Novel pharmacological chaperone compounds for human acid alpha-glucosidase and their therapeutic uses

Abstract

The present invention relates to specific compounds of imino sugars with piperidine rings, which have a D-glucose configuration and contain a quaternary center located at the alpha position of the nitrogen of the piperidine ring. These compounds have the ability to stabilize human acid alpha-glucosidase while being selective relative to other glycosidases. The compounds are particularly useful as chaperone molecules for the enzyme for the treatment of Pompe disease.

Description

[0001] The present invention belongs to the field of treatment of lysosomal diseases, and more specifically belongs to the field of treatment of Pompe disease.

[0002] More specifically, the present invention relates to compounds belonging to the class of imino sugars, which are capable of selectively interacting with human alpha-glucosidase and in particular of stabilizing human acid alpha-glucosidase in its endogenous form (GAA) or with recombinant properties (rhGAA), whose conformation is conducive to transporting the enzyme to lysosomes, and which are used as drugs, in particular for the treatment of Pompe disease; and to pharmaceutical compositions containing such compounds. The present invention also relates to compounds belonging to the class of imino sugars, which are capable of selectively interacting with human acid alpha-glucosidase. The present invention also relates to a method for preparing such a compound.

[0003] Pompe disease or type 2 glycogen storage disease (type 2glycogenosis) is a rare genetic disease, characterized by one or more mutations of the GAA gene encoding the human acid alpha-glucosidase (GAA) lysosomal enzyme, which results in a lack of the enzyme activity and the accumulation of glycogen as a result, the hydrolytic biodegradation of glycogen is carried out by this enzyme in the lysosome, and therefore the accumulation of glycogen results in cellular dysfunction in the muscle and heart. The symptoms are varied, and their progression is faster or slower depending on whether the disease occurs at birth or in adulthood. It affects all muscles, particularly respiratory and cardiac muscles. The life expectancy of the affected object is therefore reduced, especially in infants, who die in the first year of life.

[0004] Currently, there is only one treatment licensed for Pompe disease. This treatment, called enzyme replacement therapy (ERT), involves administering Myozyme intravenously. A specific drug, whose active ingredient is recombinant human acid alpha-glucosidase (rhGAA), which makes it possible to stabilize the symptoms of the disease. However, this treatment has many disadvantages: it is very expensive, it is binding on the patient because it requires perfusion every two weeks in a hospital setting, and in many cases its efficiency is limited. The treatment can indeed cause an immune response that affects its efficiency and the tolerance of the treated subject to it. In addition, the recombinant enzyme is relatively unstable in the blood and the doses that must be administered to the patient are much larger than those administered for the treatment of other lysosomal diseases.

[0005] Therefore, there remains a need for satisfactory treatment of Pompe disease.

[0006] The present invention aims to propose such a treatment. More specifically, the present invention aims to propose compounds that are effective in treating Pompe disease and, moreover, are easy to administer and less expensive than the treatments proposed in the prior art by enzyme replacement therapy.

[0007] Another object of the present invention is that these compounds, administered simultaneously with enzyme replacement therapy treatments of the prior art, significantly increase the efficiency of the latter.

[0008] To achieve these goals, the inventors have become interested in the following treatment methods that are currently considered to be one of the most promising for the treatment of lysosomal diseases: the use of so-called pharmacological chaperones. Chaperones are small molecules that promote the correct folding of mutant enzymes and can transport them to lysosomes (Boyd et al., 2013, J. Med. Chem. 56: 2705-2725) instead of being degraded in the endoplasmic reticulum. This treatment has been successfully implemented for another lysosomal disease, Fabry disease, for which migalastat iminosugar (Galafold ) is now prescribed as a pharmacological chaperone for acid α-galactosidase (Markham, 2016, Drugs 76:1147-1152).

[0009] The inventors therefore sought compounds capable of stabilizing human acid alpha-glucosidase in its active folded form and of increasing the efficacy of recombinant human acid alpha-glucosidase used in treatment by enzyme replacement therapy, in order to use these enzymes in the treatment of Pompe disease.

[0010] Among the existing compounds, deoxynojirimycin (DNJ) has been proposed in the prior art as a potential partner molecule of human acid α-glucosidase (Flanagan et al., 2009, Hum. Mutat. 30: 1683-1692), which is an imino sugar with the following formula:

[0011]

[0012] A DNJ derivative called NB-DNJ has also been proposed in the prior art for the same application (Parenti et al., 2007, Mol. Ther. 15(3):508-14), which has the following formula:

[0013]

[0014] However, these compounds have low selectivity for this enzyme, and they inhibit other human enzymes: both α- and β-type glycosidases and glycosyltransferases, which causes a number of undesirable side effects when they are administered to a subject.

[0015] The publication by Boisson et al., Org. Lett., 2015, 17(15), 3662-5 describes specific polyhydroxylated indolizine derivatives having a good ability to inhibit α-glucosidase of S. cerevisiae and rice α-glucosidase.

[0016] The publication by Tangara et al., Org. Lett., 2017, 19(18), 4842-5 describes specific aziridinyl-imino sugars.

[0017] The publication by Vieira Da Cruz et al., J. Org. Chem., 2017, 82(18), 9866-72 describes specific polyhydroxylated quinolines and their ability to inhibit α-glucosidase from yeast and rice.

[0018] The inventors have now discovered that specific compounds belonging to the class of iminosugars (which conform to a specific structure derived from DNJ) bind to and stabilize human acid alpha-glucosidase (GAA), and this in a highly selective manner, i.e. at least significantly without interacting with other human glycosidases, in particular without interacting with human β-glucocerebrosidase (GBA1 and GBA2), human β-glucosylceramide transferase (GCS) or human endoplasmic reticulum alpha-glucosidase II (GANAB). In addition, the effect of stabilizing GAA by these compounds is particularly large. Thus, the administration of these compounds to patients suffering from Pompe disease enables the patient's endogenous acid alpha-glucosidase to be stabilized in a correctly folded form to improve its transport to lysosomes and to increase its activity in hydrolyzing glycogen, and thereby effectively treat this disease while reducing undesired side effects during treatment. These compounds, which are associated with enzyme replacement therapy (ERT), also enable the recombinant enzyme (rhGAA) to be stabilized, thereby increasing its efficacy.

[0019] Molecules with similar but different structures, such as DNJ or NB-DNJ, were unable to achieve this particularly favorable outcome at therapeutic levels.

[0020] Thus, according to a first aspect, the present invention relates to a compound of the following general formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, in particular as a pharmacological partner, in particular for the treatment of Pompe disease, in particular for stabilizing human acid alpha-glucosidase:

[0021]

[0022] in:

[0023] -R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0024] And R 2 represents a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or multiple optionally fused rings, when R 1 When represents a hydrogen atom, the hydrocarbon group contains at least 2 carbon atoms,

[0025] - or R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 3- to 6-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by one or more groups, which may be identical or different, each selected from a hydroxyl group, an amino group or a carbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a monocyclic or multiple optionally fused rings. Such configurations include the case where the carbon group is branched into a 3- to 6-membered heterocyclic ring via a carbon atom, as well as the case where the carbon group is branched into a 3- to 6-membered heterocyclic ring via the heteroatoms it contains.

[0026] In the present description, the term heteroatom itself generally refers to any atom belonging to an element other than carbon and hydrogen, such as atoms of nitrogen, oxygen, sulfur, phosphorus, silicon, halogens, and the like.

[0027] Preferably, when R 1 When R represents a hydrogen atom, 2 It does not represent a methyl group or a benzyl group.

[0028] In the present description, "pharmaceutically acceptable salt" itself generally means any salt of a compound of formula (I) which contains a substance as a counter ion and does not produce any adverse, allergic or other undesirable reaction when administered to a subject, especially a mammal.

[0029] Any conventional pharmaceutically acceptable salt of the compound of general formula (I) can be used according to the present invention. By way of example, chloride, bromide, formates, acetates and the like can be mentioned.

[0030] In the present description, the term "treatment" means obtaining a desired pharmacological or physiological effect. The term "treatment" as used in the present description includes the prevention or partial prevention of one or more symptoms of a disease and / or the partial or complete cure of a disease and / or the total or partial disappearance of one or more symptoms thereof.

[0031] Human acid α-glucosidase is a protein with 952 amino acids and GenBank accession number ABI53718.1.

[0032] The compounds of the general formula (I) used according to the invention are ligands thereof. In addition, they have a particularly strong selectivity for this enzyme. This selectivity is particularly much greater than the selectivity of DNJ or NB-DNJ or other imino sugars that interact with glycosidases.

[0033] The characteristics of the compounds used according to the invention, in particular those related to their three-dimensional structure, which allow the compounds to obtain such advantageous properties, are not prejudged here. However, it can be assumed that the following characteristics are involved: the presence of a quaternary center in the alpha position relative to the nitrogen of the piperidine nucleus, the D-glucose configuration of the compound, and the presence of specific substituents on the quaternary carbon in the alpha position relative to the nitrogen of the piperidine nucleus and on the nitrogen. Because of, at least in part, these characteristics, the compounds used according to the invention will bind non-covalently to the enzyme and stabilize its folding, thereby conferring on it the role of a chaperone to enable it to restore the activity of the enzyme that is deficient in transport and lysosomes.

[0034] Therefore, the compounds used according to the present invention stabilize human acid α-glucosidase at low concentrations and have the necessary properties of a pharmacological chaperone suitable for the treatment of Pompe disease. Specifically, at a concentration of 100 μM, it increases the thermal denaturation temperature of human acid α-glucosidase from 8°C to 12°C at pH 4.0 in vitro, and increases the thermal denaturation temperature of human acid α-glucosidase from 10°C to 13°C at pH 7.4. The chaperone effect of the compounds used according to the present invention on human acid α-glucosidase has been confirmed by experiments on human cells in culture, more precisely fibroblasts of patients with the disease, and fibroblasts in mice.

[0035] Therefore, the compounds used according to the invention are perfectly suitable and advantageous for use as pharmacological chaperones for the treatment of Pompe disease by selectively binding to and stabilizing human acid alpha-glucosidase, thereby restoring the activity of the deficient enzyme in the patient and / or improving the bioavailability of the rhGAA recombinant enzyme administered during rhGAA enzyme replacement therapy when this therapy is associated with the use of the compounds used according to the invention.

[0036] Therefore, the compounds of general formula (I) can be used to stabilize the active folded form of human acid α-glucosidase and to improve the efficacy of recombinant human acid α-glucosidase used in enzyme replacement therapy, by co-administering the compounds of general formula (I) and recombinant human acid α-glucosidase to patients.

[0037] The compounds used according to the invention can advantageously be easily administered to patients, particularly orally, and are inexpensive to prepare.

[0038] The compound has low toxicity risk and good bioavailability.

[0039] Furthermore, the compounds used according to the invention in combination with enzyme replacement therapy advantageously increase the bioavailability of the injected recombinant enzyme, which makes it possible to reduce its dosage in order to obtain the same therapeutic efficacy, or even a superior efficacy.

[0040] The compounds of general formula (I) used according to the present invention can be administered to any subject in need thereof, ie a subject suffering from or likely to be infected with the disease. The subject can be in particular a mammal, and in particular a human.

[0041] The compounds used according to the present invention are preferably administered to a subject in a therapeutically effective amount.

