectfluor"" (45 mg, 0.128 mmol) was added to a solution of the compound from stage A (38 mg, 0.0853 mmol) in 0.4 mL of a mixture of acetonitrile:methanol (1:1, v:06). The reaction mixture was stirred at room temperature and the completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with 2 ml of saturated aqueous solution

MNaCl and extracted with diethyl ether (2x5 ml). The organic extract was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (5-10 95 ethyl acetate/hexanes) yielded a fluorinated product. Then potassium carbonate (5 mg) was added to a solution of the isolated product in 0.5 ml of methanol.

The reaction mixture was stirred at room temperature for 2 hours, quenched with 2 ml of water and extracted with ethyl acetate (2x4 ml). The organic layer was filtered through a layer of silica and concentrated to give 6.3 g of (25, ZE, 4, 5, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5-fluoro-6- methoxytetrahydro-2H-pyran-3,4-diol in the form of a clear oil.

IN NMR (400 MHz, chloroform-d, o: anomers at a ratio of 3:2, axial:equatorial fluorine at a ratio of 2:1, isomers due to the insignificant content of equatorial fluorine in the structure are marked in italics) b.m.: 7.41 ( dd, U-8.34, 2.78 Hz, 1H), 7.20-7.33 (m, 2H), 7.11 (d, U-8.59 Hz, 2H), 6.83 (d , U-8.59 Hz, 2H), 4.92-5.02 (m, 1H), 4.30-4.52 (m, 1H), 3.96-4.27 (m, 6H), 3.74 (t, 9U-9.09 Hz, 0.66Н о), 3.57/3.56 (с, ЗН), 3.49 (t, У-9.09 Hz, 0.33Н р) , 3,42/3,A41 (c, ZN). MS (EZUMAMNA) -428.

Example 10. Synthesis of (25, ZE, 4, 55)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

SSO p, but t on on

A. Preparation of (4-(5-bromo-2-chlorobenzyl)phenoxy|tert-butyldimethylsilane

This compound was prepared as described in US Patent Application Publication No. 2006/0251728, filed in the name of Nitte!5rasni ei ai!. and published on November 9, 2006.

B. (5)-3-(4-«(tert-butyldimethylsilanyloxy)benzyl|-4-chlorophenyl(Zaz, 55, be, bab)-6-(tert-butyldimethylsilanyloxy)-2,2-dimethyltetrahydrofuroi(2,3 -α111,3|dioxol-5-yl|methanol

A solution of 0.85 g (2.07 mmol) of the compound from stage A in 4.14 ml of diethyl ether was cooled to -78 "С in an inert atmosphere. 2.66 ml of tert-butyllithium (1.55 M solution in hexanes, 4.14 mmol) for 5 minutes. The reaction mixture was stirred at -78 "C for 30 minutes. A solution of 0.5 g (1.65 mmol) of the compound of example 1, stage B, in 1.65 ml of diethyl ether was added. The reaction mixture was stirred at -78 °C for 30 minutes and then for 1.5 hours at 0 °C. The crude reaction mixture was filtered through a layer of silica gel with an excess of diethyl ether, which was then removed in vacuo. The resulting product consisted of diastereomers at a ratio of approximately 1.2:1 in freshly prepared secondary alcohol. Diastereomers were easily separated by chromatography on silica gel (4-8 95 gradient mixture of ethyl acetate/hexanes). Yield: 40 95 (required diastereomer), 58 9o (undesired diastereomer).

IN NMR (400 MHz, chloroform-4) 6 m.h.: 7.17 (d, 928.34 Hz, 1H), 7.07-7.11 (m, 1H), 7.03 (d, 9U -1.77 Hz, 1H), 6.85 (d, U-8.59 Hz, 2H), 6.56 (d, U-8.34 Hz, 2H), 5.80 (d, 9-3 .79 Hz, 1H), 4.70 (d, 9U-4.80 Hz, 1H), 4.20 (d, 9-3.79 Hz, 1H), 4.07 (dd, U-4.80 , 3.03 Hz, 1H), 3.97 (d, U-3.03 Hz, 1H), 3.85 (d, U-3.03 Hz, 2H), 3.16 (width s, 1H ), 1.27 (s, ZN), 1.13 (s,

ЗН), 0.80 (с, 9Н), 0.73 (с, 9Н), 0.00 (с, 6Н), -0.06 (с, ЗН), -0.18 (с, ЗН).

C. Preparation of (25, ZK, AK, 55)-2-I4-chloro-3-(4-hydroxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4,5-triol

Acetyl chloride (0.17 mL) was added to 7 mL of methanol and stirred for 15 minutes at room temperature. The resulting solution was transferred to an ampoule containing 0.446 g of the compound from stage B, which was then sealed and heated to 80 "C for 1 hour. The reaction mixture was cooled to room temperature and quenched with 50 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3x50 The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (0-2095 methanol/dichloromethane gradient) to give a mixture of c:p anomers at a ratio of about 1: 1. Output: 65 95.

IN NMR (400 MHz, acetone) 5 m.h.: 8.12 (width s, 1H), 7.33-7.40 (m, 2H), 7.29 (dd, 9U-8.08, 1.77 Hz, 1H), 7.06 (d, y-8.34 Hz, ЗН), 6.75 (d, y-8.34 Hz, 2H), 4.73 (d, 9-3, 54 Hz, 0.5N axis), 4.A1 (d, U-9.60 Hz, 0.5N axis), 4.33 (d, 9U-7.58 Hz,

O,BN B), 4.19 (d, 9U-9.35 Hz, 0.5Н 5), 4.01 (t, U-3.28 Hz, 2Н), 3.72 (t, U-9 .09 Hz, 0.5N), 3.44-3.55 (m, 1N), 3.41 (s, 1.5N

B), 3.935 (s, 1.5H o), 3.27-3.37 (m, 1.5H). MS (Eb5-) |MAMNA| -398.

Example 11. Synthesis of (25, ZE, 45, 5K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|tetrahydropyran-3,4,5-triol

KO) SI s no N on one (5)-(tetrahydrofuran-3-yl) toluene-4-sulfonic acid ester (31 mg, 0.126 mmol) was added to a suspension of the compound of Example 10, stage C (16 mg, 0.042 mmol) and of cesium carbonate (46 mg, 0.126 mmol) in 0.22 ml of M, M-dimethylformamide. The reaction vessel was sealed and heated to 80 °C for 15 hours. The crude reaction mixture was cooled to room temperature, quenched with 2 ml of saturated salt solution and extracted with ethyl acetate (3x2 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo.

Chromatography on silica gel (0-10 95 gradient of a methanol/dichloromethane mixture) yielded (25, ZE, 45, 58)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|tetrahydropyran-3,4,5 -triol in the form of a clear viscous oil, which was concentrated in dichloromethane to give a white solid (10 mg, yield 55 9).

IN NMR (400 MGu, acetone) 5 ppm: 7.35-7.41 (m, 2H), 7.30 (dd, 9U-8.34, 2.02 Hz, 1H), 7.16 (d, U-7.58 Hz, 2H), 6.83 (d, --8.59 Hz, 2H), 4.93-5.01 (m, 1H), 4.74 (d, 9- 3.79 Hz, 0.5N o), 4.42 (d, U-9.60 Hz, 0.5N so), 4.33 (d, 9-7.58 Hz, 0.5N

B), 4.20 (d, --9.60 Hz, 0.5Н p), 4.05 (t, 9У-2.53 Hz, 2Н), 4.05 (д, 9У-5.31 Hz , 2H), 3.93 (dd, 9U-10.11, 4.80 Hz, 1H), 3.75- 3.89 (m, 2H), 3.72 (t, --9.09 Hz, 1H), 3.50 (t, 929.09 Hz, 1H), 3.41 (s, 1.5H p), 3.35 (s, 1.5H so), 3.29-3.34 (m , ZN), 2.16-2.27 (m, 1H), 1.97-2.04 (m, 1H). MS (Eb.-u) (MAMNA)"-468.

Example 12. Synthesis of (25, 35, 45, 5K)-2-|14-chloro-3-(4-hydroxybenzyl)phenyl|piperidine-3,4,5-triol

NzS 0 SI lo, M «o on

A. Preparation of (Zav, 55, be, base)-5--azido|(5)-4-chloro-3-(4-ethoxybenzyl)phenyl|methyl)-2,2-

dimethyltetrahydrofuroi|2,3-41/1,3|dioxol-b-yloxy)tert-butyldimethylsilane

To a solution of the C5-epimer of the alcohol of example 1, stage O (682 mg, 1.24 mmol) and PP3 (489 mg, 1.87 mmol) in THF (6.2 ml) was added OIAO (366 μl, 1.87 mmol) and then diphenylphosphorylazide (ORPA, 323 μl, 1.49 mmol). The reaction mixture was stirred for 1.5 hours, quenched with a saturated aqueous solution of MNACI, diluted with ESO, washed with HgO and a saturated salt solution (with reverse extraction), dried over Md5Ox and concentrated in vacuo. The residue was purified by flash chromatography (40 g 5iO, 0-8 95 EtOAc:hexanes), obtaining ((Zaz5, 55, b, bab)-5--azido|(5)-4-chloro-3-(4- ethoxybenzyl)phenyl|methyl)-2,2-dimethyltetrahydrofuroi|2,3-4111,3|dioxol-b-yloxy)tert-butyldimethylsilane (636 mg, 1.11 mmol, 89 95) as a yellow oil.

