The invention describes novel conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein allowing a reversible release of the pharmaceutical agent depending on the glucose concentration.
Over the last decades the number of patients suffering from diseases, particulary from type 2 diabetes, has increased dramatically. Despite education and treatment the growth rate is exploding. The disease evolves slowly and in the beginning the pancreas can compensate decreasing insulin sensitivity by an increased release of insulin. At this stage oral antidiabetics like insulin sensitizers and -releasers can support this compensation mechanism, but cannot cure the disease. So after this period of time external insulin has to be injected.

Several insulins are on the market, which are classified by their duration of action. The intrinsic danger of hypoglycemia is counteracted by very flat insulin profiles (so called basal insulins), but is neither conceptionally addressed nor finally overcome by these basal insulins.

The development of a real glucose sensing insulin accomplishing a glucose dependent release from a depot simulating the natural release by the pancreas is still one of the holy grails in diabetes research. Such an insulin would generate a local (eg intraparenteral) or moving depot (blood streem) from where it is released in a glucose concentration dependent manner and finally recaptured by the system on decreasing glucose concentrations.

The blood glucose concentration is under hormonal regulation. While several hormones like glucagon, epinephrine, norepinephrine, Cortisol, and hormones from the thyroid gland provoke elevated glucose levels, insulin is the only hormone which lowers glucose levels. In addition the glucose level is of course influenced by timing and composition of meals, physical stress, and infections.

In healthy persons the fasting blood glucose level is around 5 mM (900 mg/L) and can after a meal increase to 40 mM for several hours. In diabetic patients where blood glucose is out of control, the level can vary between 1 -30 mM and can unpredictable fluctuate between the borders of hyperglycemia (>10 mM) and hypoglycemia (< 3 mM). Despite the possibility of exact blood glucose measurement and titration of insulins, hypoglycemia is still a serious problem. This problem can be solved by glucose sensitive and -responsive delivery of pharmaceutical agents effecting the glucose level.

Non glucose-sensitive depots to protect drugs (small molecules and proteins like insulin) from degradation and elongate their half life are used frequently in medicine. For insulin for example a static subcutanous depot can be realized. Insulin is stored as insoluble hexamers. From this depot soluble monomers are released to the blood following law of mass equation.

An additional opportunity is the non-covalent binding of modified insulins to albumin. Since unmodified insulin is not binding to albumin, noncovalent hydrophobic binding is enabeled by hydrophobic modification (eg by myristic acid). Coupling of fatty acids to insulin enable protection of insulin from degradation and dramatically increases half life by hours to days.

The release of insulin from such a circulating depot can be described by the law of mass equation and is a function of the amount of insulin, the albumin depot, and the affinity of the insulin derivative to albumin. Since the depot is fixed, the amount and affinity of insulin have to be adjusted. The release of basal insulin can be controlled, but the release is glucose independent.

Within the last decade efforts have been started to establish glucose sensitive insulin depots. These efforts can be summarized and assigned to three classical principles:

- Chemical recognition of glucose by boronic acids

- Biochemical recognition of glucose by carbohydrate binding proteins like such as lectins (Concanavalin A, wheat germ agglutinin)

- Glucose converting enzymes like glucose oxidase or hexokinase. Here binding affinity can be used as a signal. More frequently associated pH shift or change of charge is measured.

These principles can be used for glucose measurement or to translate the signals into direct or indirect glucose release. Four possibilities for realization are described below.

• Direct modification of insulins

• "Glucose responsive" hydrogels, these are synthetic pores, which are modified with a glucose sensing molecule (boronic acid- or glucose oxidase based). These gels are filled with insulins. In the presence of glucose they expand, get leaky, and finally release insulin on increasing glucose levels.

• „Device-approaches": In this case insulin levels are only measured by a sensor.

• Closed loop approaches: This describes a technical solution. A sensor measures glucose levels. The signal is transmitted to an independent insulin depot (eg a pump) which releases insulin triggered by the signal. An independent insulin reservoir is triggered and releases insulin, controlled by the sensor signal. An advantage may be a large insulin depot which is not necessarily in the body.

Several patent applications, e.g. WO 2001/92334, WO 201 1/000823, or WO 2003/048195 describe the use of boronic acid modified insulin derivatives in combination with albumin for a glucose sensitive insulin release. With this approach the floating insulin/albumin depot shall be further developed to a glucose sensing floating depot.

A different approach for a glucose sensing approach has been described in WO 2010/088294, WO 2010/88300, WO 2010/107520, WO 2012/015681 , WO 2012/015692, or WO 2015/051052. These documents describe the concomitant administration of concanavalin A and a glucose binding protein preferably recognizing mannose. Accordingly mannose modified insulins can be released by mannose from a

depot. In addition an intrinsic mannose binding protein is described which may be responsible for the binding of mannose without the need of concanavalin.

Erythrocytes have been used as a vehicle for the transport of drugs, e.g. for tumor starvation, enzyme replacement and immunotherapy as described in WO 2015/121348, WO 2014/198788 and WO 2013/139906.

Liu et al. (Bioconjugate Chem. 1997, 8, 664-672) discloses a glucose induced release of glucosylpoly(ethylene glycol) insulin bound to a soluble conjugate of concanavalin A wherein the insulin is linked at the B1 amino group with a poly(ethylene glycol) spacer to the 1 -position of the sugar.

WO2012/177701 discloses conjugates of 68Ga-DOTA labelled sugars for tissue specific disease imaging and radiotherapy.

The use of erythrocytes as a classical depot, by binding drugs to the surface of erythrocytes is described in WO 2013/121296. Here peptides are described, which bind to the surface with a very high affinity (KD= 6,2 nM). These peptides are used for immunmodulation e.g. in transplantation medicine.

The present invention relates to a novel conjugate comprising a pharmaceutical agent and a sugar moiety.

Futher the present invention relates to a novel conjugate comprising a pharmaceutical agent and a sugar moiety for use as a pharmaceutical.

Further the present invention relates to a novel conjugate comprising a pharmaceutical agent and a sugar moiety which binds to the insulin dependent glucose transporter GluT1 , which provides a release of the pharmaceutical agent dependent on the glucose concentration in blood. The insulin dependent glucose transporter GluT1 is present on erythrocytes. Binding of glucose to GluT1 is reversible based on the blood glucose concentration.

In one embodiment the conjugate of the invention is bound to GluT1 at low glucose concentrations of e.g. 1 -10 mM, which are found under fasting conditions. Under these conditions, the stable floating depot of the active agent is formed. After an increase in the glucose concentration from e.g. 30 mM to 40 mM after a meal, the free glucose competes for the GluT1 binding site and the conjugate is released in a glucose concentration dependent manner and the pharmaceutical agent is available to exert its effect. As the glucose concentration decreases again, the conjugate molecules are recaptured by GluT1 . Thus, the presence of undesired high amounts of free pharmaceutical agents is avoided.

The present invention relates to conjugates of formula (I) :

wherein P is a pharmaceutical agent, particularly a peptide,

L1 , L2, and L3 are independently of each other a linker having a chain length of 1 -20 atoms,

A1 and A2 are independently of each other a 5 to 6 membered monocyclic ring or a 9 to 12 membered bicyclic ring, or two 5 to 6 membered monocyclic and/or 9 to 12 membered bicyclic rings connected to each other, wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring and wherein each ring may carry at least one substituent,

S is a sugar moiety which binds to the insulin independent glucose transporter GluT1 , and

m, o, p, r, and q are independently of each other 0 or 1 , and wherein at least one of r and o is 1 ,

or a pharmaceutically acceptable salt or solvate thereof.

The present invention relates also to conjugates of formula (I) :

wherein P is an insulin or an insulinotropic peptide,

L1, L2, and L3 are independently of each other a linker having a chain length of 1 -20 atoms,

A1 and A2 are independently of each other a 5 to 6 membered monocyclic ring or a 9 to 12 membered bicyclic ring, or two 5 to 6 membered monocyclic and/or 9 to 12 membered bicyclic rings connected to each other, wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring and wherein each ring may carry at least one substituent,

S is a sugar moiety which binds to the insulin independent glucose transporter GluT1 , and comprises a terminal pyranose S1 moiety which is attached via position 2, 4, or 6 to the conjugate of formula (I),

m, o, p, r, and q are independently of each other 0 or 1 , and wherein at least one of r and o is 1 ,

or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention are compounds of formula (la) and (lb):

wherein L1 , L2, L3, A1 , A2, S, m, o, p, r, and q are defined as indicated above and R is H, halogen, OH, O-alkyl-, an anhydride forming group or another active ester forming group for coupling reactions, like 4-nitrophenylester, succinate or N-hydroxy benzotriazol.

or pharmaceutically acceptable salts or solvates thereof.

Compounds (la) and (lb) are suitable as intermediates for the synthesis of the conjugates of formula (I).

Another aspect of the present invention is the conjugate of formula (I) as described above for the use in medicine, particularly in human medicine.

Another aspect of the present invention is a pharmaceutical composition comprising a conjugate of formula (I) as described above as an active agent and a pharmaceutically acceptable carrier.

Another aspect of the present invention is a method of preventing and/or treating a disorder associated with, caused by, and/or accompanied by a dysregulated glucose metabolism, comprising administering a conjugate of formula (I) or a composition as described above to a subject in need thereof, particularly a human patient.

Another aspect of the present invention is a method of preventing and/or treating diabetes type 1 or diabetes type 2.

The conjugates of formula (I) of the present invention comprise a pharmaceutical agent P, which may a biomolecule, such as a peptide. Preferably, the pharmaceutical agent has an effect of directly or indirectly lowering the glucose concentration in blood. For example, the pharmaceutical agent may be an insulin or an insulinotropic peptide.

The term "insulin" according to the present invention encompasses human insulin, porcine insulin, or analogs thereof, e.g. prandial insulins with fast action or basal insulins with long action. For example, the term "insulin" encompasses recombinant human insulin, insulin glargine, insulin detemir, insulin glulisine, insulin aspart, insulin lispro, etc. or an insulin conjugated to a polyethylene, e.g. a low molecular weight PEG having a molecular weight of 10 kDa or less. If P is an insulin, it may be attached via an amino group to form the conjugate of formula (I) , e.g. via an amino side chain, particularly via the amino side chain of an insulin B29Lys residue or via the amino terminus of an insulin B1 Phe residue.

Further, the pharmaceutical agent may be an insulinotropic peptide such as GLP-1 , an exendin such as exendin-4, or a GLP-1 agonist such as lixisenatide, liraglutide.

The conjugate of formula (I) further comprises a sugar moiety which binds to the insulin independent glucose transporter GluT1 , also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1 ). The amino acid sequence of the human protein is NP_006507, which is encoded by a nucleic acid sequence NM_006516. GluT1 is an integral membrane protein which facilitates diffusion of glucose into the erythrocyte. The highest expression of GluT1 is found in erythrocytes.

For interaction with GluT1 , the conjugate of formula (I) comprises a moiety binding to GluT1 but preventing transport through the erythrocyte membrane. A sugar moiety binding to GluT1 is preferably in an anomeric form, particularly in an anomeric 6-membered ring form such as a pyranose moiety. The sugar moiety comprises an anomeric O atom as well as a hydroxy group or a protected hydroxy group at position 3 and position 4 of a pyranose backbone. In one embodiment, the sugar moiety S of the conjugate of formula (I) comprises a terminal pyranose moiety which is attached via position 2, position 4, or position 6 of the pyranose backbone moiety.

Further, an aspect of the present invention is that introduction of at least one cyclic residue A1 and/or A2 adjacent to the sugar moiety causes a substantial increase in the affinity to GluT1 in comparison to glucose.

Thus, the present invention provides a pharmaceutical agent in form of a conjugate of formula (I) which forms an erythrocyte-based circulating depot that after administration releases/delivers the agent as a function of glucose concentration. Accordingly at low glucose concentrations (below 3 mM) no or only low concentration of free unbound levels of the conjugate should be detectable. On increasing blood glucose levels after a meal the conjugate is released from the circulating depot into the blood stream. The release is a consequence of a direct competition of glucose with the conjugate of formula (I). Thus, release is described by the law of mass equation und self adjusts to tiniest changes in glucose levels. The same should be true for the re-capturing process of the conjugate of formula (I) on decreasing glucose levels.

These characteristics constitute an essential advantage in comparison to the glucose sensing depots from the prior art.

By means of the present invention, the drawbacks of prior art insulins with regard to glycemia are diminished or avoided. The control of glucose recognition and associated release/retrapping will be realized within a single molecule. This minimizes delays in release/retrapping. Glucose sensitive binding and -release is controlled by interaction with endogenous transport and recognition processes. The biological recognition system based on GluT1 transport in erythrocytes is constantly regenerated by the organism.

The present conjugate of formula (I) binds to the ubiquitary glucose transporter GluT1 , which has a binding affinity to glucose in the same range as glucose oxidase, a protein frequently used in glucose recognition. GluT1 is highly expressed in erythrocytes and is responsible for the basal supply of these cells. The size of the depot is large enough to accommodate the amount of pharmaceutical agent needed without affecting the erythrocyte glucose supply.

The affinity of the present conjugate of formula (I) is within an affinity window which guarantees binding at low (e.g. <3 mM) glucose levels. With increasing glucose levels (e.g. >10 mM) the conjugate of formula (I) is released accordingly. With decreasing glucose levels the unbound conjugate of formula (I) is recaptured by the transporter.

The release is following the law of mass equation and is dependent on the size of the depot, the loading, and the affinity of the conjugate of formula (I) to GluT1. Since the depot is fixed, the free conjugate fraction is defined by the affinity to GluT1.

In certain embodiments, the conjugate of formula (I) has an affinity of 10-500 nM to the insulin independent glucose transporter GluT1 as determined by affinity measurements for example by a ligand displacement assay, by MST (microscale thermophoresis) technology.

In the conjugate of formula (I) of the present invention, the individual structural moieties P, A1, A2, and S may be connected by linkers L-i, L2, and L3. If present, L-i, L2, and L3 are linkers having a chain length of 1 -20 atoms, particularly 3 to 10, or 3 to 6 atoms.

In some embodiments, L-i, L2, and L3 are independently of each other (C1-C20) alkylene, (C2-C20) alkenylene, or (C2-C20) alkynylene, wherein one or more C-atoms may be

replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C1- ) alkyl, S, SO2, O-SO2, O-SO3, O-PHO2 or O-PO3, and/or wherein one or more C-atoms may be substituted with (C1-4) alkyl, (C1- ) alkyloxy, oxo, carboxyl, halogen, e.g. F, CI, Br, or I, or a phosphorus-containing group. The carboxyl group may be a free carboxylic acid group or a carboxylic acid ester, e.g. C1-C4 alkyl ester or a carboxamide or mono(C1-C4) alkyl or di(C1-C4) alkyl carboxamide group. An example of a phosphorus-containing group is a phosphoric acid or phosphoric acid (C1- ) alkyl ester group.