[0042] "Therapeutically effective amount" means that amount of a compound which, when administered to a subject for treating a disease, is sufficient to ensure such treatment for the disease.

[0043] The therapeutically effective amount of the compound used according to the present invention depends on several factors, such as the disease and its severity, the age, weight, etc. of the subject to be treated, the specific compound used, the route and form of administration, etc. The therapeutically effective amount of the compound used according to the present invention will be determined by the physician in each individual case.

[0044] The compounds used according to the invention can be administered to the subject to be treated by any conventional method per se, in particular parenteral administration, for example subcutaneous, subdural, intravenous, by intramuscular, intrathecal, intraperitoneal, intracerebral, intraarterial or intralesional routes; intranasally; rectally; by the pulmonary route, for example by aerosol or inhalation, or even topical administration. Oral administration is preferred.

[0045] It is within the physician's ability to determine the administration posology of the compounds used according to the invention. The compounds can be administered to a subject in need thereof, for example, once or twice daily, chronically, periodically, or in a targeted manner during relevant treatment with enzyme replacement therapy.

[0046] As discussed above, the compounds used according to the present invention may advantageously be administered to a subject in combination with an enzyme used for enzyme replacement therapy, particularly with recombinant human acid alpha-glucosidase (e.g., as Myozyme The compound then advantageously increases its effectiveness.

[0047] In some specific embodiments of the present invention, in the general formula (I), R 1 and R 2 are independent of each other, that is, R 1 and R 2 Not bonded to each other, especially R 1 and R 2 They do not come together to form a ring fused to the piperidine core of the compound.

[0048] Specifically, in the general formula (I):

[0049] -R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0050] And R 2 Can represent -CH(R 3 )-R 4 Group, where R 3 and R 4 may be identical or different, each representing a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or multiple optionally fused rings, when R 1 When R represents a hydrogen atom, 3 and R 4 They do not represent hydrogen atoms at the same time.

[0051] In some specific embodiments of the present invention, R 3 and R 4 They do not represent hydrogen atoms at the same time.

[0052] In some specific embodiments of the present invention, R 1 and R 2 It is like this: 1 and R 2 They do not represent a propyl group and an ethyl group respectively.

[0053] Prioritize, R 3 and R 4 It is like this: When R 1 and R 3 When each represents a hydrogen atom, R 4 It does not represent a phenyl group.

[0054] In some specific embodiments of the present invention, R 2 Represents -CH(R 3 )-R 4 Group, where R 3 As defined above and R 4 represents a hydrocarbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing a single ring or multiple rings (optionally fused), and containing one or more heteroatoms each selected from oxygen, nitrogen, sulfur and silicon and / or one or more such groups, which contain at least one heteroatom each selected from carbonyl, sulfoxide, sulfonyl and silane groups.

[0055] In other cases, R 1 represents a hydrogen atom or a hydrocarbon group, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 Can represent - (CHR 7 )-SO2-Ar 1 Group, where Ar 1 represents an aryl or heteroaryl group, which is optionally substituted, in particular containing 5 to 18 atoms, and R 7 represents a hydrogen atom or a hydrocarbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings. In some specific embodiments of the invention, Ar 1 represents an aromatic heterocyclic ring, in particular a pyridine ring, which is optionally substituted, and / or R 7Represents a hydrogen atom.

[0056] In some specific embodiments of the present invention, R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 M may represent a triazole group, which is optionally substituted.

[0057] In other variations of the present invention, R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 Represents -(CH2)2-R 8 Group, where R 8 represent:

[0058] - Hydrogen atoms;

[0059] - a C1 to C12 alkyl or cycloalkyl group, which optionally contains a single ring or multiple condensed rings, such as, for example, an adamantyl group;

[0060] --(CH2) a -OH group, wherein a is an integer from 0 to 18, preferably from 0 to 12, and in particular from 0 to 6;

[0061] --(CH2) b -Ar 2 Group, where Ar 2 represents an aryl or heteroaryl group, which is optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a single ring or a plurality of optionally fused rings, and b is an integer from 0 to 18, preferably from 0 to 12, and in particular an integer from 0 to 6;

[0062] --(CH2) c -Si(R 9 )3 groups, wherein R 9 represents a hydroxyl group, a C1 to C4 alkyl group, a C1 to C4 alkoxy group, or a phenyl group, and c is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6;

[0063] -or-(CH2) d -ZR 10A group, wherein Z is a heteroatom selected from oxygen, nitrogen and sulfur, R 10 represents a hydrogen atom or a C1 to C18, preferably C1 to C12 and in particular C1 to C6 alkyl, cycloalkyl, alkylaryl, aryl or acyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom, in particular a sulfonyl group, and d is an integer from 0 to 18, preferably from 0 to 12 and in particular from 0 to 6.

[0064] In some specific preferred embodiments of the present invention, R 1 represents a hydrogen atom or a C1 to C18, preferably C1 to C6, for example C1 to C3 and more particularly C1 to C2, linear, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0065] The compounds used according to the invention may in particular correspond to the general formula (I'a):

[0066]

[0067] in:

[0068] R 1 represents a hydrogen atom or a C1 to C18, preferably C1 to C6, linear, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom,

[0069] And R 8 represent:

[0070] - Hydrogen atoms;

[0071] - methyl, ethyl, propyl, butyl, pentyl, hexyl, cycloalkyl, adamantyl, alkylcycloalkyl, alkylaryl or aryl radicals, in particular phenyl radicals, which are optionally interrupted and / or substituted by one or more heteroatoms and / or one or more radicals comprising at least one heteroatom;

[0072] - hydroxyl groups;

[0073] --Si(R 12 )3 groups, wherein R 12 represents a hydroxyl group, a C1 to C4 alkyl group, a C1 to C4 alkoxy group, or a phenyl group;

[0074] --(CH2) f -YR 13 A group, wherein f is an integer from 0 to 6, Y is a heteroatom selected from oxygen, nitrogen and sulfur, and R13 represents a C1 to C18, preferably C1 to C12 and especially C1 to C6 alkyl group, or a C1 to C18, preferably C1 to C12 and especially C1 to C6 aryl or heteroaryl group;

[0075] --(CH2) g -CO-R 13 A group, wherein g is an integer from 0 to 6 and R 13 As defined above;

[0076] -or-(CH2) h -SO e -R 13 A group wherein h is an integer from 0 to 6, e is equal to 1 or 2 and R 13 As defined above,

[0077] When R 1 When R represents a propyl group, 8 It does not represent hydrogen atoms.

[0078] In some specific embodiments of the present invention, the compound used conforms to the general formula (I"a):

[0079]

[0080] in:

[0081] R 1 represents a hydrogen atom or a C1 to C18 straight-chain, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom,

[0082] R 18 represents a linear, branched and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, containing 4 to 18 carbon atoms, preferably 4 to 12 carbon atoms and in particular 5 to 12 carbon atoms, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0083] Specifically, R 18 It may represent a butyl, pentyl, hexyl, cyclohexyl, phenyl, benzyl or adamantyl group.

[0084] Preferably, in formula (I"a), R 1 Represents a hydrogen atom.

[0085] Specific compounds that can be used according to the present invention conform to the following formulae (IIa), (IIb), (IIb1), (IIb2), (IIb3), (IIb4), (IIb5), (IIb6), (IIb7), (IIc), (IIc1), (IId), (IIe), (IIo), (IIp), (IIp1), (IIq), (IIr), (IIs), (IIt), (IIu), (IIv), (IIw), (IIw1), (IIx), (IIx1) and (IIy):

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] In some alternative embodiments of the present invention, the compounds used are such that in the general formula (I), R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 6-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by one or more groups which may be identical or different, each selected from a hydroxyl group, an amino group, a carbonyl group or a carbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0095] Specific compounds that can be used according to the present invention conform to formula (IIf):

[0096]

[0097] In other embodiments of the present invention, the compounds used are as follows: In the general formula (I), R 1 and R 2Together with the atoms of the piperidine ring to which they are attached, they form a 5-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by one or more groups which may be identical or different, each selected from a hydroxyl group, an amino group, a carbonyl group or a carbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0098] Specific compounds that can be used according to the present invention conform to formula (IIg):

[0099]

[0100] In another alternative embodiment of the present invention, the compound used is such that in the general formula (I), R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 4-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by one or more groups which may be identical or different, each selected from a hydroxyl group, an amino group or a carbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0101] The compound may specifically conform to the general formula (I'b):

[0102]

[0103] in

[0104] R 14 represents a hydrogen atom, a carbonyl group or a C1 to C18, preferably C1 to C12 and in particular C1 to C16 alkyl, alkenyl, alkynyl, alkylaryl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom,

[0105] And R 15 represents a hydrogen atom, a hydroxyl group, an amino group or a C1 to C18, preferably C1 to C12 and in particular C1 to C6 alkyl, alkenyl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0106] Specific compounds that can be used according to the present invention specifically conform to formula (IIh), (IIz1), (IIz2), (IIz3), (IIz4) and (IIz5):

[0107]

[0108]

[0109] Still in some alternative embodiments of the present invention, the compound used is such that in the general formula (I), R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 3-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by -XR 5 Group substitution, where:

[0110] -X represents -C(=O)- or -CH(OR 6 )-group, where R 6 represents a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, and R 5 represents a hydrogen atom, an amino group or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0111] - or X represents a -CH(OH)- group and R 5 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings. In the latter configuration, in particular, R 5 Preferably it does not represent an unsubstituted n-propyl group, an unsubstituted c-hexyl group or an unsubstituted phenyl group.

[0112] The compounds used according to the invention may in particular conform to the general formula (I'c):

[0113]

[0114] Where R 16represents a hydrogen atom or a C1 to C18, preferably C1 to C12 and preferentially C1 to C6 alkyl group, said group being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0115] Specifically, R 16 It may represent a -CH2-OH group, a methyl group or an ethyl group.

[0116] Specific compounds that can be used according to the present invention conform to formula (IIj), (IIk), (IIm) and (IIn):

[0117]

[0118] The present invention may also be described as a method for the therapeutic treatment of a subject suffering from or likely to be infected with a disease, in particular Pompe disease, comprising the step of administering to said subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method may comply with one or more of the features described above for the therapeutic use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament.

[0119] The present invention also relates to the use of a compound of general formula (I) as defined above or a pharmaceutically acceptable salt thereof for the preparation of a medicament, in particular a medicament for the treatment of Pompe disease.

[0120] According to another aspect, the present invention relates to a pharmaceutical composition comprising as active ingredient a compound according to general formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

[0121] In this description, "pharmaceutically acceptable carrier" means any carrier that can be used to prepare a pharmaceutical composition and which is generally safe, non-toxic, and biologically or otherwise desirable for the subject to be treated, particularly mammals and especially humans.

[0122] The carrier of the pharmaceutical composition according to the present invention may be solid or semi-solid or liquid. It may be a diluent, adjuvant or any other carrier conventionally used to form a pharmaceutical composition.

[0123] The pharmaceutical composition according to the invention may be in any galenic form, in particular in a form suitable for administration parenterally, intranasally, rectally or by a pulmonary or topical route. Preferentially, it is in a form suitable for oral administration. By way of non-limiting examples of such galenic forms of the invention, mention may be made of granules, powders, tablets, capsules, pills, syrups, solutions or drinkable suspensions.