IN NMR (400 MHz, chloroform-4) 6 m.h.: 7.40 (d, 928.08 Hz, 1H), 7.16-7.20 (m, 1H), 7.15 (d, 9U -2.02 Hz, 1H), 7.10 (d, --8.59 Hz, 2H), 6.80-6.85 (m, 2H), 5.79 (d, 9U-3.54 Hz , 1H), 4.58 (d, U-9.85 Hz, 1H), 4.36 (d, U-3.54 Hz, 1H), 4.30 (d, 92.53 Hz, 1H), 4.14 (dd, U-9.98, 2.65 Hz, 1H), 3.98-4.10 (m, 4H), 1.38-1.43 (m, 6H), 1.29 ( c, ZN), 0.96 (c, 9H), 0.20 (c, 6H). MO (EBBU) (MAMNA) -591.

B. Preparation of (2, 35, 45, 55)-5-azido|(5)-4-chloro-3-(4-ethoxybenzyl)phenyl|methylutetrahydrofuran-2,3,4-triol

Acetyl chloride (0.175 mL, 2.45 mmol) was added to Men (7 mL). The solution was stirred for 15 minutes, then added to the azide from step A (392 mg, 0.68 mmol). The reaction mixture was stirred for 16 hours, concentrated in vacuo, vortexed twice with Meon, and placed under high vacuum to give a white solid. The solid was treated with 1:1 ASON:NgO (7 mL) at 10022 for 2.5 h. The reaction mixture was concentrated under vacuum, vortexed twice with toluene and placed under high vacuum. The residue was purified by flash chromatography (40 g 5i0", 0-695 mMeon:snesi"), obtaining (2, 35, 45, 55)-5-azido|(5)-4-chloro-3-(4-ethoxybenzyl )phenyl|methyltetrahydrofuran-2,3,4-triol (223 mg, 0.53 mmol, 78 95) in the form of a mixture of anomers.

IN NMR (400 MGu, Meob) 5 m.h.: 7.39 (dd, uU-8.46, 3.41 Hz, 1H), 7.24-7.30 (m, 2H), 7.09 (d, 9-8.84 Hz, 2H), 6.81 (dd, U-8.59, 1.77 Hz, 2H), 5.33 (d, U-3.54 Hz, 0.5H) , 4.98 (s, 0.5H), 4.84 (d, 9U-10.17 Hz, 0.5H), 4.66 (d, 9U-9.09 Gu, 0.5H), 4, 10-4.23 (m, 2H), 3.97-4.05 (m, 4.5H), 3.89 (dd, uU-3.66, 1.89 Hz, 0.5H), 1, 36 (t, 9U-6.95 Hz, ZN). MC (EBU)

IMAMNA|-437.

C. Preparation of (25, 35, 45, 5K)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|piperidine-3,4,5-triol

The compound from stage B (216 mg, 0.52 mmol) was hydrogenated at atmospheric pressure of Neo over RIO3 (6 mg, 0.026 mmol) in

Meon (5 ml) with ASON (0.25 ml) for b hours. The reaction mixture was filtered, concentrated in a vacuum, diluted with EOAc, washed with 10 96 aqueous solution of K»CO3 and saturated salt solution, dried over Mag»5Ox, filtered and concentrated in a vacuum. A portion of the substance (approximately 55 mg) was purified by preparative HPLC (column C18 Ziyipiige 30x100 mm, 20-70 95 Mesm:Nho (10 mM MNAOAc), 15 minutes, 45 ml/min.) and lyophilized, obtaining (25, 35, 45, 5K)-2-|N4-chloro-3-(4-ethoxybenzyl)phenyl|piperidine-3,4,5-triol (27 mg, 0.071 mmol) as a white solid.

IN NMR (400 MHz, Meob) 5 m.h.: 7.35 (d, U-8.08 Hz, 1H), 7.29 (d, 922.02 Hz, 1H), 7.21-7, 25 (m, 1H), 7.10 (d, y-8.34 Hz, 2H), 6.79 (d, y-8.59 Hz, 2H), 4.02 (s, 2H), 3, 99 (q, U9-7.07 Hz, 2H), 3.57 (ddd, U-10.55, 8.65, 5.05 Hz, 1H), 3.33-3.40 (m, 2H) , 3.25-3.29 (m, 1H), 3.12 (dd, 9U-12.00, 5.18 Hz, 1H), 2.56 (dd, U-11.87, 10.86 Hz , 1H), 1.35 (t, U-6.95

Hz, ZN). MS (E5.y (MANI -378.

Example 13. Synthesis of (25, ZE, AK, 55, 6K)-2-I(I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-ethanesulfinyltetrahydropyran-3,4,5-triol and (25, ZK , AK, 55, 6K)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-6-ethanesulfonyltetrahydropyran-3,4,5-triol

NS o SI o Nzb. o SI ro ra v no t on no t on

ON ON

A. Preparation of (25, ZE, 4, 55, 6K)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-b-ethylsulfanyltetrahydropyran-3,4,5-triol

Mabkey (84 mg, 1.0 mmol) was added to a solution of the bromide of Example 5, stage B (291 mg, 0.50 mmol) in EYN (5 ml) at 02C. The reaction mixture was stirred for 30 minutes, diluted with EAs, washed with a diluted aqueous Mahon solution and a saturated salt solution (with reverse extraction), dried over Mag50O4, filtered and concentrated in a vacuum. The residue was purified by flash chromatography (40 g of 5iO", 0-7 96 MEOH:СНоСиг), suspended in H2O and oleophilized, obtaining (25, ZK, 4K, 55, 6K)-2-|(4-chloro-3-( 4-ethoxybenzyl)phenyl|-6-ethylsulfanyltetrahydropyran-3,4,5-triol (126 mg, 0.29 mmol, 58 95) as a white powder.

IN NMR (400 MHz, chloroform-4) 5 m.h.: 7.39 (d, U-8.08 Hz, 1H), 7.18-7.26 (m, 2H), 7.10 (d , U9-8.59 Hz, 2H), 6.80- 6.85 (m, 2H), 4.46 (d, 9U-9.60 Hz, 1H), 4.17 (d, 9U-9, 35 Hz, 1H), 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H), 3.49-3.57 (m, 2H), 2.79 (d , U-2.27 Hz, 1H), 2.67-2.77 (M, 2H), 2.53 (d, 9U-1.77 Hz, 1H), 2.04 (d, 9U-2, 78 Hz, 1H), 1.41 (t, U-6.95 Hz, ЗН), 1.29 (t, 9-7.45 Hz, ЗН). MS (Ebu) (MAMNA)"-456.

B. Preparation of (25, ZK, AK, 55, 6K)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-ethanesulfinyltetrahydropyran-3,4,5-triol and (25, ZE, AG, 55, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-ethanesulfonyltetrahydropyran-3,4,5-triol

To a solution of the compound from stage A (10 mg, 0.023 mmol) in ASON (0.5 ml) was added HgO: (35 wt. 95 solution in HO, 3 mg, 0.092 mmol, 9 μl). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The mixture was purified by chromatography on silica gel (5 95 Meon/SNesig), obtaining (25, ZK, AK, 55, 6K)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-ethanesulfinyltetrahydropyran-3,4 ,5-triol (as a mixture of diastereomers in the position of the sulfur atom) (2 mg, 1995) and (25, z, 4K, 55, 6)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|- 6- ethanesulfonyltetrahydropyran-3,4,5-triol (5 mg, 46 95) in the form of white solids. (25, ZA, 48, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl|-6-ethanesulfinyltetrahydropyran-3,4,5-triol

IN NMR (400 MGu, methanol) b.pp.: 7.37 (m, ЗН), 7.31 (m, 1Н), 7.24 (m, 2Н), 7.10 (m, 4Н), 6.81 (m, 4H), 4.46 (d, 9-9.9 Hz, 1H), 4.28 (d, U-9.6 Hz, 1H), 4.25 (d, 9U-9 .6 Hz, 1H), 4.19 (d, U-9.9 Hz, 1H), 4.03 (m, 4H), 4.00 (m, 4H), 3.85 (t, 9-9 .6 Hz, 1H), 3.76 (t, 9U-9.6 Hz, 1H), 3.57 (m, 2H), 3.37 (m, 2H), 3.09 (m, 1H), 2.99 (m, 1H), 2.91 (m, 1H), 2.80 (m, 1H), 1.31 (m, 12H). MS (Eb-5 (MANI -455. (25, ZA, 48, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-ethanesulfonyltetrahydropyran-3,4,5-triol

IN NMR (400 MHz, methanol) 6 ppm: 7.28 (m, 1H), 7.16 (m, 2H), 6.99 (d, 9U-8.6 Hz, 2H), 6, 71 (d, 9-8.6 Hz, 2H), 4.46 (d, 9-9.6 Hz, 1H), 4.19 (d, 9U-9.4 Hz, 1H), 3.90 ( m, 4H), 3.81 (t, U-9.3 Hz, 1H), 3.46 (t, 9U-9.1 Hz, 1H), 3.24 (t, 9-91 Gu, 1H) , 2.98 (m, 2H), 1.26 (t, U-6.8 Hz, ЗН), 1.18 (t, 9-7.6 Hz, ЗН). MS (Eb.yu) (MAMNA) -488.

Example 14. Synthesis of (2K, 35, 4, 55, 65)-4,5-diacetoxy-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-2-methylsulfanyltetrahydropyran-3-yl acetic acid ovo ;

I (6) Kk

oh sun

And oh b. ro ne To wa

SNz

A. Preparation of (25, ZE, 4, 55, 6kK)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-b6-methylsulfanyltetrahydropyran-3,4,5-triol

Mazme (70 mg, 0.72 mmol) was added to a solution of the bromide of Example 5, stage B (347 mg, 0.60 mmol) in EN (6 mL) at 02C. The reaction mixture was stirred for 30 minutes, then diluted with EAs, washed with a diluted aqueous solution of Mmaon and a saturated salt solution (with reverse extraction), dried over Mag5Ox, filtered and concentrated in a vacuum. The residue was purified by flash chromatography (40 g 5iO", 0-7 956 MeOHn:SNesig), suspended in H2O and lyophilized, obtaining (25, ZK, JA, 55, 6E)-2-I(D4-chloro-3-( 4-ethoxybenzyl)phenyl|-6-methylsulfanyltetrahydropyran-3,4,5-triol (212 mg, 0.43 mmol, 72 95) as a white powder.