In certain embodiments, the linker L3 has a chain length of 1 to 15 atoms, particularly 1 to 6 or 1 to 4 atoms. For example, L3 may be a (C1-C6) alkylene, particularly (C1- ) alkylene group, wherein one or two C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C1 -4) alkyl, S, S02, 0-S02, 0-S03, O-PHO2 or 0-P03, and/or wherein one or more C-atoms may be substituted with (C1-4) alkyl, (C1 - ) alkyloxy, oxo, carboxyl, halogen, e.g. F, CI, Br, or I, or a phosphorus-containing group.

In one embodiment, the linker L3 is C=0.

In one embodiment, the linker L3 is absent.

In one embodiment, the linker L2 is -CO-(CH2)3-.

In one embodiment, the linker L2 is -(CH2)6-NH-.

In one embodiment, the linker L2 is -(CH2)2-CO-(CH2-CH2-0)2-(CH2)2- H-.

In one embodiment, the linker L2 is -CH2-0-(CH2-CH2-0)3-.

The conjugate of formula (I) of the present invention comprises at least one cyclic group, particularly a cyclic group A2 and optionally a further cyclic group A1. An aspect of the present invention is that the presence of a cyclic group adjacent to the sugar moiety S significantly enhances the binding affinity of the sugar moiety S to the glucose transporter GluT1 . The cyclic groups A1 and A2 may be a 5 to 6 membered monocyclic ring, a 9 to 12 membered bicyclic ring, or two 5 to 6 membered monocyclic and/or 9 to 12 membered bicyclic rings connected to each other by a bond or 1 -atom bridge, e.g. such as -O- or -CH2-. Each ring may be a saturated, unsaturated, or aromatic

carbocyclic or heterocyclic ring. Each ring may be unsubstituted or carry at least one substituent, for example, 1 to 3 substituents selected from halogen, NO2, CN, (C1-4) alkyl, (C1- ) alkoxy, (C1- )alkyl-(C3-7)cycloalkyl, (C3-7) cycloalkyl, OH, benzyl, -O-benzyl, carboxyl, carboxyester, carboxamide, or mono (C1- ) alkyl, or di (C1- ) alkyl carboxamide.

In a further embodyment, A2 and/or A1 are a heterocyclic ring wherein 1 to 4 ring atoms, e.g. 1 , 2, 3, or 4 ring atoms are selected from nitrogen, sulfur and/or oxygen and wherein the ring may be unsubstituted or may carry at least one substituent as described above. In an especially preferred embodiment, A2 and A1 , if present, are independently of each other a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring, particularly selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, piperazinyl, piperidinyl, morpholinyl, wherein the ring may carry at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heteroalkyl ring with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent.

In an especially preferred embodiment, A2 and A1 , if present, are selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, piperazinyl, piperidinyl, morpholinyl.

In a further embodiment A2 and/or A1 are 1 ,2,3-triazolyl.

In a further embodiment A2 is 1 ,2,3-triazolyl.

In a further embodiment A2 is piperazinyl.

A further group of embodiments are conjugates of formula (I) wherein A2 is piperazinyl, L2 is absent and A1 is cyclohexanyl.

A further group of embodiments are conjugates of formula (I) wherein A2 is piperazinyl, L2 is absent and A1 is cyclohexanyl.

A further group of embodiments are conjugates of formula (I) wherein A2 is piperazinyl, L2 is -CH2- and A1 is cyclohexanyl.

A further group of embodiments are conjugates of formula (I) wherein A2 is piperazinyl, L2 is absent and A1 is phenyl.

A further group of embodiments are conjugates of formula (I) wherein A2 is1 ,2,3-triazolyl, L2 is absent and A1 is phenyl.

A further group of embodiments are conjugates of formula (I) wherein

5 L3 is -CO-, A1 is phenyl, L2 is -O- and A1 is phenyl wherein each ring may be unsubstituted or carry at least one substituent, for example, 1 to 3 substituents selected from halogen, NO2, CN, (C1-4) alkyl, (C1-4) alkoxy, (C1-4)alkyl-(C3-7)cycloalkyl, (C3-7) cycloalkyl, OH, benzyl, -O-benzyl, carboxyl, carboxyester, carboxamide, or mono (C1-4) alkyl, or di (C1-4) alkyl carboxamide.

o

A further group of embodiments are conjugates of formula (I) wherein

the group -A2-L3- is selected from

In a further embodiment of the present invention, the conjugate of formula (I) comprises a single cyclic group A2 and the second cyclic group A1 is absent. In such embodiments, the conjugate of formula (I) may have a structure wherein m=1 , o=0, p=0, and q=0 or 1. In other embodiments, a second cyclic group A1 is present. In such embodiments, the conjugates of formula (I) may have a structure wherein m=1 , o=1 , p=1 , and q=0 or 1 .

The conjugate of formula (I) comprises a sugar moiety S which binds to the insulin independent glucose transporter GluT1 . This sugar moiety S may comprise a terminal pyranose moiety which is attached via position 2, 4, or 6 to the conjugate of formula (I). In one embodiment the terminal pyranose moiety is attached via position 6 to the conjugate of formula (I).

In some embodiments, the sugar moiety S may comprise a terminal pyranose moiety S1 having a backbone structure of Formula (II)

(II)

wherein 1 , 2, 3, 4, 5, and 6 denote the positions of the C-atoms in the pyranose moiety,

wherein is a single bond and is a single or a double bond, and

R1 and R3 are H or a protecting group,

and wherein S1 is attached via position 2, 4, or 6 to the conjugate of formula (I) .

The protecting group may be any suitable protecting group known in the art, e.g. an acyl group such as acetyl or benzoyl, an alkyl group such as methyl, an aralkyi group such as benzyl, or 4-methoxybenzyl (PMB) including divalent protecting groups such as isopropylidene or benzylidene.

In some embodiments, the terminal pyranose moiety may be selected from glucose, galactose, 4-deoxyglucose, and 4,5-dehydroglucose derivatives, wherein the terminal

pyranose moiety is attached via position 2, 4, or 6 to the conjugate of formula (I) or is mannose attached via position 6.

In another embodiment, the terminal pyranose moiety S1 is of the Formula (Ilia) or (lllb):

wherein R1 is H or a protecting group such as methyl or acetyl,

R2 is OR8, or NHR8 or an attachment site to the conjugate of formula (I), wherein R8 is H or a protecting group such as acetyl or benzyl,

R3 is H or a protecting group such as acetyl or benzyl,

R4 is H, OR8, or NHR8 or an attachment site to the conjugate of formula (I), wherein R8 is H or a protecting group such as acetyl or benzyl,

or R1 and R2 and/or R3 and R4 form together with the pyranose ring atoms to which they are bound a cyclic group, e.g. an acetal,

R5 and R6 are H or together form together with the carbon atom to which they are bound a carbonyl group,

R7 is OR8, or NHR8 or an attachment site to the conjugate of formula (I) , wherein R8 is H or a protecting group such as acetyl or benzyl, and

wherein one of R2, R4, and R7 is the attachment site to the conjugate of formula (I) .

In another embodiment of the terminal pyranose moiety S1 of the formula (Ilia) and (lllb), R1 and R3 are H. In further embodiments of the terminal pyranose moiety S1 of the formula (Ilia) and (lllb), R2 is OR8, or an attachment site to the conjugate of formula (I), R4 is H, OR8, or an attachment site to the conjugate of formula (I), R7 is OR8 or an attachment site to the conjugate of formula (I), and wherein R8 is H or a protecting group.

In another embodiment of the terminal pyranose moiety S1 of the formula (Ilia) and (Mlb), position 6 of the pyranose moiety and particularly substituent R7 is the attachment site of the terminal pyranose moiety S1 to the conjugate of formula (I).

In specific embodiments, the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe):

(IVe)

wherein R1 , R2, R3, R5, R6, and R7 are defined as indicated above,

wherein R4a is H or the attachment site to the conjugate of formula (I),

and wherein R4 is H, a protecting group, or the attachment site to the conjugate of formula (I) .

The sugar moiety S of the conjugate of formula (I) may comprise one or more, e.g. 2, or 3 saccharide units. For example, the sugar moiety has a structure of formula (V):

(V)

wherein Xi is a bond or O, particularly a bond,

X2 is a bond, NH or O, particularly a bond,

S2 is a mono- or disaccharide moiety, particularly comprising at least one hexose or pentose moiety,

S1 is a terminal pyranose moiety as defined above, and

s is 0 or 1.

The saccharide moiety S2 may be a pyranose moiety, particularly selected from glucose, galactose, 4-deoxyglucose, and 4,5-dehydroglucose derivatives or a furanose moiety, particularly selected from fructose derivates.

In specific embodiments, the saccharide moiety S2 is of formula (Via), (Vlb), (Vic), (Vld), or (Vie):

wherein R1 1 is a bond to X1,

R12 is OR8 or NHR8 or an attachment site to X2, wherein R8 is H or a protecting group such as acetyl or benzyl,

R13 is H or a protecting group such as acetyl or benzyl,

R14 is R8 or an attachment site to X2, wherein R8 is H or a protecting group such as acetyl,

R14a is H or an attachment site to X2,

R15 and R16 are H or together form together with the carbon atom to which they are bound a carbonyl group,

R17 is OR8 or an attachment site to X2, wherein R8 is H or a protecting group such as acetyl or benzyl,

or R1 1 and R12 and/or R13 and R14 form together with the ring atoms to which they are bound a cyclic group such as an acetal,

and wherein one of R12, R14, R14a and R17 is an attachment site to X2.

In further embodiments, the conjugate of formula (I) reversibly binds to the insulin independent glucose transporter GluT1 , dependent from the glucose concentration in the surrounding medium, which is blood after administration. In a further embodiment the conjugate of formula (I) of the present invention is not transported through the cell membrane upon binding to GluT1 . In a further embodiment the sugar moiety S comprises a single terminal saccharide moiety. In still further embodiments, the sugar moiety S does not comprise a mannose unit, particularly a terminal mannose unit.

Definitions

"Alkyl" means a straight-chain or branched carbon chain. Alkyl groups may be unsubstituted or substituted, wherein one or more hydrogens of an alkyl carbon may be replaced by a substituent such as halogen. Examples of alkyl include methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

"Alkylene" means a straight-chain or branched carbon chain bonded to each side. Alkylene groups may be unsubstituted or substituted.

"Aryl" refers to any substituent derived from a monocyclic or polycyclic or fused aromatic ring, including heterocyclic rings, e.g. phenyl, thiophene, indolyl, naphthyl, pyridyl, which may optionally be further substituted.

"Acyl" means a chemical functional group of the structure R-(C=0)-, wherein R is an alkyl, aryl, or aralkyl.

"Halogen" means fluoro, chloro, bromo, or iodo. Preferably, halogen is fluoro or chloro.

A "5 to 7 membered monocyclic ring" means a ring with 5 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms may be replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)2-), oxygen and nitrogen (including =N(0)-). Examples for 5 to 7 membered rings include carbocycles such as cyclopentane, cyclohexane, and benzene, or heterocycles such as furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, triazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepame, azepine, or homopiperazine.

"9 to 12 membered bicyclic ring" means a system of two rings with 9 to 12 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms may be replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)2-), oxygen, and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 9 to 12 membered rings include carbocycles such as naphthalene and heterocycles such as indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, or pteridine. The term 9 to 12 membered heterobicycle also includes spiro

structures of two rings like 1 ,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1 ]octane.

The term "protecting group" means a chemical protecting group for protecting OH-groups, known in the art of sugar chemistry as described in Theodora W. Greene, Peter G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley &Sonc, Inc. 1999. Examples of a protecting group are: acetyl, benzyl, or p-methoxybenzyl; or isopropylidene groups for protecting two hydroxy groups.

The term "anhydride forming group" means a chemical group which forms with the carbonyl group to which it is attached an anhydride. An example is acetic anhydride which acetylates said carbonyl group.

The term "active ester forming group" means a chemical group which forms with the carbonyl group to which it is attached an ester which activates said carbonyl group for a coupling reaction with an amino group containing conpound forming an amide group.

Examples of active ester forming groups are 4-Nitrophenylester, N-Hydroxybenzotriazol (HOBt), 1 -Hydroxy-7-azabenzotriazol Oder N-Hydroxysuccinimid (HOSu).

The term "pharmaceutically acceptable" means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, and/or in humans.

The conjugate of formula (I) of the present invention is suitable for use in medicine, e.g. in veterinary medicine or in human medicine. Particularly, the conjugate of formula (I) is suitable for human medicine. Due to the glucose dependent release/recapture mechanism, the conjugate of formula (I) is particularly suitable for use in the prevention and/or treatment of disorders associated with, caused by, and/or accompanied by a dysregulated glucose mechanism, for example for use in the prevention and/or treatment of diabetes mellitus, particularly of diabetes type 2 or type 1.

The invention also provides a pharmaceutical composition comprising a conjugate of formula (I) as described above as an active agent and a pharmaceutically acceptable carrier.

The term "pharmaceutical composition" indicates a mixture containing ingredients that are compatible when mixed and which may be administered. A pharmaceutical composition includes one or more medicinal drugs. Additionally, the pharmaceutical composition may include one or more pharmaceutically acceptable carriers such as solvents, adjuvants, emollients, expanders, stabilizers, and other components, whether these are considered active or inactive ingredients.

The conjugates of formula (I) of the present invention, or salts thereof, are administered in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition. A "pharmaceutically acceptable carrier" is a compound or mixture of compounds which is physiologically acceptable while retaining the therapeutic properties of the substance with which it is administered. Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins. One exemplary pharmaceutically acceptable carrier is physiological saline solution.

Acceptable pharmaceutical carriers include those used in formulations suitable for oral, rectal, nasal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration. The compounds of the present invention will typically be administered parenterally.

The term "pharmaceutically acceptable salt" means salts of the conjugates of formula (I) of the invention which are safe and effective for use in mammals. Pharmaceutically acceptable salts may include, but are not limited to, acid addition salts and basic salts. Examples of acid addition salts include chloride, sulfate, hydrogen sulfate, (hydrogen) phosphate, acetate, citrate, tosylate, or mesylate salts. Examples of basic salts include salts with inorganic cations, e.g. alkaline or alkaline earth metal salts such as sodium, potassium, magnesium, or calcium salts and salts with organic cations such as amine salts. Further examples of pharmaceutically acceptable salts are described in

Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins or in Handbook of Pharmaceutical Salts, Properties, Selection and Use, e.d. P. H. Stahl, C. G. Wermuth, 2002, jointly published by Verlag Helvetica Chimica Acta, Zurich, Switzerland, and Wiley-VCH, Weinheim, Germany.

The term "solvate" means complexes of the conjugates of formula (I) of the invention or salts thereof with solvent molecules, e.g. organic solvent molecules and/or water.

