Novel pharmacological chaperone compounds of human acidic α-glucosidase and their therapeutic uses

Abstract

The present invention relates to certain compounds of the iminosugar class that contain a piperidine ring, a D-gluco configuration, and a quaternary center 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 over other glycosidases. They are particularly advantageous for use as chaperone molecules for this enzyme in the treatment of Pompe disease.

Description

Technical Field

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

[0002] More specifically, the present invention relates to compounds belonging to a class of iminosugars that are capable of selectively interacting with human α-glucosidase and of stabilizing human acidic α-glucosidase, in particular endogenous (GAA) or recombinant (rhGAA), in a form that is advantageous for transport to lysosomes; and to pharmaceutical compositions containing such compounds. The present invention also relates to compounds belonging to a class of iminosugars that are capable of selectively interacting with human acidic α-glucosidase. Furthermore, the present invention relates to methods for preparing such compounds.

Background Art

[0003] Pompe disease, also known as glycogenosis type II, is a rare genetic disorder characterized by a deficiency in the activity of the human acidic α-glucosidase (GAA) lysosomal enzyme due to one or more mutations in the GAA gene, resulting in the accumulation of glycogen, which this enzyme hydrolyzes for biodegradation, in lysosomes, thereby causing cellular dysfunction in muscles and the heart. Symptoms vary widely and the progression can be rapid or slow depending on whether onset occurs at birth or in adulthood. Muscles throughout the body, particularly the respiratory and cardiac muscles, are affected. As a result, the lifespan of patients is shortened and, in particular, in infants, death can occur within the first year of life.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non - Patent Document 16

Non - Patent Document 17

Non - Patent Document 18

Non - Patent Document 19

Non - Patent Document 20

Non - Patent Document 21

Non - Patent Document 22

Summary of the Invention

Problems to be Solved by the Invention

[0005] Currently, there is only one treatment for Pompe disease that has obtained marketing approval. This treatment, known as enzyme replacement therapy (ERT), involves intravenous administration of Myozyme® containing recombinant human acid α-glucosidase (rhGAA) as the active ingredient, which can stabilize the symptoms of the disease. However, this treatment has many drawbacks. It is very expensive, requires intravenous infusion every two weeks in a hospital environment, which places a heavy burden on patients. Also, in many cases, its effectiveness is limited, and it may cause immune reactions that affect effectiveness and the tolerance of treated patients. Furthermore, the recombinant enzyme is relatively unstable in the blood, and the required dosage is much higher than that administered for the treatment of other lysosomal diseases.

[0006] Therefore, there is still a need for a satisfactory treatment for Pompe disease.

Means for Solving the Problems

[0007] The present invention aims at such a treatment. More specifically, the present invention aims to provide a compound that brings about an effective treatment for Pompe disease, and further, this treatment is easy to administer and less expensive than the treatment by enzyme replacement therapy based on the prior art.

[0008] Another object of the present invention is to significantly improve the effectiveness of the latter by administering these compounds simultaneously with the enzyme replacement therapy of the prior art.

[0009] To achieve these objectives, the inventors were interested in using so-called pharmacological chaperone molecules, a treatment approach that is currently considered one of the most promising for the treatment of lysosomal diseases. Chaperone molecules are small molecules that induce the correct folding of mutant enzymes and enable them to be transported to lysosomes without being degraded in the endoplasmic reticulum (Non-Patent Document 1). This treatment approach has been successful in another lysosomal disease, Fabry disease, for which the iminosugar miglustat (Galafold®) is currently prescribed as a pharmacological chaperone for acid alpha-galactosidase (Non-Patent Document 2).

[0010] Therefore, the inventors searched for compounds that could stabilize human acid alpha-glucosidase in its active folded form for use in the treatment of Pompe disease and further enhance the efficacy of recombinant human acid alpha-glucosidase used in enzyme replacement therapy.

[0011] Among existing compounds, deoxynojirimycin (DNJ), an iminosugar represented by the following formula, has been presented in the prior art as a promising chaperone molecule for human acid alpha-glucosidase (Non-Patent Document 3).

[0012]

Chemical formula

[0013] A derivative of DNJ called NB-DNJ, represented by the following formula, has also been presented in the prior art for the same use (Non-Patent Document 4).

[0014]

Chemical formula

[0015] However, these compounds have low selectivity for this enzyme and inhibit other human enzymes, namely α-glycosidase and β-glycosidase, and glycosyltransferase, and thus when administered to a subject, cause many undesirable side effects.

[0016] Non-Patent Document 5 describes specific polyhydroxylated derivatives of indolizidine that have a high ability to inhibit α-glucosidases from S. cerevisiae and rice.

[0017] Non-Patent Document 6 describes specific aziridinyl-imino sugars.

[0018] Non-Patent Document 7 describes specific polyhydroxylated quinolizidines and their ability to inhibit α-glucosidases from yeast and rice.

[0019] Currently, the inventors have found that specific compounds belonging to the imino sugar class and conforming to a specific structure derived from DNJ bind to and stabilize human acidic α-glucosidase (GAA), and further do so with high selectivity, that is, with at least little significant interaction with other human glycosidases, specifically human β-glucocerebrosidase (GBA1 and GBA2), human β-glucosylceramide transferase (GCS), or human endoplasmic reticulum α-glucosidase II (GANAB). In addition, the effect of these compounds in stabilizing GAA is particularly excellent. Therefore, when administered to patients with Pompe disease, these compounds can correctly fold and stabilize the patient's endogenous acid α-glucosidase, improve its transport to lysosomes, enhance the glycogen hydrolysis activity, thereby effectively treating this disease while reducing undesirable side effects during treatment. These compounds can also stabilize recombinant enzyme (rhGAA) when used in combination with enzyme replacement therapy (ERT), thereby enhancing their effectiveness.

[0020] In molecules having similar but different structures such as DNJ and NB-DNJ, such particularly advantageous results cannot be obtained at therapeutic levels.

[0021] Thus, according to a first aspect, the present invention relates to a compound of the following general formula (I) for use as a medicament, in particular as a pharmacological chaperone, in particular for treating Pompe disease, in particular for stabilizing human acidic α-glucosidase, or to one of pharmaceutically acceptable salts thereof,

[0022]

Chemical formula

[0023] wherein, - R 1 represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and R 2 represents a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and when R 1 represents a hydrogen atom, the hydrocarbon radical contains at least 2 carbon atoms, - or R 1 and R 2Together with the atoms of the piperidine ring to which each is attached, form a 3- to 6-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, or a carbon radical, preferably containing 1 to 18, preferentially 1 to 12, and particularly 1 to 6 carbon atoms, 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 optionally fused polycyclic ring. Such a configuration includes cases where the carbon radical branches to a 3- to 6-membered heterocyclic ring by a carbon atom, as well as cases where the carbon radical branches to it by a heteroatom it contains.

[0024] As used herein, the term "heteroatom" conventionally refers to any atom belonging to an element other than carbon and hydrogen, such as nitrogen, oxygen, sulfur, phosphorus, silicon, halogen, etc.

[0025] Preferentially, when R 1 represents a hydrogen atom, R 2 does not represent a methyl radical or a benzyl group.

[0026] As used herein, "pharmaceutically acceptable salts" conventionally mean any salts of the compounds of general formula (I) that, when administered to a subject, particularly a mammal, do not cause any undesirable reactions such as harmful or allergic reactions, with counterions that are substances that do not cause such reactions.

[0027] Any of the conventional pharmaceutically acceptable salts of the compounds of general formula (I) can be used in accordance with the present invention. Examples include chlorides, bromides, formates, acetates, etc.

[0028] As used herein, the term "treatment" means obtaining a desired pharmacological or physiological effect. The term "treatment" as used herein includes the prevention or partial prevention of one or more disease symptoms, and / or the partial or complete cure of a disease, and / or the complete or partial disappearance of one or more of those symptoms.

[0029] Human acidic α-glucosidase is a 952-amino acid protein with GenBank Accession number ABI53718.1.

[0030] The compounds having the general formula (I) used according to the present invention are these ligands. Furthermore, they have particularly strong selectivity for this enzyme. In particular, this selectivity is much stronger than that of other iminosugars such as DNJ or NB-DNJ that interact with glycosidase.

[0031] The characteristics of the compounds used according to the present invention, particularly the characteristics related to their three-dimensional structure that enable such advantageous properties, will not be prematurely judged here. However, it can be assumed that the presence of a quaternary center at the α-position of the nitrogen of the piperidine nucleus, the D-glucose configuration of the compound, as well as the quaternary carbon at the α-position of the nitrogen of the piperidine nucleus and the specific substituents present on this nitrogen are involved. At least in part, due to these properties, the compounds used according to the present invention will, by non-covalently binding to the enzyme, stabilize its folding and thereby give it the role of a chaperone that enables the transport and restoration of the activity of the defective enzyme in lysosomes.

[0032] Thus, the compounds used according to the present invention stabilize human acidic α-glucosidase at low concentrations and have the essential properties of a pharmacological chaperone suitable for the treatment of Pompe disease. In particular, at a concentration of 100 μM, in vitro, the thermal denaturation temperature of human acidic α-glucosidase is increased from 8 °C to 12 °C at pH 4.0 and from 10 °C to 13 °C at pH 7.4. The chaperone effect of the compounds used according to the present invention on human acidic α-glucosidase has been confirmed by experiments in human cells in culture, more specifically, fibroblasts from patients with the disease, and in vivo in mice.

[0033] Thus, the compounds used according to the present invention selectively bind to and stabilize human acidic α-glucosidase, thereby restoring the activity of the patient's deficient enzyme and / or improving the bioavailability of the rhGAA recombinant enzyme administered when used in combination with the compounds used according to the present invention in rhGAA enzyme replacement therapy, and are thus fully suitable and advantageous for use as pharmacological chaperones for the treatment of Pompe disease.

[0034] Therefore, the compounds of general formula (I) stabilize human acidic α-glucosidase in its active folded form and can further be used to enhance the effectiveness of recombinant human acidic α-glucosidase used in enzyme replacement therapy in which the compounds of general formula (I) and recombinant human acidic α-glucosidase are co-administered to a patient.

[0035] The compounds used according to the present invention can advantageously be easily administered to a patient, particularly orally, and can be prepared inexpensively.

[0036] This compound has a low toxicity risk and good bioavailability.

[0037] Furthermore, when used in combination with enzyme replacement therapy, the compounds used according to the invention advantageously improve the bioavailability of the administered recombinant enzyme, thereby making it possible to obtain the same or even better effectiveness in treatment while reducing its dosage.

[0038] The compounds of general formula (I) used according to the invention can be administered to any subject in need thereof, i.e., having or at risk of having a disease. This subject can in particular be a mammal, especially a human.

[0039] The compounds used according to the invention are preferably administered to the subject in a therapeutically effective amount.

[0040] "Therapeutically effective amount" means an amount of the compound sufficient to effect such treatment of a disease when administered to a subject for treating the disease.

[0041] The therapeutically effective amount of the compounds used according to the invention varies depending on several factors such as the disease and its severity, the age, weight of the subject, the particular compound used, the route of administration, the dosage form, etc. The therapeutically effective amount of the compounds used according to the invention is determined by the physician on a case-by-case basis.

[0042] The compounds used according to the invention can be administered to the subject to be treated by any conventional method, in particular parenterally, for example subcutaneously, subdurally, intravenously, intramuscularly, intrathecally, intraperitoneally, intracerebrally, intraarterially, intralesionally, intranasally, rectally, into the lungs by spraying or inhalation, or locally. Preferentially, it is administered orally.

[0043] Determining the dosage of the compounds used according to the invention is within the competence of the physician. The compound can be administered, for example, once or twice a day, over a long period, at regular intervals or in a targeted manner, to subjects in need thereof, in combination therapy with enzyme replacement therapy.

[0044] As disclosed above, the compounds used according to the present invention can advantageously be administered to a subject in combination with an enzyme used in enzyme replacement therapy, in particular in combination with a recombinant human acid α-glucosidase such as a recombinant enzyme sold under the name Myozyme®. Subsequently, the compound advantageously improves its effectiveness.

[0045] In general formula (I), which is a specific embodiment of the present invention, R 1 and R 2 are independent of each other in the sense that they are not bonded to each other, in particular they do not together form a ring condensed with the piperidine nucleus of the compound.

[0046] In particular, in general formula (I), - R 1 here represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally condensed polycyclic ring, and R 2 may represent a -CH(R 3 )-R 4 group, in which formula R 3 and R 4 may be the same or different and each represents a hydrogen atom or a linear, branched and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally condensed polycyclic ring, and when R 1 represents a hydrogen atom, R 3 and R 4 do not simultaneously represent hydrogen atoms.

[0047] In a specific embodiment of the present invention, R 3 and R 4does not represent a hydrogen atom simultaneously.

[0048] In a particular embodiment of the present invention, R 1 and R 2 do not represent a propyl radical and an ethyl radical simultaneously, respectively.