[0124] The pharmaceutical composition according to the present invention may contain one or more excipients / additives conventionally used in forming pharmaceutical compositions per se, for example, selected from preservatives, sweeteners, flavoring agents, fillers, disintegrants, wetting agents, emulsifiers, surfactants, dispersants, lubricants, stabilizers, buffers, antibacterial agents, antifungal agents, etc., or any mixture thereof; and / or any compound that allows rapid, prolonged or delayed and / or targeted release of the active ingredient after administration thereof to a subject.

[0125] The pharmaceutical composition according to the present invention may also contain, in addition to the compound of general formula (I) or a pharmaceutically acceptable salt thereof, one or more active ingredients which may or may not act synergistically with said compound.

[0126] The pharmaceutical composition according to the present invention is preferably formulated in unit dosage form.

[0127] The present invention also relates to the therapeutic use of a pharmaceutical composition according to the invention as defined above for the treatment of a disease, in particular Pompe disease. This use may comply with one or more of the features described above with respect to the therapeutic use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0128] According to another aspect, the present invention relates to compounds conforming to the following general formula (I'), which defines a subfamily of compounds of the above general formula (I) or a pharmaceutically acceptable salt thereof:

[0129]

[0130] in:

[0131] -R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0132] And R 2 Represents -CH(R 3 )-R 4 Group, where R 3 and R 4 may be identical or different, each representing a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 3 and R 4 It is like this: When R 1 and R3 When each represents a hydrogen atom, R 4 does not represent a hydrogen atom or a phenyl group,

[0133] And R 1 and R 2 is such that they do not represent a propyl group and an ethyl group at the same time,

[0134] - or R 1 and R 2 together with the atoms of the piperidine ring to which they are attached, form a 4-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by one or more groups which may be identical or different, each selected from a hydroxyl group, an amino group or a carbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0135] - or R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 3-membered heterocyclic ring fused to the piperidine ring, which is optionally substituted by -XR 5 Group substitution, where:

[0136] ·X represents -C(=O)- or -CH(OR 6 )-group, where R 6 represents a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, and R 5 represents a hydrogen atom, an amino group or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings;

[0137] or X represents a -CH(OH)- group, and R 5 represents a hydrogen atom or a hydrocarbon group, for example containing 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 5does not represent an n-propyl group, a c-hexyl group or a phenyl group. Here, an n-propyl group, a c-hexyl group and a phenyl group are understood to mean these groups in unsubstituted form. 5 may represent a substituted n-propyl group, a substituted c-hexyl group or a substituted phenyl group.

[0138] In some specific embodiments of the present invention, the compound is such that: in formula (I'):

[0139] R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings,

[0140] And R 2 Represents -CH(R 3 )-R 4 Group, where R 3 As defined above, and R 4 represents a hydrocarbon group, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing a single ring or multiple rings (optionally fused), and containing one or more heteroatoms each selected from oxygen, nitrogen, sulfur and silicon and / or one or more such groups, which contain at least one heteroatom each selected from carbonyl, sulfoxide, sulfonyl and silane groups; when R 1 and R 3 When each represents a hydrogen atom, R 4 It does not represent a phenyl group.

[0141] Specifically, in formula (I'), when R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 Can represent - (CHR 7 )-SO2-Ar 1 Group, where Ar 1 represents an aryl or heteroaryl group, which is optionally substituted, preferably contains 5 to 18 atoms, and R 7represents a hydrogen atom or a hydrocarbon radical, preferably containing 1 to 18, preferentially 1 to 12 and in particular 1 to 6 carbon atoms, which is linear, branched and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0142] The compounds according to the invention may, for example, conform to the general formula (I'd):

[0143]

[0144] Where R 1 , R 7 and Ar 1 As defined above.

[0145] In other cases, in formula (I'), when R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 may represent a triazole group, which is optionally substituted.

[0146] The compounds according to the invention may in particular conform to formula (I'e):

[0147]

[0148] Where R 1 As defined above and R 19 represents a hydrogen atom or a C1 to C18 alkyl, alkylaryl, trialkylsilyl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0149] In some variations of the present invention, in the general formula (I'), R 1 represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon group, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings, R 2 Represents -(CH2)2-R 8 Group, where R 8 represent:

[0150] - Hydrogen atoms;

[0151] - a C1 to C12 alkyl or cycloalkyl group, which is optionally substituted, optionally containing a single ring or multiple condensed rings, for example an adamantyl group;

[0152] --(CH2) a -OH group, wherein a is an integer from 0 to 18, preferably from 0 to 12 and especially from 0 to 6; optionally, when R 1 When it represents a hydrogen atom, a may not be 1;

[0153] --(CH2) b -Ar 2 Group, where Ar 2 represents an aryl or heteroaryl group, which is optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a single ring or a plurality of optionally fused rings, and b is an integer from 0 to 18, preferably an integer from 0 to 12 and in particular from 0 to 6; optionally, when R 1 represents hydrogen atoms and Ar 2 When it represents a phenyl group, b may not be 1;

[0154] --(CH2) c -Si(R 9 )3 groups, wherein R 9 represents a hydroxyl group, a C1 to C4 alkyl group, a C1 to C4 alkoxy group, or a phenyl group, and c is an integer from 0 to 18, preferably an integer from 0 to 12 and in particular from 0 to 6;

[0155] -or-(CH2) d -ZR 10 A group, wherein Z is a heteroatom selected from oxygen, nitrogen and sulfur, R 10 represents a C1 to C18, preferably a C1 to C12 and in particular a C1 to C6 alkyl, cycloalkyl, alkylaryl, aryl or acyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom (e.g. a sulfonyl group), and d is an integer from 0 to 18, preferably from 0 to 12 and in particular from 0 to 6.

[0156] In some particularly preferred embodiments of the present invention, R 1 represents a C1 to C18, preferably C1 to C6, straight-chain, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or more groups comprising at least one heteroatom.

[0157] The compounds according to the invention may, for example, conform to the general formula (I'a):

[0158]

[0159] in:

[0160] R 1 represents a hydrogen atom or a C1 to C18, preferably C1 to C12, in particular C1 to C6, for example C1 to C3 and more in particular C1 to C2 straight-chain, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom,

[0161] R 8 represent:

[0162] - Hydrogen atoms;

[0163] - hydroxyl groups;

[0164] - methyl, ethyl, propyl, butyl, pentyl, hexyl, cycloalkyl, adamantyl, alkylcycloalkyl, alkylaryl or aryl radicals, which are optionally interrupted and / or substituted by one or more heteroatoms and / or one or more radicals comprising at least one heteroatom;

[0165] --Si(R 12 )3 groups, wherein R 12 represents a hydroxyl group, a C1 to C4 alkyl group, a C1 to C4 alkoxy group, or a phenyl group;

[0166] --(CH2) f -YR 13 A group, wherein f is an integer from 0 to 6, Y is a heteroatom selected from oxygen, nitrogen and sulfur, and R 13 represents a C1 to C18, preferably C1 to C12 and in particular C1 to C6 alkyl group, or an aryl or heteroaryl group, preferably C1 to C18, preferably C1 to C12 and in particular C1 to C6;

[0167] --(CH2) g -CO-R 13 A group, wherein g is an integer from 0 to 6 and R 13 As defined above;

[0168] -or-(CH2) h -SO e -R 13 A group, wherein h is an integer from 0 to 6, and e is equal to 1 or 2, and R 13 As defined above;

[0169] When R 1 When R represents a propyl group, 8 It does not represent hydrogen atoms.

[0170] The compounds according to the present invention may conform to the general formula (I"a):

[0171]

[0172] in:

[0173] R 1 represents a hydrogen atom or a C1 to C18 straight-chain, branched and / or cyclic alkyl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom,

[0174] R 18 represents a linear, branched and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, containing 4 to 18 carbon atoms, preferably 4 to 12 carbon atoms and preferentially 5 to 12 carbon atoms, optionally containing one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally containing a single ring or a plurality of optionally fused rings.

[0175] Specifically, R 18 It may represent a butyl, pentyl, hexyl, cyclohexyl, phenyl, benzyl or adamantyl group.

[0176] Some specific compounds according to the present invention are compounds of formula (IIa), (IIb), (IIb1), (IIb2), (IIb3), (IIb4), (IIb5), (IIb6), (IIb7), (IIc), (IIc1), (IId), (IIo), (IIp), (IIp1), (IIq), (IIr), (IIs), (IIt), (IIu), (IIv), (IIw), (IIw1), (IIx), (IIx1) and (IIy) as described above.

[0177] In some alternative embodiments of the present invention, the compound conforms to the general formula (I'b):

[0178]

[0179] in

[0180] R 14 represents a hydrogen atom, a carbonyl group or an alkyl, alkenyl, alkynyl or alkylaryl group, for example a benzyl group or a C1 to C18, preferably a C1 to C12 and in particular a C1 to C6 aryl group, said group being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom; examples of such groups conform to the formula -CH2-TMS, in which TMS represents a trimethylsilyl residue;

[0181] And R 15 represents a hydrogen atom, a hydroxyl group, an amino group or a C1 to C18, preferably C1 to C12 and in particular C1 to C6 alkyl, alkenyl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0182] Specific compounds meeting this definition are compounds of formula (IIh), (IIz1), (IIz2), (IIz3), (IIz4) and (IIz5) described above.

[0183] In other variations of the present invention, the compound conforms to the general formula (I'c):

[0184]

[0185] Where R 16 represents a hydrogen atom or a C1 to C18, preferably C1 to C12 and preferentially C1 to C6 alkyl group, said group being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom.

[0186] Specifically, R 16 It may represent a -CH2-OH group, a methyl group or an ethyl group.

[0187] Specific compounds meeting this definition are compounds of formula (IIj) and (IIk) above.

[0188] All compounds according to the invention which conform to the general formula (I') can advantageously be used as medicaments according to the invention, in particular for the treatment of Pompe disease.

[0189] The compounds of the general formula (I) used according to the invention (particularly compounds conforming to the general formula (I') as defined above) can be synthesized by any method conventional per se to a person skilled in the art. For each specific compound, it is within the capabilities of a person skilled in the art to determine which starting product to use and which synthesis method to apply.

[0190] The present invention also relates to a novel synthetic process developed by the present inventors for preparing compounds of general formula (I), and in particular compounds of general formula (I').

[0191] Some preparation methods according to the invention make it possible to obtain compounds of general formula (I') in which R 1 and R 2 Independently of each other, specifically conform to the above general formula (I'a) or general formula (I"a).

[0192] An example of this specific preparation method according to the present invention comprises the following consecutive steps:

[0193] a / reacting a compound of general formula (III) or (IV) with a compound of general formula (V) in the presence of an organometallic compound:

[0194]

[0195] Where Bn represents a benzyl group, where R 8 As defined above according to the present invention with respect to compounds of general formula (I'), except that R 8 It represents neither a hydrogen atom nor a hydroxyl group -OH or an amino group -NH2,

[0196] b / Optionally, reducing the hydroxylamine functional group to an amine,

[0197] c / Optionally, alkylating the nitrogen atom of the piperidine ring,

[0198] d / and, where step b / or step c / is applicable, in particular for achieving cleavage of the benzyl group to form a hydroxyl group and, where applicable, conversion of the hydroxylamine function into an amine and hydrogenation of the triple bond, subjecting the product obtained at the end of step a / to hydrogenolysis.