The compounds of the present invention will be administered in a "therapeutically effective amount". This term refers to a nontoxic but sufficient amount of the conjugate of formula (I) to provide the desired effect. The amount of a conjugate of formula (I) of the formula (I) necessary to achieve the desired biological effect depends on a number of factors, for example the specific conjugate of formula (I) chosen, the intended use, the mode of administration, and the clinical condition of the patient. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

Pharmaceutical compositions of the invention are those suitable for parenteral (for example subcutaneous, intramuscular, intradermal, or intravenous), oral, rectal, topical, and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the conjugate of formula (I)) used in each case.

Suitable pharmaceutical compositions may be in the form of separate units, for example capsules, tablets, and powders in vials or ampoules, each of which contains a defined amount of the conjugate of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. It may be provided in single dose injectable form, for example in the form of a pen. The compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.

The conjugates of formula (I) of the present invention can be widely combined with other pharmacologically active compounds, such as all drugs mentioned in the Rote Liste 2016 e.g. with all antidiabetics mentioned in the Rote Liste 2016, chapter 12.

The active ingredient combinations can be used especially for a synergistic improvement in action. They can be applied either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. When the active ingredients are administered by separate administration of the active ingredients, this can be done simultaneously or successively.

General methods for the synthesis of conjugates of formula (I) and intermediates thereof are described in the following schemes:

Scheme 1 :

4 5 6 2aa

OH-protected glucuronic acid compounds 4, where the protecting groups (PG) are e.g. acetyl, benzyl, or p-methoxybenzyl, or isopropylidene groups for protecting two hydroxy groups at the same time, or the like, can be coupled with amines 5 using well known amide coupling procedures e.g. using HATU, TBTU, BEP, TOTU, or other activating methods for carboxylic acids in common known solvents like dimethylformamide, tetrahydrofuran, dichlormethane, acetonitrile, or the like. Dependent on the protecting group, the deprotection to compounds 2aa takes place under different conditions such as basic, acidic, hydrogenating or oxidative conditions. For example, acetyl groups are cleaved under basic conditions using sodium or lithium hydroxide in solvents like methanol, water, tetrahydrofuran, or combinations thereof. Isopropylidene groups are cleaved under acidic conditions, e.g. using trifluoroacetic acid in water, hydrogenating conditions using e.g. palladium on charcoal or other hydrogenating catalysts under hydrogen atmosphere in solvents like methanol, ethanol, toluene, acetic acid, tetrahydrofuran or the like, or oxidative conditions like cerium ammonium nitrate or DDQ, like for p-methoxybenzyl.

Unsaturated compounds of formula 2ba can be synthesized like shown in scheme 2:

Scheme 2:

Starting from acetyl protected glucuronic acid, deacetylation using acetic acid anhydride and triethylamine generates compound 7, which can be coupled with compounds 5 using coupling reagents for amide bond syntheses, like described above, to give compounds 2ba.

A further method to synthesize compounds 2ba is shown in scheme 3:

Scheme 3:

Starting from 1 ,2,3,4-tetra acetyl protected glucose, oxidation using Swern conditions leads to aldehyde 8. Reductive amination of aldehyde 8 and amines 5 using reductive amination conditions like sodium cyanoborohydride, sodium triacetoxyborohydride or the like, in solvents like dichloroethane, dichloromethane, methanol, and/or acetic acid leads to compounds 2ba.

Compounds 10, 1 1 , and 12 can be synthesized as described in scheme 4.

Scheme 4:

copper catalyzed azide-alkyne cycloaddition

Compounds of formula 10, 1 1 , and 12 can be synthesized using copper catalysed [3+2]-cycloaddition conditions, also known as azide-alkyne or click cycloaddition. 1 -, 2- or 6-azido-deoxyglucose and alkynes 9, are reacted with CuS0 *5H20, tris(3-hydroxypropyltriazolylmethyl)amine (THPTA) and sodium ascorbate.

Alkynes 9 can be synthesized as shown in scheme 5.

Scheme 5:

Alkynes 9 can be synthesized using propargylamine under different reaction conditions: alkylation conditions using bases like diisopropylamine, triethylamine or the like, in presence of different chlorides or halides like for 9a and 9c, or peptide coupling conditions like for 9b.

Compounds 14, 17, and 18 can be synthesized as described in scheme 6.

Scheme 6:

Compounds 14 can be synthesized using known deprotection methods. When protecting group PG is, for example, a benzyl group, it can be deprotected under hydrogenation conditions as described above. Alkynes 15 can be converted into alkylating reagents 16 with R describing a leaving group like O-tosyl, O-mesyl, halogen or the like. Compounds 14 and compounds 16 can be reacted to obtain compounds 17 under alkylating conditions, e.g. using bases like triethylamine, diisopropylamine, sodium hydride or the like in aprotic solvents like dimethylformamide, tetrahydrofuran, toluene or the like. Deprotection of compounds 17 to compounds 18 is dependent of the used protecting groups, the conditions are as described above.

Galactosyl derivatives 20 can be synthesized like described in scheme 7.

Scheme 7:

Reductive amination of isopropylidene protected galactosyl-aldehyde and amines 5 using known reductive amination conditions as described in scheme 3 lead to compounds 19. Deprotection of the isopropylidene groups can be done as described in scheme 1.

The synthesis of compounds 1 is described in scheme 8.

Scheme 8:

The synthesis of compounds 22 can be done under reductive amination conditions for compounds 21 and protected carbohydrate aldehydes as described in scheme 3. Deprotection of compounds 22 to compounds 23 can be done as described in scheme 1. Compounds 23 can be coupled using copper-catalyzed azide-alkyne cycloaddition conditions as described in scheme 4 to yield compounds 1.

The synthesis of compounds 24 is described in scheme 9.

25 24

The synthesis of compounds 24 can be carried out by reaction of compounds 25 with insulin under basic conditions, e.g. pH 10. Therefore the insulin is dissolved in a dimethylformamide-water mixture and brought to pH 10 by an organic base like triethylamine. At low temperatures (e.g. 0°C) the activated azido-dioxopyrrolidines 25 are added to yield compounds of formula 24.

Abbreviations:

BEP 2-bromo-1 -ethyl pyridinium tetrafluoroborate

d Dublet

dd Double dublet

ddd Double double dublet

DDQ 2,3-dichloro-5,6-dicyano-1 ,4-benzochinone

DMSO dimethylsulfoxide

ELSD Evaporative Light Scattering Detector

Eq. Equivalent/s

ES-API Electro spray atmospheric pressure ionisation

FCS Fetal calf serum

HATU 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium

3-oxide hexafluorophosphate

HOBt 1 -hydroxybenzotriazole

HPLC High pressure liquid chromatography

Hz Hertz

J coupling constant

KRB Krebs-Ringer bicarbonate buffer

LG leaving group

LC/MS Liquid chromatography/mass spectra

m multiplet

MEM Minimum-Essential-Medium

MHz Megahertz

MPLC Medium pressure liquid chromatography

NEAA Non-essential amino acids

NMR Nuclear magnetic resonance

PG Protecting group

q quadruplet

s singulet

t triplet

td dublet of triplets

TBTU N,N,N',N'-Tetramethyl-0-(benzotriazol-1 -yl)uronium tetrafluoroborate

TLC Thin layer chromatography

THPTA tris(3-hydroxypropyltriazolylmethyl)amine

TOTU 0-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate

tR Retention time

Rf Relative to front value

UV Ultra violet

v/v Volume by volume

Experimental Part

Chromatographic and spectroscopic methods

TLC/UV-Lamp

Thin layer chromatography (TLC) was done on glass plates from Merck coated with silica gel 60 F254. Detection was done with an UV-Lamp from Lamag at wavelenghts of 254 nm and 366 nm.

Compounds which could not be detected by UV were stained by different methods: (a) 10 % H2S04 in ethanol, b) 1 % KM n04 -solution, c) molybdatophosphoric acid-cerium(IV)sulfate solution in sulfuric acid (6 mL concentrated sulfuric acid and 94 mL water, 2,5 g molybdatophosphoric acid, 1 g cerium(IV)sulfate).

MPLC

Chromatography on normal phase was done on a CombiFlash® Rf (Teledyne ISCO). The used gradients were given in the description of the examples.

HPLC

Preparative reversed phase HPLC was done using acetonitrile/water on an Agilent 1200 preparative HPLC machine and an Agilent Prep-C18 column (10 μm, 21.5x150 mm).

1H-NMR

For 1H-NMR-spectra a Bruker ARX, 400 MHz device was used.

13C-NMR

For 13C-NMR- spectra a Bruker Avance, 600 MHz device was used.

LC/MS

For retention time and mass detection a LC/MS-system from Waters Acquity SDS with a Waters Acquity BEH C18 (1.7 μm, 2.1x50 mm) column was used. The injection volume was 0.5 μΙ. Molecular weights are given in gramm per mol [g/mol], detected masses in mass per charge [m/e].

LC/MS-Method 1

95% H20 (0.05% formic acid) to 95% acetonitrile (0.035% formic acid) in 2 min, 95% acetonitrile till 2.60 min, 0.9 mL/min, 10x2 mm Phenomenex LunaC18 3 μm.

LC/MS-Method 2

93% H20 (0.05% trifluoroacetic acid) to 95% acetonitrile (0.05% trifluoroacetic acid) in 1 min, 95% acetonitrile till 1.45 min, 1 .1 mL/min, 10x2.0 mm LunaC-ie 3 μm

LC/MS-Method 3

99% H20 (0.05% trifluoroacetic acid) to 93% H20 (0.05%) in 0.4 min, 95% acetonitrile (0.05% trifluoroacetic acid) in 0.8 min, 95% acetonitrile till 1.8 min, 1.1 mL/min, 10x2.0 mm LunaC18 3 μm

LC/MS-Method 4

10% acetonitrile (0.1 % formic acid) till 90% acetonitrile (0.1 % formic acid) in 10 min, 90% acetonitrile till 10.67 min, 10% acetonitrile from 1 1 to 12 min, 0.5 mL/min, Aeris Widepore 3, 3μηι, 100x2.1 mm, 40°C

Syntheses

Method A

Amide coupling with 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid

To a solution of 0.55 mmol 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid in 5 mL dimethylformamide were added 1 .4 eq. (0.77 mmol) 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and 1.4 eq. (0.77 mmol) amine. The reaction mixture was stirred for 2-6 hours at room temperature. Reaction control was done by TLC. As work up 5-10 mL dichloromethane were added and the organic phase was washed with 1 M HCI, water, saturated aqueous NaHCC>3 solution, and water. The organic phases were dried with Na2S04, filtered, and evaporated. If needed the crude mixture was purified by MPLC.

Example 1

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-methylpiperazine-1 - carbonyl)tetrahydropyran-4-yl] acetate

Example 1 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 - methylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO): column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient:

Yield: 137 mg (0.308 mmol, 55.8 %), white solid.

TLC: Rf = 0.250 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 445.13 [M + H]+; calculated: 445.44; tR (λ = 220 nm): 0.93 min (LC/MS-method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.96 (d, J = 8.3 Hz, 1 H, CH), 5.37 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.97 (m, 2H, 2xCH), 3.63 (m, 1 H, NCH2), 3.55 (m, 1 H, CH2), 3.39 (m, 1 H, NCH2), 3.23 (m, 1 H, NCH2), 2.36 (m, 2H, NCH2), 2.16 (s, 3H, CH3), 2.1 1 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1 .93 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 2

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-ethylpiperazine-1 - carbonyl)tetrahydropyran-4-yl] acetate

Example 2 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 - ethylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

4.8 4.8 6.0

4.8 10.1 6.0

10.1 10.1 9.1

Yield: 201 mg (0.438 mmol, 79.4 %), white solid.

TLC: Rf = 0.492 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 459.12 [M + H]+; calculated: 459.46; tR (λ = 220 nm): 0.98 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.97 (d, J = 8.3 Hz, 1 H, CH), 5.38 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.97 (m, 2H, 2xCH), 3.58 (m, 2H, NCH2), 3.40 (m, 1 H, NCH2), = 3.24 (m, 1 H, NCH2), 2.41 (m, 2H, NCH2), 2.32 (m, 2H, CH2), 2.16 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.89 (s, 3H, CH3), 0.99 (t, J = 7.1 Hz, 3H, CH3) ppm.

Example 3

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-propylpiperazine-1 -carbonyl)tetrahydropyran-4-yl] acetate (8)

Example 3 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -n- propylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 144 mg (0.305 mmol, 55.2 %), white solid.

TLC: Rf = 0.417 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 473.14 [M + H]+; calculated: 473.89; tR (λ = 220 nm): 1.06 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.96 (d, J = 8.3 Hz, 1 H, CH), 5.38 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.98 (m, 2H, 2xCH), 3.58 (m, 2H, NCH2), 3.40 (m, 1 H, NCH2), 3.24 (m, 1 H, NCH2), 2.39 (m, 2H, NCH2), 2.22 (m, 2H, NCH2), 2.15 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.43 (m, 2H, CH2), 0.85 (t, J = 7.3 Hz, 3H, CH3) ppm.

Example 4

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-butylpiperazine-1 - carbonyl)tetrahydropyran-4-yl] acetate

Example 4 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -n- butylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 191 mg (0.393 mmol, 71.1 %), white solid.

TLC: Rf = 0.458 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 487.19 [M + H]+; calculated: 487.51 ; tR (λ

(LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.96 (d, J = 8.4 Hz, 1 H, CH), 5.38 (t, J = 9.4 Hz, 1 H, CH), 5.25 (t, J = 9.4 Hz, 1 H, CH), 4.97 (m, 2H, 2xCH), 3.57 (m, 2H, NCH2), 3.40 (m, 1 H, NCH2), 3.24 (m, 1 H, NCH2), 2.40 (m, 2H, NCH2), 2.26 (m, 2H, NCH2), 2.15 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.90 (s, 3H, CH3), 1.39 (m, 2H, CH2), 1.28 (m, 2H, CH2), 0.87 (t, J = 7.4 Hz, 3H, CH3) ppm.

Example 5

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-hexylpiperazine-1 - carbonyl)tetrahydropyran-4-yl] acetate

Example 5 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -n- hexylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

20.2 20.2 2.9

20.2 0.0 0.0

0.0 0.0 1.0

Yield: 226 mg (0.439 mmol, 79.6 %), white solid.

TLC: Rf = 0.489 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 515.24 [M + H]+; calculated: 515.57; tR (λ = 220 nm): 1.34 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, 26.9 °C, DMSO-d6): δ = 5.96 (d, J = 8.3 Hz, 1 H, CH), 5.37 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.97 (m, 2H, CH), 3.57 (m, 2H, NCH2), 3.40 (m, 1 H, CH2), 3.23 (m, 1 H, NCH2), 2.39 (m, 2H, NCH2), 2.25 (t, J = 7.1 Hz, 2H, NCH2), 2.15 (m, 2H, NCH2), 2.16 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.40 (m, 2H, CH2), 1.26 (m, 6H, 3xCH2), 0.86 (t, J = 6.9 Hz, 2H, CH3) ppm.