[0049] Preferably, when R 3 and R 4 each represent a hydrogen atom, R 1 and R 3 do not represent a phenyl radical. 4 That is, when R

[0050] In a particular embodiment of the present invention, R 2 represents a -CH(R 3 )-R 4 group, where R 3 is defined as above, and R 4 represents a hydrocarbon radical, preferably containing 1 to 18, preferably 1 to 12, and particularly 1 to 6 carbon atoms, linear, branched, and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally containing a monocyclic or optionally fused polycyclic ring, and each containing one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one heteroatom selected from a carbonyl group, a sulfoxide group, a sulfonyl group, and a silane group.

[0051] Otherwise, R 1 represents a hydrogen atom or a hydrocarbon radical, 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 optionally fused polycyclic ring, and R 2 may represent a -(CHR 7 )-SO2-Ar 1 group, where Ar 1represents an aryl radical or a heteroaryl radical, which is optionally substituted, particularly contains 5 to 18 atoms, and R 7 represents a hydrogen atom or a hydrocarbon radical, preferably containing 1 to 18, preferably 1 to 12, and particularly 1 to 6 carbon atoms, 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 optionally fused polycyclic ring. In a particular embodiment of the present invention, Ar 1 represents an aromatic heterocyclic ring, particularly a pyridine ring, which is optionally substituted, and / or R 7 represents a hydrogen atom.

[0052] In a particular embodiment of the present invention, R 1 represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical, 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 optionally fused polycyclic ring, R 2 may represent a triazole group, which is optionally substituted.

[0053] In another variant of the present invention, R 1 represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical, 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 optionally fused polycyclic ring, R 2 represents a -(CH2)2-R 8 group, wherein R 8 represents the following. - a hydrogen atom; - a C1-C12 alkyl group or a cycloalkyl group, optionally containing a monocyclic or polycyclic fused ring, such as an adamantyl group; - -(CH2) a -OH group, wherein a is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; - -(CH2) b -Ar 2 group, wherein Ar 2 represents an aryl radical or a heteroaryl radical, 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 monocyclic or optionally fused plurality of rings, and b is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; - -(CH2) c -Si(R 9 )3 group, wherein R 9 represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical, and c is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; - Or -(CH2) d -Z-R 10 group, wherein Z is a heteroatom selected from oxygen, nitrogen, and sulfur, and R 10 represents a hydrogen atom, or a C1-C18, preferably C1-C12, and particularly C1-C6 alkyl radical, cycloalkyl radical, alkylaryl radical, aryl radical, or acyl radical, and the said radical is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, particularly a sulfonyl radical, and d is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6.

[0054] In a particularly preferred embodiment of the present invention, R 1represents a hydrogen atom, or a linear, branched, and / or cyclic alkyl group having 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms, such as 1 to 3 carbon atoms, and more particularly 1 to 2 carbon atoms, which alkyl group is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0055] The compounds used according to the present invention may in particular conform to general formula (I’a),

[0056] [Chemical formula]

[0057] wherein, R 1 represents a hydrogen atom, or a linear, branched, and / or cyclic alkyl group having 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms, which is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, and R 8 represents the following. - a hydrogen atom; - a methyl radical, an ethyl radical, a propyl radical, a butyl radical, a pentyl radical, a hexyl radical, a cycloalkyl radical, an adamantyl radical, an alkylcycloalkyl radical, an alkylaryl radical, or an aryl radical, particularly a phenyl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom; - a hydroxyl group; - a -Si(R 12 )3 group, wherein R 12 represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical; - -(CH2) f -Y-R 13a 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-C18, preferably C1-C12, and particularly C1-C6 alkyl radical, or a C1-C18, preferably C1-C12, and particularly C1-C6 aryl radical or heteroaryl radical; - -(CH2) g -CO-R 13 a group, wherein g is an integer from 0 to 6, and R 13 is as defined above; - 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 is as defined above, R 1 when represents a propyl radical, R 8 does not represent a hydrogen atom.

[0058] In a particular embodiment of the present invention, the compound used conforms to the general formula (I’’a),

[0059]

Chemical formula

[0060] wherein, R 1 represents a hydrogen atom, or a linear, branched, and / or cyclic alkyl group of C1-C18, optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, R 18represents a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, contains 4 to 18 carbon atoms, preferably 4 to 12 carbon atoms, and particularly 5 to 12 carbon atoms, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or a plurality of optionally fused rings.

[0061] R 18 may particularly represent a butyl group, a pentyl group, a hexyl group, a cyclohexyl group, a phenyl group, a benzyl group, or an adamantyl group.

[0062] Preferentially, in formula (I''a), R 1 represents a hydrogen atom.

[0063] Specific compounds that can be used according to the present invention conform to the following formulas (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).

[0064]

Chemical formula

[0065] In another embodiment of the present invention, the compound to be used is such that in general formula (I), R 1 and R2 together with the atoms of the piperidine ring to which each is attached, form a 6-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, a carbonyl group, or a carbon radical, preferably containing from 1 to 18, preferably from 1 to 12, and particularly from 1 to 6 carbon atoms, 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 optionally fused polycyclic ring.

[0066] Certain compounds that can be used according to the invention conform to formula (IIf).

[0067]

Chemical formula

[0068] In another embodiment of the invention, the compound to be used, in general formula (I), R 1 and R 2 together with the atoms of the piperidine ring to which each is attached, form a 5-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, a carbonyl group, or a carbon radical, preferably containing from 1 to 18, preferably from 1 to 12, and particularly from 1 to 6 carbon atoms, 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 optionally fused polycyclic ring.

[0069] Certain compounds that can be used according to the invention conform to formula (IIg).

[0070] [Chemical formula]

[0071] In yet another embodiment of the present invention, the compound to be used, in general formula (I), R 1 and R 2 together with the atoms of the piperidine ring to which each is attached form a 4-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, or a carbon radical, preferably containing 1 to 18, preferentially 1 to 12, and particularly 1 to 6 carbon atoms, 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 optionally fused polycyclic ring.

[0072] This compound may in particular conform to general formula (I’b),

[0073] [Chemical formula]

[0074] wherein, R 14 represents a hydrogen atom, a carbonyl radical, or an alkyl radical, alkenyl radical, alkynyl radical, alkylaryl radical, or aryl radical of C1-C18, preferably C1-C12, and particularly C1-C16, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, and R 15represents a hydrogen atom, a hydroxyl radical, an amino radical, or an alkyl radical, alkenyl radical, or aryl radical of C1-C18, preferably C1-C12, and particularly C1-C6, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0075] Specific compounds that can be used according to the present invention are particularly compatible with formulas (IIh), (IIz1), (IIz2), (IIz3), (IIz4), and (IIz5).

[0076] [Chemical formula] JPEG0007698664000017.jpg113132

[0077] In yet another embodiment of the present invention, the compound to be used, in general formula (I), R 1 and R 2 together with the atoms of the piperidine ring to which each is attached form a 3-membered heterocyclic ring fused to the piperidine ring, optionally substituted with -X-R 5 groups, wherein -X represents a -C(=O)- or -CH(OR 6 )- radical, wherein R 6 represents a linear, branched, and / or cyclic hydrocarbon radical, 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 optionally fused polycyclic ring, and R 5 represents a hydrogen atom, an amino group, or a linear, branched, and / or cyclic hydrocarbon radical, 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 optionally fused polycyclic ring. - Or X represents a -CH(OH)- radical, and R 5 represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring. In the latter configuration, in particular, R 5 does not preferably represent an unsubstituted n-propyl radical, an unsubstituted c-hexyl radical, or an unsubstituted phenyl radical.

[0078] The compounds used according to the present invention may in particular conform to general formula (I’c),

[0079]

Chemical formula

[0080] wherein R 16 represents a hydrogen atom, or a C1-C18, preferably C1-C12, and preferably C1-C6 alkyl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0081] In particular, R 16 may represent a -CH2-OH group, a methyl radical, or an ethyl radical.

[0082] Specific compounds that can be used according to the present invention conform to formulas (IIj), (IIk), (IIm), and (IIn).

[0083]

Chemical formula

[0084] The present invention can also be represented with respect to a method for treating a subject having a disease, particularly Pompe disease, or a subject likely to be affected by the same, the method comprising administering to said subject in need thereof a therapeutically effective amount of a compound conforming to general formula (I) or one of these pharmaceutically acceptable salts. The method may relate to the therapeutic use of a compound of general formula (I) or one of these pharmaceutically acceptable salts as a medicament, and may conform to one or more of the above-described features.

[0085] The present invention also relates to the use of a compound of general formula (I) or one of these pharmaceutically acceptable salts, as defined above, for the manufacture of a medicament, particularly a medicament for treating Pompe disease.

[0086] According to another aspect, the present invention relates to a pharmaceutical composition containing, as an active ingredient, a compound conforming to general formula (I) or one of these pharmaceutically acceptable salts in a pharmaceutically acceptable excipient.

[0087] As used herein, "pharmaceutically acceptable excipient" means any excipient that is useful for preparing a pharmaceutical composition, is generally safe, non-toxic, and is not biologically or otherwise undesirable for the subject to be treated, particularly a mammal, especially a human.

[0088] The excipient of the pharmaceutical composition according to the present invention may be solid or semi-solid or liquid. It may also be a diluent, an adjuvant, or any other conventional excipient per se for forming a pharmaceutical composition.

[0089] The pharmaceutical composition according to the present invention may be in any galenic form, particularly a form suitable for parenteral, intranasal, rectal, pulmonary, or topical administration. Preferably, the pharmaceutical composition is in a form suitable for oral administration. Non-limiting examples of such galenic forms of the present invention include forms such as granules, powders, tablets, capsules, pills, syrups, solutions, or oral suspensions.

[0090] The pharmaceutical composition according to the present invention may comprise, for example, one or more excipients / additives that are conventional per se for forming a pharmaceutical composition, selected from any one of, for example, preservatives, sweeteners, flavors, fillers, disintegrants, wetting agents, emulsifiers, surfactants, dispersants, lubricants, stabilizers, buffers, antibacterial agents, antifungal agents, or mixtures thereof; and / or may contain any compound that enables rapid, sustained, or delayed, and / or targeted release of the active ingredient after administration thereof to a subject.

[0091] Furthermore, the pharmaceutical composition according to the present invention may contain one or more active ingredients other than one of the compounds of general formula (I) or pharmaceutically acceptable salts thereof, and these active ingredients may or may not act synergistically with the said compound.

[0092] The pharmaceutical composition according to the present invention is preferably formulated in unit dosage form.

[0093] The present invention also relates to the therapeutic use of the pharmaceutical composition according to the present invention as defined above for treating diseases, particularly Pompe disease. This use may conform to one or more of the characteristics defined above in relation to the therapeutic use of one of the compounds of general formula (I) or pharmaceutically acceptable salts thereof.

[0094] According to another aspect, the present invention relates to a compound conforming to the following general formula (I'), which general formula (I') defines a subgroup of one of the compounds of general formula (I) or pharmaceutically acceptable salts thereof described above,

[0095]

Chemical formula

[0096] wherein, - R 1represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and R 2 represents a -CH(R 3 )-R 4 group, wherein R 3 and R 4 may be the same or different and each represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring. When R 3 and R 4 each represent a hydrogen atom, R 1 and R 3 does not represent a hydrogen atom or a phenyl radical. 4 and R and R 1 and R 2 do not simultaneously represent a propyl radical and an ethyl radical respectively. - 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, and are optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, or a carbon radical, preferably containing 1 to 18, preferably 1 to 12, and particularly 1 to 6 carbon atoms, 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 optionally fused polycyclic ring. - or R 1 and R 2 together with the atoms of the piperidine ring to which each is attached form a 3-membered heterocyclic ring fused to the piperidine ring and optionally substituted with -X-R 5 group, wherein · X represents a -C(=O)- or -CH(OR 6 )- radical, wherein R 6 represents a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and R 5 represents a hydrogen atom, an amino group, or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring; · or X represents a -CH(OH)- radical, and R 5 represents a hydrogen atom or a hydrocarbon radical, for example containing 1 to 6 carbon atoms, linear, branched, and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and R 5 does not represent an n-propyl radical, a c-hexyl radical, or a phenyl radical. Here, the n-propyl radical, the c-hexyl radical, and the phenyl radical mean these radicals in their unsubstituted forms. Therefore, R 5 may represent a substituted n-propyl radical, a substituted c-hexyl radical, or a substituted phenyl radical.

[0097] In certain embodiments of the present invention, the compound has the following in formula (I’). R 1 represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, and R 2 represents a -CH(R 3 )-R 4 group, wherein R 3 is as defined above, and R 4 represents a hydrocarbon radical, preferably containing 1 to 18, preferentially 1 to 12, and particularly 1 to 6 carbon atoms, which is linear, branched, and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains a monocyclic or optionally fused polycyclic ring, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one heteroatom selected from a carbonyl group, a sulfoxide group, a sulfonyl group, and a silane group; when R 1 and R 3 each represent a hydrogen atom, R 4 does not represent a phenyl radical.

[0098] In particular, in formula (I’), when R 1 represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, then R 2 may represent a -(CHR 7 )-SO2-Ar 1 group, wherein Ar 1represents an aryl radical or a heteroaryl radical, which is optionally substituted, preferably contains 5 to 18 atoms, and R 7 represents a hydrogen atom or a hydrocarbon radical, preferably contains 1 to 18, preferably 1 to 12, and in particular 1 to 6 carbon atoms, is linear, branched, and / or cyclic, saturated or unsaturated, aromatic or non-aromatic, is optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring.