IN YAMRE (400 MHz, chloroform-4) b m.h.: 7.39 (d, 9U-8.34 Hz, 1H), 7.22 (dd, 958.08, 2.27 Hz, 1H), 7.17 (d, 952.02

Hz, 1), 7.10 (d, 9U-8.59 Hz, 2H), 6.83 (d, U-8.84 Hz, 2H), 4.38 (d, U-9.60 Gu, 1H), 4.19 (d, 9U-9.35 Hz, 1H), 3.98-4.11 (m, 4H), 3.67-3.73 (m, 1H), 3.48-3 .59 (m, 2H), 2.80 (d, 9-2.27 Hz, 1H), 2.53 (d, U9-2.02 Hz, 1H), 2.19 (s, ЗН), 2 .04 (d, 9U-2.78

Hz, 1H), 1.41 (t, U-6.95 Hz, ЗН). MS (Ebyu (MAMNa | -442.

B. Preparation of (2E, 35, Ak, 55, 65)-4,5-diacetoxy-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-2-methylsulfanyltetrahydropyran-3-yl acetic acid ester

The triol from step A (45 mg, 0.11 mmol) was treated with acetic anhydride (60 μL, 0.64 mmol) in pyridine (0.5 mL) for 16 h. The reaction mixture was diluted with Eb2O, washed with 1 M aqueous solution of Manzoh, HgO, saturated aqueous solution of ManHsSoOz and saturated salt solution (with reverse extraction), dried over Madzoh, filtered and concentrated in vacuo. The residue was purified by flash chromatography (4 g of 5iO, 0-25 95

EOAc/hexanes), suspended in Neo and lyophilized, obtaining (2, 35, 4K, 55, 65)-4,5-diacetoxy-6-I4-chloro-3-(4-ethoxybenzyl)phenyl|-2-methylsulfanyltetrahydropyran- Acetic acid 3-yl ester (46 mg, 0.087 mmol, 79 95) as a white solid.

IN NMR (400 MHz, chloroform-9) 5 m.h.: 7.36 (d, U-8.08 Hz, 1H), 7.18 (dd, 98.21, 2.15 Hz, 1H), 7.02-7.10 (m, ZN), 6.83 (d, U-8.59 Hz, 2H), 5.27-5.34 (m, 1H), 5.19 (t, U- 9.60 Hz, 1H), 5.04 (t, 9U-9.60 Hz, 1H), 4.50 (d, U-9.85 Hz, 1H), 4.37 (d, U-9, 85 Hz, 1H), 3.95-4.08 (m, 4H), 2.16 (s, ЗН), 2.10 (s, ЗН), 2.00 (s, ЗН), 1.72 ( s, ZN), 1.41 (t, 9-7.07 Hz, ZN). MS (E5A) (MAMNA) -568.

Example 15. Synthesis of (25, ZE, Ak, 55, bE)-2-(D-chloro-3-(4-ethoxybenzyl)phenyl|-6-methanesulfonyltetrahydropyran-3,4,5-triol

NzS o SI o.o

SA, o V no N on on

To a solution of the compound of example 14, stage A (41 mg, 0.097 mmol) in ASON (0.5 ml) was added HgO" (35 mab. bo solution in HgO, 20 mg, 0.58 mmol, 57 μl). The mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The mixture was purified by chromatography on silica gel (5 96 MeOH/CHNeosCl3), obtaining (25, ZE, 4v, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methanesulfonyltetrahydropyran-3,4 ,5-triol (20 mg, 45905) as a white solid.

NMR (400 MGu, methanol) 6 ppm: 7.28 (m, 1H), 7.27 (m, 2H), 7.10 (d, 9-84 Hz, 2H), 6.81 ( d, 9-8.4 Hz, 2H), 4.53 (d, 9U-9.6 Hz, 1H), 4.30 (d, 9U-9.6 Hz, 1H), 4.00 (m, 4H), 3.88 (t, 9-91 Hz, 1H), 3.55 (t, 9-91 Hz, 1H), 3.35 (t, 9-91 Hz, 1H), 2.92 (s , ZN), 1.36 (t, U-6.8 Hz, ZN); MS (Eb.'u (MAMNA)-474.

Example 16. Synthesis of 1-(25, 35, 45, 5H)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxypiperidin-1-yl)ethanone

NzS about SI this

But he is HIM

He

Preparation of 1-(25, 35, 45, 58)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5-trihydroxypiperidin-1-yl)ethanone

To a solution of the crude compound of example 12, stage C (38 mg, 0.1 mmol) in MeOH (1 mL) was added acetic anhydride (19 μL, 0.2 mmol). The reaction mixture was stirred for 4 hours, an additional amount of acetic anhydride (10 μL, 0.1 mmol) was added and the mixture was continued to stir overnight. The reaction mixture was diluted with EAs, washed with a saturated aqueous Mansoz solution and a saturated salt solution, dried over

Mag25O4, filtered and concentrated in a vacuum. The residue was purified by flash chromatography (12 g 5iO", 0-8 95

Meon:-cCH»cSiI»), suspended in HgO and lyophilized, obtaining 1-(25, 35, 45, 5H)-2-(I4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5 -trihydroxypiperidine-1-yl)ethanone (14 mg, 0.033 mmol, 33 95 when performing 2 stages) as a white solid.

IN NMR (400 MHz, Meob) 5 m.h.: 7.33 (d, 9U-8.34 Hz, 1H), 7.18 (dd, 9U-8.46, 2.15 Hz, 1H), 7.11 (d, 91.77 Hz, 1H), 7.07 (d, 9U-8.84 Hz, 2H), 6.81 (d, U-8.84 Hz, 2H), 3.96- 4.03 (m, 4H), 3.83-3.89 (m, 1H), 3.73-3.77 (m, 1H), 3.55-3.59 (m, 1H), 2, 09 (width s, ZN), 1.36 (t, U-6.95 Hz, ZN); MS (Ebu) (MANI -420.

Example 17. Synthesis of methyl ether (25, 35, 45, 5K)-2-|14-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxypiperidine-1-carboxylic acid

NIS o si Ou no y on on

To a solution of the crude compound of example 12, stage C (38 mg, 0.1 mmol) and Manso»z (42 mg, 0.5 mmol) in a mixture

Methyl chloroformate (23 μl, 0.3 mmol) was added to EUACEUN:H2H0 in a ratio of 1:1:1 (1.5 ml) at 02C.

The reaction mixture was stirred for 1 hour, diluted with EtOAc, washed with HO and saturated salt solution (with reverse extraction), dried over Mag50O, filtered and concentrated in vacuo. The residue was purified by flash chromatography (4 g of 5iO", 0-10 96 MeOH:SNex", suspended in Neo and lyophilized, obtaining methyl ether (25, 35, 45, 58)-2-I(4-chloro-3-( 4-ethoxybenzyl)phenyl|-3,4,5-trihydroxypiperidine-1-carboxylic acid (12 mg, 0.026 mmol, 26 95 for 2 steps) as a white solid.

IN NMR (400 MHz, Meo0b) 5 m.h.: 7.32 (d, 9-8.34 Hz, 1H), 7.15 (dd, U-8.34, 2.02 Hz, 1H), 7.10 (d, 9-2.27 Hz, 1H), 7.04-7.09 (m, 2H), 6.81 (d, 9-8.59 Hz, 2H), 4.80 (d , 9U-6.06 Hz, 1H), 4.00 (sq., 9U-7.07 Hz, 5H), 3.81-3.86 (m, 1H), 3.70- 3.73 (m, 1H), 3.60 (s, ЗН), 3.54-3.59 (m, 1H), 3.46 (dd, 9U-14.40, 3.28 Hz, 1H), 1.36 (t , 9-6.95 Hz, ZN). MS (Ebu

IMANI-436.

Example 18. Synthesis of allylamide (25, 35, 45, 5K)-2-I4-(chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-trihydroxypiperidine-1-carboxylic acid

N vl no N ОН on

Allyl isocyanate (18 μl, 0.2 mmol) was added to a solution of the crude compound of example 12, stage C (38 mg, 0.1 mmol) in a 1:1 ratio (1 mL) of ЕНЭЕХАСС. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The residue was purified by flash chromatography (4 g of 5iO", 0-10 95 Meon:SnHesi", suspended in HO and lyophilized, obtaining allylamide (25, 35, 45, 5K)-2-I(4-(chloro-3-( 4-Ethoxybenzyl)phenyl|-3,4,5-trihydroxypiperidine-1-carboxylic acid (14 mg, 0.030 mmol, 30,956 in the performance of 2 stages) as a white solid.

IN NMR (400 MHz, Meob) 5 m.h.: 7.32 (d, 98.1 Hz, 1H), 7.16-7.20 (m, 2H), 7.07 (d, 928.8 Hz, 2H), 6.80 (d, 9-88

Hz, 2H), 5.68-5.79 (m, 9U-17.2, 10.2, 5.3, 5.2 Hz, 1H), 4.92-5.00 (m, 2H), 4.77 (d, 9U-6.3 Hz, 1H), 3.94-4.05 (m, 4H), 3.86 (dd, U-14.0, 3.4 Hz, 1H), 3 ,69-3.81 (m, ЗН), 3.59-3.68 (m, 1H), 3.56 (dd, U9-7.3, 5.1 Hz, 1H), 3.47 (dd , U-13.9, 3.5 Hz, 1H), 1.36 (t, U-6.9 Hz, ZN). MS (EB) (MANI -461.