Example 6

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-isopropylpiperazine-1 -carbonyl)tetrahydropyran-4-yl] acetate

Example 6 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 - isopropylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 129 mg (0.273 mmol, 49.5 %), white solid.

TLC: Rf = 0.412 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 473.18 [M + H]+; calculated: 473.47; tR (λ = 220 nm): 1.02 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, 26.9 °C, DMSO-d6): δ = 5.97 (d, J = 8.3 Hz, 1 H, CH), 5.38 (t, J = 9.4 Hz, 1 H, CH), 5.25 (t, J = 9.4 Hz, 1 H, CH), 4.97 (m, 2H, 2xCH), 3.56 (m, 2H, NCH2), 3.39 (m, 1 H, CH2), 3.24 (m, 1 H, NCH2), 2.66 (m, 1 H, CH), 2.43 (m, 2H, NCH2), 2.27 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.90 (s, 3H, CH3), 0.95 (dd, 6H, CH3) ppm.

Example 7

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-tert-butylpiperazine-1 - carbonyl)tetrahydropyran-4-yl] acetate

Example 7 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -tert- butylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 139 mg (0.286 mmol, 51.8 %), white solid.

TLC: Rf = 0.464 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 487.20 [M + H]+; calculated: 487.51 ; tR: 1.06 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.97 (d, J = 8.3 Hz, 1 H, CH), 5.38 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.97 (m, 2H, CH), 3.53 (m, 2H, NCH2), 3.39 (m, 1 H, CH2), 3.26 (m, 1 H, NCH2), 2.67 (m, 2H, NCH2), 2.32 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.90 (s, 3H, CH3), 0.99 (s, 9H, 3xCH3) ppm.

Example 8

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-allylpiperazine-1 -carbonyl)tetrahydropyran-4-yl] acetate

Example 8 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -allylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 1.0

0 9.9 9.9

Yield: 184 mg (0.260 mmol, 70.8 %), white solid.

TLC: Rf = 0.479 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 471.26 [M + H]+; calculated: 471.19; tR: 1.02 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.97 (d, J = 8.1 Hz, 1 H, CH), 5.81 (m, 1 H, H2C=CH), 5.36 (t, J = 9.4 Hz, 1 H, CH), 5.24 (t, J = 9.4 Hz, 1 H, CH), 5.17 (m, 2H, HC=CH2), 4.98 (m, 2H, CH), 3.61 (m, 2H, NCH2), 3.42 (m, 1 H, NCH2), 3.23 (m, 1 H, NCH2), 2.96 (m, 2H, NCH2), 2.41 (m, 2H, NCH2), 2.17 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 9

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-cyclohexylpiperazine-1 -carbonyl)tetrahydropyran-4-yl] acetate

Example 9 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -cyclohexylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 227 mg (0.443 mmol, 80.2 %), white solid.

TLC: Rf = 0.610 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 513.15 [M + H]+; calculated: 513.24; tR: 1.22 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, 1 16.9 °C, DMSO-d6): 5.93 (d, J = 7.8 Hz, 1 H, CH), 5.33 (m, 2H, 2xCH), 4.99 (m, 1 H, CH), 4.88 (m, 1 H, CH), 3.71 (m, 4H, NCH2), 3.04 (m, 6H, NCH2), 3.23 (m, 2H, NCH2), 2.36 (m, 2H, NCH2), 2.06 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.90 (s, 3H, CH3), 1.82 (m, 2H, CH2), 1.63 (m, 1 H, CH), 1.30 (m, 8H, CH2) ppm.

Example 10

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(cyclohexylmethyl)piperazine-1 - carbonyl]tetrahydropyran-4-yl] acetate

Example 10 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 - cyclohexylmethylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 178 mg (0.338 mmol, 61.2 %), white solid.

TLC: Rf = 0.346 (ethylacetate/n-heptan, 2: 1 ).

LC/MS (ES-API): m/z = 527.22 [M + H]+; calculated: 527.25; tR: 1.31 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 5.97 (d, J = 8.3 Hz, 1 H, CH), 5.39 (t, J = 9.4 Hz, 1 H, CH), 5.27 (t, J = 9.4 Hz, 1 H, CH), 4.96 (m, 2H, CH), 3.58 (m, 2H, NCH2), 3.40 (m, 1 H, CH2), 3.25 (m, 1 H, NCH2), 2.37 (m, 2H, NCH2), 2.13 (m, 2H, NCH2), 2.19 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.69 (m, 4H, 2xCH2), 1.47 (m, 1 H, CH), 1.18 (m, 2H, 2xCH2), 0.82 (m, 2H, CH2) ppm.

Example 11

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-cyclohexylethyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 1 1 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -cyclohexylethylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 1.0

0 18.7 18.7

Yield: 183 mg (0.339 mmol, 61.3 %), white solid.

TLC: Rf = 0.51 1 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 541.24 [M + H]+; calculated: 541.27; tR: 1.41 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, 1 16.9 °C, DMSO-d6): δ = 5.93 (d, J = 7.8 Hz, 1 H, CH), 5.33 (m, 2H, 2xCH), 4.99 (m, 1 H, CH), 4.88 (m, 1 H, CH), 3.71 (m, 4H, NCH2), 3.04 (m, 6H, NCH2), 3.23 (m, 2H, NCH2), 2.36 (m, 2H, NCH2), 2.06 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.90 (s, 3H, CH3), 1.71 (m, 1 H, CH), 1.61 (m, 6H, CH2), 1.24 (m, 4H, CH2), 1.02 (m, 2H, CH2) ppm.

Example 12

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-phenylpiperazine-1 -carbonyl)tetrahydropyran-4-yl] acetate

Example 12 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -phenylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 260 mg (0.514 mmol, 62.0 %),white solid.

TLC: Rf = 0.695 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 507.14 [M + H]+; calculated: 507.19; tR: 1.70 min (LC/MS- Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.24 (t, J = 8.2 Hz, 2H, ArH), 6.95 (d, J = 8.2 Hz, 2H, ArH), 6.81 (t, J = 7.4 Hz, 1 H, ArH), 6.00 (d, J = 8.4 Hz, 1 H, CH), 5.40 (t, J = 9.9 Hz, 1 H, CH), 5.29 (t, J = 9.9 Hz, 1 H, CH), 5.05 (d, J = 9.6 Hz, 1 H, CH), 5.00 (m, 1 H, CH), 3.81 (m, 1 H, NCH2), 3.75 (m, 1 H, NCH2), 3.57 (m, 1 H, CH2), 3.39 (m, 1 H, NCH2), 3.24 (m, 2H, NCH2), 2.82 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1 .94 (s, 3H, CH3), 1.91 (s, 3H, CH3) ppm.

13C-NMR (150 MHz, DMSO-d6): δ = 169.64 (s, C), 169.04 (s, C), 169.02 (s, C), 168.43 (s, C), 163.04 (s, C), 150.69 (s, C), 128.99 (s, CH), 1 19.47 (s, CH), 1 15.97 (s, CH), 90.94 (s, CH), 72.02 (s, CH), 69.37 (s, CH), 69.15 (s, CH), 68.55 (s, CH), 49.14 (s, CH2), 48.07 (s, CH2), 44.78 (s, CH2), 41.41 (s, CH3), 20.44 (s, 2 CH3), 20.30 (s, 2 CH3) ppm.

Example 13

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-[(E)-cinnamyl]piperazine-1 - carbonyl]tetrahydropyran-4-yl] acetate

Example 13 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and trans- 1 -cinnamylpiperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 253 mg (0.463 mmol, 83.8 %), white solid.

TLC: Rf = 0.644 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 547.27 [M + H]+; calculated: 547.22; tR: 1.34 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.44 (d, J = 7.2 Hz, 2H, ArH), 7.32 (t, J = 7.2 Hz, 2H, ArH), 7.23 (t, J = 7.2 Hz, 2H, ArH), 6.54 (d, J = 15.9 Hz, 1 H, CH), 6.29 (m, 1 H, CH), 5.96 (d, J = 8.4 Hz, 1 H, CH), 5.37 (t, J = 9.5 Hz, 1 H, CH), 5.25 (t, J = 9.5 Hz, 1 H, CH), 4.97 (m, 2H, CH), 3.61 (m, 2H, NCH2), 3.42 (m, 1 H, CH2), 3.26 (m, 1 H, NCH2), 3.12 (m, 2H, NCH2), 2.47 (m, 2H, NCH2), 2.22 (m, 2H, NCH2), 2.06 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.89 (s, 3H, CH3) ppm.

Example 14

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-chlorophenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 14 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(4-chlorophenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 2.4

0 5.0 7.9

5.0 5.0 3.7

Yield: 153 mg (0.282 mmol, 51.3 %), white solid.

TLC: Rf = 0.619 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 541.19 [M + H]+; calculated: 541.15; tR: 1.80 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.25 (d, J = 9.0 Hz, 2H, ArH), 6.96 (d, J = 9.0 Hz, 2H, ArH), 6.00 (d, J = 8.3 Hz, 1 H, CH), 5.40 (t, J = 9.5 Hz, 1 H, CH), 5.28 (t, J = 9.5 Hz, 1 H, CH), 5.01 (m, 2H, 2xCH), 3.76 (m, 2H, NCH2), 3.56 (m, 1 H, NCH2), 3.37 (m, 1 H, NCH2), 3.25 (m, 2H, NCH2), 2.92 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 15

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-chlorophenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 15 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(2- chlorophenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC gradient

Yield: 148 mg (0.274 mmol, 49.6 %), white solid.

TLC: Rf = 0.589 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 541.10 [M + H]+; calculated: 541.15; tR: 1.80 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.44 (dd, J = 1.4 Hz, 2H, ArH), 7.33 (m, 2H, ArH), 7.14 (dd, J = 1.4 Hz, 2H, ArH), 7.07 (m, 2H, ArH), 5.98 (d, J = 8.3 Hz, 1 H, CH), 5.39 (t, J = 9.4 Hz, 1 H, CH), 5.29 (t, J = 9.4 Hz, 1 H, CH), 5.01 (m, 2H, 2xCH), 3.84 (m, 1 H, NCH2), 3.76 (m, 1 H, NCH2), 3.57 (m, 1 H, CH2), 3.38 (m, 1 H, NCH2), 3.02 (m, 2H, NCH2), 2.80 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.92 (s, 3H, CH3) ppm.

Example 16

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-bromophenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 16 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(4-bromophenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 1.0

0 20.2 20.0

20.2 20.2 2.9

20.2 0.0 0.0

0.0 0.0 1.0

Yield: 168 mg (0.287 mmol, 52.0 %), white solid.

TLC: Rf = 0.635 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 585.14 [M + H]+; calculated: 585.10; tR: 1.82 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.37 (d, J = 9.0 Hz, 2H, ArH), 6.92 (d, J = 9.0 Hz, 2H, ArH), 6.00 (d, J = 8.3 Hz, 1 H, CH), 5.40 (t, J = 9.4 Hz, 1 H, CH), 5.28 (t, J = 9.4 Hz, 1 H, CH), 5.01 (m, 2H, 2xCH), 3.76 (m, 2H, NCH2), 3.56 (m, 1 H, NCH2), 3.37 (m, 1 H, NCH2), 3.25 (m, 2H, NCH2), 2.93 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 17

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-methoxyphenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 17 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(4- methoxyphenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC gradient

Yield: 192 mg (0.320 mmol, 58.0 %), white solid.

TLC: Rf = 0.508 (ethylacetate/n-heptane, 2: 1 ).

LC/MS (ES-API): m/z = 537.14 [M + H]+; calculated: 537.20; tR: 1.64 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.91 (d, J = 9.1 Hz, 2H, ArH), 6.83 (d, J = 9.1 Hz, 2H, ArH), 5.99 (d, J = 8.0 Hz, 1 H, CH), 5.40 (t, J = 9.9 Hz, 1 H, CH), 5.28 (t, J = 9.9 Hz, 1 H, CH), 5.00 (m, 2H, 2xCH), 3.77 (m, 2H, NCH2), 3.69 (s, 3H, OCH3), 3.56 (m, 1 H, CH2), 3.37 (m, 1 H, NCH2), 3.08 (m, 2H, NCH2), 2.80 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 18

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(3-methoxyphenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 18 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(3-methoxyphenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC gradient

start %B end %B duration [min]

0 0 1.0

0 10.0 20.0

10.0 10.0 3.0

10.0 0.0 0.0

0.0 0.0 1.0

Yield: 120 mg (0.224 mmol, 40.6 %), white solid.

TLC: Rf = 0.571 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 537.12 [M + H]+; calculated: 537.20; tR: 1.70 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.12 (d, J = 8.2 Hz, 1 H, ArH), 6.83 (d, J = 8.2 Hz, 1 H, ArH), 6.47 (s, 1 H, ArH), 6.41 (d, J = 8.2 Hz, 1 H, ArH), 6.00 (d, J = 8.0 Hz, 1 H, CH), 5.39 (t, J = 9.9 Hz, 1 H, CH), 5.28 (t, J = 9.9 Hz, 1 H, CH), 5.00 (m, 2H, 2xCH), 3.78 (m, 2H, NCH2), 3.72 (s, 3H, OCH3), 3.56 (m, 1 H, CH2), 3.37 (m, 1 H, NCH2), 3.24 (m, 2H, NCH2), 2.92 (m, 2H, NCH2), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.96 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm.

Example 19

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-methoxyphenyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 19 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(2- methoxyphenyl)-piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 150 mg (0.280 mmol, 50.6 %), white solid.

TLC: Rf = 0.492 (ethylacetate/n-heptane, 2: 1 ).

LC/MS (ES-API): m/z = 537.14 [M + H]+; calculated: 537.20; tR: 1.67 min (LC/MS- Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.98 (t, J = 4.1 Hz, 1 H, ArH), 6.96 (t, J = 4.1 Hz, 1 H, ArH), 6.89 (d, J = 2.2 Hz, 2H, ArH), 6.86 (d, J = 2.2 Hz, 2H, ArH), 5.98 (d, J = 8.4 Hz, 1 H, CH), 5.40 (t, J = 9.5 Hz, 1 H, CH), 5.29 (t, J = 9.5 Hz, 1 H, CH), 5.00 (m, 2H, 2xCH), 3.83 (m, 1 H, NCH2), 3.79 (s, 3H, OCH3), 3.74 (m, 1 H, NCH2), 3.70 (m, 1 H, CH2), 3.54 (m, 1 H, NCH2), 3.03 (m, 2H, NCH2), 2.74 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.91 (s, 3H, CH3) ppm.