[0099] The compounds according to the invention may, for example, conform to general formula (I’d),

[0100]

Chemical formula

[0101] wherein R 1 , R 7 , and Ar 1 are as defined above.

[0102] Otherwise, in formula (I’), when R 1 represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical, saturated or unsaturated, aromatic or non-aromatic, is optionally substituted, optionally contains one or more heteroatoms and / or one or more groups containing at least one heteroatom, and optionally contains a monocyclic or optionally fused polycyclic ring, R 2 may represent a triazole group, which is optionally substituted.

[0103] The compounds according to the invention may in particular conform to formula (I’e),

[0104]

Chemical formula

[0105] wherein R 1 is as defined above, and R 19 represents a hydrogen atom, or a C1-C18 alkyl radical, alkylaryl radical, trialkylsilyl radical, or aryl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0106] In a variant of the invention, in general formula (I’), R 1 represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical, 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 a plurality of optionally fused rings, and R 2 represents a -(CH2)2-R 8 group, wherein R 8 represents the following. - a hydrogen atom; - a C1-C12 alkyl or cycloalkyl group, optionally substituted, optionally containing a monocyclic or a plurality of fused rings, such as an adamantyl radical; - -(CH2) a -OH group, wherein a is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; optionally, when R 1 represents a hydrogen atom, a may be different from 1; - -(CH2) b -Ar 2 group, wherein Ar 2 represents an aryl radical or a heteroaryl radical, 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 a plurality of optionally fused rings, and b is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; optionally, when R 1 represents a hydrogen atom, b may be different from 1, and Ar 2represents a phenyl radical; - -(CH2) c -Si(R 9 )3 group, wherein R 9 represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical, and c is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6; - or -(CH2) d -Z-R 10 group, wherein Z is a heteroatom selected from oxygen, nitrogen, and sulfur, and R 10 represents a C1-C18, preferably C1-C12, and particularly C1-C6 alkyl radical, cycloalkyl radical, alkylaryl radical, aryl radical, or acyl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, such as a sulfonyl group, and d is an integer from 0 to 18, preferably from 0 to 12, and particularly from 0 to 6.

[0107] In a particularly preferred embodiment of the present invention, R 1 represents a C1-C18, preferably C1-C6, linear, branched, and / or cyclic alkyl group, optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0108] The compounds according to the present invention may, for example, conform to general formula (I’a),

[0109]

Chemical formula

[0110] wherein, R 1represents a hydrogen atom, or a linear, branched, and / or cyclic alkyl group having from C1-C18, preferably C1-C12, particularly C1-C6, for example C1-C3, and more specifically C1-C2, which alkyl group is optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, R 8 represents the following: - a hydrogen atom; - a hydroxyl group; - a methyl radical, ethyl radical, propyl radical, butyl radical, pentyl radical, hexyl radical, cycloalkyl radical, adamantyl radical, alkylcycloalkyl radical, alkylaryl radical, or aryl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom; - -Si(R 12 )3 group, wherein R 12 represents a hydroxyl radical, C1-C4 alkyl radical, C1-C4 alkoxyl radical, or phenyl radical; - -(CH2) f -Y-R 13 group, wherein f is an integer from 0 to 6, Y is a heteroatom selected from oxygen, nitrogen, and sulfur, and R 13 represents an alkyl radical having from C1-C18, preferably C1-C12, and particularly C1-C6, or an aryl radical or heteroaryl radical, preferably having from C1-C18, preferably C1-C12, and particularly C1-C6; - -(CH2) g -CO-R 13 group, wherein g is an integer from 0 to 6, and R 13 is as defined above; - or -(CH2) h -SO e -R 13a base, where h is an integer from 0 to 6, and e is equal to 1 or 2, and R 13 is as defined above; R 1 when represents a propyl radical, R 8 does not represent a hydrogen atom.

[0111] The compounds according to the invention may conform to general formula (I''a),

[0112]

Chemical formula

[0113] wherein, R 1 represents a hydrogen atom, or a linear, branched and / or cyclic C1-C18 alkyl group, optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom, R 18 is a linear, branched and / or cyclic hydrocarbon radical, saturated or unsaturated, aromatic or non-aromatic, optionally substituted, containing 4 to 18 carbon atoms, preferably 4 to 12 carbon atoms, and preferably 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 monocyclic or optionally fused polycyclic ring.

[0114] R 18 in particular, may represent a butyl group, a pentyl group, a hexyl group, a cyclohexyl group, a phenyl group, a benzyl group, or an adamantyl group.

[0115] Compounds according to a particular invention are compounds of the above formulas (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).

[0116] In another embodiment of the invention, the compound may conform to general formula (I’b),

[0117]

Chemical formula

[0118] wherein R 14 represents a hydrogen atom, a carbonyl radical, or an alkyl radical, an alkenyl radical, an alkynyl radical, or an alkylaryl radical, such as benzyl, or an aryl radical of C1-C18, preferably C1-C12, and especially C1-C6, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom; an example of such a radical conforms to the formula -CH2-TMS, wherein TMS represents a trimethylsilyl residue; and R 15 represents a hydrogen atom, a hydroxyl radical, an amino radical, or an alkyl radical, an alkenyl radical, or an aryl radical of C1-C18, preferably C1-C12, and especially C1-C6, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0119] Particular compounds conforming to this definition are compounds of the above formulas (IIh), (IIz1), (IIz2), (IIz3), (IIz4), and (IIz5).

[0120] In another variant of the invention, the compound conforms to general formula (I’c),

[0121]

Chemical formula

[0122] wherein R 16 represents a hydrogen atom, or a C1-C18, preferably C1-C12, and preferentially C1-C6 alkyl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom.

[0123] In particular, R 16 may represent a -CH2-OH group, a methyl radical, or an ethyl radical.

[0124] Specific compounds conforming to this definition are the compounds of formulas (IIj) and (IIk) described above.

[0125] All compounds according to the invention conforming to general formula (I’) can advantageously be used as medicaments according to the invention, in particular for the treatment of Pompe disease.

[0126] The compounds of general formula (I) used according to the invention, in particular the compounds conforming to general formula (I’) described above, can be synthesized by any conventional method per se known to those skilled in the art. In particular, for each specific compound, it is within the ability of those skilled in the art to determine which starting materials to use and which synthetic methods to apply.

[0127] Furthermore, the invention relates to a novel synthetic method developed by the inventors for preparing compounds of general formula (I), and in particular general formula (I’).

[0128] By means of part of the preparation method according to the invention, compounds of general formula (I’) can be obtained, wherein R 1 and R 2In particular, they conform to the above general formula (I’a) or general formula (I’’a) and are independent of each other.

[0129] An example of such a specific preparation method according to the present invention has the following consecutive steps. a / A reaction of a compound of general formula (III) or (IV) with a compound of general formula (V),

[0130]

Chemical formula

[0131] wherein Bn represents a benzyl radical, and R 8 is defined above in relation to the compound of general formula (I’) according to the present invention, but when an organometallic compound is present, R 8 represents neither a hydrogen atom, nor a hydroxyl group —OH, nor an amino group —NH2, b / Optionally, reduction of the hydroxylamine functional group to an amine, c / Optionally, alkylation of the nitrogen atom of the piperidine ring, d / And, in particular, cleavage of the benzyl radical to form a hydroxyl group by hydrogenolysis of the product obtained at the end of step a / , and, if applicable, at the end of step b / or step c / , and, if applicable, conversion of the hydroxylamine functional group to an amine, and hydrogenation of the triple bond.

[0132] The organometallic compound used in step a / can be any one of compounds such as organozinc, organolithium, organomagnesium, organoalane, organocopper, or mixtures thereof. Preferentially, in step a / , the reaction is carried out in the presence of a dialkylzinc, in particular diethylzinc Et2Zn or butyllithium.

[0133] More generally, the organometallic compound may conform to general formula (VII), R 17 -M (VII) wherein, R 17represents a C1-C18 alkyl radical, alkenyl radical, alkynyl radical, alkylaryl radical, or aryl radical, said radical being 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, for example, lithium, zinc, copper, aluminum, or magnesium, or M represents Mg-X 2 represents, in the formula, X 2 represents a halogen atom.

[0134] Step b / of reducing the hydroxylamine functional group to an amine, and step c / of N-alkylation can be carried out according to any conventional method per se known to those skilled in the art.

[0135] Step d / of hydrocracking can be carried out by any conventional method per se known to those skilled in the art, in particular by catalytic hydrogenation.

[0136] Quite surprisingly, advantageously, such a method makes it possible to prepare compounds of general formula (I’), in particular of general formula (I’a), or of general formula (I’’a) completely stereoselectively.

[0137] An example of such a method can be represented by synthetic scheme 1 shown in FIG. 1 for a specific example of a compound conforming to general formula (I’a).

[0138] Otherwise, compounds of general formula (I’a) or (I’’a) may be prepared, for example, by a method comprising the following successive steps. a / Cycloaddition reaction of a compound of general formula (III) with trimethylsilylacetylene, b / Reaction of the resulting cycloaddition adduct with a fluoride such as tetrabutylammonium fluoride according to a protocol similar to that described in Non-Patent Document 8, Reduction with a metal hydride, such as sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), or diisobutylaluminum hydride (DIBAL-H), or reduction with a borane, such as a dimethyl sulfide-borane complex (BH3·Me2S), a borane-tetrahydrofuran complex (BH3·THF), a borane-pyridine complex (BH3·pyridine), diborane B2H6, lithium aluminum hydride (LiAlH4), etc., is particularly preferred. d / Optionally, a step of O-alkylation, O-acylation, or O-sulfonylation, which can be carried out according to any method conventional per se for a person skilled in the art. e / Optionally, a step of N-alkylation, which can be carried out according to any method conventional per se for a person skilled in the art. f / And, in particular, hydrogenolysis of the product obtained at the end of step c / , and, where applicable, at the end of step d / or step e / , to effect cleavage of the benzyl radical to form a hydroxyl group.

[0139] This synthetic method is particularly advantageous in the following cases. - Step a / is easy to carry out and is advantageously completely regioselective and diastereoselective for the product of the D-gluco configuration; - The cycloaddition adduct formed in step a / is easily and effectively converted to a β-lactam, which itself is easily and effectively reduced to a piperidine alcohol (otherwise, the obtained β-lactam can be converted to a saturated four-membered ring by reduction with a silane or by reductive alkylation in the presence of a metal catalyst).

[0140] An example of such a method can be represented by synthetic scheme 2 shown in Figure 2 for a specific example of a compound conforming to general formula (I’a).

[0141] The compound of the above formula (I’d) is obtained from a compound of the above formula (III) or (IV) and a compound of general formula (VI):

[0142]

Chemical formula

[0143] 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 a low temperature, preferably -78 °C, with a compound of ; then, optionally, reducing the hydroxylamine functional group to an amine, and optionally, after the step of alkylating the nitrogen atom of the piperidine ring, hydrogenolyzing the resulting product. It can be prepared by a method comprising:

[0144] An example of such a method can be represented by synthetic scheme 3 shown in Figure 3 for a specific example of a compound conforming to general formula (I’d).

[0145] Otherwise, the compounds of general formula (I) and especially of general formula (I’) can be prepared from compounds of formula (III) or (IV) by a method comprising the following consecutive steps. - a / A reaction with a compound of general formula (VII), especially in the presence of a Lewis acid, R 17 -M (VII) wherein, R 17 represents a C1-C18 alkyl radical, alkenyl radical, alkynyl radical, alkylaryl radical, or aryl radical, said radicals being 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 wherein X 2 represents a halogen atom, - b / Then, optionally, reducing the hydroxylamine functional group to an amine in an acidic medium, according to any conventional method per se known to those skilled in the art, especially by treatment with zinc powder, - c / then, optionally, alkylation of the nitrogen atom of the piperidine ring by any method known per se to those skilled in the art; - d / then, optionally, a step of ring-closing metathesis of the olefin catalyzed by a ruthenium-based complex, preferably a second-generation Grubbs catalyst; - e / and finally, at the end of step a / , and if applicable, at the end of step b / , step c / , or step d / , the product obtained is subjected to hydrocracking in an acidic medium according to any method known per se to those skilled in the art, in particular in the presence of hydrogen and a catalytic amount of palladium on carbon.

[0146] The synthetic route used to obtain the compounds conforming to general formula (I) corresponds to general synthetic scheme 4 shown in Figure 4.

[0147] By other preparation methods according to the invention, compounds of general formula (I') can be obtained, in which R 1 and R 2 together with the atoms of the piperidine ring to which each is attached form a 4-membered heterocycle fused to the piperidine ring.