Example 19. Synthesis of (25, 35, 45, 5K)-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|-1-methylpiperidine-3,4,5-triol

Nis i SI os no N (Fin

He

To a solution of the compound of example 12, stage C (50 mg, 0.13 mmol) and Kg2CO3 (55 mg, 0.40 mmol) in DMF (0.65 mL) was added methyl iodide (10 μL, 0.16 mmol). The reaction mixture was stirred for 3 hours, diluted with EAS, washed with H2O and saturated salt solution (with reverse extraction), dried over Ma»5O»4, filtered and concentrated in a vacuum. The residue was purified by flash chromatography (12 g 5iO", 2-1295 Meon:cSnNesi"), suspended in H2O and lyophilized, obtaining (25, 35, 45, 5)-2-(4-chloro-3-(4-ethoxybenzyl) )phenyl|-1-methylpiperidine-3,4,5-triol (16 mg, 0.040 mmol, 31 95) as a white solid.

IN YAMRE (400 MHz, Meob) 5 m.h.: 7.35 (d, 928.1 Hz, 1H), 7.20-7.24 (m, 1H), 7.17 (dd, 9U-8 ,2, 1.9 Hz, 1H), 7.09 (d, 98.6 Hz, 2H), 6.80 (d, 9-86 Hz, 2H), 4.03 (s, 2H), 3, 99 (kv, 97.1 Hz, 2H), 3.64 (ddd, 9-10.5, 9.2, 4.8 Hz, 1H), 3.33-3.37 (m, 1H), 3 .21 (t, 929.0 Hz, 1H), 3.03 (dd, 9U-11.1, 4.8 Hz, 1H), 2.74 (d, 929.3 Hz, 1H), 2.15 (t, 9-10.9 Hz, 1H), 1.95 (s,

ZN), 1.36 (t, U-6.9 Hz, ZN). MS (E5:.yu) (MANI -392.

Example 20. Synthesis of (25, 35, AK, 5, 6K)-2-I3-(4-ethoxybenzyl)phenyl|-b-hydroxymethyl-1-methylpiperidine-3,4,5-triol os i, M KU no H ON ON

A. Preparation of (ZE, 45, 5, 6K)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one

Tetra-O-benzyl-O-glucopyranose (2.07 g, 3.8 mmol) was dissolved in DMSO (10.1 mL). Acetic anhydride (7.0 mL) was added to the resulting mixture and stirred at room temperature overnight. Ice was added to the reaction mixture and stirred for 1 hour. The mixture was extracted with ether (3x20 ml). The extract was washed with water (2x10 ml), aqueous sodium bicarbonate solution (2x10 ml), saturated salt solution, dried (sodium sulfate) and concentrated under vacuum. Flash chromatography on a silica gel column with a mixture of 0-2595 ethyl acetate/hexane yielded 1.712 g of (ЗЕ, 45, 5К, 6К)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H- of pyran-2-one (83 95).

B. Preparation of (ZE, 45, 5E, 6)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H- pyran-2-ol n-Butyllithium (2.5N solution in hexane) (1.263 mL, 3.16 mmol) was added dropwise to a solution of the compound of Example 1, stage C (1.028 g, 3.16 mmol) in anhydrous THF (15 ml) at -782C. The reaction mixture was stirred for 30 minutes at -782C, a solution of the compound from stage A (1.7 g, 3.16 mmol) in anhydrous THF (10 mL) was added dropwise and stirred for 1 hour, allowing the mixture to warm to room temperature. An aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture, THF was removed in vacuo and the aqueous layer was extracted with ethyl acetate (2x20 ml). The combined organic phases were washed with saturated salt solution, dried (sodium sulfate) and concentrated in vacuo. The crude mixture was purified by flash chromatography on a silica gel column using a mixture of 0-20 95 ethyl acetate/hexane to give 712 mg of (ZK, 45, 58, 6H)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl )-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2-ol (29 95). MANgO-802.1.

C. Preparation of (2, ZE, 45)-2,3,4,6-tetrakis(benzyloxy)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexane-1,5-dione

To a stirred solution of Dess-Martin reagent (500 mg, excess) in SNeoSi (10 mL) was added the compound from Step B (500 mg, 0.6 mmol) in anhydrous dichloromethane (10 mL) and stirred overnight. The reaction mixture was quenched with 1N sodium hydroxide solution (3 ml), extracted with dichloromethane (2x10 ml), the combined organic fractions were washed with saturated salt solution, dried over sodium sulfate, concentrated under reduced pressure, obtaining the crude product (487 mg). M-NgO-800.1. Production of (ZE, Ak, 55)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)piperidine

A solution of the compound from stage C (400 mg, 0.5 mmol), 7N ammonia solution in MeonH (1.0 mL) and freshly activated molecular sieves 4A (250 mg) in dichloromethane (20 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, sodium cyanoborohydride (160 mg, 2.55 mmol) was added and heated under reflux for another 2 hours. The reaction mixture was filtered, diluted with dichloromethane (20 ml), washed with water, saturated salt solution, dried (sodium sulfate) and concentrated under reduced pressure. Chromatography on silica gel (50-100 95 acetonitrile containing 0.1 95 ammonium acetate/water gradient) yielded (ZK, 4, 55)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl) -6-(4-chloro-3-(4-ethoxybenzyl)phenyl)piperidine (136 mg, 34 Ob).

IN NMR (400 MHz, chloroform-y) 5 m.h.: 1.41 (t, 927.07 Hz, ZN), 2.98 (ddd, uU-9.40, 8.50, 2.53 Hz , 1H), 3.40 (t, 9-9.22 Hz, 1H), 3.41 (t, U-8.59 Hz, 1H), 3.43 (t, 5-9.09 Hz, 1H ), 3.56 (d, 9U-9.35 Hz, 1H), 3.68 (t, U-8.84 Gu, 1H), 3.79 (dd, 8.97, 2.65 Hz, 1H ), 3.84 (d, U-10.36 Hz, 1H), 3.97 (d, 913.60 Hz, 1H), 3.99 (q, 9U-7.07 Hz, 2H), 4, 10 (d, 915.30

Hz, 1H), 4.43 (d, 9U-10.36 Hz, 1H), 4.48 (d, 9U-2.53 Hz, 2H), 4.56 (d, U-10.86 Hz, 1H), 4.88 (d, U-10.86 Hz, 1H), 4.89 (d, 9-11.12 Gu, 1H), 4.93 (d, 9U-10.86 Hz, 1H) , 6.77 (d, U-8.59 Hz, 2H), 6.88 (dd, 9U-7.71, 1.64 Hz, 2H), 7.07 (d, 9U-8.59 Hz, 2), 7.16-7.38 (m, 21H). MS (Evu) (MANI -768.2.

E. Preparation of (ZE, 4, 55)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine

The compound from step O (50 mg, 0.065 mmol) was dissolved in acetonitrile (1 mL) and treated with potassium carbonate (18 mg, 0.13 mmol) for 30 minutes. To the resulting mixture was added iodomethane (20 μL, 0.32 mmol) and stirred overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography on silica gel (50-100 95 acetonitrile containing 0.195 gradient of ammonium acetate/water) yielded (ZK, 4K, 55)-3,4,5-

tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine (29 mg, 56 95). MN

E. Preparation of (25, 35, 4, 5, 6K)-2-|I3-(4-ethoxybenzyl)phenyl|-6-hydroxymethyl-1-methylpiperidine-3,4,5-triol

The compound from step E (50 mg) in methanol and acetic acid (25 μl) was treated with 5 95 wet Ra-C (10 mg) under Neo for 4 h. The reaction mixture was filtered through a layer of celite and concentrated. Chromatography on silica gel (10-100 95 acetonitrile containing 0.1 95 ammonium acetate/water gradient) yielded (25, 35, ЯК, ЗК, 6К)-2-I3-(4-ethoxybenzyl)phenyl|- 6-hydroxymethyl-1-methylpiperidine-3,4,5-triol (6 mg, 70 Ob).

IN YAMRE (400 MHz, chloroform-a) b m.h.: 1.40 (t, U-6.95 Hz, ZN), 2.02 (s, ZN), 2.05 (width s, ZN ), 2.15 (d, 928.84

HC, 1H), 3.01 (d, 9U-4.55 Hz, 2H), 3.50 (d, U-5.05 Hz, 2H), 3.77 (width, 2H), 3, 85 (d, 9U-8.59 Hz, 2H), 3.91 (width, s, 2H), 3.99 (sq., 9-7.24 Hz, 2H), 6.81 (d, 9U-8 .59 Hz, 2H), 7.06 (d, 9U-8.59 Hz, 2H), 7.09 (width s, 1H), 7.18 (width s, 2H), 7.24 (d , 97.58 Hz, 1H). MO (Ebu) in (MANI -387.0.

Example 21. Synthesis of (25, ZE, AG, 55, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-b6-methoxytetrahydro-2H-thiopyran-3,4,5-triol-o SI

M, o» but Y ОН on

A. Preparation of (5-(15)-((Za5, 65, bab)-6-(tert-butyldimethylsilyloxy)-2,2-dimethyltetrahydrofuro|2,3-a)|11,3|dioxol-5-yl) (4-chloro-3-(4-ethoxybenzyl)phenyl)methylbenzothioate

Diethyl azodicarboxylate (150 μL, 0.914 mmol) was added to a solution of triphenylphosphine (240 mg, 0.914 mmol) in 1.0 mL of THF at room temperature. After one hour, C5-epimer of example 1, stage O (167 mg, 0.305 mmol) in 0.5 mL of THF was added by syringe and then thiobenzoic acid (110 μL, 0.914 mmol) was added by syringe.

The resulting yellow-hot solution was stirred for 22 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (0-10 90 ethyl acetate/hexanes gradient) to afford the title compound as a light yellow oil (104 mg, 50 95 yield). MS (E5B-)

IM-AAMNA)-566.