Example 20

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(1 ,3-benzodioxol-5-ylmethyl)piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetate

Example 20 was synthesized from 1 ,2,3,4-tetra-0-acetyl-β-D-glucuronic acid and 1 -(1 ,3-benzodioxol-5-ylmethyl)piperazine following the procedure described in synthesis method A.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 1.0

0 10.0 20.0

10.0 10.0 3.0

10.0 0.0 0.0

0.0 0.0 1.0

Yield: 221 mg (0.391 mmol, 70.9 %), white solid.

TLC: Rf = 0.478 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 565.14 [M + H]+; calculated: 565.19; tR: 1.24 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.84 (m, 2H, ArH), 6.73 (dd, J = 1 .4 Hz, 1 H, ArH), 5.99 (s, 2H, 0-CH2-0), 5.95 (d, J = 8.4 Hz, 1 H, CH), 5.36 (t, J = 9.5 Hz, 1 H, CH), 5.24 (t, J = 9.5 Hz, 1 H, CH), 4.96 (m, 2H, 2xCH), 3.62 (m, 2H, NCH2), 3.55 (m, 1 H, CH2), 3.39 (m, 1 H, NCH2), 3.23 (m, 1 H, NCH2), 2.39 (m, 2H, NCH2), 2.21 (m, 2H, NCH2), 2.07 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.88 (s, 3H, CH3) ppm.

Method B

Deacetylation of glucuronic acid amides

20 mg of [(2,3,5-triacetoxy-6-piperazine-1 -carbonyl]tetrahydropyran-4-yl] acetates were dissolved in 2 mL methanol/H20/tetrahydrofuran (5:4:1 ) and cooled to 0°C. 20 μΙ of a 2 M lithium hydroxide solution in water were added and stirred for 2-12 hours at 0°C. The reaction control was done by TLC and LC/MS. As work-up procedure the reaction mixture was neutralized with 1 M HCI, and the organic solvents were evaporated. The residue was diluted with water and lyophilized. The enantiomers were not separated. NMR signals were listed for only one enantiomer.

Example 21

(4-Methylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 21 was synthesized from example 1 following the deacteylation procedure described in synthesis method B.

Yield: 1 1.9 mg (43.07 μηιοΙ, 95.7 %), colorless oil.

LC/MS (ES-API): m/z = 277.15 [M + H]+; calculated: 277.13; tR (ELSD): 0.21 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.51 (d, J = 4.5 Hz, 1 H, CH), 5.0-4.3 (m, 4H, 4xOH), 3.5-3.0 (m, 12H, 4xCH2, 4xCH), 2.21 (m, 3H, CH3) ppm.

Example 22

(4-Ethylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 22 was synthesized from example 2 following the deacteylation procedure described in synthesis method B.

Yield: 1 1.8 mg (40.65 μηιοΙ, 93.2 %), colorless oil.

LC/MS (ES-API): m/z = 291.23 [M + H]+; calculated: 291.15; tR (ELSD): 0.20 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.48 (d, J = 4.6 Hz, 1 H, CH), 4.8-4.3 (m, 4H, 4xOH), 3.5-3.0 (m, 12H, 4xCH2, 4xCH), 2.20 (m, 5H, CH2CH3) ppm.

Example 23

(4-n-Propylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 23 was synthesized from example 3 following the deacteylation procedure described in synthesis method B.

Yield: 12.4 mg (40.74 μηιοΙ, 96.3 %), colorless oil.

LC/MS (ES-API): m/z = 305.21 [M + H]+; calculated: 305.16; tR (ELSD): 0.19 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.51 (d, J = 4.4 Hz, 1 H, CH), 4.9-4.1 (m, 4H, 4xOH), 3.6-3.0 (m, 12H, 4xCH2, 4xCH), 2.32 (m, 2H, NCH2), 1.49 (m, 2H, CH2), 0.89 (t, J = 7.3 Hz, 3H, CH3) ppm.

Example 24

(4-n-Butylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 24 was synthesized from example 4 following the deacteylation procedure described in synthesis method B.

Yield: 12.7 mg (39.89 μηιοΙ, 97.0 %), colorless oil.

LC/MS (ES-API): m/z = 319.21 [M + H]+; calculated: 319.18; tR (ELSD): 0.23 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.52 (d, J = 4.5 Hz, 1 H, CH), 4.87 (dd, J = 4.2 Hz, 1 H, OH), 4.75 (dd, J = 4.9 Hz, 1 H, OH), 4.29 (d, J = 8.9 Hz, 1 H, OH), 4.02 (d, J = 9.4 Hz, 1 H, OH), 3.6-3.15 (m, 12H, 4xCH2, 4xCH), 2.32 (m, 2H, NCH2), 1.46 (m, 2H, CH2), 1.29 (m, 2H, CH2), 0.89 (t, J = 7.1 Hz, 3H, CH3) ppm.

Example 25

(4-n-Hexylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 25 was synthesized from example 5 following the deacteylation procedure described in synthesis method B.

Yield: 12.6 mg (36.37 μηιοΙ, 93.6 %), white solid.

LC/MS (ES-API): m/z = 347.17 [M + H]+; calculated: 347.21 ; tR1 (λ = 220 nm): 0.50 min; tR2 (λ = 220 nm): 0.53 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.50 (d, J = 4.4 Hz, 1 H, CH), 4.85 (dd, J = 4.4 Hz, 1 H, OH), 4.76 (dd, J = 4.8 Hz, 1 H, OH), 4.27 (d, J = 8.8 Hz, 1 H, OH), 4.12 (d, J = 9.3 Hz, 1 H, OH), 3.6-3.1 (m, 12H, 4xCH2, 4xCH), 2.32 (m, 2H, NCH2), 1.43 (m, 8H, 4xCH2), 0.90 (t, J = 7.2 Hz, 3H, CH3) ppm.

Example 26

(4-lsopropylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 26 was synthesized from example 6 following the deacteylation procedure described in synthesis method B.

Yield: 12.2 mg (40.09 μηιοΙ, 94.7 %), colorless oil.

LC/MS (ES-API): m/z = 305.23 [M + H]+; calculated: 305.16; tR (ELSD): 0.21 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.48 (d, J = 4.6 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.5-3.1 (m, 12H, 4xCH2, 4xCH), 2.43 (m, 2H, NCH), 1.01 (m, 6H, 2xCH3) ppm.

Example 27

(4-tert-Butylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 27 was synthesized from example 7 following the deacteylation procedure described in synthesis method B.

Yield: 12.5 mg (39.26 μηιοΙ, 95.5 %), white solid.

LC/MS (ES-API): m/z = 319.25 [M + H]+; calculated: 319.18; tR (ELSD): 0.22 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.49 (d, J = 4.9 Hz, 1 H, CH), 4.9-4.0 (m, 4H, 4xOH), 3.5-3.1 (m, 12H, 4xCH2, 4xCH), 1 .04 (m, 9H, 3xCH3) ppm.

Example 28

(4-Allylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 28 was synthesized from example 8 following the deacteylation procedure described in synthesis method B.

Yield: 12.4 mg (41.02 μηιοΙ, 96.5 %), colorless oil.

LC/MS (ES-API): m/z = 303.22 [M + H]+; calculated: 303.15; tR (ELSD): 0.21 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.29 (d, J = 4.5 Hz, 1 H, CH), 4.7-4.0 (m, 4H, 4xOH), 3.4-3.1 (m, 12H, 4xCH2, 4xCH), 2.41 (m, 5H, 2xCH2, CH) ppm.

Example 29

(4-Cyclohexylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 29 was synthesized from example 9 following the deacteylation procedure described in synthesis method B.

Yield: 12.9 mg (37.46 μηιοΙ, 96.0 %), white solid.

LC/MS (ES-API): m/z = 345.25 [M + H]+; calculated: 345.19; tR1 (ELSD): 0.28 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.51 (d, J = 4.8 Hz, 1 H, CH), 4.6-4.0 (m, 4H, 4xOH), 3.4-2.9 (m, 12H, 4xCH2, 4xCH), 1.71 (m, 4H, 2xCH2), 1.54 (m, 1 H, CH), 1.19 (m, 6H, 3xCH2) ppm.

Example 30

(4-Cyclohexylmethylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 30 was synthesized from example 10 following the deacteylation procedure described in synthesis method B.

Yield: 13.1 mg (36.55 μηιοΙ, 96.2 %), white solid.

LC/MS (ES-API): m/z = 359.16 [M + H]+; calculated: 359.21 ; tR1 (λ = 220 nm): 0.46 min; tR2 (λ = 220 nm): 0.48 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.47 (d, J = 4.5 Hz, 1 H, CH), 4.9-4.3 (m, 4H, 4xOH), 3.5-2.9 (m, 12H, 4xCH2, 4xCH), 2.07 (m, 2H, NCH2), 1.74 (m, 4H, 2xCH2), 1.52 (m, 1 H, CH), 1.21 (m, 4H, 2xCH2), 0.87 (m, 2H, CH2) ppm.

Example 31

(4-Cyclohexylethylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 31 was synthesized from example 1 1 following the deacteylation procedure described in synthesis method B.

Yield: 12.2 mg (32.76 μηιοΙ, 88.5 %), white solid.

LC/MS (ES-API): m/z = 373.17 [M + H]+; calculated: 373.23; tR1 (λ = 220 nm): 0.81 min; tR2 (λ = 220 nm): 0.84 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.42 (d, J = 4.8 Hz, 1 H, CH), 4.6-4.1 (m, 4H, 4xOH), 3.6-3.0 (m, 12H, 4xCH2, 4xCH), 2.05 (m, 2H, NCH2), 1.72 (m, 4H, 2xCH2), 1.50 (m, 1 H, CH), 1.23 (m, 4H, 2xCH2), 0.90 (m, 2H, CH2), 0.87 (m, 2H, CH2) ppm.

Example 32

(4-Phenylpiperazin-1 -yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 32 was synthesized from example 12 following the deacteylation procedure described in synthesis method B.

Yield: 1 1.8 mg (34.87 μηιοΙ, 88.3 %), white solid.

LC/MS (ES-API): m/z = 339.13 [M + H]+; calculated: 339.15; tR1 (λ = 220 nm): 0.90 min; tR2 (λ = 220 nm): 0.95 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.23 (t, J = 7.9 Hz, 2H, ArH), 6.95 (d, J = 7.8 Hz, 2H, ArH), 6.81 (t, J = 7.3 Hz, 1 H, ArH), 6.66 (d, J = 7.0 Hz, 1 H, OH), 4.81 (d, J = 4.7 Hz, 1 H, OH), 4.74 (d, J = 5.3 Hz, 1 H, OH), 4.62 (d, J = 6.4 Hz, 1 H, OH), 4.43 (t, J = 7.3 Hz, 1 H, CH), 4.09 (d, J = 9.3 Hz, 1 H, CH), 3.70-3.45 (m, 8H, 4xNCH2), 3.25-3.00 (m, 3H, 3xCH) ppm.

13C-NMR (150 MHz, DMSO-d6): δ = 166.48 (s, CO), 150.76 (s, C), 129.06 (s, CH), 1 19.28 (s, CH), 1 15.78 (s, CH), 93.06 (s, CH), 74.52 (s, CH), 72.71 (s, CH), 71 .33 (s, CH), 70.98 (s, CH), 48.93 (s, CH2), 48.22 (s, CH2), 44.59 (s, CH2), 41.15 (s, CH2) ppm.

Example 33

[4-[(E)-Cinnamyl]piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 33 was synthesized from example 13 following the deacteylation procedure described in synthesis method B.

Yield: 12.7 mg (33.56 μηιοΙ, 91.7 %), white solid.

LC/MS (ES-API): m/z = 379.25 [M + H]+; calculated: 379.19; tR1 (λ = 220 nm): 0.56 min; tR2 (λ = 220 nm): 0.60 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.40 (d, J = 7.0 Hz, 2H, ArH), 7.33 (t, J = 7.0 Hz, 2H, ArH), 7.21 (t, J = 7.0 Hz, 2H, ArH), 6.44 (d, J = 4.6 Hz, 1 H, CH), 4.6-4.1 (m, 4H, 4xOH), 3.65 (m, 2H, NCH2), 3.51 (m, 2H, 2xCH), 3.4-2.9 (m, 12H, 4xNCH2, 4xCH) ppm.

Example 34

[4-(4-Chlorophenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 34 was synthesized from example 14 following the deacteylation procedure described in synthesis method B.

Yield: 13.6 mg (36.48 μηιοΙ, 98.7 %), white solid.

LC/MS (ES-API): m/z = 373.16 [M + H]+; calculated: 373.1 1 ; tR1 (λ = 220 nm): 1.20 min; tR2 (λ = 220 nm): 1.24 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.40 (d, J = 7.8 Hz, 4H, ArH), 6.49 (d, J = 4.7 Hz, 1 H, CH), 4.9-4.3 (m, 4H, 4xOH), 3.7-3.0 (m, 12H, 4xNCH2, 4xCH) ppm.

Example 35

[4-(2-Chlorophenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 35 was synthesized from example 15 following the deacteylation procedure described in synthesis method B.

Yield: 13.3 mg (35.68 μηιοΙ, 96.5 %), white solid.

LC/MS (ES-API): m/z = 373.06 [M + H]+; calculated: 373.1 1 ; tR1 (λ = 220 nm): 1.23 min; tR2 (λ = 220 nm): 1.26 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.45 (d, J = 7.8 Hz, 1 H, ArH), 7.31 (t, J = 7.8 Hz, 1 H, ArH), 7.14 (d, J = 7.8 Hz, 1 H, ArH), 7.03 (t, J = 7.8 Hz, 1 H, ArH), 6.52 (d, J = 4.7 Hz, 1 H, CH), 4.9-4.3 (m, 4H, 4xOH), 3.7-3.0 (m, 12H, 4xNCH2, 4xCH) ppm.

Example 36

[4-(4-Bromophenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 36 was synthesized from example 16 following the deacteylation procedure described in synthesis method B.

Yield: 12.9 mg (30.92 μηιοΙ, 90.5 %), white solid.

LC/MS (ES-API): m/z = 416.1 1 [M + H]+; calculated: 416.06; tR1 (λ = 220 nm): 1.25 min; tR2 (λ = 220 nm): 1.28 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.69 (d, J = 8.0 Hz, 4H, ArH), 6.52 (d, J = 4.9 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.6-3.1 (m, 12H, 4xNCH2, 4xCH) ppm.

Example 37

[4-(4-Methoxyphenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 37 was synthesized from example 17 following the deacteylation procedure described in synthesis method B.

Yield: 13.4 mg (36.38 μηιοΙ, 97.6 %), white solid.

LC/MS (ES-API): m/z = 369.1 1 [M + H]+; calculated: 369.16; tR1 (λ = 220 nm): 0.74 min; tR2 (λ = 220 nm): 0.80 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.91 (d, J = 8.2 Hz, 2H, ArH), 6.83 (d, J = 8.2 Hz, 2H, ArH), 6.53 (d, J = 4.4 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.69 (s, 3H, OCH3), 3.6-2.9 (m, 12H, 4xNCH2, 4xCH) ppm.