[0148] Examples of such methods include the following successive steps. - a / a cycloaddition reaction of a compound of general formula (III) with trimethylsilylacetylene, followed by reaction with a fluoride such as tetrabutylammonium fluoride according to a protocol similar to that described in Non-Patent Document 8, for example; then - b / reduction of the β-lactam carbonyl by a silane such as phenylsilane PhSiH3 in the presence of a rhodium-based catalyst such as [Rh(COD)2]BF4 and 1,3-bis(diphenylphosphino)propane according to a protocol similar to that described in Non-Patent Document 9; Either the reduction alkylation of β-lactam carbonyl by reaction with tetramethyldisiloxane at ambient temperature in the presence of a buscal catalyst according to a protocol similar to that described in Non-Patent Document 10 or b’ / , followed by the addition of the compound of formula (VII) as defined above at -78°C; and finally - c / In particular, the hydrogenolysis of the product obtained at the end of step b / or b’ / to cleave the benzyl radical and form a hydroxyl group.

[0149] The hydrogenolysis step c / can be carried out according to any conventional method per se for those skilled in the art, in particular by catalytic hydrogenation.

[0150] Steps b / and b’ / are particularly advantageous and novel in that they enable the reduction or reduction alkylation of β-lactam in which the nitrogen atom is contained in the piperidine ring to form a conidine-based heterocyclic ring.

[0151] An example of such a method can be represented by synthetic scheme 5 shown in FIG. 5 for a specific example of a compound conforming to general formula (I’b).

[0152] Another example of such a method comprises the following consecutive steps. a / The Kishner reaction between a compound of general formula (III) and a compound of general formula (VIII) as described in the considerations according to Non-Patent Document 11 or 12,

[0153]

Chemical formula

[0154] wherein R 15 represents a C1-C18 alkyl radical, alkenyl radical, or aryl radical, optionally interrupted and / or substituted by one or more heteroatoms and / or one or more groups containing at least one heteroatom in the presence of a Cu(I) salt and an amine; then Reductive alkylation of β-lactam carbonyl by reaction with tetramethyldisiloxane at ambient temperature in the presence of a Busacca catalyst according to a protocol similar to that described in Non-Patent Document 10, followed by addition of the compound of formula (VII) as defined above at -78°C; and finally - c / Hydrocracking of the product obtained at the end of step b / , in particular to cause cleavage of the benzyl radical to form a hydroxyl group.

[0155] The hydrocracking step c / can be carried out according to any conventional method per se known to those skilled in the art, in particular by catalytic hydrogenation.

[0156] Step b / is particularly advantageous and novel in that it enables the reductive alkylation of a β-lactam in which a nitrogen atom is included in the piperidine ring to form a conidine-based heterocyclic ring.

[0157] An example of such a method can be represented by synthetic scheme 6 shown in FIG. 6 for a specific example of a compound conforming to general formula (I’b).

[0158] By another preparation method according to the present invention, a compound of general formula (I’) can be obtained, wherein R 1 and R 2 together with the atoms of the piperidine ring to which each is attached form a 3-membered heterocyclic ring fused to the piperidine ring.

[0159] An example of such a method comprises the following consecutive steps. - a / A cycloaddition reaction between a compound of general formula (III) or a compound of general formula (III’) and the compound of general formula (V) described above, wherein

[0160]

Chemical formula

[0161] wherein Ac represents an acetyl radical, R 8is defined above in connection with the compounds of general formula (I’), but represents neither a hydrogen atom, nor a hydroxyl group —OH, nor an amino radical —NH2, - b / a Baldwin thermal rearrangement that enables the formation of acylaziridine, according to a protocol similar to that described in Non-Patent Document 6, this step being preferably carried out at 110° C. under irradiation with microwave radiation, - c / reduction of the acylaziridine carbonyl thus obtained by reaction with a metal hydride, preferably LiAlH4 or NaBH4, - d / and debenzylation by Birch reduction according to any method known per se to those skilled in the art, in particular in the presence of a metal dissolved in liquid ammonia at low temperature, preferably −78° C., the metal used being preferably lithium.

[0162] An example of such a method can be represented by Synthesis Scheme 7 shown in FIG. 7 for a specific example of a compound conforming to general formula (I’c).

[0163] An example of the method for preparing the compound of general formula (I’e) above can be represented by Synthesis Scheme 8 shown in FIG. 8, where R 20 is identical to R 19 but R 20 does not represent a hydrogen atom.

[0164] The features and advantages of the present invention will become clearer by referring to FIGS. 1 to 8 in the light of the following exemplary embodiments, which are by way of simple illustration and in no way limit the present invention.

Brief Description of the Drawings

[0165]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0166] A / Synthesis and Characterization of Compounds Used According to the Present Invention Except for the reactions under microwave irradiation, all reactions were carried out under an inert atmosphere using pre-dried glassware, placing the apparatus on a magnetic stirrer and stirring with a magnetic bar. The reactions under microwave irradiation were carried out in a sealed tube equipped with a magnetic bar installed in a microwave reactor while adjusting the temperature with an internal infrared probe. Toluene, ether, and dichloromethane used as reaction solvents were pre-filtered with an Inert PureSolv® purification system. Acetonitrile and dichloroethane were CaH 2It was distilled. THF was distilled with sodium in the presence of benzophenone. Commercially available reagents, methanol, and ethanol were used without purification. The reaction was monitored by thin-layer chromatography (TLC) using aluminum plates coated with silica (Merck, Kieselgel 60 F254), irradiated with ultraviolet light, and then with a 3% potassium permanganate solution in a 10% (w / v) potassium hydroxide solution. Purification by column chromatography was performed using Macherey-Nagel® Silica Gel 60 (70 - 230 mesh). The optical rotation was measured with a PerkinElmer 341 polarimeter. The infrared spectrum was obtained with a Nicolet Magna 550 spectrometer equipped with an ATR (attenuated total reflection) module, and the product was deposited here in the form of a pure solid or liquid. The data is in cm -1 is represented. 1 1H NMR and 13 13C NMR{DEPT-Q} were obtained with an Avance 500( 1 1H: 500 MHz, 13 13C: 125 MHz) or an Avance 400( 1 1H: 400 MHz, 13 13C: 100 MHz) spectrometer. 1 The chemical shifts of the 1H spectrum are reported relative to the chemical shifts of the residual solvents contained in CDCl3 (δ 7.26 ppm) or CD3OD (δ 3.31 ppm). 13 The chemical shifts of the 13C spectrum are reported relative to the solvent CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 ppm). 1 The 1H NMR spectra are reported with chemical shifts (ppm), multiplicity (br: broad; s: singlet; d: doublet; dd: double doublet; t: triplet; pst: pseudo triplet; m: multiplet), coupling constants (Hz), and integration. High-resolution mass spectra (HRMS) were recorded with a Thermo Scientific ESI / LTQ Orbitrap XL® or a Waters G2-S Q-TOF mass spectrometer.

[0167] A.1 / Synthetic Method 1 The synthetic method used to obtain the compounds conforming to the above general formula (I’a) corresponds to the general synthetic scheme shown in Figure 1.

[0168] 1) General protocol A - Alkynylation of the nitrone of formula (III) to obtain the propargyl hydroxyamine of formula A-1 A 1M solution of diethylzinc in hexane (1.5 equivalents) is added dropwise at 0 °C under an argon atmosphere to a solution of the alkyne of formula (V) in anhydrous toluene (4 equivalents). The resulting mixture is stirred at 0 °C for 30 minutes. Subsequently, a solution of the ketonitrone of formula (III) in anhydrous toluene (1 equivalent) is added dropwise at 0 °C, and then the reaction mixture is stirred until the reaction is complete (TLC is then performed). A saturated aqueous solution of NaHCO3 is added, and then the resulting mixture is 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 over MgSO4, and then evaporated under reduced pressure. The hydroxylamine of formula A-1 thus formed is purified by silica gel chromatography and then reduced and debenzylated according to the following general protocol B.

[0169] 2) General protocol A’ - Alkynylation of the nitrone of formula (III) to obtain the propargyl hydroxyamine of formula A-1 A 1.4M solution of n-butyllithium in hexane (2.5 equivalents) is added dropwise at -10 °C under an argon atmosphere to a solution of the alkyne of formula (V) in anhydrous THF (2.5 equivalents). The resulting mixture is stirred at -10 °C for 15 minutes and then cooled to -78 °C. Subsequently, a solution of the ketonitrone of formula (III) in anhydrous THF (1 equivalent) is added dropwise at -78 °C, and then the reaction mixture is stirred until the reaction is complete (TLC is then performed). A saturated aqueous solution of NH4Cl is added, the mixture is brought to ambient temperature, and then extracted three times with ethyl acetate. The organic phase is recovered, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The hydroxylamine of formula A-1 isolated thereby is purified by silica gel chromatography and then reduced and debenzylated according to the following general protocol B.

[0170] 3) General Protocol B 1.5 equivalents of hydrochloric acid HCl (2 M solution in anhydrous ether) and 0.2 equivalents of 10% Pd / C are added to an O-benzylated iminosugar solution (1 equivalent) in anhydrous ethanol. The resulting suspension is stirred at room temperature for 17 h under a hydrogen pressure (5 bar) and then filtered through Celite®. The Celite® is rinsed with methanol and the filtrate is concentrated under reduced pressure to give the iminosugar hydrochloride. This salt is purified on Dowex® 50W-X2 ion exchange resin pre-activated with HCl and eluted with aqueous NH4OH, and after evaporation of the solvent, the corresponding neutral compound of formula (I’a) is obtained.

[0171] Compound of formula (IIc) The compound of formula (IIc) above ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-phenethylpiperidine-3,4,5-triol: 36.7 mg; 73% in two steps) was prepared from the nitrone of formula (III) (110.0 mg, 0.205 mmol) and phenylacetylene (Va: R 8 = Ph, 0.034 mL; 0.307 mmol) according to General Procedures A and B.

[0172] A yellow solid having the following characteristics is obtained. [α] 20 D +4.7 (c 0.98, CH3OH); IR ν 3291, 2918, 2864, 1632, 1494, 1455, 1363, 1270, 1198, 1094, 1076, 1040, 1004 cm -1 ; 1 H NMR (500 MHz, CD3OD) δ 7.31 - 7.08 (m, 5H), 3.73 (d, J = 10.4 Hz, 1H), 3.55 (d, J = 10.5 Hz, 1H), 3.55 - 3.43 (m, 2H), 3.45 - 3.34 (m, 1H), 3.00 - 2.90 (m, 1H), 2.68 - 2.51 (m, 3H), 1.91 - 1.72 (m, 2H) ppm; 13 C NMR (125 MHz, CD3OD) δ 144.4(Ar Cq), 129.4( Ar CH), 129.3( Ar CH), 126.7( Ar CH), 76.5(CH), 75.2(CH), 73.8(CH), 65.6(CH2), 60.5(Cq), 45.9(CH2), 30.7(CH2), 29.9(CH2) ppm; HRMS(ESI + ) calcd for C 14 H 22 NO4 [M + H] + : m / z = 268.15433; Found m / z = 268.15372。

[0173] Compound (IIx1) 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% in two steps) was prepared from the nitrone of formula (III) (102.1 mg, 0.189 mmol) and trimethylsilylacetylene (Vb: R 8 = TMS, 0.105 mL; 0.759 mmol) according to General Procedures A and B.

[0174] A white foam having the following characteristics was obtained. [α] 20 D +4.51 (c 0.71, MeOH); 1 H NMR (400 MHz, CD3OD) δ 3.57 (d, J = 10.9 Hz, 1H), 3.52 (d, J = 9.3 Hz, 1H), 3.44 (t, J = 4.0 Hz, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.39 - 3.33 (m, 1H), 2.85 (dd, J = 12.8, 5.5 Hz, 1H), 2.42 (dd, J = 12.8, 10.8 Hz, 1H), 1.62 - 1.51 (m, 2H), 0.56 - 0.44 (m, 1H), 0.39 - 0.29 (m, 1H), 0.02 (s, 9H) ppm; 1313C NMR (100 MHz, CD3OD) δ 76.6 (CH), 75.5 (CH), 73.8 (CH), 65.6 (CH2), 60.5 (Cq), 45.8 (CH2), 21.0 (CH2), 8.60 (CH2), -1.86 (CH3) ppm; HRMS (ESI + ) calcd for C 11 H 26 NO4Si [M + H] + : m / z = 264.16256; Found: m / z = 264.16282.

[0175] Compound (IIr) The compound of 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% in two steps) was prepared from the nitrone of formula (III) (100 mg, 0.185 mmol) and adamantylacetylene (Vh: R 8 = adamantyl, 74.5 mg, 0.465 mmol) according to General Procedures A’ and B.

[0176] A yellowish lacquer having the following characteristics was obtained. [α] 20 D +7.46 (c 0.63, MeOH); 1 1H NMR (500 MHz, CD3OD) δ 3.79 (d, J = 10.9 Hz, 1H), 3.64 - 3.48 (m, 4H), 3.11 (br d, J = 11.3 Hz, 1H), 2.78 - 2.66 (m, 1H), 2.00 - 1.91 (m, 3H), 1.82 - 1.63 (m, 8H), 1.58 - 1.49 (m, 6H), 1.19 - 1.03 (m, 2H) ppm; 13 13C NMR (100 MHz, CD3OD) δ 74.9 (CH), 72.5 (CH), 70.8 (CH), 63.7 (Cq), 62.5 (CH2), 44.2 (CH2), 43.3 (CH2), 38.2 (CH2), 37.0 (CH2), 30.1 (CH), 20.7 (CH2) ppm; HRMS(ESI + )calcd for C 18 H 31 NO4[M+H] + :m / z=326.23258;Found m / z=326.23225。

[0177] Compound (IIb7) The compound of formula (IIb7) above ((2R,3R,4R,5S)-2-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol: 57.3 mg; 59% in two steps) was prepared from the nitrone of formula (III) (99.8 mg; 0.185 mmol) and 1-ethynylcyclohexene (Vd: R 8 = cyclohexene; 87 μL; 0.742 mmol) according to General Procedures A and B.