[0199] The organometallic compound used in step a / can be a compound such as organozinc, organolithium, organomagnesium, organoaluminum, organocopper, or any mixture thereof. Preferably, in step a / , the reaction is carried out in the presence of dialkylzinc, particularly diethylzinc Et2Zn or butyllithium.

[0200] More generally, the organometallic compound may conform to the general formula (VII):

[0201] R 17 -M (VII)

[0202] in

[0203] R 17 represents a C1 to C18 alkyl, alkenyl, alkynyl, alkylaryl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, and M represents a metal element such as lithium, zinc, copper, aluminum or magnesium, or M represents Mg-X 2 , where X 2 Represents a halogen atom.

[0204] Step b / of reducing the hydroxylamine function to an amine and step c / of N-alkylation can be carried out according to any method which is conventional per se to a person skilled in the art.

[0205] Step d / of the hydrogenolysis can also be carried out by any method which is customary per se to a person skilled in the art, in particular by catalytic hydrogenation.

[0206] Completely unexpectedly and advantageously, this process enables the completely stereoselective preparation of compounds of general formula (I'), in particular compounds of general formula (I'a) or general formula (I"a).

[0207] An example of this approach can be found by Figure 1 The synthetic scheme 1 shown in FIG. 1 represents a specific example of a compound conforming to the general formula (I'a).

[0208] In other cases, the compound of general formula (I'a) or (I"a) can be prepared, for example, by a process comprising the following consecutive steps:

[0209] a / Cycloaddition reaction of a compound of general formula (III) with trimethylsilyl acetylene,

[0210] b / Reaction of the cycloadduct obtained with a fluoride, such as tetrabutylammonium fluoride, for example by a protocol analogous to that described in the publication by Ahn et al., 1994, J. Org. Chem. 59: 6282-6286.

[0211] c / reduction by: metal hydride such as sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4) or diisobutylaluminum hydride (DIBAL-H); or borane such as dimethyl sulfide-borane complex (BH3·Me2S), borane-tetrahydrofuran complex (BH3·THF), borane-pyridine complex (BH3·pyridine), diborane B2H6, particularly preferably lithium aluminum hydride (LiAlH4),

[0212] d / optionally, a step of O-alkylation, O-acylation or O-sulfonylation, which can be carried out according to any method conventional per se to a person skilled in the art,

[0213] e / optionally, a step of N-alkylation, which can be carried out according to any method conventional per se to a person skilled in the art,

[0214] f / and, where step d / or step e / is applicable, in particular for carrying out the cleavage of the benzyl group to form a hydroxyl group, the hydrogenolysis of the product obtained at the end of step c / .

[0215] This synthesis method is particularly advantageous because:

[0216] - Step a / is easy to implement and is completely regio- and diastereoselective, favoring the production of the D-glucose configuration;

[0217] - the cycloadduct formed in step a / is easily and efficiently converted into the β-lactam, which itself is easily and efficiently reduced to the piperidine-alcohol (in other cases, the β-lactam obtained can be converted into the saturated 4-membered ring by reduction carried out by silane or by reductive alkylation in the presence of a metal catalyst).

[0218] An example of this approach can be achieved by Figure 2 The synthetic scheme 2 shown in FIG. 2 represents a specific example of a compound conforming to the general formula (I'a).

[0219] The compound of the above formula (I'd) can be prepared by a method comprising: reacting the compound of the above formula (III) or (IV) with a compound of the general formula (VI) in the presence of a lithiated base such as lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LiHMDS) (preferably in the presence of LiHMDS) at low temperature (preferably -78°C); then, after an optional step of reducing the hydroxylamine functional group to an amine and an optional step of alkylating the nitrogen atom of the piperidine ring, hydrogenolyzing the obtained product.

[0220]

[0221] An example of this approach can be obtained by Figure 3 The synthetic scheme 3 shown in FIG. 3 represents a specific example of a compound that conforms to the general formula (I'd).

[0222] In other cases, compounds of general formula (I) and in particular general formula (I') can be prepared, for example, from compounds of formula (III) or (IV) by a process comprising the following consecutive steps:

[0223] -a / reacting with a compound of the general formula (VII), in particular in the presence of a Lewis acid:

[0224] R 17 -M (VII)

[0225] in

[0226] R 17 represents a C1 to C18 alkyl, alkenyl, alkynyl, alkylaryl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom,

[0227] and M represents a metal element, such as lithium, zinc, copper, aluminum or magnesium, or M represents Mg-X 2 , where X 2 Represents a halogen atom.

[0228] -b / then, optionally, reducing the hydroxylamine function to an amine according to any method conventional per se to a person skilled in the art, in particular by treatment with zinc powder in an acidic medium,

[0229] -c / then, optionally, alkylating the nitrogen atom of the piperidine ring by any method conventional per se to a person skilled in the art,

[0230] -d / then, optionally, a step of cyclometathesis of the olefin catalyzed by a ruthenium-based complex, preferably a second generation Grubbs catalyst,

[0231] -e / and finally, hydrogenolysis of the product obtained at the end of step a / (if applicable, at the end of step b / , step c / or step d / ) according to any method conventional per se to a person skilled in the art, in particular in an acidic medium in the presence of hydrogen and a catalytic amount of palladium on carbon.

[0232] The synthetic route for obtaining compounds conforming to the general formula (I) falls into Figure 4 The general synthetic scheme shown in 4.

[0233] Other preparation processes according to the invention make it possible to obtain compounds of general formula (I') in which R 1 and R 2 Together with the atoms of the piperidine ring to which they are attached, they form a 4-membered heterocyclic ring fused to the piperidine ring.

[0234] An example of such a method includes the following consecutive steps:

[0235] -a / subjecting a compound of the general formula (III) to a cycloaddition reaction with trimethylsilyl acetylene and subsequent reaction with a fluoride such as tetrabutylammonium fluoride, for example according to a protocol similar to that previously described in the publication of Ahn et al., 1994, J. Org. Chem. 59: 6282-6286; then

[0236] -b / According to a protocol similar to that previously described in the publication of Bornschein et al, 2015, Eur J. Org. Chem. 1915-1919, the β-lactam carbonyl group is reduced by a silane (e.g. phenylsilane PhSiH3) in the presence of a rhodium-based catalyst (e.g. [Rh(COD)2]BF4 and 1,3-bis(diphenylphosphino)propane).

[0237] or b' / reductive alkylation of the β-lactam carbonyl by reaction with tetramethyldisiloxane in the presence of a Vaska catalyst at ambient temperature according to a protocol similar to that described in the publication of Xie and Dixon, 2017, Chem. Sci. 8: 7492-7497, and subsequent addition of a compound of formula (VII) as defined above at -78°C;

[0238] And finally

[0239] -c / hydrogenolysis of the product obtained at the end of step b / or b' / , in particular for cleaving the benzyl group to form a hydroxyl group.

[0240] The hydrogenolysis step c / can be carried out according to any method which is conventional per se to a person skilled in the art, in particular by catalytic hydrogenation.

[0241] Steps b / and b' / are particularly advantageous and novel since they enable the reduction and the reductive alkylation of the β-lactam, the nitrogen atom of which is contained in the piperidine ring, to form a heterocycle of the clothianidin type.

[0242] An example of this approach can be found by Figure 5 The synthetic scheme 5 shown in FIG. 5 represents a specific example of a compound that conforms to the general formula (I'b).

[0243] Another example of this method includes the following consecutive steps:

[0244] a / Kinugasa reaction of a compound of formula (III) with a compound of formula (VIII) in the presence of a Cu(I) salt and an amine (as described in the review by Stecko et al., 2014, Tetrahedron 70:7817-7844 or Khangarot & Kaliappan, 2013, Eur. J. Org. Chem. 7664-7677):

[0245]

[0246] Where R 15 represents a C1 to C18 alkyl, alkenyl or aryl group, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups comprising at least one heteroatom; then

[0247] b / According to a similar protocol to that described in the publication of Xie and Dixon, 2017, Chem. Sci. 8: 7492-7497, reductive alkylation of the β-lactam carbonyl group is carried out by reaction with tetramethyldisiloxane in the presence of a Vaska catalyst at ambient temperature, followed by addition of a compound of formula (VII) as defined above at -78°C, and finally

[0248] c / hydrogenolysis of the product obtained at the end of step b / , in particular for carrying out the cleavage of the benzyl group to form a hydroxyl group.

[0249] The hydrogenolysis step c / can be carried out according to any method which is conventional per se to a person skilled in the art, in particular by catalytic hydrogenation.

[0250] Step b / is particularly advantageous and novel since it enables the reductive alkylation of a β-lactam, the nitrogen atom of which is contained in the piperidine ring, to be carried out to form a heterocycle of the clothianidin type.

[0251] An example of this approach can be obtained by Figure 6 Synthesis Scheme 6 is shown as a representation of a particular example of a compound conforming to the general formula (I'b).

[0252] Other preparation processes according to the invention make it possible to obtain compounds of general formula (I') in which R 1 and R 2 Together with the atoms of the piperidine ring to which they are respectively attached, they form a 3-membered heterocyclic ring condensed to the piperidine ring.

[0253] An example of such a method includes the following consecutive steps:

[0254] a / subjecting a compound of the general formula (III) or the compound of the general formula (III') to a cycloaddition reaction with a compound of the general formula (V) as described above, wherein Ac represents an acetyl group, wherein R 8 As defined above according to the present invention with respect to compounds of general formula (I'), except that R 8 It represents neither a hydrogen atom nor a hydroxyl group -OH or an amino group -NH2,

[0255]

[0256] -b / thermal Baldwin rearrangement according to a protocol similar to that described in the publication by Tangara et al., 2017, Org. Lett. 19: 4842-4845, which enables the formation of the acylaziridine, this step being preferentially carried out at 110° C. under irradiation with microwave radiation,

[0257] -c / reducing the acylaziridine carbonyl group thus obtained by reaction with a metal hydride (preferably LiAlH4 or NaBH4),

[0258] -d / and debenzylation according to any method conventional per se to a person skilled in the art, in particular by Birch reduction at low temperature, preferably at -78°C, in the presence of a metal dissolved in liquid ammonia, preferably lithium.

[0259] An example of this approach can be obtained by Figure 7 The synthetic scheme 7 shown in FIG. 7 represents a specific example of a compound that conforms to the general formula (I'c).

[0260] An example of a method for preparing the compound of the above general formula (I'e) can be obtained by Figure 8 The synthetic scheme 8 shown in FIG. 8 represents that R 20 With R 19 Same, but R 20 It does not represent hydrogen atoms.

[0261] The features and advantages of the present invention will become more apparent from the following exemplary embodiments, which are described in detail by way of simple illustration and in a manner that does not limit the present invention. Figures 1 to 8 Provided with support from:

[0262] Figure 1 A first example of a general synthetic scheme (Synthetic Scheme 1) for preparing compounds of formula (I'a) according to the present invention is shown.

[0263] Figure 2 A second example of a general synthetic scheme (Synthetic Scheme 2) for preparing compounds of formula (I'a) according to the present invention is shown.

[0264] Figure 3 An example of a general synthetic scheme (Synthetic Scheme 3) for preparing compounds of formula (I'd) according to the present invention is shown.