Example 38

[4-(3-Methoxyphenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 38 was synthesized from example 18 following the deacteylation procedure described in synthesis method B.

Yield: 13.1 mg (35.56 μηιοΙ, 95.4 %), white solid.

LC/MS (ES-API): m/z = 369.10 [M + H]+; calculated: 369.16; tR1 (λ = 220 nm): 1.01 min; tR2 (λ = 220 nm): 1.04 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 7.14 (d, J = 8.2 Hz, 1 H, ArH), 6.84 (d, J = 8.2 Hz, 1 H, ArH), 6.57 (s, 1 H, ArH), 6.51 (d, J = 8.2 Hz, 1 H, ArH), 6.43 (d, J = 4.4 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.72 (s, 3H, OCH3), 3.60-3.45 (m, 4H, 4xCH), 3.25-3.00 (m, 8H, 4xNCH2) ppm.

Example 39

[4-(2-Methoxyphenyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 39 was synthesized from example 19 following the deacteylation procedure described in synthesis method B.

Yield: 12.8 mg (34.75 μηιοΙ, 93.2 %), white solid.

LC/MS (ES-API): m/z = 369.19 [M + H]+; calculated: 369.16; tR1 (λ = 220 nm): 0.85 min; tR2 (λ = 220 nm): 0.90 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.98 (m, 2H, ArH), 6.87 (d, J = 7.2 Hz, 2H, ArH), 6.49 (d, J = 4.4 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.70 (s, 3H, OCH3), 3.6-3.2 (m, 4H, 4xCH), 3.0-2.8 (m, 8H, 4xNCH2) ppm.

Example 40

[4-(1 ,3-Benzodioxol-5-ylmethyl)piperazin-1 -yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

Example 40 was synthesized from example 20 following the deacteylation procedure described in synthesis method B.

Yield: 12.6 mg (31.79 μηιοΙ, 89.7 %), white solid.

LC/MS (ES-API): m/z = 397.1 1 [M + H]+; calculated: 397.15; tR1 (λ = 220 nm): 0.95 min; tR2 (λ = 220 nm): 0.99 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 6.82 (m, 2H, ArH), 6.75 (dd, J = 1 .4 Hz, 1 H, ArH), 6.00 (s, 2H, 0-CH2-0), 6.49 (d, J = 4.4 Hz, 1 H, CH), 4.8-4.1 (m, 4H, 4xOH), 3.6-3.2 (m, 4H, 4xCH), 3.0-2.8 (m, 8H, 4xNCH2), 2.41 (m, 2H, NCH2) ppm.

Example 41

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-butylpiperazine-1 -carbonyl)-3,4-dihydro-2H-pyran-4-yl] acetate

Step 1 : (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid

A solution of 2 g (5.52 mmol) 1 ,2,3,4-tetra-O-acetyl-β-D-glucuronic acid in 6 mL (63.59 mmol) acetic acid anhydride and 3 mL (22.08 mmol; 4 eq.) triethylamine was stirred at room temperature for 8 hours. The reaction mixture was diluted with water and lyophillized.

Yield: 1.6 g (5.38 mmol, 95.8 %), colorless oil.

LC/MS (ES-API): not detectable.

1H-NMR (400 MHz, CDCI3): δ = 7.99 (s, 1 H, COOH), 6.33 (s, 1 H, CH), 6.27 (m, 1 H, CH), 5.19 (m, 1 H, CH), 5.10 (m, 1 H, CH), 2.05 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm.

Method C

Amide coupling with (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid (example 41 , step 1)

To a solution of 0.66 mmol (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid (example 41 , step 1 ) in 2 mL dimethylformamide were added 1.2 eq. (0.79 mmol) HATU and 1.4 eq. (0.93 mmol) amine. The reaction mixture was stirred at room temperature for 2 hours. The reaction was controlled by TLC and LC/MS. After completion the reaction mixture was extracted with 5-10 mL dichloromethane. The organic phase was washed with 1 M aqueous HCI, water, saturated aqueous NaHC03 solution, and water. The organic phase was dried with Na2S04, filtered, and evaporated. The crude material was purified by MPLC.

Step 2: [(2S,3R,4S)-2,3-diacetoxy-6-(4-butylpiperazine-1 -carbonyl)-3,4-dihydro-2H-pyran-4-yl] acetate

Example 41 was synthesized from example 41 , step 1 and 1 -n-butylpiperazine following the amide coupling procedure described in synthesis method C.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 2.2

0 4.8 2.8

4.8 4.8 6.0

4.810.0 10.1 6.0

10.1 10.1 9.1

Yield: 141 mg (0.331 mmol, 50.8 %), orange oil.

LC/MS (ES-API): m/z = 427.20 [M + H]+; calculated: 427.20; tR (λ = 220 nm): 0.57 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, CDCI3): δ = 6.28 (d, J = 3.6 Hz, 1 H, C=CH), 5.67 (d, J = 3.8 Hz, 1 H, CH), 5.25 (m, 1 H, CH), 5.19 (m, 1 H, CH), 3.73 (m, 4H, 2xNCH2), 2.60 (m, 4H, 2xNCH2), 2.15 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.10 (s, 3H, CH3) ppm.

Example 42

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-tert-butylpiperazine-1 -carbonyl)-3,4-dihydro-2H-pyran-4-yl] acetate

Example 42 was synthesized from example 41 , step 1 and 1 -tert-butylpiperazine following the amide coupling procedure described in synthesis method C.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

start %B end %B duration [min]

0 0 2.2

0 4.8 2.8

4.8 4.8 6.0

4.810.0 10.1 6.0

10.1 10.1 9.1

Yield: 81 mg (0.190 mmol,28.7 %), orange oil.

LC/MS (ES-API): m/z = 427.15 [M + H]+; calculated: 427.20; tR (λ = 220 nm): 0.53 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, CDCI3): δ = 6.29 (d, J = 3.6 Hz, 1 H, C=CH), 5.69 (d, J = 3.8 Hz, 1 H, CH), 5.24 (m, 1 H, CH), 5.20 (m, 1 H, CH), 3.75 (m, 4H, 2xNCH2), 2.62 (m, 4H, 2xNCH2), 2.16 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.10 (s, 3H, CH3), 1 .27 (s, 9H, 3xCH3) ppm.

Example 43

[(2S,3R,4S)-2,3-Diacetoxy-6-[4-(cyclohexylmethyl)piperazine-1 -carbonyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Example 43 was synthesized from example 41 , step 1 and 1 - cyclohexylmethylpiperazine following the amide coupling procedure described in synthesis method C.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 145 mg (0.31 1 mmol, 47.0 %), orange oil.

LC/MS (ES-API): m/z = 467.20 [M + H]+; calculated: 467.23; tR (λ = 220 nm): 0.64 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, CDCI3): δ = 6.29 (d, J = 3.2 Hz, 1 H, C=CH), 5.63 (d, J = 3.2 Hz, 1 H, CH), 5.24 (m, 1 H, CH), 5.19 (m, 1 H, CH), 3.75 (m, 4H, 2xNCH2), 2.62 (m, 4H, 2xNCH2), 2.16 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.1 1 (s, 3H, CH3), 1.73 (m, 1 H, CH), 1.62 (m, 4H, 2xCH2) , 1.13 (m, 4H, 2xCH2) , 0.92 (m, 2H, CH2) ppm.

Example 44

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-phenylpiperazine-1 -carbonyl)-3,4-dihydro-2H-pyran- 4-yl] acetate

Example 44 was synthesized from example 41 , step 1 and 1 -phenylpiperazine following the amide coupling procedure described in synthesis method C.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 135 mg (0.303 mmol, 45.5 %), orange oil.

LC/MS (ES-API): m/z = 447.13 [M + H]+; calculated: 447.17; tR (λ

(LC/MS-Method 1 ).

1H-NMR (400 MHz, CDCI3): δ = 7.31 (t, J = 7.9 Hz, 2H, ArH), 7.00 (m, 3H, ArH), 6.32 (dd, J = 0.9 Hz, 1 H, C=CH), 5.67 (dd, J = 0.8 Hz, 1 H, CH), 5.27 (m, 1 H, CH), 5.21 (m, 1 H, CH), 3.76 (m, 4H, 2xNCH2), 3.22 (m, 4H, 2xNCH2), 2.15 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.10 (s, 3H, CH3) ppm.

Example 45

[(2S,3R,4S)-2,3-Diacetoxy-6-[(4-phenylpiperazin-1 -yl)methyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Step 1 : [(2S,3R,4S)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl] acetate

A solution of 2.87 mL dry DMSO (40.31 mmol; 2.6 eq.) in 3 mL dry dichloromethane was dropped slowly to a solution of 1.61 mL oxalylchloride (18.60 mmol; 1 .2eq.) in 4 mL dry dichloromethane at -70°C. After stirring the reaction mixture at -70°C for 30 minutes, a solution of 5.4 g 1 ,2,3,4-tetra-0-acetyl-β-D-glucopyranose in 20 mL dry dichloromethane was added. After stirring the reaction mixture at -70°C for 30 minutes, 1 1 mL triethylamine were added slowly. The reaction mixture was warmed to room temperature and diluted with 20 mL water. After stirring for 10 minutes at room temperature, the aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried with Na2S04, filtered, and evaporated.

Yield: 3.13 g (10.94 mmol, 70.5 %), colorless oil.

TLC: Rf = 0.509 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 304.05 [M + H20]+; calculated: 287.07; tR (λ = 254 nm): 0.63 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 9.28 (s, 1 H, CHO), 5.19 (d, J = 4.2 Hz, 1 H, CH), 5.10 (m, 2H, 2xCH), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

Method D

Reductive amination with [(2S,3R,4S)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl] acetate (example 45, step 1)

To a solution of 0.52 mmol [(2S,3R,4S)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl] acetate (example 45, step 1 ) in 10 mL dichloroethane were added 0.57 mmol (1.1 eq.) amine and 0.74 mmol (1 .41 eq.) sodiumtriacetoxyboronhydride. The reaction mixture was stirred at room temperature over night. The reaction was controlled by TLC and LC/MS. The reaction mixture was filtered and evaporated. The crude material was purified by MPLC.

Step 2: [(2S,3R,4S)-2,3-diacetoxy-6-[(4-phenylpiperazin-1 -yl)methyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Example 45 was synthesized from example 45, step 1 and 1 -phenylpiperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 154 mg (0.356 mmol, 68.0 %), yellow oil.

TLC: Rf = 0.639 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 433.20 [M + H]+; calculated: 433.19; tR (λ = 220 nm): 1.26 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.20 (t, J = 8.0 Hz, 2H, ArH), 6.92 (d, J = 8.0 Hz, 2H, ArH), 6.76 (d, J = 7.2 Hz, 1 H, ArH), 5.96 (dd, J = 3.6 Hz, J = 1.0 Hz 1 H, CH), 5.12 (d, J = 4.2 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.12 (m, 4H, 2xNCH2), 3.02 (AB-system, q, J = 14.3 Hz, 2H, CH2), 2.50 (m, 4H, 2xNCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

13C-NMR (150 MHz, DMSO-d6): δ = 169.83 (s, C), 168.62 (s, C), 168.40 (s, C), 151.31 (s,2x C), 129.16 (s, CH), 1 18.98 (s, CH), 1 15.23 (s, CH), 97.54 (s, CH), 93.66 (s, C), 88.92 (s, CH), 66.82 (s, CH), 64.19 (s, CH), 52.04 (s, 2xCH), 47.96 (s,2x CH), 21.13 (s, CH3), 20.85 (s, CH3), 20.74 (s, CH3) ppm.

Example 46

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-[(E)-cinnamyl]piperazin-1 -yl]methyl]-3,4-dihydro- 2H-pyran-4-yl] acetate

Example 46 was synthesized from example 45, step 1 and trans-1 -cinnamylpiperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 194 mg (0.41 1 mmol, 78.3 %), yellow oil.

TLC: Rf = 0.136 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 473.23 [M + H]+; calculated: 473.22; tR (λ = 220 nm): 1.32 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.42 (d, J = 7.3 Hz, 2H, ArH), 7.31 (t, J = 7.3 Hz, 2H, ArH), 7.23 (t, J = 7.3 Hz, 1 H, ArH), 6.52 (d, J = 15.9 Hz, 1 H, CH), 6.27 (m, 1 H, CH), 6.18 (dd, J = 1.2 Hz, 1 H, CH), 5.08 (d, J = 4.1 Hz, 1 H, CH), 5.03 (m, 2H, 2xCH), 3.33 (m, 6H, 3xNCH2), 2.96 (q, J = 14.2 Hz, 2H, CH2), 2.41 (m, 4H, 2xNCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

Example 47

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(1 ,3-benzodioxol-5-ylmethyl)piperazin-1 -yl]methyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Example 47 was synthesized from example 45, step 1 and 1 -(1 ,3-benzodioxol-5-ylmethyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 249 mg (0.508 mmol, 96.9 %), yellow oil.

TLC: Rf = 0.242 (ethylacetate/n-heptane, 2: 1 ).

LC/MS (ES-API): m/z = 491.24 [M + H]+; calculated: 491.19; tR (λ = 220 nm): 1.19 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 6.84 (m, 2H, ArH), 6.73 (dd, J = 1 .4 Hz, 1 H, ArH), 6.28 (dd, J = 1.0 Hz, 1 H, CH), 5.97 (s, 2H, 0-CH2-0), 5.08 (d, J = 4.2 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.31 (m, 4H, 2xNCH2), 2.94 (q, J = 14.4 Hz, 2H, CH2), 2.38 (m, 4H, 2xNCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm.

Example 48

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-chlorophenyl)piperazin-1 -yl]methyl]-3,4-dihydro- 2H-pyran-4-yl] acetate

Example 48 was synthesized from example 45, step 1 and 1 -(4-chlorophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 131 mg (0.281 mmol, 53.5 %), yellow oil.

TLC: Rf = 0.636 (ethylacetate/n-heptane, 2: 1 ).

LC/MS (ES-API): m/z = 467.16 [M + H]+; calculated: 467.91 ; tR (λ = 220 nm): 1.40 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.21 (d, J = 9.1 Hz, 2H, ArH), 6.93 (d, J = 9.1 Hz, 2H, ArH), 6.20 (dd, J = 1 .1 Hz, 1 H, CH), 5.12 (d, J = 4.4 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.12 (m, 4H, 2xNCH2), 3.02 (q, J = 14.1 Hz, 2H, CH2), 2.51 (m, 4H, 2xNCH2), 2.07 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

Example 49

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(2-chlorophenyl)piperazin-1 -yl]methyl]-3,4-dihydro- 2H-pyran-4-yl] acetate

Example 49 was synthesized from example 45, step 1 and 1 -(2-chlorophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 144 mg (0.308 mmol, 58.9 %), yellow oil.