B. Preparation of (25, ZE, 4, 55, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-thiopyran-3,4,5-triol

Sodium methoxide (0.3 ml of a 4.3M solution in methanol) was added to a solution of the compound from stage A (104 mg, 0.152 mmol) in 6 ml of methanol. After 30 minutes, the reaction mixture was diluted with 20 ml of ethyl acetate and washed with water and saturated salt solution (20 ml of each substance). The organic layer was dried over magnesium sulfate, filtered and the solvents were removed in vacuo. The residue was rapidly purified by flash chromatography (595 ethyl acetate/hexanes) and the product was used immediately to prevent disulfide formation.

One drop of acetyl chloride was added to 1 ml of methanol and stirred for 15 minutes at room temperature. The obtained acidic solution was added to the previously obtained free thiol and heated for 42 hours at 802C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo.

The crude residue was purified by preparative HPLC (column C18 30x250 mm, mixture 5-75 95 acetonitrile:water (10 mm ammonium acetate), 15 minutes, 45 mL/min.), obtaining the title compound (alpha-anomer, 1-13, 82 minutes, 8.7 mg, output 13 9o when performing 2 stages).

IN NMR (400 MGu, acetone-av) 6 ppm: 7.33 (m, 2H), 7.25 (dd, 4-2.27, 8.34 Hz, 1H), 7.13 (d , U-8.59 Hz, 2H), 6.82 (d, 9-8.59 Hz, 2H), 4.48 (d, 9U-3.03 Hz, 1H), 4.02 (s, 2H ), 3.99 (sq, 9U-7.07 Hz, 2H), 3.91 (d, 9U-10.36 Hz, 1H), 3.80-3.85 (m, 2H), 3.68 (dd, U-8.37, 9.35 Hz, 1H), 3.42 (s, ЗН), 1.33 (t, 9-7.07 Hz, ЗН). MS (Ebu) |(MAMNA) -424.

Example 22. Synthesis of (25, 35, AK, 5, 6K)-2-|I4-chloro-3-(4-ethoxybenzyl)phenyl|-6-hydroxymethylpiperidine-3,4,5-triol - o SI : t, M j OH in on

A. Preparation of (2K, ZK, 45, ZK, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-b-methoxytetrahydropyran

Man (60 95 dispersion in mineral oil, 3.34 g, 0.14 mol) was added to a solution of o-Y-methylglucoside (3 g, 15.45 mmol) in DMF (50 ml). An additional amount of DMF (15 ml) was added to the thick suspension formed during the addition to return to solution. The mixture was stirred at room temperature for 30 minutes, cooled to 02C, and allyl bromide (17 g, 0.14 mol, 12 mL) was slowly added. The mixture was then allowed to warm to room temperature and stirred for 18 hours. MeonN was carefully added to the light brown mixture to quench excess Man, then the mixture was concentrated. The residue was diluted

SnOsiI" and washed with H2O, dried (M9504) and concentrated to give a yellow oil. The product was purified by chromatography on silica gel (20 95 EtOAc/hexanes), obtaining (2K, ZK, 45, 5K, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-b-methoxytetrahydropyran (4.06 g, 11.47 mmol, 74 95) in the form of a colorless oil. TLC: K-0.20, 96 EoAc/hexanes.

B. Preparation of (ZK, 45, 5K, 6K)-3,4,5-trisalyloxy-b-allyloxymethyltetrahydropyran-2-ol

A solution of the compound from stage A (10 g, 0.028 mol) in ASON (400 ml) was heated to 902C. TON (2N solution of

NgO, 16.69 g, 0.112 mol, 56 ml) and the mixture was stirred at 902C for 75 minutes. The solution was cooled and diluted with SiO2, washed with H2O (3 times), saturated Mansoz solution, dried (MdzOi) and concentrated to give a yellow solid. The product was purified by chromatography on silica gel (20 95-40 95 EIAs/hexanes), obtaining (ZK, 45, 5, 6K)-3,4,5-trisalyloxy-b6-allyloxymethyltetrahydropyran-2-ol, which is a mixture of anomers, ( 5.85 g, 17.2 mmol, 61 95), as a white solid. TLC: -0.40, 40 96 EAs/hexanes.

C. Preparation of (ZK, 45, 5K, 6K)-3,4,5-trisalyloxy-6-allyloxymethyltetrahydropyran-2-one

Oxalyl chloride (2.75 g, 21.7 mmol, 1.89 mL) was dissolved in SiOCl (90 mL) and the mixture was cooled to -7826.

DMSO (3.39 g, 43.4 mmol, 3.08 ml) was added as a solution in СНоСи (60 ml). The mixture was stirred at -782C for 15 minutes and the compound from stage B (6.70 g, 19.7 mmol) was added as a solution in СНоСи (150 ml).

The reaction mixture was stirred for another 15 minutes at -782C and EizM (9.97 g, 98.5 mmol, 13.7 ml) was added. The mixture was stirred at -782C for another 5 minutes and allowed to warm to room temperature for 30 minutes.

The reaction mixture was quenched with H2O, the organic layer was separated, washed twice with H2O, dried and concentrated to give a light yellow oil. The product was purified by chromatography on silica gel (1595 E(Ac/hexanes), obtaining (ZK, 45, 5, 6K)-3,4,5-trisalyloxy-b-allyloxymethyltetrahydropyran-2-one (2.49 g, 7.37 mmol , 37 90) in the form of a colorless oil. TLC: -0.40, 20 95 E10As/hexanes. Obtaining (ZK, 45, 5, 6k)-3,4,5-trisalyloxy-b-allyloxymethyl-2-| 4-chloro-3-(4-ethoxybenzyl)phenyl|tetrahydropyran-2-ol

The compound of example 1, stage C (2.37 g, 7.31 mmol) was dissolved in THF (25 mL) and cooled to -7820. They added p-Vy drop by drop!| and (2.5N solution in hexanes, 0.47 g, 7.31 mmol, 2.92 mL) and stirred the solution for 15 minutes. The compound from stage C (2.47 g, 7.31 mmol) was added as a solution in THF (25 ml), the reaction mixture was stirred at -782C for another 15 minutes and allowed to warm to room temperature for 30 minutes.

The reaction mixture was quenched with a saturated solution of MNACI and the organic layer was separated. The aqueous layer was back-extracted with ESO, the combined organic parts were dried and concentrated to give a yellow oil.

The product was purified by chromatography on silica gel (10 95-20 95 EAs/hexanes), obtaining (ZK, 45, 5K, 6K)-3,4,5-trisalyloxy-b-allyloxymethyl-2-I4-chloro-3-(4- ethoxybenzyl)phenyl|hetrahydropyran-2-ol (0.95 g, 1.63 mmol, 22 95) as a colorless oil. MS (EbB-x) (MAMNa)"-602.

E. Preparation of (2, ZE, 45)-2,3,4,6-tetrakysalyloxy-1-(4-chloro-3-(4-ethoxybenzyl)phenyl|hexane-1,5-dione

Dess-Martin periodinan (0.68 g, 1.59 mmol) was added to a solution of the compound from stage O (0.93 g, 1.59 mmol) in SNCl (25 mL). The mixture was stirred at room temperature for 1 hour and a second portion of Dess-Martin periodinan (1 eq.) was added. The reaction mixture was stirred for another hour, quenched with Mahon's solution (approximately 4 ml). NgO was added and the organic layer was separated. The aqueous layer was back-extracted with SNaSi, dried and concentrated to form a yellow waxy solid.

The product was purified by chromatography on silica gel (15 95-20 95 EAs/hexanes), obtaining (2К, ЗК, 45)-2,3,4,6-tetrakysalyloxy-1-(4-chloro-3-(4-ethoxybenzyl)phenyl) |hexane-1,5-dione (0.60 g, 1.03 mmol, 65 95) as a white solid. MS (Ebu) (MAMNa|"-600.

E. Preparation of (2kE, ZE, A, 55, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-6-|(4-chloro-3-(4-ethoxybenzyl)phenyl|piperidine

Molecular sieves 4A and ammonium formate (0.13 g, 2.06 mmol) were added to a solution of the compound from stage E (0.60 g, 1.03 mmol) in Men (12 mL). Then Mavnzsm (0.14 g, 2.3 mmol) was added in one portion and the mixture was stirred at room temperature for 1 hour 30 minutes. The reaction mixture was filtered and concentrated. The product was purified by chromatography on silica gel (10 95-20 95 EAs/hexanes), obtaining (2, ZK, 4, 55, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-6-I4-chloro-3-( 4-ethoxybenzyl)phenyl|piperidine (155 mg, 0.27 mmol, 27 95). MS (EbB..)

IMANI-568. b. Preparation of (25, 35, AK, 5, 6E)-2-I(D-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5-tris|(E)-propenyl)oxy|-6- |(E)-propenyl)uoxymethyl|piperidine

ISSOHCHCHRSNzRNYg|PEv (8 mg, 30 mol. 95) in THF (0.3 mL) was stirred under NO until the color changed from red to light yellow (about 5 minutes). The compound from step E (19 mg, 0.033 mol) in THF (0.5 mL) was added, the mixture was stirred at room temperature for 45 minutes and concentrated. The product was purified by chromatography on silica gel (2095 E (OAc/hexanes), obtaining (25, 35, 4, 5K, 6K)-2-I(4-chloro-3-(4- ethoxybenzyl)phenyl/|-3,4, 5-tris((E)-propenyl)oxy|-6-((E)-propenyl)oxymethyl|piperidine (15 mg, 0.026 mmol, 80 95) in the form of a colorless oil. MS (E5'u) (MANI -568 .