[0178] A white solid having the following characteristics was obtained. [α] 20 D +3.63 (c 1.43, MeOH); 1 H NMR (400 MHz, CD3OD) δ 3.60 (d, J = 10.6 Hz, 1H, 7 CH2), 3.52 - 3.43 (m, 2H, 3 CH, 4 CH), 3.43 - 3.33 (m, 2H), 2.87 (dd, J = 12.8, 5.0 Hz), 2.49 (ps t, J = 11.7 Hz, 1H), 1.83 - 1.62 (m, 5H), 1.60 - 1.47 (m, 2H), 1.34 - 1.06 (m, 6H), 1.01 - 0.86 (m, 2H) ppm; 13 C NMR (100 MHz, CD3OD) δ 76.5 (CH), 75.1 (CH), 73.8 (CH), 65.5 (CH2), 60.3 (Cq), 45.8 (CH2), 39.9 (CH), 34.6 (CH2), 34.5 (CH2), 30.6 (CH2), 27.8 (CH2), 27.5 (CH2), 24.8 (CH2) ppm; HRMS(ESI + )calcd for C 14 H20 NO4[M+H] + : m / z = 274.20128; Found m / z = 274.20139。

[0179] Compound (IIb1) The compound of formula (IIb1) above ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-pentylpiperidine-3,4,5-triol: 32.8 mg; 67% in two steps) was reacted with nitrone of formula (III) (96.8 mg; 0.180 mmol) and 1-pentyne (Ve: R 8 = C3H7; 71 μL; 0.720 mmol) according to General Procedures A and B.

[0180] A yellow solid having the following characteristics was obtained. [α] 20 D -1.29 (c 1.01, MeOH); 1 1H NMR (400 MHz, CD3OD) δ 3.61 (d, J = 10.6 Hz, 1H), 3.52 - 3.33 (m, 4H), 2.87 (dd, J = 12.8, 5.3 Hz, 1H), 2.49 (ps t, J = 11.8 Hz, 1H), 1.62 - 1.43 (m, 2H), 1.43 - 1.17 (m, 6H), 0.92 (t, J = 6.7 Hz, 3H) ppm; 13 13C NMR (100 MHz, CD3OD) δ 76.5 (CH), 75.2 (CH), 73.9 (CH), 65.7 (CH2), 60.2 (Cq), 45.9 (CH2), 33.9 (CH2), 27.7 (CH2), 23.6 (CH2), 22.9 (CH2), 14.4 (CH3) ppm; HRMS (ESI + ) calcd for C 11 H 24 NO4[M+H] + : m / z = 234.16998; Found m / z = 234.17004。

[0181] Compound (IIb3) The compound of formula (IIb3) above ((2R,3R,4R,5S)-2-heptyl-2-(hydroxymethyl)piperidine-3,4,5-triol: 33.2 mg; 69% in two steps) was prepared from the nitrone of formula (III) (100.7 mg; 0.187 mmol) and 1-heptyne (Vf:R 8 =C5H 11 ; 98 μL; 0.749 mmol) according to General Procedures A and B.

[0182] A yellow solid having the following characteristics was obtained. [α] 20 D +1.04 (c 0.96, MeOH); 1 1H NMR (400 MHz, CD3OD) δ 3.61 (d, J = 10.6 Hz, 1H), 3.51 - 3.44 (m, 2H), 3.41 (d, J = 10.8 Hz), 3.39 - 3.33 (m, 1H), 2.87 (dd, J = 13.0, 5.4 Hz, 1H), 2.49 (ps t, J = 11.4 Hz, 1H), 1.58 - 1.47 (m, 2H), 1.43 - 1.18 (m, 10H), 0.90 (t, J = 6.2 Hz, 3H) ppm; 13 13C NMR (100 MHz, CD3OD) δ 76.5 (CH), 75.1 (CH), 73.8 (CH), 65.6 (CH2), 60.3 (Cq), 45.9 (CH2), 33.0 (CH2), 31.7 (CH2), 30.4 (CH2), 23.7 (CH2), 23.2 (CH2), 27.8 (CH2), 14.4 (CH3) ppm; HRMS (ESI + ) calcd for C 13 H 28 NO4 [M + H] + : m / z = 261.20128; Found m / z = 261.20131.

[0183] Compound (IIc1) The compound of formula (IIc1) above ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-(3-phenylpropyl)piperidine-3,4,5-triol: 20.2 mg; 45% in two steps) was prepared from the nitrone of formula (III) (96.7 mg; 0.179 mmol) and 3-phenyl-1-propyne (Vg: R 8 =CH2Ph; 89 μL; 0.719 mmol) according to General Procedures A and B.

[0184] A yellow lacquer having the following characteristics is obtained. [α] 20 D +1.68 (c 1.37, MeOH); 1 H NMR (400 MHz, CD3OD) δ 7.10 - 7.10 (m, 5H), 3.60 (d, J = 10.6 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.37 - 3.32 (m, 1H), 2.84 (dd, J = 13.1, 5.4 Hz, 1H), 2.69 - 2.53 (m, 2H), 2.42 (dd, J = 13.0, 10.8 Hz, 1H), 1.75 - 1.49 (m, 4H) ppm; 13 C NMR (100 MHz, CD3OD) δ 143.6( Ar Cq), 129.4( Ar CH), 129.3( Ar CH), 126.7( Ar CH), 76.5 (CH), 75.1 (CH), 73.8 (CH), 65.6 (CH2), 60.3 (Cq), 45.8 (CH2), 37.6 (CH2), 27.5 (CH2), 25.3 (CH2) ppm; HRMS (ESI + ) calcd for C 15 H 24 NO4 [M + H] + : m / z = 282.16998; Found m / z = 282.16968.

[0185] A.2 / Synthetic Method 2 The synthetic method used to obtain a compound conforming to the following general formula (I’a) corresponds to General Synthetic Scheme 2 shown in Figure 2.

[0186] Compound of formula (IId) The compound of formula (IId) above, (2R,3R,4R,5S)-2-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, is prepared by the following method. A mixture of nitrone (III) (566 mg, 1.05 mmol) and trimethylsilylacetylene alkyne (Vb: R 8 =SiMe3, 2.2 mL, 15.75 mmol) was stirred at ambient temperature for 21 h, then the excess alkyne was evaporated under reduced pressure. The thus-obtained crude isoxazoline B-2 (667 mg, 1.05 mmol) was dissolved in anhydrous THF (20 mL), and a TBAF solution (1 M in THF, 1.05 mL, 1.05 mmol) was added at 0 °C. The solution was stirred at 0 °C for 45 min, then CH2Cl2 and water were added. The aqueous phase was extracted three times with CH2Cl2. The organic phase was washed with brine, dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography to give bicyclic β-lactam C-2 (440.6 mg, 74% in two steps). To a solution of this β-lactam C-2 (71.3 mg, 0.13 mmol) in ether (1.5 mL) was added LiAlH4 (9.6 mg, 0.25 mmol) at 0 °C. The mixture was stirred at ambient temperature for 2 h, then diluted with CH2Cl2, aqueous NH4Cl, and a few drops of aqueous NaOH to a basic pH. The aqueous phase was extracted with CH2Cl2 (3 times). The organic phase was washed with brine, dried over MgSO4, and then the solvent was evaporated under reduced pressure, and after purification by chromatography, piperidine D-2 (translucent oil, 61.1 mg, 85%) was obtained. This compound (26.3 mg, 0.463 mmol) was debenzylated according to General Procedure B to give piperidine (IId) (9.3 mg, 97%).

[0187] A pale yellow lacquer having the following characteristics was obtained. [α] 20 D +8.2 (c 0.61, CH3OH); IR ν 3287, 2920, 1644, 1431, 1081 cm -1 ; 1 1H NMR (500 MHz, CD3OD) δ 1.86 (t, J = 6.5 Hz, 2H), 2.65 (dd, J = 11.2, 12.6 Hz, 1H), 2.92 (dd, J = 5.4, 13.1 Hz, 1H), 3.33 - 3.43 (m, 2H), 3.48 (d, J = 9.1 Hz, 1H), 3.58 (d, J = 10.8 Hz, 1H), 3.64 - 3.76 (m, 3H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 30.5 (CH2), 45.8 (CH2), 58.8 (CH2), 60.9 (Cq), 65.7 (CH2), 73.5 (CH), 74.6 (CH), 76.3 (CH) ppm; HRMS (ESI + ) calcd for C8H 18 NO5[M + H] + : m / z = 208.1185; Found m / z = 208.1184。

[0188] A.3 / Synthesis Method 3 The synthesis method used to obtain the compound conforming to the following general formula (I’d) corresponds to the general synthesis scheme 3 shown in Figure 3.

[0189] Compound of formula (IIw) The above compound of formula (IIw), (2S,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-2-(pyridin-2-ylsulfonyl)piperidin-1-ol, is prepared by the following method. A solution of nitrone of formula (III) (196 mg; 0.366 mmol) and 2-pyridyl-methyl sulfone (VIa) (74.6 mg; 0.475 mmol) in anhydrous THF (10 mL) under an argon atmosphere was cooled to -78 °C. 1 M LiHMDS in THF (548 μL; 0.548 mmol) was added dropwise, and then the reaction mixture was 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 recovered organic phase was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The obtained residue was purified by chromatography to give the compound of formula A-3a (R 7=H)(115 mg; 55%) was obtained. This compound was debenzylated according to a modification of General Procedure B to obtain piperidine (IIw).

[0190] A.4 / Synthetic Method 4 The synthetic method used to obtain a compound conforming to the general formula (I), particularly a compound conforming to the following general formula (I’a), corresponds to General Synthesis Scheme 4 shown in Figure 4.

[0191] Compound of formula (IIa) The above compound of formula (IIa) ((2R,3R,4R,5S)-2-ethyl-2-(hydroxymethyl)piperidine-3,4,5-triol) was prepared from piperidine D-4b (R 17 = vinyl, 74.0 mg, 0.137 mmol) according to the general protocol B described in Synthetic Method 1 and isolated in a yield of 95% (24.9 mg).

[0192] A pale yellow lacquer having the following characteristics is obtained. [α] 20 D +1.6 (c 1.22, CH3OH); IR ν 3286, 2939, 1643, 1445, 1096 cm -1 ; 1 H NMR (500 MHz, CD3OD) δ 0.86 (t, J = 7.6 Hz, 3H), 1.55 - 1.68 (m, 2H), 2.51 (dd, J = 10.8, 12.8 Hz, 1H), 2.89 (dd, J = 5.4, 13.0 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.42 (d, J = 10.7 Hz, 1H), 3.44 - 3.51 (m, 2H), 3.62 (d, J = 10.7 Hz, 1H) ppm; 13 C NMR (125 MHz, CD3OD) δ 7.0 (CH3), 20.1 (CH2), 45.7 (CH2), 60.5 (Cq), 65.0 (CH2), 73.6 (CH), 75.1 (CH), 76.4 (CH) ppm; HRMS (ESI + ) calcd for C8H 17NO4 [M+H] + : m / z = 192.1236; Found m / z = 192.1237。

[0193] Compound of formula (IIb) The above compound of formula (IIb) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-propylpiperidine-3,4,5-triol) was prepared from piperidine D-4a (R 17 = allyl, 39.7 mg, 0.071 mmol) according to the general protocol B described in Synthetic Method 1 and isolated in 79% (11.4 mg) yield.