[0265] Figure 4 A third exemplary embodiment of a general synthetic scheme (Synthetic Scheme 4) for the preparation of compounds of formula (I'a) and more generally compounds of formula (I) used according to the invention is shown.

[0266] Figure 5 A first example of a general synthetic scheme (Synthetic Scheme 5) for preparing compounds of formula (I'b) according to the present invention is shown.

[0267] Figure 6 A second example of a general synthetic scheme (Synthetic Scheme 6) for preparing compounds of formula (I'b) according to the present invention is shown.

[0268] Figure 7 An example of a general synthetic scheme (Synthetic Scheme 7) for preparing compounds of formula (I'c) according to the present invention is shown.

[0269] Figure 8 An example of a general synthetic scheme (Synthetic Scheme 8) for preparing compounds of formula (I'e) according to the present invention is shown.

[0270] A / Synthesis and characterization of compounds used according to the invention

[0271] All reactions were performed under inert atmosphere in pre-dried glassware with magnetic bar stirring, except in the case of reactions under microwave irradiation, where the assembly was placed above a magnetic stirrer. Reactions under microwave irradiation were carried out in sealed tubes equipped with magnetic bars placed in a microwave reactor at a temperature regulated by an internal infrared probe. Toluene, ether and dichloromethane used as reaction solvents were pre-dried in an inert PureSolv The reaction was filtered on a purification system. Acetonitrile and dichloroethane were distilled on CaH2. THF was distilled on sodium in the presence of benzophenone. Commercial reagents, methanol and ethanol were used without purification. The reaction was followed by thin layer chromatography (TLC) on silica on aluminum plates (Merck, Kieselgel 60F254), visualized under UV radiation, and then by a solution of 3% potassium permanganate in 10% potassium hydroxide solution (w / v). Purification by column chromatography was performed by Macherey-Nagel The results were carried out using silica gel 60 (70 to 230 mesh). The optical rotation was measured on a PerkinElmer 341 polarimeter. The infrared spectra were obtained on a Nicolet "Magna 550" spectrometer including an ATR (attenuated total reflection) module on which the product was deposited in pure solid or liquid form. The data are in cm -1 Indicates. Use Avance 500( 1 H:500MHz, 13 C:125MHz) or Avance 400( 1 H:400MHz, 13 C: 100MHz) spectrometer 1 H NMR and 13 C NMR {DEPT-Q}. 1 The chemical shifts of the H spectra are expressed relative to the residual solvent contained in CDCl3 (δ 7.26 ppm) or CD3OD (δ 3.31 ppm). 13The chemical shifts of the C spectra are expressed relative to the solvent CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 ppm). 1 H NMR spectra are reported as follows: chemical shift (ppm), multiplicity (br: broad; s: singlet; d: doublet; dd: doublet of doublet; t: triplet; pst: pseudotriplet; m: multiplet), coupling constant (Hz), and integration. High-resolution mass spectra (HRMS) were recorded on a Thermo Scientific ESI / LTQ Orbitrap XL or WatersG2-S Q-TOF mass spectrometer.

[0272] A.1 / Synthesis method 1

[0273] The synthetic method for obtaining the compound conforming to the above general formula (I'a) falls into Figure 1 The general synthetic scheme shown in .

[0274] 1) General Solution A - Alkynylation of the nitrone of formula (III) gives the propargylhydroxylamine of formula A-1.

[0275] At 0°C, under an argon atmosphere, a 1M diethylzinc solution (1.5 equivalents) in hexane is added dropwise to an alkyne solution (4 equivalents) of formula (V) in anhydrous toluene. The resulting mixture is stirred at 0°C for 30 minutes. A ketone nitrone solution (1 equivalent) of formula (III) in anhydrous toluene is then added dropwise at 0°C, and the reaction mixture is then stirred until the reaction is complete (subsequently subjected to TLC). A saturated NaHCO3 aqueous solution is added, and the resulting mixture is then diluted with diethyl ether. The organic phase is separated, and the aqueous phase is extracted twice with diethyl ether. The organic phase is washed with brine, dried on MgSO4 and evaporated under reduced pressure. The hydroxylamine of formula A-1 thus formed is purified by silica gel chromatography, and then reduced and debenzylated (performed according to the following general scheme B).

[0276] 2) General Solution A' - Alkynylation of the nitrone of formula (III) gives the propargylhydroxylamine of formula A-1.

[0277] At -10 ° C, under an argon atmosphere, 1.4M n-butyl lithium solution (2.5 equivalents) in hexane is added dropwise to an alkyne solution (2.5 equivalents) of formula (V) in anhydrous THF. The resulting solution is stirred at -10 ° C for 15 minutes and then cooled to -78 ° C. Then a solution (1 equivalent) of the ketone nitrone of formula (III) in anhydrous THF is added dropwise at -78 ° C, and the reaction mixture is stirred until the reaction is complete (subsequently TLC is performed). Saturated NH4Cl aqueous solution is added, and the mixture is allowed to rise to ambient temperature, and then extracted 3 times with ethyl acetate. The organic phase is collected and washed with brine, dried on MgSO4 and concentrated under reduced pressure. The hydroxylamine of the thus separated formula A-1 is purified by silica gel chromatography, then reduced and debenzylated (performed according to the following general scheme B).

[0278] 3) General Solution B

[0279] 1.5 equivalents of hydrochloric acid HCl (2M solution in anhydrous ether) and 0.2 equivalents of 10% Pd / C were added to a solution of O-benzylated iminosugar in anhydrous ethanol (1 equivalent). The obtained suspension was stirred at room temperature under hydrogen pressure (5 bar) for 17 hours and then heated to 40 °C under Celite Filter on the Celite with methanol. , and the filtrate was concentrated under reduced pressure to give the iminosugar hydrochloride. The salt was pre-activated with HCl in Dowex The product was purified on 50W-X2 ion exchange resin and eluted with NH4OH aqueous solution to obtain the corresponding neutral compound of formula (I'a) after evaporation of the solvent.

[0280] Compound of formula (IIc)

[0281] According to the general schemes A and B, a nitrone of formula (III) (110.0 mg, 0.205 mmol) and phenylacetylene (Va: R 8 =Ph, 0.034 mL; 0.307 mmol) to prepare the compound of the above formula (IIc) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-phenethylpiperidine-3,4,5-triol: 36.7 mg; 73% for two steps).

[0282] A yellow solid was obtained which had the following characteristics:

[0283]

[0284] Compound (IIx1)

[0285] According to the general schemes A and B, a nitrone of formula (III) (102.1 mg, 0.189 mmol) and trimethylsilyl acetylene (Vb: R 8 =TMS, 0.105 mL; 0.759 mmol) to prepare the compound of the above formula (IIx1) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-(2-(trimethylsilyl)ethyl)piperidine-3,4,5-triol: 7.1 mg; 29%, for two steps).

[0286] A white foam was obtained which had the following characteristics:

[0287]

[0288] Compound (IIr)

[0289] According to the general schemes A' and B, a nitrone of formula (III) (100 mg, 0.185 mmol) and adamantyl acetylene (Vh: R 8 =adamantyl, 74.5 mg, 0.465 mmol) to prepare the compound of the above formula (IIr) ((2R,3R,4R,5S)-2-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol: 15.0 mg; 27%, for two steps).

[0290] A pale yellow varnish was obtained, which had the following characteristics:

[0291]

[0292] Compound (IIb7)

[0293] According to the general schemes A and B, a nitrone of formula (III) (99.8 mg; 0.185 mmol) and 1-ethynylcyclohexene (Vd: R 8 =cyclohexene; 87 μL; 0.742 mmol) to prepare the compound of the above formula (IIb7) ((2R,3R,4R,5S)-2-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol: 57.3 mg; 59%, for two steps).

[0294] A white solid was obtained which had the following characteristics:

[0295]

[0296] Compound (IIb1)

[0297] According to the general schemes A and B, a nitrone of formula (III) (96.8 mg; 0.180 mmol) and 1-pentyne (Ve:R 8 =C3H7; 71 μL; 0.720 mmol) to prepare the compound of the above formula (IIb1) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-pentylpiperidine-3,4,5-triol: 32.8 mg; 67%, for two steps).

[0298] A yellow solid was obtained which had the following characteristics:

[0299]

[0300] Compound (IIb3)

[0301] According to the general schemes A and B, a nitrone of formula (III) (100.7 mg; 0.187 mmol) and 1-heptyne (Vf: R 8 =C5H 11 ; 98 μL; 0.749 mmol) to prepare the compound of the above formula (IIb3) ((2R,3R,4R,5S)-2-heptyl-2-(hydroxymethyl)piperidine-3,4,5-triol: 33.2 mg; 69%, for two steps).

[0302] A yellow solid was obtained which had the following characteristics:

[0303]

[0304] Compound (IIc1)

[0305] According to the general schemes A and B, a nitrone of formula (III) (96.7 mg; 0.179 mmol) and 3-phenyl-1-propyne (Vg: R 8 =CH2Ph; 89 μL; 0.719 mmol) to prepare the compound of the above formula (IIc1) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-(3-phenylpropyl)piperidine-3,4,5-triol: 20.2 mg; 45%, for two steps).

[0306] A yellow varnish was obtained, which had the following characteristics:

[0307]

[0308] A.2 / Synthesis Method 2

[0309] The synthetic method for obtaining compounds conforming to the following general formula (I'a) falls within Figure 2 The general synthetic scheme shown in 2.

[0310] Compound of formula (IId)

[0311] The compound (2R,3R,4R,5S)-2-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol of the above formula (IId) was prepared in the following manner.

[0312] Nitrone (III) (566 mg, 1.05 mmol) and trimethylsilyl acetylene (Vb: R 8 =SiMe3, 2.2 mL, 15.75 mmol) was stirred at ambient temperature for 21 hours and then the excess alkyne was evaporated under reduced pressure. The crude isocyanate thus obtained was Oxazoline B-2 (667mg, 1.05mmol) is dissolved in anhydrous THF (20mL), and TBAF solution (1M in THF, 1.05mL, 1.05mmol) is added at 0 ℃. The solution is stirred for 45 minutes at 0 ℃, and CH is added subsequently Cl and water. Use CH Cl The aqueous phase is extracted 3 times. The organic phase is washed with salt water, at MgSO Upper drying, and the solvent is evaporated under reduced pressure subsequently. The residue obtained by chromatographic purification provides bicyclic β-lactic acid C-2 (440.6mg, 74%, in two steps). At 0 ℃, LiAlH (9.6mg, 0.25mmol) is added to the solution of the β-lactam C-2 (71.3mg, 0.13mmol) in ether (1.5mL). The mixture is stirred at ambient temperature for 2 hours, and CH is used subsequently Cl , NH The Cl aqueous solution and a few drops of NaOH aqueous solution are diluted to alkaline pH. The aqueous phase was extracted with CH2Cl2 (3 times). The organic phase was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give piperidine D-2 (translucent oil, 61.1 mg, 85%) after chromatography purification. This compound (26.3 mg, 0.463 mmol) was debenzylated according to General Scheme B to give piperidine (IId) (9.3 mg, 97%).