H. Preparation of (25, 35, 48, 5H, 6H)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-hydroxymethylpiperidine-3,4,5-triol

The compound from stage C (15 mg, 0.026 mmol) was dissolved in a solution of THF/ASON/n NOSI solution (0.2 ml:0.3 ml:0.15 ml) and heated to 702C for 30 minutes. The mixture was concentrated to give a light yellow oil. The product was purified by preparative HPLC (column C18 Zipige 30x100 mm, 5 μm, 10 945-100 95 V for 15 minutes), obtaining (25, 35, 4K, 5K, 6K)-2-|4-chloro-3-(4- ethoxybenzyl)phenyl|-b-hydroxymethylpiperidine-3,4,5-triol (5 mg, 0.012 mmol, 46 95) as a white solid. MS (Eb-yu) (Ma-NI" -408.

IN NMR (400 MHz, MeOb) 5 m.h.: 7.36 (m, 2H), 7.28 (m, 1H), 7.12 (d, 9U-8.6 Hz, 2H), 6, 10 .8 Hz, 1H), 3.58 (dd, 9-7.6 Hz, 11.1 Gu, 1H), 3.47 (m, 1H), 3.26-3.36 (m, ZN), 2 .70 (m, 1Н), 1.37 (t, 9-71 Hz, ЗН).

Example 23. Synthesis of (25, 35, 4, 5, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-hydroxymethyl-1-methylpiperidine-3,4,5-triol

- lo IF

Me no t on on

A. Preparation of (2, ZK, AK, 55, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-1-methylpiperidine

To a solution of the compound of example 22, stage E (135 mg, 0.24 mmol) in MeSM was added CoCoOz (164 mg, 1.19 mmol).

The mixture was stirred for 30 minutes and Me! (676 mg, 4.76 mmol). The mixture was continued to stir at room temperature for 8 hours, filtered and concentrated. The product was purified by silica gel chromatography (1095 EtOAc/hexanes), obtaining (2, ZK, 4K, 55, 65)-3,4,5-trisalyloxy-2-allyloxymethyl-6-I(4-chloro-3-(4- ethoxybenzyl)phenyl|-1-methylpiperidine (90 mg, 0.15 mmol, 6595) as a colorless oil. MS (Eb5') (MANI -582.

B. Preparation of (25, 35, A, 5, 6K)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-1-methyl-3,4,5-tris|(E)-propenyl) oxy|- 6-((E)-propenyl)uoxymethyl|piperidine

ISSOSDTHRSNzRIg|REv (27 mg, 30 mol. 90) in THF (1 mL) was stirred under NO until the color changed from red to light yellow (approximately 5 minutes). The compound from stage A (62 mg, 0.11 mol) in THF (1.5 mL) was added, the mixture was stirred at room temperature for 45 minutes and concentrated. The product was purified by chromatography on silica gel (2095 E (OAc/hexanes), obtaining (25, 35, 4, 5K, 6K)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-1-methyl-3 ,4,5-tris((E)-propenyl)oxy|-6-((E)-propenyl)oxymethyl|piperidine (62 mg, 0.11 mmol, 100 95) in the form of a colorless oil. MS (E5'u ) (MN) -582.

C. Preparation of (25, 35, 4K, 5, 6K)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-b-hydroxymethyl-1-methylpiperidine-3,4,5-triol

The compound from stage B (54 mg, 0.093 mmol) was dissolved in a solution of THF/AcSO/1Tn NOSI solution (0.5 ml:0.6 ml:0.30 ml) and heated to 702C for 30 minutes. The mixture was concentrated to give a light yellow oil. The product was purified by preparative HPLC (column C18 Zypiige, 30x100 mm, 5 μm, 10 95-100 95 V for 15 minutes), obtaining (25, 35, AK, ZK, 6K)-2-I(4-chloro-3-( 4-ethoxybenzyl)phenyl|-6-hydroxymethyl-1-methylpiperidine-3,4,5-triol (22 mg, 0.052 mmol, 56 95) as a white solid. MS (Eb) (MANI -422.

IN NMR (400 MHz, MeOb) 5 m.h.: 7.31 (m, 2H), 7.22 (m, 1H), 7.07 (d, 9U-8.8 Hz, 2H), 6, 77 (d, U-8.8 Hz, 2H), 4.00 (m, 2H), 3.96 (q, U-7.1 Hz, 2H), 3.90 (m, 2H), 3, 52 (dd, 9-94 Hz, 9.4 Hz, 1H), 3.23-3.32 (m, ЗН), 2.88 (d, U-8.8 Hz, 1H), 2.00 (s , ZN), 1.34 (t, 9-71 Hz, ZN).

Additional compounds

Using techniques described herein and methods known in the art, additional compounds were prepared below in Table 1. Potent 501 T2 inhibitors are marked with an asterisk.

Table 1 phone number; (25, ZA, 48, 55)-2-I3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-34B-triol" Ca NovOv 374 (25, ZB, 48, 55, 65)-2-(4 -chloro-3-(4-ethoxybenzyl)phenyl|-6-(2- San»ysI 4381 hydroxyethoxy)tetrahydropyran-3,4,5-triol" M Y " (35, 48, 58, 65)-2-benzyloxy -6-(4-chloro-3-(4-ethoxybenzyl)phenyltetrahydropyran-3,4,5-triol" SetNeoSiO" 4 (25, ZA, 48, 55)-2-(4-ethoxybiphenyl-3-yl)- 6-methoxytetrahydropyran- and 34B-triol" SgoHg2aOv 378 (MAMNZz) (25, ZB, 4B, 55)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2,2,2 - Senisitvoi | Yavy trifluoroethoxy)tetrahydropyran-3,4,5-triol" SgaNo"SIEZOv 476 (25, ZV, 48, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-( 2- Son CO 4524 methoxyethoxy)tetrahydropyran-3,4,5-triol (25, ZB, 48, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2 - dimethylaminoethoxy)tetrahydropyran-3,4,5-triol SgaNzeSIMO" 466, (25, ZB, AB, 55)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-senses | 4525000 propylsulfanyltetrahydropyran- 3,4,5-triol" SgaNgeSiO55 452 (25, ZA, 48, 55)-2-(D4-chloro-3-(4-ethoxybenzyl)phenyl|- b-imidazol-1-yltetrahydropyran-3,4,5-triol SozNavSIM2Ov 445 methyl ether (35, 4P, 5, 65)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|- ooCyanizes | Manifestations of 3,4,5-trihydroxytetrahydropyran-2-yloxyacetic acid" СгаНа7СИЙУ" in 466.1 (25, ЗВ, 48, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-( 4-methylpiperidin-1-yl)tetrahydropyran-3,4,5-triol SovNaa"SIMO" 475 (25, ZB, 48, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6 -(5-methylthiazol-2-ylamino)tetrahydropyran-3,4,5-triol SgaNatSIM»O55 491 (25, ZB, 4H8, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl |-6-phenoxytetrahydropyran-3,4,5-triol" SevNatSU Ye shcha

M-(25, 35, 4B, 58, 65)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- Senyasimoye | 4500 trihydroxytetrahydropyran-2-yl"u"M- methylacetamide SgaNovSIMO" 450 (25, 35, 48, 55, 65)-4,5-diacetoxy-6-I(4-chloro-3-(4-ethoxybenzyl)phenyl|- SlnisCI BB2 (MeMNiI" 2-methoxytetrahydropyran-3 -yl ester of acetic acid TV Z Z (25, ZB, AB, 55)-2-(D-chloro-3-(4-ethoxyphenoxy)phenyl|-6- oShnesyu, | 428 (Memnou methoxytetrahydropyran-3,4, 5-triol SgoNazSiIU; 428 (MUMN) (25, ZV, 48, 55)-2-(I4-chloro-3-(4-methoxyphenylsulfanyl)phenyl|-6-Sizna Svv 430 (MeMNiU)" methoxytetrahydropyran-3,4 ,5-triol" tat Y Z (25, ZB, AB, 55)-2-ID-chloro-3-(4-methoxybenzenesulfinyl)phenyl|-6- Syna SIU" methoxytetrahydropyran-3,4,5-triol tat 7 (25, ЗВ, АВ, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(3-oxSyanyusu,. | 4522 hydroxypropoxy)tetrahydropyran-3,4,5-triol" CozNeeSiU 452.2 (25, ZB, 48, 55, 68)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2- o Senisyuev | 472(Memnu hydroxyethylsulfanyl)tetrahydropyran-3, 4,5-triol SgaNat7C1Yuv5 472 (MUMNz) (25, ZV, AB, 55)-2-|(D-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2-) Sensitizes | 4563 mercaptoethoxy)tetrahydropyran-3,4,5-triol" SgaNatC1Ov5 456.3 (25, ZB, AB, 55)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2,3 - oSyanyusuiv | 4682 dihydroxypropoxy)tetrahydropyran-3,4,5-triol SozNeeSiUv 468.2 (25, ZB, 48, 55)-2-(4-chloro-3-I4-(2-methoxyethoxy)benzyl|phenyl)- 6- oSenisyu, | 4Bb(memn methoxytetrahydropyran-3,4,5-triol" SgaNatClU; 456 (MUMNz) (25, ZB, AB, 55, 68)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl|-6- Senisyuev | 456(MemNo ethylsulfanyltetrahydropyran-3,4,5-triol" SgaNatC1O55 456 (MEMN") (25, ZB, AB, 55, 68)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl|-6- Synzhsyuv | 442(MeMnou methylsulfanyltetrahydropyran-3,4,5-triol Cg1NavSiU55 442 (MUMNz) (g-chloro-5-(25, ZB, 48, 55, 65)-3,4,5 -trihydroxy-6-ocyanates | 00428000 methoxytetrahydropyran-2-yl)phenyl|-(4-ethoxyphenyl)methanone" SiNozSiU; 423 (25, ZB, AB, 55, 65)-2-(4-chloro-3-I( (4-ethoxyphenyl)hydroxymethyl(phenyl)y-Sanya b-methoxytetrahydropyran-3,4,5-triol" 217725 Y (25, ZB, AB, 55)-2-I|3-(4-ethoxybenzyl)-4- methylphenyl |-6- o Syanyaov | 4ov (memnou m ethoxytetrahydropyran-3,4,5-triol" SgaNavOv 406 (MUMN z) (25, ZV, 48, 55)-2-(4-chloro-3-I4-(2-methylsulfonylethoxy)benzyl|phenyl)-b-methoxytetrahydropyran -3,4,5- Cg2H27Siov5 472 (MAMH3)"triol" (25, ZB, 48, 55)-2-(4-xpor-3-I4-(pyridin-4-yloxy)benzylphenyl-6- CyanNaSIMOE methoxytetrahydropyran- 3,4,5-triol (25, ZB, 4B, 55, 65)-2-(4-chloro-3-(4-ethoxyphenyl)-|(7)- Yellowish | 46400 propylimino|methyl)phenyl)-6-methoxytetrahydropyran-3,4,5-triol SgaNaoSiI MO» 464 (25, ZB, 48, 55)-2-(4-chloro-3-Ia-(thiazol-2-yloxy) )benzylphenyl- 6- Sen SIMOvv methoxytetrahydropyran-3,4,5-triol (25, ZB, AB, 55)-2-(4-chloro-3-I(4-(pyrimidin-5-yloxy)benzyl|phenyl) у-б- Senestoi | 458000 methoxytetrahydropyran-3,4,5-triol" СгзНозСиМОв 459 (25, ЗВ, АВ, 55)-2-14-chloro-3-I(4-(2,6-dimethoxypyrimidine-4- Senysite | 519 yloxy)benzyl|phenyl)-b-methoxytetrahydropyran-3,4,5-triol" SovNatSIM2Ov 513 2-cene, 35, 48, A, 65)-64-chloro-3-(4-ethoxybenzyl)phenyl- 3,4,5- SenNoSIMOv5 4687 trihydroxytetrahydropyran-2-ylulfanilyacetamide (25, ZB, AB, 55, 68)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(furan-2- ylmethylsulfanyl)tetrahydropyran-3,4,5-triol" СгвНатС1О65 490, (25, ЗВ, АВ, 55, 65)-2-4-chloro-3-I((4-ethoxyphenyl)iminomethyl|phenyl)-6 - blue | 422 methoxytetrahydropyran-3,4,5-triol SiNe"SIMO" 422 (25, ЗВ, 48, 55, 65)-2-(3-((4-ethoxyphenyl)hydroxymethyl|phenyl)-6- osianoi | in methoxytetrahyde ropyran-3,4,5-triol SgiNavO? 511 allylamide (25, 35, 45, 52)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- Senecithioe | 46100 trihydroxypiperidine-1-carboxylic acid" SgaNozSIIMaO" 461