TLC: Rf = 0.621 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 467.16 [M + H]+; calculated: 467.91 ; tR (λ = 220 nm): 1.38 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.39 (d, J = 7.9 Hz, 1 H, ArH), 7.28 (t, J = 7.7 Hz, 1 H, ArH), 7.17 (d, J = 8.1 Hz, 1 H, ArH), 7.03 (t, J = 7.6 Hz, 1 H, ArH), 6.21 (dd, J = 1 .2 Hz, 1 H, CH), 5.13 (d, J = 4.1 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.07 (q, J = 14.4 Hz, 2H, CH2), 2.98 (m, 4H, 2xNCH2), 2.59 (m, 4H, 2xNCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm.

Example 50

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-methoxyphenyl)piperazin-1 -yl]methyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Example 50 was synthesized from example 45, step 1 and 1 -(4-methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 151 mg (0.326 mmol, 62.3 %), yellow oil.

TLC: Rf = 0.530 (ethylacetate/n-heptane, 2: 1 ).

LC/MS (ES-API): m/z = 463.19 [M + H]+; calculated: 463.20; tR (λ = 220 nm): 1.25 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 6.88 (d, J = 9.1 Hz, 2H, ArH), 6.80 (d, J = 9.1 Hz, 2H, ArH), 6.20 (dd, J = 1 .0 Hz, 1 H, CH), 5.12 (d, J = 4.1 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.69 (s, 3H, OCH3), 3.00 (m, 6H, CH2+NCH2), 2.52 (m, 4H, NCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

Example 51

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(3-methoxyphenyl)piperazin-1 -yl]methyl]-3,4- dihydro-2H-pyran-4-yl] acetate

Example 51 was synthesized from example 45, step 1 and 1 -(3- methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 135 mg (0.292 mmol, 55.7 %), yellow oil.

TLC: Rf = 0.591 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 463.24 [M + H]+; calculated: 463.20; tR (λ = 220 nm): 1.28 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.09 (t, J = 8.2 Hz, 1 H, ArH), 6.51 (d, J = 8.2 Hz, 1 H, ArH), 6.43 (s, 1 H, ArH), 6.35 (dd, J = 1.1 Hz, 1 H, CH), 5.12 (d, J = 4.3 Hz, 1 H, CH), 5.04 (m, 1 H, CH), 3.71 (s, 3H, OCH3), 3.1 1 (m, 4H, 2xNCH2), 3.01 (q, J = 14.3 Hz, 2H, CH2), 2.52 (m, 4H, 2xNCH2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm.

Example 52

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(2-methoxyphenyl)piperazin-1 -yl]methyl]-3,4- dihydro-2H-pyran-4-yl] acetate

Example 52 was synthesized from example 45, step 1 and 1 -(2-methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 167 mg (0.361 mmol, 68.9 %), yellow oil.

TLC: Rf = 0.533 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 463.24 [M + H]+; calculated: 463.20; tR (λ = 220 nm): 1.26 min (LC/MS-Method 1 ).

MPLC gradient

start %B end %B duration [min]

0.0 0.0 1.3

0.0 100.0 13.7

100.0 100.0 3.6

1H-NMR (400 MHz, DMSO-d6): δ = 6.90 (m, 4H, ArH), 6.21 (dd, J = 1.0 Hz, 1 H, CH), 5.12 (d, J = 4.4 Hz, 1 H, CH), 5.03 (m, 1 H, CH), 3.68 (s, 3H, OCH3), 3.04 (q, J = 14.3 Hz, 2H, CH2), 2.96 (m, 4H, 2xNCH2), 2.54 (m, 4H, 2xNCH2), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.05 (s, 3H, CH3) ppm.

Example 53

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-bromophenyl)piperazin-1 -yl]methyl]-3,4-dihydro-2H-pyran-4-yl] acetate

Example 53 was synthesized from example 45, step 1 and 1 -(4-bromophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 248 mg (0.485 mmol, 92.5 %), yellow oil.

TLC: Rf = 0.644 (ethylacetate/n-heptane, 2:1 ).

LC/MS (ES-API): m/z = 51 1.14 [M + H]+; calculated: 51 1.10; tR (λ = 220 nm): 1.42 min (LC/MS-Method 1 ).

MPLC gradient

1H-NMR (400 MHz, DMSO-d6): δ = 7.33 (d, J = 9.0 Hz, 2H, ArH), 6.88 (d, J = 9.0 Hz, 2H, ArH), 6.20 (dd, J = 1 .2 Hz, 1 H, CH), 5.12 (d, J = 4.3 Hz, 1 H, CH), 5.04 (m, 2H, 2xCH), 3.12 (m, 4H, 2xNCH2), 3.03 (q, J = 14.2 Hz, 2H, CH2), 2.52 (m, 4H, 2xNCH2), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.05 (s, 3H, CH3) ppm.

Example 54

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

Step 1 : 5-(dimethylamino)-N-prop-2-ynyl-naphthalene-1 -sulfonamide

To a solution of 405 mg (1.5 mmol) dansylchloride in 4 mL dimethylformamide were added 91 mg (1.65 mmol) propargylamine and 530 μΙ (3 mmol, 2 eq.) N,N- diisopropylethylamine. The reaction mixture was stirred at 100°C in the microwave for 45 minutes. The reaction mixture was filtered and evaporated.

Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 24 g Gold; flow rate: 40 mL/min; wavelength for detection: 254 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC gradient

Yield: 92 mg (0.319 mmol, 21.5 %), yellow oil.

TLC: Rf = 0.510 (dichloromethane/ethanol, 19:1 ).

LC/MS (ES-API): m/z = 289.13 [M + H]+; calculated: 289.09; tR (λ = 220 nm): 1.62 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.48 (d, J = 8.6 Hz, 1 H, ArH), 8.40 (s, 1 H, S02NH), 8.25 (d, J = 8.6 Hz, 1 H, ArH), 8.13 (dd, J = 1.1 Hz, 1 H, ArH), 7.60 (m, 2H, ArH), 7.26 (d, J = 7.4 Hz, 1 H, ArH), 3.71 (s, 2H, NCH2), 2.91 (s, 1 H, CH), 2.84 (s, 6H, 2xNCH3) ppm.

Method E

Copper-catalyzed Azide-Alkyne-Cycloaddition (CuAAC) with azidodeoxyglucose

To a solution of 146 μmοΙ azidodeoxyglucose (1 -azido-1 -deoxyglucose, 2-azido-2- deoxyglucose, or 6-azido-6-deoxyglucose) in 0.5 mL water 1.1 eq. alkyne were added. If needed dimethylformamide was added untill the reaction mixture was a clear solution. A mixture of 0.1 eq. CuS0 * 5 H20 (0.1 M in water), 0.25 eq. sodium ascorbate (1 M in water), and 0.4 eq. THPTA (0.5 M in water) was added. The reaction mixture was stirred at room temperature for 2-6 hours. The reaction was controlled by TLC and LC/MS. The reaction mixture was evaporated and purified by HPLC. Alpha/beta isomers were not separated, NMR data belong to only one isomer.

Purification: Agilent 1200 preparative HPLC; column: Agilent Prep-C18 column (10 μm, 21 .5x150 mm); flow rate: 40 mL/min; wavelength for detection: 220 nm; 254 nm; 324 nm; eluent: (A) water, (B) acetonitrile.

HPLC-gradient

Step 2: 5-(dimethylamino)-N-[[1 -[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)- tetrahydropyran-3-yl]triazol-4-yl]methyl]naphthalene-1 -sulfonamide

Example 54 was synthesized from 2-azido-2-deoxyglucose and example 45, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 33 mg (67 μηιοΙ, 46.7 %), yellow oil.

TLC: Rf = 0.032 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 494.19 [M + H]+; calculated: 494.16; tR1 (λ = 220 nm): 1.17 min; tR2 (λ = 220 nm): 1.20 min (LC/MS-Method 1).

1H-NMR (400 MHz, DMSO-d6): δ = 8.47 (d, J = 8.6 Hz, 2H, ArH), 8.40 (s, 1H, SNH), 8.13 (d, J = 7.3 Hz, 1H, ArH), 7.84 (s, 1H, NCH), 7.61 (m, 2H, ArH), 7.27 (d, J = 7.4 Hz, 1H, ArH), 6.95 (d, J = 6.4Hz, 1H, OH), 5.17 (d, J = 6.2 Hz, 1H, OH), 5.09 (d, J = 6.2 Hz, 1H, OH), 4.89 (dd, J = 6.4 Hz, 1H, CH), 4.61 (dd, J = 6.4 Hz, 1H, OH), 4.07 (s, 2H, NCH2), 4.01 (m, 1H, CH), 3.85 (m, 1H, CH), 3.74 (m, 1H, CH), 3.53 (m, 2H, CH2), 3.22 (m, 1H, CH2), 2.84 (s, 6H, 2xNCH3) ppm.

Example 55

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-(4-phenyltriazol-1-yl)tetrahydropyran-2,4,5-triol

Example 55 was synthesized from 2-azido-2-deoxyglucose and ethynylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 15 mg (49 μηιοΙ, 33.4 %), white solid.

TLC: Rf = 0.333 (dichloromethane/ethanol, 4:1).

LC/MS (ES-API): m/z = 308.10 [M + H]+; calculated: 308.12; tR1 (λ = 220 nm): 0.81 min; tR2 (λ = 220 nm): 0.85 min (LC/MS-Method 1).

1H-NMR (400 MHz, DMSO-d6): δ = 8.61 (s, 1H, NCH), 7.86 (dd, J = 1.3 Hz, 2H, ArH), 7.45 (m, 2H, ArH), 7.40 (m, 1H, ArH), 7.10 (d, J = 6.2 Hz, 1H, OH), 5.48 (d, J = 6.2 Hz, 1H, OH), 5.25 (d, J = 6.6 Hz, 1H, OH), 5.25 (t, J = 4.2 Hz, 1H, CH), 4.65 (t, J = 6.1 Hz, 1H, OH), 4.65 (dd, J = 10.8 Hz, J = 3.1 Hz, 1H, CH), 4.08 (m, 1H, CH), 3.96 (m, 1H, OH), 3.76 (m, 1H, CH2), 3.52 (m, 1H, CH2), 3.36 (m, 1H, CH), 3.29 (m, 1H, CH) ppm.

1JC-NMR (150 MHz, DMSO-d6): δ = 145.70 (s, C), 131.00 (s, C), 128.90 (s, CH), 127.64 (s, CH), 125.05 (s, CH), 120.64 (s, CH), 90.80 (s, CH), 72.42 (s, CH), 70.93 (s, CH), 69.72 (s, CH), 65.24 (s, CH), 60.86 (s, CH2) ppm.

Example 56

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(p-tolyl)triazol-1 -yl]tetrahydropyran-2,4,5-triol

Example 56 was synthesized from 2-azido-2-deoxyglucose and 1 -ethynyl-4-methylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 34 mg (106 μηιοΙ, 72.4 %), white solid.

TLC: Rf = 0.349 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 322.19 [M + H]+; calculated: 322.13; tR1 (λ = 220 nm): 1.07 min; tR2 (λ = 220 nm): 1.1 1 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.47 (s, 1 H, NCH), 7.76 (d, J = 8.1 Hz, 2H, ArH), 7.24 (d, J = 8.1 Hz, 2H, ArH), 6.93 (d, J = 4.4 Hz, 1 H, OH), 5.29 (d, J = 5.4 Hz, 1 H, OH), 5.20 (d, J = 5.4 Hz, 1 H, OH), 5.00 (dd, J = 8.0 Hz, 1 H, CH), 4.56 (dd, J = 3.2 Hz, 1 H, OH), δ = 4.09 (m, 1 H, CH), 3.96 (m, 1 H, CH), 3.76 (m, 1 H, CH2), 3.53 (m, 1 H, CH2), 3.36 (m, 1 H, CH), 3.28 (m, 1 H, CH), 2.35 (s, 3H, CH3) ppm.

Example 57

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(3-phenylpropyl)triazol-1 -yl]tetrahydropyran-2,4,5-triol

Example 57 was synthesized from 2-azido-2-deoxyglucose and pent-4-yn-1 -ylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 40 mg (1 14 μηιοΙ, 78.3 %), white solid.

TLC: Rf = 0.406 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 350.19 [M + H]+; calculated: 350.16; tR1 (λ = 220 nm): 1.24 min; tR2 (λ = 220 nm): 1.26 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.78 (s, 1 H, NCH), 7.75 (m, 5H, ArH), 6.81 (d, J = 5.0 Hz, 1 H, OH), 5.22 (d, J = 5.7 Hz, 1 H, OH), 5.12 (d, J = 5.7 Hz, 1 H, OH), 4.92 (dd, J = 6.7 Hz, 1 H, CH), 4.52 (dd, J = 5.5 Hz, 1 H, OH), 4.09 (m, 1 H, CH), 3.95 (m, 1 H, CH), 3.76 (m, 1 H, CH2), 3.53 (m, 1 H, CH2), 3.36 (m, 1 H, CH), 3.28 (m, 1 H, CH), 2.61 (m, 4H, CH2), 1.90 (m, 2H, CH2) ppm.

Example 58

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

Example 58 was synthesized from 2-azido-2-deoxyglucose and 4-ethynylmethylbenzoate following the CuAAC procedure described in synthesis method E.

Yield: 31 mg (85 μηιοΙ, 58.0 %), white solid.

TLC: Rf = 0.429 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 366.12 [M + H]+; calculated: 366.12; tR1 (λ = 220 nm): 0.97 min; tR2 (λ = 220 nm): 1.00 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.80 (s, 1 H, NCH), 8.05 (d, J = 8.2 Hz, 2H, ArH), 8.00 (d, J = 8.2 Hz, 2H, ArH), 7.09 (d, J = 6.4 Hz, 1 H, OH), 5.49 (d, J = 6.3 Hz, 1 H, OH), 5.25 (d, J = 5.7 Hz, 1 H, OH), 5.00 (dd, J = 8.0 Hz, 1 H, CH), 4.65 (dd, J = 5.2 Hz, 1 H, OH), 4.09 (m, 1 H, CH), 3.95 (m, 1 H, CH), 3.87 (s, 3H, OCH3), 3.76 (m, 1 H, CH2), 3.53 (m, 1 H, CH2), 3.36 (m, 1 H, CH), 3.28 (m, 1 H, CH) ppm.

Example 59

(3R,4R,5S,6R)-3-[4-[[Benzyl(methyl)amino]methyl]triazol-1 -yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

OH N^N'

Example 59 was synthesized from 2-azido-2-deoxyglucose and N-benzyl-N-methylprop-2-yn-1 -amine following the CuAAC procedure described in synthesis method E.

Yield: 32 mg (88 μηιοΙ, 60.1 %), white solid.