[0313] A light yellow varnish was obtained, which had the following characteristics:

[0314]

[0315] A.3 / Synthesis method 3

[0316] The synthetic method for obtaining compounds conforming to the following general formula (I'd) falls within Figure 3 The general synthetic scheme shown in 3.

[0317] Compound of formula (IIw)

[0318] The compound (2S, 3S, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ((benzyloxy) methyl) -2- (pyridin-2-ylsulfonyl) piperidine -1- alcohol of formula (IIw) is prepared in the following manner. A solution of 2-pyridyl-methyl sulfone (VIa) (74.6 mg; 0.475 mmol) and nitrone (196 mg; 0.366 mmol) of formula (III) in anhydrous THF (10 mL) was cooled to -78 ° C under an argon atmosphere. 1M LiHMDS (548 μL; 0.548 mmol) in THF was added dropwise, and the reaction mixture was then stirred at the same temperature until the reaction was complete. After adding water and ethyl acetate, the aqueous phase was extracted with ethyl acetate (3 times). The collected organic phase was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. Purification of the residue obtained by chromatography provides a compound (R) of formula A-3a. 7 =H) 115 mg; 55%). This compound was debenzylated according to a variation of general procedure B to give the piperidine (IIw).

[0319] A.4 / Synthesis method 4

[0320] The synthetic method for obtaining compounds according to the general formula (I), in particular compounds according to the general formula (I'a) falls within Figure 4 The general synthetic scheme shown in 4.

[0321] Compound of formula (IIa)

[0322] The compound of formula (IIa) ((2R,3R,4R,5S)-2-ethyl-2-(hydroxymethyl)piperidine-3,4,5-triol) is prepared according to the general scheme B described for the synthetic method 1 from piperidine D-4b (R 17 =vinyl, 74.0 mg, 0.137 mmol) and isolated in 95% (24.9 mg) yield, piperidine D-4b was obtained as described in the publication of Boisson et al., 2015, Org. Lett. 17: 3662-3665.

[0323] A light yellow varnish was obtained, which had the following characteristics:

[0324]

[0325] Compound of formula (IIb)

[0326] The compound of formula (IIb) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-propylpiperidine-3,4,5-triol)) is prepared according to the general scheme B described for the synthetic method 1, from piperidine D-4a (R17 =allyl, 39.7 mg, 0.071 mmol) and isolated in 79% (11.4 mg) yield, piperidine D-4a was obtained as described in the publication of Vieira Da Cruz et al., 2017, J. Org. 82: 9866-9872.

[0327] A colorless varnish was obtained which had the following characteristics:

[0328]

[0329] Compound of formula (IIe)

[0330] The compound (2R,3R,4R,5S)-2-ethyl-2-(hydroxymethyl)-1-propylpiperidine-3,4,5-triol of the above formula (IIe) was prepared in the following manner.

[0331] Piperidine E-4b (R) obtained as described in the publication of Boisson et al., 2015, Org. Lett. 17: 3662-3665 1 =allyl, R 17 =vinyl; 62 mg, 0.105 mmol) was dissolved in anhydrous acetonitrile (0.5 mL), treated with 2-nitrobenzenesulfonyl chloride (186 mg, 0.84 mmol) at 0° C., and then hydrazine monohydrate (0.08 mL, 1.68 mmol) was added dropwise at 0° C. The reaction mixture was kept under stirring at ambient temperature for 28 hours, and then water was added and the aqueous phase was extracted with dichloromethane (3 times). The collected organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure. After purification by chromatography, the hydrogenation product of only the allyl group and a mixture of the hydrogenation products of the allyl and vinyl groups were isolated (58 mg, 94%, 3:7 mixture). The mixture was dissolved in methanol (1.5 mL) and then treated with Pearlman's reagent (20% Pd(OH)2 / C, 16.8 mg, 0.119 mmol) and HCl (2M solution in ether, 0.2 mL, 0.4 mmol) under hydrogen atmosphere (1 atm) and with vigorous stirring for 40 hours. The mixture was stirred for 2 hours. Filter and rinse with methanol The residue was dissolved in water and ion exchange resin (DOWEX 50W-X8, form H + ; eluted by 1 M aqueous NH4OH) to afford the product (IIe) (11.9 mg, 49%).

[0332] A beige solid was obtained which had the following characteristics:

[0333]

[0334] Compound of formula (IIf)

[0335] The compound (1R,2R,3S,9aR)-9a-(hydroxymethyl)octahydro-1H-quinolizine-1,2,3-triol of the above formula (IIf) was prepared in the following manner.

[0336] Piperidine E-4a (R) obtained as described in the publication of Vieira Da Cruz et al., 2017, J. Org. 82: 9866-9872 1 =R 17 =allyl; 35mg, 0.06mmol) was dissolved in anhydrous CH2Cl2 (3mL). The solution was carefully degassed and Grubbs II catalyst (1.3mg, 2.5mol%) was subsequently added. The mixture was kept under stirring at ambient temperature for 20 hours and then filtered through silica. The silica was rinsed with ethyl acetate and methanol and the solvent was evaporated under reduced pressure. After the residue thus obtained was purified by chromatography, the product obtained by metathesis cyclization of F-4a olefin was isolated (32mg, 95%). The latter (34mg, 0.06mmol) was dissolved in methanol (1mL) and then treated with Pearlman reagent (20% Pd(OH)2 / C, 14mg, 0.10mmol) and HCl (2M solution in ether, 0.045mL, 0.09mmol) under a hydrogen atmosphere (5bar) and with vigorous stirring for 17 hours. The mixture was filtered through Filter and rinse with methanol The residue was dissolved in water and filtered through a cation exchange resin (DOWEX 50W-X8, Form H + ; eluted with 1 M aqueous NH 4 OH) to afford the product (IIf) (9 mg, 73%).

[0337] A colorless oil was obtained which had the following characteristics:

[0338]

[0339] Compound of formula (IIg)

[0340] The compound (6S,7R,8R,8aR)-8a-(hydroxymethyl)-octahydroindole-6,7,8-triol of the above formula (IIg) was prepared in the following manner.

[0341] Piperidine E-4b (R) obtained as described in the publication of Boisson et al., 2015, Org. Lett. 17: 3662-3665 1 =allyl, R 17 =vinyl; 74 mg, 0.125 mmol) was dissolved in anhydrous CH2Cl2 (6.3 mL). The solution was carefully degassed and subsequently Grubbs II catalyst (5.3 mg, 0.006 mmol) was added and the mixture was heated at 40°C for 3 hours under stirring. After cooling to ambient temperature, the reaction mixture was filtered through silica, the silica was rinsed with ether and the solvent was evaporated under reduced pressure. After the residue thus obtained was purified by chromatography, the product obtained by metathesis cyclization of olefin F-4b was isolated (65 mg, 93%). The latter (50 mg, 0.089 mmol) was dissolved in methanol (1.4 mL) and then treated with Pearlman reagent (20% Pd(OH)2 / C, 17.9 mg, 0.025 mmol) and HCl (2M solution in ether, 0.066 mL, 0.133 mmol) under a hydrogen atmosphere (5 bar) and with vigorous stirring for 17 hours. The mixture was purified by Filter and rinse with methanol The residue was dissolved in water and passed through a cation exchange resin (DOWEX50W-X8, Form H + ; eluted with 1 M aqueous NH 4 OH) to afford the product (IIg) (16 mg, 89%).

[0342] A beige solid was obtained which had the following characteristics:

[0343]

[0344] A.5 / Synthesis method 5

[0345] The synthetic method for obtaining the compound conforming to the above general formula (I'b) falls into Figure 5 The general synthetic scheme shown in 5.

[0346] Compound (IIh)

[0347] The compound of the above formula (IIh) ((3S,4R,5R,6R)-6-(hydroxymethyl)-1-azabicyclo[4.2.0]octane-3,4,5-triol) was prepared in the following manner.

[0348] [Rh(COD)2]BF4 (2.5 mg, 0.006 mmol), 1,3-bis(diphenylphosphino)propane (2.7 mg, 0.006 mmol) and PhSiH3 (25 μL, 0.20 mmol) were added to a solution of β-lactam C-5 (corresponding to compound C-2 obtained as an intermediate in synthesis method 2, as described in the scheme for preparing compound (IId) above) (57.1 mg, 0.10 mmol) in distilled THF. The solution was stirred at 50°C for 4 hours. After cooling, the reaction mixture was diluted with EtOAc and aqueous NaOH solution (1 M). The aqueous phase was extracted with EtOAc (3 times). The organic phase was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure after purification by chromatography to obtain clothianidin G-5 (33.2 mg, 60%). This compound (20.0 mg, 0.04 mmol) was debenzylated according to general procedure B to give compound (IIh) (6.3 mg, 93%).

[0349] A pale yellow oil was obtained which had the following characteristics:

[0350]

[0351] General Solution C -Reductive alkylation of β-lactam C-5 to produce clothianidin of general formula (I'b)

[0352] Under an argon atmosphere, a solution of Vaska catalyst (4% mol) and a solution of β-lactam C-5 (1 equivalent) in anhydrous dichloromethane are added to tetramethyldisiloxane (TMDS, 2 equivalents) at ambient temperature. The mixture is stirred for 45 minutes and then cooled to -78°C. Grignard reagent (2 equivalents) is added dropwise, and the mixture is then stirred for 7 to 10 minutes at the same temperature and then raised to ambient temperature. Next, stirring is performed for 21 hours. Saturated NH4Cl aqueous solution is added, and the resulting mixture is then diluted with CH2Cl2. The organic phase is separated and the aqueous phase is extracted twice with CH2Cl2. The organic phase is washed with brine, dried over MgSO4, and evaporated under reduced pressure. The clothianidin of formula (I'b) thus formed is purified by chromatography over silica gel, followed by reduction and debenzylation (performed according to the above general scheme B).

[0353] Compound (IIz2)

[0354] According to general procedures C and B, 2M benzylmagnesium chloride (R) in THF was used. 14=Bn; 36.3 μL; 0.248 mmol) and β-lactam C-5 (70.1 mg; 0.124 mmol) were used to prepare the compound of the above formula (IIz2) ((3S,4R,5R,6R,8R)-8-benzyl-6-(hydroxymethyl)-1-azabicyclo[4.2.0]octane-3,4,5-triol: 20.3 mg; 65%, for two steps).

[0355] A translucent lacquer-like product was obtained, which had the following characteristics:

[0356]

[0357] Compound (IIz3)

[0358] According to general procedures C and B, 3M methylmagnesium chloride (R) in THF was used. 14 =Me; 228 μL; 0.683 mmol) and β-lactam C-5 (192.6 mg; 0.342 mmol) were used to prepare the compound of the above formula (IIz3) ((3S,4R,5R,6R,8R)-6-(hydroxymethyl)-8-methyl-1-azabicyclo[4.2.0]octane-3,4,5-triol: 8.5 mg; 46%, for two steps).

[0359] A pale yellow solid was obtained which had the following characteristics:

[0360]

[0361] Compound (IIz4)

[0362] According to general procedures C and B, 2M cyclopentylmagnesium chloride (R 14 =cPent; 36.4μL; 0.248mmol) and β-lactam C-5 (70.0mg; 0.124mmol) were used to prepare the compound of the above formula (IIz4) ((3S,4R,5R,6R,8S)-8-cyclopentyl-6-(hydroxymethyl)-1-azabicyclo[4.2.0]octane-3,4,5-triol: 14.6mg; 62%, for two steps).