M-(2-(28, 35, 4B, 58, 65)-6-I4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- o cSyenesia | 4evi trihydroxytetrahydropyran-2-ylsulfanylethyl)acetamide " SgaNzoSiMOvZ 496.1 (25, ZB, AB, 55, 68)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2,2,2- Senisivo | de trifluoroethylsulfanyl)tetrahydropyran- 3,4,5-triol" SgaNaaSIEzO55 492 (25, ЗВ, АВ, 55, 65)-2-(4-chloro-3-(1-(4-ethoxyphenyl)-1- осяниое) | 438 hydroxyethylphenyl-b-methoxytetrahydropyran -3,4,5-triol SgaNatSU; 438

O-(4-(2-chloro-5-((25, ZB, AB, 55)-3,4,5-trihydroxy-6- methoxytetrahydropyran-2-yl)benzylIphenyl)ether Cg2g2HgvSIMOvo5 468 dimethylthiocarbamic acid" (25, ZV, 48, 55, 65)-2-(3-I11-(4-ethoxyphenyl)ethyl|phenyl)-6-Sene" | 4o6(memn methoxytetrahydropyran-3,4,5-triol" SgaNavOv 406 (MUMN z)

(28, 35, 48, 5, 65)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- trihydroxytetrahydropyran-2-yl ether of diethyldithiocarbamic acid С25НзггСИМО5о2 526.2 acid (25, ZV, 48, 55, 65)-2-(4-chloro-3-4-(B)-(tetrahydrofuran-3-yl)oxy|Ibenzyluphenyl)-6-methoxytetrahydropyran-3,4,5-triol" SezNatSU 468 (MAMH") (25, ZNA, 48, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-ethanesulfinyltetrahydropyran-3,4,5-triol Cga2NatbC1O65 455 (25 . H--Ac (25, ZB, 48, 55)-2-44-chloro-3-|I4-(tetrahydropyran-4-yloxy)benzyl|phenyl)u- SmNaso 523 b-methoxytetrahydropyran-3,4,5- triol" Alya M-H--As (25, ZB, 48, 55)-2-(4-chloro-3-(4-hydroxy-3-11-(2-methylaminoethyl)allyl|benzylphenyl)-b-methoxytetrahydropyran -3,4,5- C25HzgSIMO in 478 triol (25, ZB, 48, 55)-2-(4-chloro-3-I4-(1-methylpiperidine-4-cyanesimoe | 478 yloxy)benzylIphenyl-b-methoxytetrahydropyran- 3,4,5-triol" SgvNzaSIMO" 478 (25, ZB, 4H8, 5 5, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-methanesulfinyltetrahydropyran-3,4,5-triol" СгиНавСиюв5 mi (25, 35, 45, 58)-1-benzyl- 2-I4-chloro-3-(4-ethoxybenzyl)phenyl|piperidine-3,4B-triol" C27HzoSIMOX 468 (25, ZB, AB, 55)-2-13-I4-(2-benzyloxyethoxy)benzyl|- 4-chlorophenyl)-6-ooSyanisyu, | vzg (memn methoxytetrahydropyran-3,4,5-triol" SgeNai SIU; 532 (MeMNZz) (25, ZA, 48, 55)-2-13-I4-(2-hydroxyethoxy)benzyl|phenyl)y-b-y Methoxytetrahydropyran-3,4,5-triol" Selinago; 408 (МАМН») (25, ZV, 48, 55)-2-(4-chloro-3-I4-(2-hydroxyethoxy)benzyl|phenyl)-b- and methoxytetrahydropyran-3,4,5-triol" SgiNavSiU ; 442 (MUMNz) 2-C(25, 35, 45, 58)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- trihydroxypiperidin-1-yllacetamide" SgaNot SIM » 435 (25, 35, 45, 58)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-1- 492 isobutylpiperidine-3,4,5-triol" SgaNzaSIMO" M-H--Ac (25, ZA, 4B8, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-(2-methyltetrahydrofuran-3-ylsulfanyl)tetrahydropyran-3,4,5-triol Со5На1б1Х65 512 (МУМН3) (B)-2-amino-3-(28, 35, 48, 58, 65)-6-14-chloro-3-(4-ethoxybenzyl)phenyl|- Seneiasmoy | 4980 3,4, 5-trihydroxytetrahydropyran-2-ylsulfanylpropionic acid" SgzNovSIMO?Z 498 (25, ЗВ, 4Н8, 55, 6Н8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6- and cyclopentylsulfanyltetrahydropyran-3,4 ,5-triol" SovNaiC1O55 496 (MAMH") (25, ZB, 4H8, 55, 6H8)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6- and cyclohexylsulfanyltetrahydropyran-3,4,5 -triol SovNzaSIU55 510 (MUMN z) (25, ZB, AB, 55, 68)-2-I(4-chloro-3-(4- ethoxybenzyl)phenyl|-6-(3- o Senesiyuye | 498 (MeMH methylbutylsulfanyl)tetrahydropyran-3,4,5-triol СгвНззСИО55 498 (МЕМН») (25, ZA, 48, 55)-2-I3-(4-ethoxybenzyl)phenyl|-b-methoxytetrahydropyran-3,4 ,5-triol" C27Nai SIU" 552 (MAMH») 1-(25, 35, 45, 5H8)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- trihydroxypiperidine -1-yl)iethanone" SgaNovSIMO" 420 benzyl ether (25, 35, 45, 52)-2-|(D-chloro-3-(4-ethoxybenzyl)phenyl|- SenyusymOe | 5heIMeMna 3,4,5-trihydroxypiperidine -1-carboxylic acid SgeNzoSi MO" 529 |MAMNa) (25, 35, 45, 58)-1-benzyl-2-I4-chloro-3-(4-ethoxybenzyl)phenyl|piperidine-3,4 5-triol" C27NzoSIMOX 468 2-C(25, 35, 45, 5H8)-2-I(4-chloro-3-(4-ethoxybenzyl)phenyl|-3,4,5- trihydroxypiperidine-1-ilyacetamide" SgaNot SIM" 435 ( 25, 35, 45, 58)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-1- o Synesimo: | 4-EgyMeAST isobutylpiperidine-3,4,5-triol" SgaNzaSIMO" 492 |M As ( 35, 48, 58)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl|-6-hydroxymethylpiperidine-3,4,5-triol" Sg1NovSIMO" 408

Assay of 501 T2 inhibition of human ip migo

The human sodium-glucose cotransporter type 2 (501 12; accession number RZ1639; 01:400337) was cloned into the pIRE5z rygo2 vector for expression in mammalian cells (construction: НА-5(Y.T2-рИВЕ5rygog).

NEK293 cells were transfected with the human NA-5123I.T2-rIBEZrygo2 vector and the main stable cell line was selected in the presence of 0.5 μg/ml puromycin. Cells expressing human NA-520172 were maintained in medium

OMEM containing 10 95 EU5, 1 95 ORZ and 0.5 μg/ml puromycin.