[0194] A colorless lacquer having the following characteristics is obtained. [α] 20 D +5.4 (c 0.55, CH3OH); IR ν 3291, 2932, 1625, 1454, 1090 cm -1 ; 1 1H NMR (500 MHz, CD3OD) δ 0.94 (t, J = 7.2 Hz, 3H), 1.22 - 1.42 (m, 2H), 1.49 - 1.57 (m, 2H), 2.53 (dd, J = 10.8, 13.0 Hz, 1H), 2.89 (dd, J = 5.5, 13.0 Hz, 1H), 3.34 - 3.41 (m, 1H), 3.42 (d, J = 10.7 Hz, 1H), 3.45 - 3.51 (m, 2H), 3.64 (d, J = 10.7 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 15.3 (CH3), 16.6 (CH2), 30.4 (CH2), 45.7 (CH2), 60.7 (Cq), 65.3 (CH2), 73.5 (CH), 74.9 (CH), 76.3 (CH) ppm; HRMS (ESI + ) calcd for C9H 20 NO4 [M+H] + : m / z = 206.1392; Found m / z = 206.1396。

[0195] Compound of formula (IIe) The compound (2R,3R,4R,5S)-2-ethyl-2-(hydroxymethyl)-1-propylpiperidine-3,4,5-triol of the above formula (IIe) is prepared by the following method. Piperidine E-4b (R 1 = allyl, R 17 = vinyl; 62 mg, 0.105 mmol) obtained as described in Non-Patent Document 5 was dissolved in anhydrous acetonitrile (0.5 mL), and at 0 °C, it was treated with 2-nitrobenzenesulfonyl chloride (186 mg, 0.84 mmol), and then with hydrazine monohydrate (0.08 mL, 1.68 mmol), and added dropwise at 0 °C. The reaction mixture was maintained with stirring at ambient temperature for 28 hours, then water was added, and the aqueous phase was extracted with dichloromethane (3 times). The recovered organic phase was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. After purification by chromatography, a mixture of the hydrogenation product of only the allyl group and the hydrogenation products of the allyl group and the vinyl group was isolated (58 mg, 94%, 3:7 mixture). This 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 (2 M solution in ether, 0.2 mL, 0.4 mmol) with vigorous stirring under a hydrogen atmosphere (1 atm) for 40 hours. The mixture was filtered through Celite®, the Celite® was rinsed several times with methanol, and then the filtrate was concentrated under reduced pressure. The residue was solubilized in water and purified by a cation exchange resin (DOWEX 50W-X8, H + to form; eluted with 1 M aqueous NH4OH solution) to obtain the product (IIe) (11.9 mg, 49%).

[0196] A beige solid having the following characteristics is obtained. [α] 20 D -40.7 (c 0.60, CH3OH); IR ν 3363, 2962, 2932, 2874, 2826, 1653, 1464, 1379, 1097, 1048, 1016 cm -1 11H NMR (500 MHz, CD3OD) δ 0.90 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 1.39 - 1.50 (m, 1H), 1.51 - 1.60 (m, 1H), 1.61 - 1.75 (m, 2H), 2.26 - 2.34 (m, 1H), 2.42 - 2.51 (m, 1H), 2.76 - 2.85 (m, 1H), 2.93 - 3.00 (m, 1H), 3.40 - 3.52 (m, 3H), 3.65 (d, J = 11.0 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 9.6 (CH3), 11.9 (CH3), 19.2 (CH2), 23.2 (CH2), 52.0 (CH2), 52.2 (CH2), 62.5 (CH2), 71.5 (CH), 74.9 (CH), 76.4 (CH) ppm; HRMS (ESI + ) calcd for C 11 H 24 NO4 [M + H] + : m / z = 234.1700; Found m / z = 234.1696。

[0197] Compound of formula (IIf) The compound of the above formula (IIf), (1R,2R,3S,9aR)-9a-(hydroxymethyl)octahydro-1H-quinolizine-1,2,3-triol, is prepared by the following method. Piperidine E-4a obtained as described in Non-Patent Document 7 (R 1 = R 17= Allyl; (35 mg, 0.06 mmol) was dissolved in anhydrous CH2Cl2 (3 mL). This solution was carefully degassed and then the second-generation Grubbs catalyst (1.3 mg, 2.5 mol%) was added. The mixture was maintained with stirring at ambient temperature for 20 h and then filtered through silica. The silica was rinsed with ethyl acetate and methanol, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by chromatography, and the cyclization product by metathesis of F-4a olefin (32 mg, 95%) was isolated. This product (34 mg, 0.06 mmol) was dissolved in methanol (1 mL) and then treated with Pearlman's reagent (20% Pd(OH)2 / C, 14 mg, 0.10 mmol) and HCl (2 M solution in ether, 0.045 mL, 0.09 mmol) with vigorous stirring under a hydrogen atmosphere (5 bar) for 17 h. The mixture was filtered through Celite®, the Celite® was rinsed several times with methanol, and then the filtrate was concentrated under reduced pressure. The residue was solubilized in water and purified with a cation exchange resin (DOWEX® 50W-X8, H + to form; eluted with 1 M aqueous NH4OH) to give the product (IIf) (9 mg, 73%).

[0198] A colorless oil having the following characteristics was obtained. [α] 20 D +16.6 (c 0.41, CH3OH); IR ν 3336, 2942, 2869, 1053 cm -1 ; 1 H NMR (500 MHz, CD3OD) δ 1.28 (br d, J = 11.6 Hz, 1H), 1.37 - 1.44 (m, 1H), 1.62 - 1.76 (m, 3H), 1.81 - 1.94 (m, 1H), 2.66 (dd, J = 3.0, 14.0 Hz, 1H), 2.72 (dd, J = 4.9, 11.3 Hz, 1H), 3.12 (t, J = 11.0 Hz, 1H), 3.20 (pstd, J = 3.0, 14.0 Hz, 1H), 3.38 (pst, J = 9.3 Hz, 1H), 3.45 - 3.52 (m, 2H), 3.68 (d, J = 11.1 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 18.7 (CH2), 19.2 (CH2), 20.7 (CH2), 48.5 (CH2), 53.3 (CH2), 60.7 (CH2), 62.0 (Cq), 71.4 (CH), 74.1 (CH), 75.9 (CH) ppm; HRMS (ESI + ) calculated for C 10 H 20 NO4 [M + H] + : m / z = 218.1392; Found m / z = 218.1396.

[0199] The compound of formula (IIg) The compound of formula (IIg) above, (6S,7R,8R,8aR)-8a-(hydroxymethyl)-octahydroindolizine-6,7,8-triol, is prepared by the following method. Piperidine E-4b (R 1 = allyl, R 17 = vinyl; 74 mg, 0.125 mmol) obtained as described in Non-Patent Document 5 was dissolved in anhydrous CH2Cl2 (6.3 mL). This solution was carefully degassed, then the second-generation Grubbs catalyst (5.3 mg, 0.006 mmol) was added, and the mixture was heated at 40 °C for 3 hours with stirring. After cooling to ambient temperature, it was filtered through silica, the silica was rinsed with ether, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by chromatography, and the cyclization product by metathesis of olefin F-4b (65 mg, 93%) was isolated. This product (50 mg, 0.089 mmol) was dissolved in methanol (1.4 mL), then treated with Pearlman's reagent (20% Pd(OH)2 / C, 17.9 mg, 0.025 mmol) and HCl (2 M solution in ether, 0.066 mL, 0.133 mmol) with vigorous stirring under a hydrogen atmosphere (5 bar) for 17 hours. The mixture was filtered through Celite®, the Celite® was rinsed several times with methanol, and then the filtrate was concentrated under reduced pressure. The residue was solubilized in water and purified by cation exchange resin (DOWEX 50W-X8, H + to form; eluted with 1 M aqueous NH4OH solution) to obtain the product (IIg) (16 mg, 89%).

[0200] A beige solid having the following characteristics is obtained. [α] 20 D +27.9 (c 0.41, CH3OH); IR ν 3330, 2924, 1652, 1031 cm -1 ; 1 1H NMR (500 MHz, CD3OD) δ 1.46 - 1.53 (m, 1H), 1.67 - 1.76 (m, 1H), 1.88 - 1.96 (m, 1H), 1.98 - 2.08 (m, 1H), 2.46 (pst, J = 11.0 Hz, 1H), 2.80 - 2.89 (m, 2H), 3.09 - 3.18 (m, 1H), 3.33 - 3.41 (m, 2H), 3.43 - 3.49 (m, 1H), 3.53 (d, J = 11.5 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 21.0 (CH2), 26.1 (CH2), 53.8 (CH2), 55.9 (CH2), 63.6 (CH2), 71.0 (CH), 73.0 (CH), 73.2 (Cq), 76.5 (CH) ppm; HRMS (ESI + ) calcd for C9H 18 NO4 [M + H] + : m / z = 204.1236; Found m / z = 204.1234.

[0201] A.5 / Synthesis method 5 The synthesis method used to obtain the compound conforming to the general formula (I'b) above corresponds to the general synthesis scheme 5 shown in Figure 5.

[0202] Compound (IIh) The compound of formula (IIh) ((3S,4R,5R,6R)-6-(hydroxymethyl)-1-azabicyclo[4.2.0]octane-3,4,5-triol) is prepared by the following method. [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 in distilled THF (corresponding to compound C-2 obtained as an intermediate in synthetic method 2 described in the protocol for preparing the above compound (IId)) (57.1 mg, 0.10 mmol). The solution was stirred at 50 °C for 4 h. After cooling, the reaction mixture was diluted with EtOAc and aqueous NaOH (1 M). The aqueous phase was extracted with EtOAc (3 times). The organic phase was washed with brine, dried over MgSO4, and then the solvent was evaporated under reduced pressure. After purification by chromatography, coniine G-5 (33.2 mg, 60%) was obtained. This compound (20.0 mg, 0.04 mmol) was debenzylated according to the general procedure B to give compound (IIh) (6.3 mg, 93%).

[0203] A pale yellow oil having the following characteristics is obtained. [α] 20 D -5.17 (c 0.58, CH3OH); IR ν 3234, 2917, 1429, 1030 cm -1 ; 1 1H NMR (500 MHz, CD3OD) δ 2.18 - 2.26 (m, 1H), 2.55 - 2.63 (m, 1H), 2.89 (dd, J = 5.9, 13.3 Hz, 1H), 3.21 (dd, J = 5.1, 13.3 Hz, 1H), 3.62 (d, J = 11.7 Hz, 1H), 3.69 - 3.80 (m, 5H), 3.99 (pst, J = 6.5 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 21.3 (CH2), 51.4 (CH2), 52.9 (CH2), 65.5 (CH2), 71.2 (CH), 72.7 (CH), 73.2 (Cq), 76.8 (CH) ppm; HRMS (ESI +)Calculated for C8H 16 NO4[M+H] + m / z = 190.1074; Found m / z = 190.1074.

[0204] The general protocol reduces and alkylates C-β-lactam C-5 to obtain conidine of general formula (I’b). A solution of β-lactam C-5 (1 equivalent) and a buscal catalyst (4% mol) in anhydrous dichloromethane under an argon atmosphere is added to tetramethyldisiloxane (TMDS, 2 equivalents) at ambient temperature. The mixture is stirred for 45 minutes and then cooled to -78 °C. The Grignard reagent (2 equivalents) is added dropwise, and then the mixture is stirred at the same temperature for 7 - 10 minutes until it rises to ambient temperature. Subsequently, it is stirred for 21 hours. A saturated aqueous solution of NH4Cl is added, and then the resulting mixture is 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 then evaporated under reduced pressure. The conidine of formula (I’b) thus formed is purified by silica gel chromatography and then reduced and debenzylated according to the general protocol B above.

[0205] Compound (IIz2) 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% in two steps) was prepared from β-lactam C-5 (70.1 mg; 0.124 mmol) and 2M benzylmagnesium chloride in THF (R 14 = Bn; 36.3 μL; 0.248 mmol) according to general procedures C and B.

[0206] A translucent lacquer having the following characteristics is obtained. 11H NMR (500 MHz, CD3OD) δ 7.39 - 7.20 (m, 5H), 4.45 - 4.34 (m, 1H), 3.95 (t, J = 5.7 Hz, 1H), 3.80 - 3.74 (m, 2H), 3.70 (d, J = 5.6 Hz, 1H), 3.56 (d, J = 12.1 Hz, 1H), 3.21 - 3.12 (m, 2H), 3.00 (dd, J = 13.6, 8.4 Hz, 1H), 2.94 (dd, J = 13.1, 6.5 Hz, 1H), 2.60 (dd, J = 11.9, 9.0 Hz, 1H), 2.32 - 2.20 (m, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 137.1( Ar Cq), 130.1( Ar CH), 129.7( Ar CH), 128.0( Ar CH), 76.5 (CH), 71.5 (CH), 71.1 (CH), 65.7 (CH), 64.1 (CH2), 51.4 (CH2), 41.0 (CH2), 27.3 (CH2) ppm; HRMS (ESI + ) calcd for C 15 H 22 NO4 [M + H] + : m / z = 280.15433; Found m / z = 280.15437。

[0207] Compound (IIz3) The compound of 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% in two steps) was prepared from β-lactam C-5 (192.6 mg; 0.342 mmol) and 3M methylmagnesium chloride in THF (R 14 = Me; 228 μL; 0.683 mmol) according to General Procedures C and B.

[0208] A yellowish solid having the following characteristics was obtained. [α] 20 D -22.9 (c 1.07, MeOH); 11H NMR (500 MHz, CD3OD) δ 3.99 (t, J = 6.7 Hz, 1H), 3.85 - 3.75 (m, 1H), 3.75 - 3.69 (m, 1H), 3.67 (d, J = 7.6 Hz, 1H), 3.54 (d, J = 11.2 Hz, 1H), 3.47 (d, J = 11.2 Hz, 1H), 3.10 (dd, J = 13.9, 5.5 Hz, 1H), 2.71 (dd, J = 13.8, 4.0 Hz, 1H), 2.58 (dd, J = 11.5, 8.9 Hz, 1H), 1.64 (dd, J = 10.9, 8.0 Hz, 1H), 1.21 (d, J = 6.1 Hz, 3H) ppm; 13 13C NMR (100 MHz, CD3OD) δ 77.2 (CH), 74.7 (CH), 71.7 (CH), 68.3 (Cq), 67.4 (CH2), 58.4 (CH), 52.4 (CH2), 29.1 (CH2), 22.0 (CH3) ppm; HRMS (ESI + ) calcd for C9H 18 NO4 [M + H] + : m / z = 204.12303; Found m / z = 204.12232。

[0209] Compound (IIz4) The compound of formula (IIz4) above ((3S,4R,5R,6R,8S)-8-cyclopentyl-6-(hydroxymethyl)-1-azabicyclo[4.2.0]octane-3,4,5-triol: 14.6 mg; 62% in two steps) was prepared from β-lactam C-5 (70.0 mg; 0.124 mmol) and 2M cyclopentylmagnesium chloride in ether (R 14 = cPent; 36.4 μL; 0.248 mmol) according to General Procedure C and B.