[0363] A pale yellow solid was obtained which had the following characteristics:

[0364]

[0365] Compound (IIz5)

[0366] According to general procedures C and B, 2M amylmagnesium chloride (R) in THF was used. 14=n-Pent; 33.6 μL; 0.248 mmol) and β-lactam C-5 (70.0 mg; 0.124 mmol) were used to prepare the compound of the above formula (IIz5) ((3S,4R,5R,6R,8R)-6-(hydroxymethyl)-8-pentyl-1-azabicyclo[4.2.0]octane-3,4,5-triol: 19.1 mg; 45%, for two steps).

[0367] A yellow solid was obtained which had the following characteristics:

[0368]

[0369] A.6 / Synthesis method 7

[0370] The synthetic method for obtaining compounds conforming to the following general formula (I'c) falls within Figure 7 The general synthetic scheme shown in 7.

[0371] Compound (IIk)

[0372] The compound of the above formula (IIk) ((3S,4R,5R,6R,7S)-6,7-bis(hydroxymethyl)-1-azabicyclo[4.1.0]heptane-3,4,5-triol) is obtained in the following manner.

[0373] The alkyne Vc (R 8 =NBnTs; 308 mg, 1.079 mmol) and nitrone (III) (P = Bn; 193 mg, 0.360 mmol) were stirred at ambient temperature for 3 days, and then the reaction mixture was concentrated under reduced pressure. The residue (crude cycloadduct B-7c) was dissolved in ethanol (0.1 M), transferred to a sealed tube, and heated under microwave irradiation at 110 ° C (IR probe) for 15 minutes. After concentration under reduced pressure, the residue was purified by chromatography to give acylaziridine H-7c (P = Bn, R 8 =NBnTs; 238 mg, 80% in two steps). A portion of this compound (58 mg, 0.070 mmol) was dissolved in THF (1 mL), and then LiAlH4 (6 mg, 0.157 mmol) was added at 0°C. The mixture was stirred at ambient temperature for 1.5 hours. After adding water (0.1 mL) and 10% aqueous NaOH (0.1 mL), the reaction mixture was stirred at ambient temperature for 2 hours, and then The filtrate concentrated under reduced pressure was purified by chromatography to isolate aziridine-alcohol J-7c (P = Bn, R 16=H; 34.2 mg, 86%). A solution of this aziridine-alcohol J-7c (28 mg, 0.067 mmol) in THF (2 mL) was added to a solution of lithium (54 mg, 7.78 mmol) in liquid ammonia (10 mL) at -78°C. The mixture was stirred at -78°C for 45 minutes, and then Milli-Q water (0.5 mL) and MeOH (2 mL) were added. After the solution was allowed to return to ambient temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in Milli-Q water and washed with Amberlite previously treated with 1 M HCl (15 mL). IR-120 (22.8 g) was neutralized. The resin was introduced into a column, washed with water, and then compound (IIk) was eluted with 1 M NH4OH aqueous solution. The solution obtained after evaporating the solvent under reduced pressure was purified by chromatography to obtain pure iminosugar (IIk) (R 16 =H; 7 mg, 60%).

[0374] A white solid was obtained which had the following characteristics:

[0375]

[0376] Compound (IIj)

[0377] The compound of the above formula (IIj) ((3S,4R,5R,6R,7S)-7-((S)-1,2-dihydroxyethyl)-6-(hydroxymethyl)-1-azabicyclo[4.1.0]heptane-3,4,5-triol) was obtained as follows.

[0378] Acylaziridine H-7d (P=Bn, R 8 =CH2OAc; 33 mg, 0.052 mmol) was dissolved in THF (1 mL), and then LiAlH4 (38 mg, 0.165 mmol) was added at 0°C, and the mixture was stirred at ambient temperature for 1 hour. After adding water (0.1 mL) and 10% aqueous NaOH solution (0.1 mL), the reaction mixture was stirred at ambient temperature for 2 hours, and then The filtrate was concentrated under reduced pressure and purified by chromatography to separate a translucent oil J-7d (R 16=CH2OH; 26 mg, 83%). A solution of the aziridine-alcohol J-7d (40 mg, 0.067 mmol) in THF (2 mL) was added to a solution of lithium (25 mg, 3.571 mmol) in liquid ammonia (10 mL) at -78°C. The mixture was stirred at -78°C for 45 minutes and then Milli-Q water (0.5 mL) and MeOH (2 mL) were added. After returning the solution to ambient temperature, the solvents were evaporated under reduced pressure. The residue was dissolved in Milli-Q water and washed with Amberlite previously treated with 1 M HCl (5 mL). IR-120 (8.5 g) was neutralized. The resin was introduced into a column, washed with water, and then compound (IIj) was eluted with 1 M NH4OH aqueous solution. The solid obtained after evaporation of the solvent under reduced pressure was purified by chromatography to obtain pure iminosugar (IIj) (R 16 =CH2OH; 10.1 mg, 64%).

[0379] A white solid was obtained which had the following characteristics:

[0380]

[0381] Compound(IIm)

[0382] The compound (3S,4R,5R,6R,7S)-7-((S)-hydroxy(phenyl)methyl)-6-(hydroxymethyl)-1-azabicyclo[4.1.0]heptane-3,4,5-triol of the above formula (IIm) was obtained as follows.

[0383] The cycloadduct B-7e (P = Ac, R 8 =Ph; 15.2 mg, 0.030 mmol, 4:1 mixture of diastereomers) was dissolved in dichloroethane (0.1 M solution) in a sealed tube. The solution was heated under microwave irradiation at 110 ° C. (IR probe) for 45 minutes (30+15). After evaporation of the solvent under reduced pressure, purification of the residue by chromatography made it possible to isolate the acylaziridine H-7e (P = Ac, R = Ac) in the form of a 9:1 mixture of two diastereomers. 8=Ph; 12 mg, 79%). The acyl aziridines (30 mg, 0.067 mmol) were dissolved in THF (1.2 mL), the solution was cooled to 0°C, and then LiAlH4 (5.6 mg, 0.147 mmol) was added. The reaction mixture was stirred at ambient temperature for 1.5 hours, and then water (0.1 mL) and 10% NaOH aqueous solution (0.1 mL) were added thereto. After stirring at ambient temperature for 1.5 hours, the mixture was stirred for 1.5 hours. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by chromatography to provide aziridinyl iminosugar (IIm) (R 16 =Ph; 15 mg, 82%).

[0384] A colorless oil was obtained which had the following characteristics:

[0385]

[0386] Compound (IIn)

[0387] The compound (3S,4R,5R,6R,7S)-7-((R)-cyclohexyl(hydroxy)methyl)-6-(hydroxymethyl)-1-azabicyclo[4.1.0]heptane-3,4,5-triol of the above formula (IIn) was obtained as follows.

[0388] Acylaziridine H-7f (P=Bn, R 8 =c-Hex; 77 mg, 0.119 mmol) was dissolved in ethanol (1.4 mL), cooled to 0°C, and then NaBH4 (13 mg, 0.342 mmol) was added. The mixture was stirred at the same temperature for 3.3 hours, and then water, 10% NaOH aqueous solution and CH2Cl2 were added. The aqueous phase was extracted with CH2Cl2 (3 times), the organic phases were collected, dried over MgSO4 and concentrated under reduced pressure. The residue thus obtained was filtered on silica to separate the aziridine-alcohol J-7f (R-7f) in the form of an oil. 16=c-Hex; 72 mg, 94%). A solution of the aziridine-alcohol J-7f (42 mg, 0.064 mmol) in THF (4 mL) was added to a solution of lithium (12 mg, 2.0 mmol) in liquid ammonia (10 mL) at -78°C. The reaction mixture was stirred at -78°C for 45 minutes, and then Milli-Q water (0.5 mL) and MeOH (2 mL) were added. After the solution was allowed to return to ambient temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in Milli-Q water and washed with Amberlite previously treated with 1 M HCl (2 mL). IR-120 (3.5 g) was neutralized. The resin was introduced into a column, washed with water, and then eluted with 1 M NH4OH aqueous solution (IIn). The solid obtained after evaporating the solvent under reduced pressure was purified by chromatography to obtain pure iminosugar (IIn) (R 16 =c-Hex; 13 mg, 72%).

[0389] A white solid was obtained which had the following characteristics:

[0390]

[0391] A.7 / Synthesis Method 8

[0392] The synthetic method for obtaining compounds conforming to the following general formula (I'e) falls within Figure 8 The general synthetic scheme shown in 8.

[0393] Compound (IIw1)

[0394] The compound of the above formula (IIw1) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-(1H-1,2,3-triazol-4-yl)piperidine-3,4,5-triol) was prepared in the following manner.

[0395] A solution of zinc powder (247.0 mg; 3.77 mmol) and formula A-1a hydroxylamine (240.0 mg; 0.377 mmol) in a 4:1 mixture of EtOH / AcOH (5 mL) was stirred at 65°C under ultrasound until the reaction was complete. The reaction mixture was filtered through Celite and then evaporated under reduced pressure. The crude product was redissolved in CH2Cl2 and then treated with 1M NaOH aqueous solution. The aqueous phase was extracted with CH2Cl2 (3 times). The organic phase was washed with brine, dried over MgSO4, and then evaporated under reduced pressure. Purification of the residue obtained by chromatography provided the corresponding piperidine D-8 (178.0 mg; 76%). A mixture of K2CO3 (157.0 mg; 1.14 mmol), benzyl chloroformate (121 μL; 0.852 mmol) and the piperidine D-8 (176.0 mg; 0.284 mmol) in anhydrous THF (1.7 mL) was stirred at ambient temperature until the reaction was complete. Methanol (2 mL) was added, and the reaction mixture was then stirred at ambient temperature until the reaction was complete. Purification of the residue obtained by chromatography provided a compound of formula K-8 (164.0 mg; 78% over two steps). Under an inert atmosphere, copper iodide (3.5 mg; 0.018 mmol) and DIPEA (108 μL; 0.618 mmol) were added to a solution (1.5 mL) of benzyl azide (247 μL; 0.124 mmol) and the same compound K-8 (46.8 mg; 0.062 mmol) in DMF. The reaction mixture was stirred at ambient temperature until the reaction was complete. The crude product was diluted in ethyl acetate and washed several times with brine. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue obtained by purification by chromatography provided a compound of formula L-8 (38.2 mg; 76%). This compound (32.1 mg; 0.039 mmol) was debenzylated to obtain piperidine (IIw1) (11.0 mg; 100%) according to General Scheme B.

[0396] A colorless varnish was obtained, which had the following characteristics:

[0397]

[0398] B / Biological Evaluation

[0399] The above compounds (IIa) to (IIn) were subjected to the following various biological activity tests.