HEK293 cells expressing human HA-5051712 were plated in 384-well plates (30,000 cells/well) in OMEM medium containing 10 95 EB5, 1 95 ORB and 0.5 μg/ml puromycin and incubated overnight at 372C, 956 SO". Then the cells were washed with absorbing buffer (140 mM Masi, 2 mM KSI, 1 mM Sasi», 1 mM Masi», 10

MM NEREB, 5 mm Tris buffer, 1 mg/ml bovine serum albumin (B5A), pH 7.3). Twenty microliters of absorption buffer with or without test compounds was added to the cells. Microliters of absorbing buffer containing ""C-AMO (100 psi) was then added to the cells. Tablets with cells were incubated at 372,

595 CO" for 1-2 hours. Cells were washed with absorbing buffer, scintillation fluid (40 microliters/well) was added, and C-AMO uptake was measured by counting radioactivity using a scintillation counter (TorSoshneg MHT; RaskKaga Ipzigitepiv).

Assay of human 501 T1 inhibition by migo

The human sodium-glucose cotransporter type 1 (50111; MP accession number 000334; 01:4507031) was cloned into the pIRE5zrygo2 vector for expression in mammalian cells (construction: НА-5121.Т11-рИВЕ5rygog).

NEK293 cells were transfected with the human NA-5123I.11-rIBEZrygo2 vector and the main stable cell line was selected in the presence of 0.5 μg/ml puromycin. Cells expressing HA-5051 71 people were stored in the medium

OMEM containing 10 95 EU5, 1 95 ORZ and 0.5 μg/ml puromycin.

HEK293 cells expressing human HA-551711 were plated in 384-well plates (30,000 cells/well) in OMEM medium containing 10 95 EB5, 1 95 ORB and 0.5 μg/ml puromycin and incubated overnight at 372C, 956 SO". Then the cells were washed with absorbing buffer (140 mM Masi, 2 mM KSI, 1 mM Sasi», 1 mM Masi», 10

MM NERE5B, 5 mm Tris buffer, 1 mg/ml bovine serum albumin (BSA), pH 7.3). Twenty microliters of absorption buffer with or without test compounds was added to the cells. Microliters of absorbing buffer containing ""C-AMO (100 psi) was then added to the cells. Tablets with cells were incubated at 372, 595 CO" for 1-2 hours. Cells were washed with absorbing buffer, scintillation fluid (40 microliters/well) was added, and C-AMO uptake was measured by counting radioactivity using a scintillation counter (TorSosheg MHT; RuskKaga Ipzigitepiv).

Calculation of ISvo values

The ISzo value of a compound relative to a given target is determined by substituting relevant data using the Levenburg Marquardt algorithm into the equation:

UTAN(В-АМТ СО), where A means the minimum value of y; B means the maximum value of y; C means ISvo, and OO means the angle of inclination. ISvo is calculated using XI RA software (10 Vyvipe55 ZoiIshiopv Ips., Viddezhmageg,

MU 08807) for Mysgozoa Echseia (the above equation is model 205 of the specified software).

The influence of IP mimo compounds

The pharmacological effects of the compounds of the present invention were determined by examining six male albino c57 mice injected with the drug and six male albino c57 mice injected with a filler, while the mice were stopped from feeding a diet with a fat content of 45 95 and placed in separate Nalgene metabolic cells. Mice received drinking water and high-fat diet paste (2 parts of diet to 1 part of water) as needed.

Compounds were administered in two ways. According to the first method, mice were injected with a drug or a filler through a gastric tube on the 1st day at a dose of 5 mg/kg. All urine was collected over the next 24 hours into a plastic metabolic cell urine collector. The body weight of the mice, water consumption, feed consumption (taking into account the evaporation of water in the paste) and urine volume were measured daily. Urine collected during the day was centrifuged and the glucose concentration was determined using an automatic Sora5 analyzer. The final result in milligrams of glucose excreted during the day was calculated from the total volume of urine and the concentration of glucose in urine.

According to the second method, the compounds were introduced into the diet. The test compound was mixed with a paste diet with a high fat content at a defined concentration, taking into account the basic body weight and the basic feed intake. Every day, the mice received an excess of paste containing the drug. The amount of the compound eaten by the mice during the day was confirmed by calculating the body weight of the animals and feed consumption.

In fig. 1 shows the effect of four compounds according to the present invention (A, B, C and 0) with a single oral administration at a dose of 30 mg/kg on the amount of excreted glucose within 24 hours after the introduction of the compound. As a comparison, it should be noted that control animals excreted approximately 1 mg of glucose during 24 hours.

All of the above publications (eg, patents and patent applications) are incorporated herein in their entirety by reference.

Ren!

URINARY GLUCOSE EXCRETION (mg/day)

VOYU tet neti nation tnno t tenet etan inten

AND

: about the third COCO about

ОО ННЯ s or M spo . nn

Fig.1

Claims (1)

1. A compound of the formula: (NYA (Av)n also - B, Opov or its pharmaceutically acceptable salt or solvate, where: X means 0, 5 or MK3z; U means O, 5, 50, 50", MKa, (С( B.5)2)r, (C(K5)2)a-C(O)-(C(B5)2)9; when X means 0, Ki is OKild, Kil, BOKIA, 5OKid or M(KiA) »; when X stands for 5, Ki is hydrogen, OKid, 5KiIl, 5OKiI or BOZA; when X stands for MKZz, Ki is OKA, BK, 5OKIA, BOZA or Kyl; each Kid independently stands for hydrogen, Si-lalkyl, C(O) Si lalkyl; Co stands for fluorine or OKod; each Col, Kov, and Cos independently stands for hydrogen, Si-lalkyl, C(O)C|; lalkyl; Ez stands for hydrogen, C(O)Kza, CO»Eza, COM(Kzv) » or C1-alkyl; Kzd independently means C1-ioalkyl; each Kzv independently means hydrogen, C1-alkyl or C1-alkenyl; each Ka independently means hydrogen or C1-alkyl; each K» independently means hydrogen, hydroxyl or C1-alkyl; each Ke independently means hydrogen, hydroxyl, halogen, amino, cyano, OKvl, 5Kva, 5OKvaA, 5OJKva, C(O)Kva, СО»Kvlx, SON, СОМ(Квд)ХКва), СОМН(Ква), СОМН», MNSTS(OK va , МН5О»Koa or Si-lalkil, optional substituted by aldehyde, amino, halogen or hydroxyl; each Code independently means Si lalkil; each K7 independently means hydrogen, hydroxyl, halogen, amino, cyano, OKll, 5Kla, OKA, ЗОЖла, СОО)Ко7А, СО»оКох, СОН, СОМ(КоахКоА), СОМН(Коа), СОМНО), МНеССК»а, МН5О »CoA or C-alkyl, optionally substituted with aldehyde, amino, halogen or hydroxyl; each Claude independently stands for Si lalkil; t equals 1-3, 1 n equals 1-3, p equals 0-3, 1 each d independently equals 0-2. 2. The compound according to claim 1, which has the formula: (Av)p in this he. 3. Compound according to claim 2, where X means 0. 4. Compound according to claim 2, where X means 5. 5. Compound according to claim 2, where X means MKZ. b. Compound according to claim 2, where Ki means OKA. 7. The compound according to item b, where Kiel means hydrogen. 8. The compound according to claim 6, where Kiel means Si-lalkyl. 9. Compound according to claim 2, where Ki means 5KiA. 10. A compound according to claim 9, wherein Kiel is hydrogen. 11. The compound according to claim 9, where Kyl means C -alkyl. 12. Compound according to claim 2, where Ki means SIDE A. 13. The compound of claim 12, wherein Kyl is hydrogen. 14. Compound according to claim 12, where Kil means Si -dzalkil. 15. Compound according to claim 2, where Ki means GOD. 16. The compound of claim 15, wherein Kyl is hydrogen. 17. Compound according to claim 15, where Kil means Si -dzalkil. 18. Compound according to claim 2, where Ki stands for M(Kid)". 19. The compound of claim 18, wherein Kyl is hydrogen. 20. The compound according to claim 18, where Kid means Si-lalkil. 21. The compound according to claim 2, where Ki is hydrogen. 22. Compound according to claim 2, where Ki means KA, 1 Kil means Si -alkyl. 23. The compound of claim 2, wherein C is hydrogen, hydroxyl, halogen, alkyl, or C 1 -alkyl. 24. The compound according to claim 2, where K7 is hydrogen, OKlaA or C1-dalkyl. 25. The compound according to claim 2, which has the formula: z-o SI C, Ho and o- 5 A vo on 26. The compound according to claim 2, which has the formula: kto si TO, HM same 57 VA in he 21. The compound according to claim 2, which has the formula: ZO SI o TO, x B; 5- And he 28. The compound according to claim 2, which has the formula: Shov iv) no i on on 29. The compound according to any one of claims 25-28, where X means 0. 30. The compound according to any one of claims 25-28, where X means 5. 31. The compound according to any one of claims 25-28, where X means MKZ. 32. The compound according to claim 2, which has the formula: -щиО СИ ооо о но и он он 33. The compound according to claim 2, which has the formula: -no si kh no Й on бно. 34. A compound according to any one of claims 25-28, 32 or 33, wherein Kyl is hydrogen or C 1 -alkyl. 35. The compound according to claim 1, which is (2К,3К,4К,55,6К)-2-|4-chloro-3-(4-ethoxybenzyl)phenyl|-b-methylsulfanyltetrahydropyran-3,4,5-triol , or a pharmaceutically acceptable salt thereof. 36. Pharmaceutical composition, which contains the compound according to claim 1 1 pharmaceutically acceptable diluent or excipient. 37. Pharmaceutical composition according to claim 36, in which the compound is (2K.3K.4K,55,6K)-2-|D-chloro-3-(4-ethoxybenzyl)phenyl |-b-methylsulfanyltetrahydropyran-3,4, 5-triol or a pharmaceutically acceptable salt thereof.