[0210] A yellowish solid having the following characteristics was obtained. 11H NMR (500 MHz, CD3OD) δ 3.98 (t, J = 7.0 Hz, 1H), 3.76 - 3.63 (m, 2H), 3.58 - 3.36 (m, 3H), 3.10 (dd, J = 14.5, 5.0 Hz, 1H), 2.76 (dd, J = 14.5, 4.0 Hz, 1H), 2.50 (t, J = 11.8 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.89 - 1.76 (m, 1H), 1.74 - 1.47 (m, 6H), 1.36 - 1.22 (m, 1H), 1.15 - 1.00 (m, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 77.7 (CH), 75.0 (CH), 71.9 (CH), 67.5 (CH2), 67.2 (CH), 66.3 (Cq), 54.2 (CH2), 48.9 (CH), 31.0 (CH2), 29.1 (CH2), 27.0 (CH2), 26.4 (CH2), 25.9 (CH2) ppm; HRMS (ESI + ) calcd for C 13 H 24 NO4 [M + H] + : m / z = 258.16998; Found m / z = 258.16987。

[0211] Compound (IIz5) The compound of formula (IIz5) above ((3S,4R,5R,6R,8R)-6-(hydroxymethyl)-8-pentyl-1-azabicyclo[4.2.0]octane-3,4,5-triol: 19.1 mg; 45% in two steps) was prepared from β-lactam C-5 (70.0 mg; 0.124 mmol) and 2 M pentylmagnesium chloride in THF (R 14 = n-Pent; 33.6 μL; 0.248 mmol) according to General Procedures C and B.

[0212] A yellow solid having the following characteristics was obtained. [α] 20 D -31.1 (c 0.46, MeOH); 11H NMR (500 MHz, CD3OD) δ 3.99 (t, J = 7.0 Hz, 1H), 3.74 - 3.64 (m, 2H), 3.64 - 3.55 (m, 1H), 3.51 (d, J = 11.1 Hz, 1H), 3.46 (d, J = 11.1 Hz, 1H), 3.09 (dd, J = 13.7, 5.4 Hz, 1H), 2.70 (dd, J = 13.7, 4.0 Hz, 1H), 2.52 (dd, J = 11.4, 8.9 Hz, 1H), 1.68 - 1.53 (m, 2H), 1.51 - 1.39 (m, 1H), 1.39 - 1.21 (m, 6H), 0.90 (t, J = 6.7 Hz, 3H) ppm; 13 13C NMR (100 MHz, CD3OD) δ 77.5 (CH), 75.2 (CH), 71.9 (CH), 67.8 (CH2), 66.4 (Cq), 62.4 (CH), 53.8 (CH2), 38.8 (CH2), 33.0 (CH2), 27.9 (CH2), 26.5 (CH2), 23.7 (CH2), 14.3 (CH3) ppm; HRMS (ESI + ) calcd for C 13 H 26 NO4 [M + H] + : m / z = 260.18563; Found m / z = 260.18561。

[0213] A.6 / Synthesis method 7 The synthesis method used to obtain a compound conforming to the following general formula (I'c) corresponds to the general synthesis scheme 7 shown in Figure 7.

[0214] Compound (IIk) 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 by the following method. Nitrone (III) (P = Bn; 193 mg, 0.360 mmol) and alkyne Vc (R 8=NBnTs; 308 mg, 1.079 mmol) was stirred at ambient temperature for 3 days, then the reaction mixture was concentrated under reduced pressure. The residue (untreated cycloadduct B-7c) was dissolved in ethanol (0.1 M), transferred to a sealed tube, and heated at 110 °C (IR probe) under microwave irradiation 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) was obtained. A fraction of this compound (58 mg, 0.070 mmol) was dissolved in THF (1 mL), 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 solution of NaOH (0.1 mL), the reaction mixture was stirred at ambient temperature for 2 hours, then filtered through Celite®. The filtrate concentrated under reduced pressure was purified by chromatography to give aziridine alcohol J-7c (P = Bn, R 16 =H; 34.2 mg, 86%) was isolated. A solution of this aziridine alcohol J-7c (28 mg, 0.067 mmol) in THF (2 mL) was added to a lithium solution (54 mg, 7.78 mmol) in liquid ammonia (10 mL) at -78 °C. The mixture was stirred at -78 °C for 45 minutes, then milliQ water (0.5 mL) and MeOH (2 mL) were added. After the solution was returned to ambient temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in milliQ water and neutralized with Amberlite® IR-120 (22.8 g) previously treated with 1 M HCl (15 mL). The resin was introduced into a column, washed with water, and then compound (IIk) was eluted with 1 M solution of aqueous NH4OH. The solution obtained after evaporating the solvent under reduced pressure was purified by chromatography to give pure iminosugar (IIk) (R 16 =H; 7 mg, 60%) was obtained.

[0215] A white solid having the following characteristics was obtained. [α] 20 D = +2.90 (c 0.34, CH3OH); IR ν 3409, 3010, 2926, 1084, 1032 cm -1 ; 1 1H NMR (500 MHz, CD3OD) δ 4.16 (d, J = 7.9 Hz, 1H), 3.79 (d, J = 11.6 Hz, 1H), 3.60 - 3.50 (m, 3H), 3.47 - 3.40 (m, 1H), 3.33 - 3.25 (m, 2H), 2.55 (dd, J = 10.6, 12.4 Hz, 1H), 2.19 (dd, J = 6.8, 5.3 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 76.0 (CH), 73.2 (CH), 70.6 (CH), 63.2 (CH2), 62.0 (CH2), 57.0 (CH2), 51.9 (Cq), 51.6 (CH) ppm; HRMS (ESI + ) calcd for C8H 16 NO5 [M + H] + m / z = 206.1028; Found m / z = 206.1028。

[0216] Compound (IIj) 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. The acyl aziridine H-7d (P = Bn, R 8 = CH2OAc; 33 mg, 0.052 mmol) was dissolved in THF (1 mL), then LiAlH4 (38 mg, 0.165 mmol) was added at 0 °C, and the mixture was stirred at ambient temperature for 1 h. After adding water (0.1 mL) and 10% aqueous solution of NaOH (0.1 mL), the reaction mixture was stirred at ambient temperature for 2 h, and then filtered through Celite (registered trademark). The filtrate concentrated under reduced pressure was purified by chromatography to give a translucent oil J-7d (R 16=CH2OH; 26 mg, 83%) was isolated. A solution of this aziridine alcohol J-7d (40 mg, 0.067 mmol) in THF (2 mL) was added to a lithium solution (25 mg, 3.571 mmol) in liquid ammonia (10 mL) at -78 °C. The mixture was stirred at -78 °C for 45 minutes, then milli-Q water (0.5 mL) and MeOH (2 mL) were added. After the solution was returned to ambient temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in milli-Q water and neutralized with Amberlite® IR-120 (8.5 g) previously treated with 1 M HCl (5 mL). The resin was introduced into a column, washed with water, and then compound (IIj) was eluted with a 1 M solution of aqueous NH4OH. The solid obtained after evaporation of the solvent under reduced pressure was purified by chromatography to give pure iminosugar (IIj) (R 16 =CH2OH; 10.1 mg, 64%) was obtained.

[0217] A white solid having the following characteristics was obtained. [α] 20 D = +5.90 (c 0.34, CH3OH); IR: ν 3249, 2939, 2885, 1748, 1656, 1404, 1031, 995 cm -1 ; 1 H NMR (500 MHz, CD3OD) δ 4.16 (d, J = 8.0 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.71 (dd, J = 3.5, 11.4 Hz, 1H), 3.61 (dd, J = 5.8, 11.4 Hz, 1H), 3.54 - 3.48 (m, 1H), 3.48 - 3.41 (m, 1H), 3.39 (d, J = 11.6 Hz, 1H), 3.30 - 3.25 (m, 2H), 2.52 (dd, J = 10.2, 12.2 Hz, 1H), 2.10 (d, J = 8.7 Hz, 1H) ppm; 13 C NMR (125 MHz, CD3OD) δ 75.9 (CH), 73.1 (CH), 72.4 (CH), 70.7 (CH), 66.1 (CH2), 63.8 (CH2), 56.5 (CH2), 52.0 (Cq), 51.2 (CH) ppm; HRMS (ESI +)calcd for C9H 18 NO6[M+H] + m / z = 236.1129; Found m / z = 236.1124。

[0218] Compound (IIm) 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) is obtained as follows. The cycloadduct B-7e (P = Ac, R 8 = Ph; 15.2 mg, 0.030 mmol, a mixture of 4:1 diastereomers) was dissolved in dichloroethane (0.1 M solution) in a sealed tube. The solution was heated at 110 °C (IR probe) under microwave irradiation for 45 minutes (30 + 15). After evaporating the solvent under reduced pressure, the residue was purified by chromatography to give acylaziridine H-7e (P = Ac, R 8 = Ph; 12 mg, 79%) in the form of a 9:1 mixture of two diastereomers of acylaziridine H-7e (P = Ac, R 8 = Ph; 12 mg, 79%) could be isolated. These acylaziridines (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% aqueous NaOH solution (0.1 mL) were added thereto. After stirring at ambient temperature for 1.5 hours, the mixture was filtered through Celite®, the filtrate was concentrated under reduced pressure, and then the residue was purified by chromatography to give aziridinyl iminosugar (IIm) (R 16 = Ph; 15 mg, 82%) in the form of a single diastereomer.

[0219] A colorless oil having the following characteristics is obtained. [α] 20 D -4.1 (c 1.58, CH3OH); IR ν 3296, 2931, 1557, 1409, 1053, 697 cm -1 ; 1 H NMR (500 MHz, CD3OD) δ 7.49 - 7.44 (m, 2H), 7.40 - 7.35 (m, 2H), 7.31 - 7.25 (m, 1H), 4.29 (d, J = 8.7 Hz, 1H), 4.18 (d, J = 7.9 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.56 (d, J = 11.6 Hz, 1H), 3.48 - 3.37 (m, 2H), 3.26 (dd, J = 9.1, 8.0 Hz, 1H), 2.26 - 2.18 (m, 2H) ppm; 13 C NMR (125 MHz, CD3OD) δ 144.6( Ar Cq), 129.5( Ar CH), 128.6( Ar CH), 127.1( Ar CH), 75.8 (CH), 73.8 (CH), 73.1 (CH), 70.7 (CH), 63.6 (CH2), 56.4 (CH2), 56.0 (CH), 52.8 (Cq) ppm; HRMS (ESI + ) calcd for C 14 H 20 NO5[M + H] + : m / z = 282.1341; Found m / z = 282.1346。

[0220] Compound (IIn) 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) is obtained as follows. The acyl aziridine H-7f (P = Bn, R) obtained as described in Non-Patent Document 6 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 h, and then water, 10% aqueous solution of NaOH, and CH2Cl2 were added. The aqueous phase was extracted with CH2Cl2 (3 times), the organic phase was recovered, dried over MgSO4, and then concentrated under reduced pressure. The residue thus obtained was filtered through silica to give aziridine alcohol J-7f (R 16 =c-Hex; 72 mg, 94%) was isolated in the form of an oil. A solution of this 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 min, and then milli-Q water (0.5 mL) and MeOH (2 mL) were added. After the solution was returned to ambient temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in milli-Q water and neutralized with Amberlite® IR-120 (3.5 g) previously treated with 1 M HCl (2 mL). The resin was introduced into a column, washed with water, and then the compound (IIn) was eluted with 1 M solution of aqueous NH4OH. The solid obtained after evaporation of the solvent under reduced pressure was purified by chromatography to give pure iminosugar (IIn) (R 16 =c-Hex; 13 mg, 72%).