TLC: Rf = 0.064 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 365.20 [M + H]+; calculated: 365.17; tR (ELSD): 0.34 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.00 (s, 1 H, NCH), 7.71 (m, 5H, ArH), 6.82 (d, J = 6.0 Hz, 1 H, OH), 5.25 (d, J = 5.8 Hz, 1 H, OH), 5.14 (d, J = 5.8 Hz, 1 H, OH), 4.93 (dd, J = 5.7 Hz, 1 H, CH), 4.49 (dd, J = 5.2 Hz, 1 H, OH), 4.08 (m, 1 H, CH), 3.95 (m, 1 H, CH), 3.76 (m, 2H, CH2), 3.62 (s, 3H, NCH3), 3.36 (m, 1 H, CH), 3.28 (m, 1 H, CH), 2.13 (m, 4H, 2xNCH2) ppm.

Example 60

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(6-methoxy-2-naphthyl)triazol-1 -yl]tetrahydropyran-2,4,5-triol

Example 60 was synthesized from 2-azido-2-deoxyglucose and 2-ethynyl-6-methoxynaphthalene following the CuAAC procedure described in synthesis method E.

Yield: 28 mg (72 μηιοΙ, 49.4 %), white solid.

TLC: Rf = 0.461 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 388.16 [M + H]+; calculated: 388.14; tR1 (λ = 220 nm): 1.27 min; tR2 (λ = 220 nm): 1.29 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.64 (s, 1 H, NCH), 7.88 (m, 4H, ArH), 7.34 (s, 1 H, ArH), 7.07 (d, J = 6.5 Hz, 1 H, OH), 5.47 (d, J = 6.4 Hz, 1 H, OH), 5.23 (d, J = 6.4 Hz, 1 H, OH), 5.00 (dd, J = 6.6 Hz, 1 H, CH), 4.49 (dd, J = 5.2 Hz, 1 H, OH), 4.1 1 (m, 1 H, CH), 3.98 (m, 1 H, CH), 3.89 (s, 3H, OCH3), 3.77 (m, 1 H, CH2), 3.53 (m, 1 H, CH2), 3.46 (m, 1 H, CH), 3.38 (m, 1 H, CH) ppm.

Example 61

(3R,4R,5S,6R)-3-[4-[4-Chloro-6-methyl-2-(p-tolyl)pyrimidin-5-yl]triazol-1 -yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

Example 61 was synthesized from 2-azido-2-deoxyglucose and 4-chloro-5-ethynyl-6-methyl-2-(p-tolyl)pyrimidine following the CuAAC procedure described in synthesis method E.

Yield: 51 mg (1 10 μηιοΙ, 75.5 %), white solid.

TLC: Rf = 0.556 (dichloromethane/ethanol, 4:1 ).

LC/MS (ES-API): m/z = 462.22 [M + H]+; calculated: 462.15; tR1 (λ = 220 nm): 1.51 min; tR2 (λ = 220 nm): 1.52 min (LC/MS-Method 1 ).

1H-NMR (400 MHz, DMSO-d6): δ = 8.19 (d, J = 8.2 Hz, 2H, ArH), 7.89 (s, 1 H, NCH), 7.71 (d, J = 8.2 Hz, 2H, ArH), 6.93 (d, J = 6.6 Hz, 1 H, OH), 5.21 (d, J = 6.1 Hz, 1 H, OH), 5.14 (d, J = 6.1 Hz, 1 H, OH), 4.91 (dd, J = 6.7 Hz, 1 H, CH), 4.50 (dd, J = 5.5 Hz, 1 H, OH), 4.21 (s, 3H, CH3), 4.05 (m, 1 H, CH), 3.97 (m, 1 H, CH), 3.85 (m, 2H, CH2), 3.71 (m, 1 H, CH), 3.50 (m, 1 H, CH), 2.62 (s, 3H, CH3) ppm.

Claims
1. A conjugate of formula (I)

wherein P is an insulin or an insulinotropic peptide,

L1 , L2, and L3 are independently of each other a linker having a chain length of 1 -20 atoms,

A1 and A2 are independently of each other a 5 to 6 membered monocyclic ring, or a 9 to 12 membered bicyclic ring, or two 5 to 6 membered monocyclic and/or 9 to 12 membered bicyclic rings connected to each other, wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring and wherein each ring may carry at least one substituent,

S is a sugar moiety which binds to the insulin independent glucose transporter GluT1 , and wherein the sugar moiety S comprises a terminal pyranose S1 moiety which is attached via position 2, 4, or 6 to the conjugate of formula (I),

m, o, p, r, and q are independently of each other 0 or 1 , and wherein at least one of r and o is 1 , or

a pharmaceutically acceptable salt or solvate thereof.

2. The conjugate of formula (I) of claim 1 , wherein P is an insulin which is attached via an amino group, particularly via the amino side chain of an insulin B29Lys residue or via the amino terminus of an insulin B1 Phe residue.

3. The conjugate of formula (I) of claim 1 or 2, wherein L-i , L2, and L3 are independently of each other (C1-C20) alkylene, (C-2-C20) alkenylene, or (C2-C-20) alkynylene, wherein one or more C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C1 -4) alkyl, S, SO, SO2, O-SO2, O-SO3, O-PHO2, or O-PO3 and/or wherein one or more C-atoms may be substituted with (C1-4) alkyl, (C1-4) alkyloxy, oxo, carboxyl, halogen, e.g. F, CI, Br, or I, or a phosphorus-containing group.

4. The conjugate of formula (I) of any one of claims 1 -3, wherein L3 is (C-i-Ce) alkylene, particularly (C1-4) alkylene, wherein one or two C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C1-4) alkyl, S, SO, SO2, O-SO2, O-SO3, O-PHO2, or O-PO3 and/or wherein one or more C-atoms may be substituted with (C1-4) alkyl, (C1- ) alkyloxy, oxo, carboxyl, halogen, e.g. F, CI, Br, or I, or a phosphorus-containing group.

5. The conjugate of formula (I) of any one of claims 1 -3, wherein L3 is C=O.

6. The conjugate of formula (I) of any one of claims 1 -3, wherein L2 is selected from -CO-(CH2)3-, -(CH2)6-NH-, -(CH2)2-CO-(CH2-CH2-O)2-(CH2)2-NH- or -CH2-O-(CH2-CH2-O)3-.

7. The conjugate of formula (I) of any one of claims 1 -6, wherein A1 and A2 are independently of each other a heterocyclic ring, wherein the ring may carry at least one substituent.

8. The conjugate of formula (I) of any one of claims 1 -7, wherein A1 and A2 are independently of each other selected from a 5 to 6 membered monocyclic or a 9 to 12 membered bicyclic ring, wherein the ring is heterocyclic with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent.

9. The conjugate of formula (I) of any one of claims 1 -8, wherein A1 and A2 are independently of each other a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring, particularly selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, piperazinyl, piperidinyl, morpholinyl, wherein the ring may carry at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heteroalkyl ring with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent.

10. The conjugate of formula (I) of any one of claims 1 -9, wherein A1 and A2 are independently of each other 1 ,2,3-triazolyl.

1 1 . The conjugate of formula (I) of any one of claims 1 -9, wherein A2 is 1 ,2,3-triazolyl.

12. The conjugate of formula (I) of any one of claims 1 -9, wherein A2 is piperazinyl.

13. The conjugate of formula (I) of any one of claims 1 -12, wherein r=1 and A2 is present and o=0 and A1 is absent.

14. The conjugate of formula (I) of any one of claims 1 -12, wherein r=1 and A2 is present and o=1 and A1 is present.

15. The conjugate of formula (I) of any one of claims 1 -14, wherein (i) m=1 , o=0, p=0, and q=0 or 1 , or

wherein (ii) m=1 , o=1 , p=1 , and q=0 or 1.

16. The conjugate of formula (I) of any one of claims 1 -15, wherein A2 is piperazinyl, L2 is absent and A1 is cyclohexanyl.

17. The conjugate of formula (I) of any one of claims 1 -15, wherein A2 is piperazinyl, L2 is absent and A1 is cyclohexanyl.

18. The conjugate of formula (I) of any one of claims 1 -15, wherein A2 is piperazinyl, L2 is -CH2- and A1 is cyclohexanyl.

19. The conjugate of formula (I) of any one of claims 1 -15, wherein A2 is piperazinyl, L2 is absent and A1 is phenyl.

20. The conjugate of formula (I) of any one of claims 1 -15, wherein A2 is1 ,2,3-triazolyl, L2 is absent and A1 is phenyl.

21 . The conjugate of formula (I) of any one of claims 1 -15, wherein

L3 is -CO-, A1 is phenyl, L2 is -O- and A1 is phenyl wherein each ring may be unsubstituted or carry at least one substituent, for example, 1 to 3 substituents selected from halogen, NO2, CN, (C1-4) alkyl, (C1-4) alkoxy, (C1-4)alkyl-(C3-7)cycloalkyl, (C3-7) cycloalkyl, OH, benzyl, -O-benzyl, carboxyl, carboxyester, carboxamide, or mono (C1- ) alkyl, or di (C1-4) alkyl carboxamide.

22. The conjugate of formula (I) of any one of claims 1 -15, wherein

the group -A2-L3- is selected from

23. The conjugate of formula (I) of any one of claims 1 -22, wherein the sugar moiety S comprises a terminal pyranose moiety S1 having a backbone structure of Formula (II)

wherein 1 , 2, 3, 4, 5, and 6 denote the positions of the C-atoms in the pyranose moiety,

wherein is a single bond and is a single or a double bond,

R1 and R3 are H or a protecting group,

which is attached via position 2, 4, or 6 to the conjugate of formula (I) .

24. The conjugate of formula (I) of claim 23, wherein the terminal pyranose moiety S1 is selected from glucose, galactose, 4-deoxyglucose, and 4,5-dehydroglucose derivatives,

wherein the terminal pyranose moiety S1 is attached via position 2, 4, or 6 to the conjugate of formula (I) or mannose attached via position 6.

25. The conjugate of formula (I) of any one of claims 23-24, wherein the terminal pyranose moiety S1 is of the Formula (Ilia) or (1Mb):

wherein R1 is H or a protecting group,

R2 is OR8, or NHR8 or an attachment site to the conjugate of formula (I), wherein R8 is H or a protecting group,

R3 is H or a protecting group,

R4 is H, OR8, or NHR8 or an attachment site to the conjugate of formula (I), wherein R8 is H or a protecting group,

or R1 and R2 and/or R3 and R4 form together with the pyranose ring atoms to which they are bound a cyclic group, e.g. an acetal,

R5 and R6 are H or together with the carbon atom to which they are bound form a carbonyl group,

R7 is OR8, or NHR8 or an attachment site to the conjugate of formula (I), wherein R8 is H or a protecting group, and

wherein one of R2, R4, and R7 is the attachment site to the conjugate of formula (I).

26. The conjugate of formula (I) of claim 23 or 25, wherein R1 and R3 are H.

27. The conjugate of formula (I) of any one of claims 23, 25, or 26, wherein R2 is OR8 or an attachment site to the conjugate of formula (I),

R4 is H, OR8, or an attachment site to the conjugate of formula (I), and

R7 is OR8 or an attachment site to the conjugate of formula (I),

and wherein R8 is H or a protecting group.

28. The conjugate of formula (I) of any one of claims 23-27, wherein position 6 of the pyranose moiety S1 and particularly R7 is the attachment site to the conjugate of formula (I).

29. The conjugate of formula (I) of any one of claims 23-28, wherein the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe):

(IVc) (IVd)

(IVe)

wherein R1 , R2, R3, R5, R6, and R7 are defined as in any one of claims 25-28

and wherein R4 is H, a protecting group, or an attachment site to the conjugate of formula (I),

or R4a is H, or an attachment site to the conjugate of formula (I).

30. The conjugate of formula (I) of any one of claims 1 -29, wherein the sugar moiety S is of Formula (V):

(V)

wherein Xi is a bond or O, particularly a bond,

X2 is a bond, NH or O, particularly a bond,

S2 is a mono- or disaccharide moiety, particularly comprising at least one hexose or pentose moiety, more particularly at least one pyranose or furanose moiety and S1 is a terminal pyranose moiety as defined in any one of claims 23-28, and

s is 0 or 1.

31 . The conjugate of formula (I) of any one of claims 1 -30, wherein the saccharide moiety S2 is a pyranose moiety, particularly selected from glucose, galactose, 4-deoxyglucose and 4,5-dehydroglucose derivatives, or a furanose moiety, particularly selected from fructose derivatives.

32. The conjugate of formula (I) of claim 30 or 31 , wherein the saccharide moiety S2 is of Formula (Via), (Vlb), (Vic), (Vld), or (Vie):

(Vie)

wherein R1 1 is a bond to X-i ,

R12 is OR8 or NHR8 or an attachment site to X2, wherein R8 is H or a protecting group, R13 is H or a protecting group,

R14 is R8 or an attachment site to X2, wherein R8 is H or a protecting group,

R14a is H or an attachment site to X2,

R15 and R16 are H or together with the carbon atom to which they are bound form a carbonyl group,

R17 is OR8 or an attachment site to X2, wherein R8 is H or a protecting group,

or R1 1 and R12 and/or R13 and R14 form together with the ring atoms to which they are bound a cyclic group such as an acetal,

and wherein one of R12, R14, and R17 is an attachment site to X2.

33. The conjugate of formula (I) of any one of claims 1 -32, which has an affinity of 10 -500 nM to the insulin independent glucose transporter GluT1.

34. The conjugate of formula (I) of any one of claims 1 -33 which reversibly binds to the insulin independent glucose transporter GluT1 dependent from the glucose concentration in the surrounding medium.

35. The conjugate of formula (I) of any one of claims 1 -34, wherein the sugar moiety S comprises a single terminal saccharide moiety.

36. The conjugate of formula (I) of any one of claims 1 -35 for use in medicine, particularly in human medicine.

37. The conjugate of formula (I) of any one of claims 1 -35 for use in the prevention and/or treatment of disorders associated with, caused by and/or accompanied by a dysregulated glucose metabolism.

38. The conjugate of formula (I) of any one of claims 1 -35 for use in the prevention and/or treatment of diabetes, particularly of diabetes type 2 or of diabetes type 1.

39. A pharmaceutical composition comprising a conjugate of formula (I) of any one of claims 1 -35 as an active agent and pharmaceutically acceptable carrier.

40. A method of preventing and/or treating a disorder associated with, caused by and/or accompanied by a dysregulated glucose metabolism, comprising administering a conjugate of formula (I) of any one of claims 1 -35 or a composition of claim 39 to a subject in need thereof.

41 . A compound of formula (la)

wherein L1 , L2, L3, A1 , A2, S, m, o, p, r, and q are defined as in any one of claims 1 -35,

R is H, halogen, OH, O-alkyl-, an anhydride forming group or another active ester forming group, like 4-nitrophenylester, succinate or N-hydroxy benzotriazol,

or a pharmaceutically acceptable salt or solvate thereof.

42. A compound of formula (lb)

wherein L1, L2, L3, A1, A2, S, m, o, p, r, and q are defined as in any one of claims 1 -35, or a pharmaceutically acceptable salt or solvate thereof.