[0400] B.1 / Inhibition of rhGAA determined by Fluopol-ABPP

[0401] The inhibitory activity of the compounds on recombinant human acid α-glucosidase (rhGAA) was performed using the Fluopol-ABPP method (Fluorescence Polarization Activity Based Protein Profiling) described in the publication of Lahav et al., 2017, J. Am. Chem. Soc. 139: 14192-14197. This technique is based on competition between an inhibitor and a fluorescent probe that can covalently bind to the active site of the enzyme, which enables the measurement of the affinity of this inhibitor to the active site of the rhGAA enzyme, which is the enzyme used for these experiments in the laboratories of Professors Herman S. Overkeleft and Johanes M.F. G. Aerts at the Leiden Institute of Chemistry, Leiden University (NL), which is a Myozyme The median inhibitory concentration (IC) was determined in 150 mM Mcllvaine buffer (citrate-phosphate) at pH 5.0 in a 96-well plate (Griener) in the presence of 0.1% bovine γ-globulin (p / v) and 0.5 mg / mL Chaps detergent (Sigma). 50 ). The rhGAA enzyme (10 μg / mL) was pre-incubated with inhibitor solutions of different concentrations [I] in buffer (containing 2.5% DMSO, which was used to prepare the master solution of the compound) at 37°C for 45 minutes. Next, tetraaminomethylrhodamine (TAMRA) fluorescent probe (25 nM) in a dissolved state in buffer was added to the mixture. After 4 hours, the sample was irradiated with polarized light (λ=530 nm) and the sample was illuminated by Infinite The emitted fluorescence (λ=580 nm) was measured using a M1000Pro (Tecan) spectrofluorometer. For each inhibitor concentration, the percentage of enzyme inhibition was determined by the following formula:

[0402] % inhibition = [(F 测量的 -F 对照1 ) / F 对照2 )×100

[0403] Among them, F 测量的 corresponds to the fluorescence measured in the presence of iminosugar; F 对照1 corresponds to the fluorescence measured in the presence of CF 022 ((1S,2R,3S,4R,5R,6R)-2,3,4-trihydroxy-5-(hydroxymethyl)-7-(8-azidooctyl)-7-aza-bicyclo[4.1.0]heptane), a potent inhibitor of human acid α-glucosidase, used as a positive control (100% inhibition), and F 对照2Represents the fluorescence of the probe measured in the absence of inhibitor (0% inhibition).

[0404] IC 50 Values ​​were calculated by nonlinear regression of % inhibition as a function of concentration [I] using GraphPad Prism 6.0 software. Results are the mean of three identical experiments (triplicate).

[0405] B.2 / Inhibition of rhGAA is determined by measuring residual activity in the presence of the inhibitor in vitro

[0406] In addition, the inhibitory activity of the compound against recombinant human acid α-glucosidase (rhGAA) was evaluated by the group of Professor Marco Moracci of the Department of Biology of the University of Naples Federico II (IT) using the method described in the publication of Porto et al., 2012, Molecular Therapy 20:2201-2211. The rhGAA enzyme sold under the name of ANTIGATOR comes from the perfusion fluid remainder of the recombinant enzyme used for the treatment of patients with Pompe disease by enzyme therapy at the Department of Translational Medical Sciences of the University of Naples Federico II (IT).

[0407] The compound was dissolved in 100 mM sodium acetate buffer (pH 4.0) at different concentrations, as was the 4-nitrophenyl-α-D-pyranoglucopyranoside substrate (20 mM). After equilibration at 37°C for 2 minutes, a rhGAA enzyme solution (total volume: 200 μL) in the same buffer was added. After reacting at 37°C for 2 minutes, a 1 M sodium carbonate solution (800 μL, pH 11.0) was added and the mixture was cooled in ice. The absorbance of the solution was measured at 420 nm at ambient temperature. The spontaneous hydrolysis of the substrate was subtracted by measuring the absorbance of the control (blank) without enzyme. The results obtained are the average of at least two identical experiments. Data were processed and analyzed using Prism 5.0 software (GraphPad).

[0408] B.3 / Determination of the thermal stability of rhGAA

[0409] The stability of rhGAA in the presence of compounds was determined according to the method described in the publication of Niesen et al., 2007, Nat. Protoc. 2: 2212-2221. The rhGAA enzyme (2.5 μg, 0.1 mg / mL) was incubated in the presence of each compound (concentration [I] = 100 μM), SYPRO Orange dye (Life Technologies), and sodium phosphate buffer (25 mM) and NaCl (150 mM) (pH 7.4) or sodium acetate buffer (25 mmol) and NaCl (150 mM) (pH 4.0) were incubated in the presence and absence of the enzyme. The thermostability of the enzyme under these different conditions was evaluated by DSF (differential scanning fluorimetry) by changing the temperature at a rate of 1 ° C / min in the interval from 25 to 95 ° C and measuring the SYPRO The relative fluorescence is calculated by comparing each fluorescence value measured with the SYPRO The maximum fluorescence value of the orange dye (for each scan) was determined by comparison. The results are the average of three identical experiments (triplicate).

[0410] B.4 / Yes Evaluation of inhibition of other enzymes from other sources

[0411] The selectivity of the compounds was evaluated in the laboratory of Professor Herman S. Overkeleft and Johanes M. FG Aerts at the Leiden Institute of Chemistry, Leiden University (NL). The enzymes used to determine the selectivity of the compounds relative to the inhibition of various human enzymes are α-glucosidase II (GANAB) of the endoplasmic reticulum, recombinant human lysosomal β-glucocerebrosidase (GBA1), human non-lysosomal β-glucosylceramidase (GBA2) and β-glucosylceramide synthase (GCS). The inhibitory activity of the compounds against these various enzymes was determined as described in the publication of Artola et al., 2017, ACS Cent. Sci. 3: 784-793. Cerezyme was used to determine the selectivity of the compounds relative to the inhibition of various human enzymes. The GBA1 enzyme is marketed under the name Myozyme The rhGAA enzyme sold under the name of . The human GANAB enzyme used in this study is an enzyme of fibroblasts from patients with Pompe disease diagnosed as lacking active GAA and voluntary donors. These fibroblasts were cultured on HAMF12-DMEM medium (Sigma) supplemented with 10% (v / v) FCS (fetal bovine serum). The GBA2 enzyme was overexpressed in HEK298T cells, which were cultured at 37°C in glucose-rich DMEM medium (Gibco) (which was supplemented with 10% NBS (newborn calf serum) and 100 units / mL penicillin / streptomycin (Gibco) and 5% CO2). The activity of the compound on human β-glucosylceramide synthase (GCS) was evaluated in situ for RAW 264.7 cells cultured on RPMI medium (Gibco) supplemented with 10% FCS, 1mM glutamax, 100 units / mL penicillin / streptomycin (Gibco) and 5% CO2 at 37°C.

[0412] IC of GANAB, GBA2 and GCS enzymes 50 The values ​​were determined from cell lysates prepared in a buffer (20 mM hepes, 2 mM DTT, 0.25 M sucrose, 1 mM MgCl2, 2.5 U / mL benzonase) at pH 7.0 and placed on ice for 30 min. The lysates were lysed using a SilentCrusher (Heidolph ) The cell lysates were homogenized and then ultracentrifuged at 32,000 rpm for 30 minutes at 4°C. The Bradford BioRad Quick Start Total protein concentration was determined using a PCR agarose gel electrophoresis kit (Pierce) and BSA (Sigma). The lysate was then aliquoted and stored at -80°C until use.

[0413] IC of GANAB enzyme 50 The values ​​were determined as follows: cell lysate of fibroblasts from a patient with Pompe disease using as buffer Mcllvaine 150 mM (pH 7.0), 0.1% bovine serum albumin (BSA) (p / v), a substrate concentration of 2.4 mM (4-methyl-umbelliferyl-α-D-glucopyranoside), and an incubation time of 2 hours.

[0414] IC of GBA1 enzyme 50The values ​​were determined as follows: using Mcllvaine 150 mM (pH 5.2) as buffer, 0.2% taurocholate (p / v), 0.1% Triton X-100 (v / v), 0.1% bovine serum albumin (BSA) (p / v), an enzyme concentration of 0.7 nM, a substrate concentration of 3.0 mM (4-methyl-umbelliferyl-β-D-pyranoglucopyranoside), and an incubation time of 30 minutes.

[0415] After preincubation of homogenates of HEK298T cells overexpressing GBA2 with the GBA1 inhibitor cyclohexene tetraol β-epoxide (Sigma) at a concentration of 1 mM for 30 min, the residual activity of GBA2 was determined in the presence of this compound. 50 The values ​​were determined for cell lysates using Mcllvaine 150 mM (pH 5.8), 0.1% bovine serum albumin (BSA) (p / v) as buffer, 3.0 mM concentration of substrate (4-methyl-umbelliferyl-β-D-glucopyranoside), and an incubation time of 1 hour.

[0416] After preincubation of RAW264.7 cell homogenates with the GBA1 inhibitor cyclohexene tetraol β-epoxide (Sigma) at a concentration of 300 μM for 1 h, the residual activity of GCS was determined in the presence of this compound. IC of GCS enzyme 50 Values ​​are obtained using 1 μM NBD-ceramide (N-[12-[(7-nitro-2-1,3-benzo The results were determined in situ in cell culture medium at pH 7.0 using oxadiazole-4-yl)amino]dodecanoyl]-D-erythro-sphingosine) as substrate, as described in the above-mentioned publication by Lahav et al.

[0417] The results obtained from all these tests are listed in the following Tables 1 and 2. In these tables, by way of comparison, the values ​​obtained for compounds of the prior art DNJ and NB-DNJ described in the literature are also indicated. In these tables: a Instructions Porto et al., 2012, Mol Ther. 20:2201-2211; b Instructions Bruckmann et al., 2012, ChemMedChem 7:1943-1953; c Indications Flanagan et al., 2009, Human Mut. 30:1683-1692; d Indications D'Alonzo et al., 2017, J. Med. Chem. 60:9462-9469; *Indicates where [compound] = K i ΔTm measured at 10 times the value; e Indications Asano et al., 1995, J. Med. Chem. 38: 2349-56; f Instructions Wennekes et al., 2010, J. Med. Chem. 53:689-698.

[0418] Table 1

[0419]

[0420]

[0421] Table 2

[0422]

[0423] All these results show the selectivity of the compounds used according to the invention for human acid alpha-glucosidase compared to other human enzymes tested. This selectivity is much greater than the selectivity of the molecules proposed by the prior art DNJ and NB-DNJ. Compared to DNJ and NB-DNJ, the compounds used according to the invention also have the important role of stabilizing rhGAA.

[0424] Furthermore, compounds (IIb7), (IIb3), (IIc1), (IIr) and (IIc) as well as compound (IIx1) conforming to the general formula (I"a) have properties superior to those of other compounds according to the present invention.

Claims

1. Use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Pompe disease: in -R 1 represents a hydrogen atom, And R 2 Representative - (CH 2 ) 2 -R 8 Group, where R 8 represent: - cyclohexyl or adamantyl; --(CH 2 ) b -Ar 2 Group, where Ar 2 represents a phenyl group, and b is an integer from 0 to 6; --(CH 2 ) c -Si(R 9 ) 3 Group, where R 9 represents a C1-C4 alkyl group, and c is an integer from 0 to 6.

2. The use according to claim 1, wherein the compound of general formula (I) has general formula (I'a): in: R 1 represents a hydrogen atom, R 8 represents: benzyl or phenyl group; or -Si(R 12 ) 3 Group, where R 12 represents a C1 alkyl group.

3. The use according to claim 1 or 2, which is used to stabilize human acid α-glucosidase.

4. The use according to claim 1 or 2, wherein the compound is contained in a composition having a form suitable for oral administration.

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