[0221] A white solid having the following characteristics was obtained. [α] 20 D +2.8 (c 0.80, CH3OH); IR ν 3335, 2916, 2846, 1451, 1087, 1054, 1008, 660 cm -1 ; 11H NMR (500 MHz, CD3OD) δ 4.17 (d, J = 7.8 Hz, 1H), 3.88 (d, J = 11.7 Hz, 1H), 3.50 - 3.44 (m, 2H), 3.42 (d, J = 11.7 Hz, 1H), 3.33 - 3.29 (m, 1H), 2.95 (dd, J = 8.6, 6.6 Hz, 1H), 2.51 (dd, J = 11.8, 9.0 Hz, 1H), 2.08 (d, J = 8.7 Hz, 1H), 1.99 - 1.66 (m, 5H), 1.53 - 1.45 (m, 1H), 1.36 - 1.03 (m, 5H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 76.3 (CH), 76.0 (CH), 73.3 (CH), 70.8 (CH), 64.1 (CH2), 56.0 (CH2), 52.9 (CH), 51.1 (Cq), 45.3 (CH), 30.1 (CH2), 29.7 (CH2), 27.7 (CH2), 27.4 (CH2), 27.2 (CH2) ppm; HRMS (ESI + ) calcd for C 14 H 26 NO5 [M + H] + : m / z = 288.1811; Found m / z = 288.1810。

[0222] A.7 / Synthesis method 8 The synthesis method used to obtain a compound conforming to the following general formula (I’e) corresponds to the general synthesis scheme 8 shown in Figure 8.

[0223] Compound (IIw1) The compound of formula (IIw1) ((2R,3R,4R,5S)-2-(hydroxymethyl)-2-(1H-1,2,3-triazol-4-yl)piperidine-3,4,5-triol) is prepared by the following method. A solution of hydroxylamine of formula A-1a (240.0 mg; 0.377 mmol) and zinc powder (247.0 mg; 3.77 mmol) in a 4:1 mixture of EtOH / AcOH (5 mL) was stirred at 65 °C under ultrasonic 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 aqueous 1M NaOH. 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. The residue obtained was purified by silica gel chromatography to give the corresponding piperidine D-8 (178.0 mg; 76%). A mixture of this piperidine D-8 (176.0 mg; 0.284 mmol) and K2CO3 (157.0 mg; 1.14 mmol) with benzyl chloroformate (121 μL; 0.852 mmol) in anhydrous THF (1.7 mL) was stirred at ambient temperature until the reaction was complete. Methanol (2 mL) was added and then the reaction mixture was stirred at ambient temperature until the reaction was complete. The residue obtained was purified by silica gel chromatography to give the compound of formula K-8 (164.0 mg; 78% in two steps). Copper iodide (3.5 mg; 0.018 mmol) and DIPEA (108 μL; 0.618 mmol) were added under an inert atmosphere to a solution of the same compound K-8 (46.8 mg; 0.062 mmol) and benzyl azide (247 μL; 0.124 mmol) in DMF (1.5 mL). The reaction mixture was stirred at ambient temperature until the reaction was complete. The crude product was diluted with ethyl acetate and washed several times with brine. The organic phase was dried over MgSO4 and then evaporated under reduced pressure. The residue obtained was purified by chromatography to give the compound of formula L-8 (38.2 mg; 76%). This compound (32.1 mg; 0.039 mmol) was debenzylated according to General Procedure B to give piperidine (IIw1) (11.0 mg; 100%).

[0224] A colorless lacquer having the following characteristics is obtained. [α] 20 D -17.2 (c 1.09, CH3OH); 1 1H NMR (500 MHz, CD3OD) δ 7.90 (s, 1H), 3.80 (d, J = 10.9 Hz, 1H), 3.69 (d, J = 9.7 Hz, 1H), 3.59 (d, J = 11.1 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.27 (t, J = 9.3 Hz, 1H), 2.99 (dd, J = 12.6, 5.5 Hz, 1H), 2.54 (dd, J = 12.3, 11.2 Hz, 1H) ppm; 13 13C NMR (125 MHz, CD3OD) δ 144.5 (Cq), 131.0 (CH), 76.9 (CH), 74.5 (CH), 73.0 (CH), 68.1 (CH2), 62.5 (Cq), 47.2 (CH2) ppm; HRMS (ESI + ) calcd for C8H 15 N4O4 [M + H] + : m / z = 231.10878; Found m / z = 231.10861。

[0225] B / Biological evaluation The following various biological activity tests are carried out with the above-mentioned compounds (IIa) - (IIn).

[0226] B.1 / Determination of the inhibition rate of rhGAA by Fluopol-ABPP The inhibitory activity of the compound against recombinant human acid α-glucosidase (rhGAA) is confirmed using the Fluopol-ABPP method (protein profiling based on fluorescence polarization activity) described in Non-Patent Document 14. This technique is based on the competition between a fluorescent probe that can covalently bind to the active site of the enzyme and the inhibitor, and it is possible to measure the affinity of this inhibitor for the active site of the rhGAA enzyme used in this experiment in the laboratories of Professor Herman S. Overkleeft and Professor Johanes M.F.G.Aerts of the Leiden Institute of Chemistry, Leiden University (the Netherlands). The enzyme is commercially available under the name Myozyme (registered trademark). The half-maximal inhibitory concentration (IC 50) is measured in a 96-well plate (Griener) in 150 mM McIlvaine buffer (citric acid-phosphate) (pH 5.0) in the presence of 0.1% (w / v) bovine γ-globulin and 0.5 mg / mL of the Chaps surfactant (Sigma). The rhGAA enzyme (10 μg / mL) is pre-incubated in buffer at 37 °C for 45 minutes with inhibitor solutions at various concentrations [I] (containing 2.5% DMSO used for the preparation of the stock solution of the compound). Next, a fluorescent probe solution of tetraminomethylrhodamine (TAMRA) (25 nM) in buffer is added to the mixture. After 4 hours, the sample is irradiated with polarized light (λ = 530 nm), and the emitted fluorescence (λ = 580 nm) is measured using an Infinite® M1000Pro spectrofluorometer (Tecan). For each inhibitor concentration, the inhibition rate of the enzyme is determined by the formula: Inhibition rate (%) = [F 測定 - F 対照1 ) / F 対照2 ) X 100 wherein, F 測定 corresponds to the fluorescence measured in the presence of iminosugar; F 対照1 corresponds to CF022 ((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 acidic α-glucosidase that serves as a positive control (inhibition rate 100%); and F 対照2 represents the fluorescence of the probe measured in the absence of inhibitor (inhibition rate 0%).

[0227] IC 50 values are calculated by non-linear regression of the inhibition rate (%) as a function of the concentration [I] using GraphPad Prism 6.0 software. The results are the average values of the same experiment performed three times (triplicates).

[0228] B.2 / Determination of the inhibition rate of rhGAA by measuring the residual activity in the presence of inhibitors in vitro Completely, the team of Professor Marco Moracci from the Department of Biology, Federico II University of Naples (Italy) evaluated the inhibitory activity of compounds against recombinant human acid α-glucosidase (rhGAA) using the method described in Non-Patent Document 15. The rhGAA enzyme sold under the name of Myozyme® used was obtained from the residues of the recombinant enzyme used to treat Pompe disease patients by enzyme therapy at the Department of Translational Medical Sciences, Federico II University of Naples (Italy).

[0229] The compounds are solubilized at various concentrations in 100 mM sodium acetate buffer (pH 4.0) and 4-nitrophenyl-α-D-glucopyranoside substrate (20 mM). After temperature equilibration at 37 °C for 2 minutes, rhGAA enzyme in the same buffer is added (total volume: 200 μL). After reacting at 37 °C for 2 minutes, 1 M sodium carbonate solution (800 μL) (pH 11.0) is added and the mixture is cooled on ice. The absorbance of the solution is measured at 420 nm at ambient temperature. The natural hydrolysis of the substrate is subtracted by measuring the absorbance of the enzyme-free control (blank). The results presented are the average values of at least two identical experiments. The data are processed and analyzed using Prism 5.0 software (GraphPad).

[0230] B.3 / Determination of the Thermal Stability of rhGAA The stability of rhGAA in the presence of compounds is determined according to the method described in Non-Patent Document 16. The rhGAA enzyme (2.5 μg, 0.1 mg / mL) is incubated in the absence or 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). The thermal stability of the enzyme under these various conditions is evaluated by differential scanning fluorimetry (DSF), by changing the temperature by 1 °C per minute in the range of 25 to 95 °C and measuring the fluorescence of the SYPRO® Orange dye every minute using a Real-Time Cycler spectrofluorometer (Biorad). For each scan, the relative fluorescence is determined by comparing each measured fluorescence value with the maximum fluorescence value of the SYPRO® Orange dye. The results are the average values of the same experiment three times (triplicates).

[0231] B.4 / Evaluation of the inhibition rate of other human-derived enzymes The selectivity of the compounds was determined in the laboratories of Professors Herman S. Overkleeft and Johanes M.F.G.Aerts at the Leiden Institute of Chemistry, Leiden University (The Netherlands). The enzymes used to determine the selectivity of the inhibition of the compounds against various human enzymes are α-glucosidase II of the endoplasmic reticulum (GANAB), 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 Non-Patent Document 17. The enzyme GBA1 sold under the name Cerezyme® and the enzyme rhGAA sold under the name Myozyme® were used. The human GANAB enzyme used in this study was from fibroblasts of Pompe disease patients and volunteer donors diagnosed with a deficiency in GAA activity. These fibroblasts were cultured in HAM F12-DMEM medium (Sigma) supplemented with 10% (v / v) FCS (fetal bovine serum). The GBA2 enzyme was overexpressed in HEK298T cells cultured at 37 °C with 5% CO2 in DMEM medium containing glucose (Gibco) supplemented with 10% NBS (newborn bovine serum) and 100 units / mL of penicillin / streptomycin (Gibco). The activity of the compounds against human β-glucosylceramide synthase (GCS) was evaluated in situ in RAW264.7 cells cultured at 37 °C with 5% CO2 in RPMI medium (Gibco) supplemented with 10% FCS, 1 mM GlutaMAX, and 100 units / mL of penicillin / streptomycin (Gibco).

[0232] IC of GANAB, GBA2, and GCS enzymes 50Values are determined using cell lysates prepared in buffer (20 mM hepes, 2 mM DTT, 0.25 M sucrose, 1 mM MgCl2, 2.5 U / mL benzonase) at pH 7.0 and incubated on ice for 30 minutes. These cell lysates are homogenized using a SilentCrusher grinder (Heidolph (registered trademark)) and then ultracentrifuged at 32,000 rpm at 4 °C for 30 minutes. Total protein concentration is determined according to the Bradford method (Non-Patent Document 18) using a Bradford BioRad Quick Start (registered trademark) kit (Pierce) and BSA (Sigma). Next, aliquots of the lysate are taken and stored at -80 °C until use.

[0233] IC of the GANAB enzyme 50 Values are determined by incubating for 2 hours using 150 mM Mcllvaine (pH 7.0) as buffer, 0.1% (w / v) bovine serum albumin (BSA), and a substrate (4-methylumbelliferyl-α-D-glucopyranoside) at a concentration of 2.4 mM.

[0234] IC of the GBA1 enzyme 50 Values are determined by incubating for 30 minutes using 150 mM Mcllvaine (pH 5.2) as buffer, 0.2% (w / v) taurocholate, 0.1% (v / v) Triton X-100, 0.1% (w / v) bovine serum albumin (BSA), an enzyme at a concentration of 0.7 nM, and a substrate (4-methylumbelliferyl-β-D-glucopyranoside) at a concentration of 3.0 mM.

[0235] The residual activity of GBA2 in the presence of the compound is determined after pre-incubating the homogenate of HEK298T cells overexpressing GBA2 for 30 minutes using conduritols B epoxide (Sigma), an inhibitor of GBA1, at a concentration of 1 mM. IC 50The value is determined by incubating for 1 hour using 150 mM Mcllvaine (pH 5.8) as the buffer, 0.1% (w / v) bovine serum albumin (BSA), and a substrate (4-methylumbelliferyl-β-D-glucopyranoside) with a concentration of 3.0 mM.

[0236] The residual activity of GCS in the presence of the compound is determined after pre-incubating the homogenate of RAW264.7 cells for 1 hour using conduritol B epoxide (Sigma), an inhibitor of GBA1, at a concentration of 300 μM. The IC 50 value is determined in situ in cell culture medium at pH 7.0 using 1 μM NBD-ceramide (N-[12-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-D-erythro-sphingosine) as the substrate, as described in Non-Patent Document 14 mentioned above.

[0237] The results obtained for all of these tests are shown in Tables 1 and 2 below. These tables also show, for comparison, the values obtained for the DNJ and NB-DNJ compounds described in the prior art documents. In the tables, a indicates Non-Patent Document 15; b indicates Non-Patent Document 19; c indicates Non-Patent Document 3; d indicates Non-Patent Document 20; * indicates [compound]=K i and shows the ΔTm measured at 10 times the value; e indicates Non-Patent Document 21; f indicates Non-Patent Document 22.

[0238]

Table 1

[0239] All of these results demonstrate the selectivity of the compounds used according to the invention for human acid α-glucosidase compared to the other human enzymes tested. This selectivity is much higher than that proposed for the prior art molecules DNJ and NB-DNJ. Furthermore, the compounds used according to the invention have a significant rhGAA stabilizing effect comparable to that of DNJ and NB-DNJ.

[0240] Furthermore, the compounds (IIb7), (IIb3), (IIc1), (IIr), and (IIc) that conform to general formula (I’’a), as well as the compound (IIx1), have performance superior to that of the other compounds according to the invention.

Claims

A pharmaceutical composition for treating Pompe disease, comprising, as an active ingredient, one of the compounds of the following general formula (I) or pharmaceutically acceptable salts thereof, 【Chemical 1】 wherein, -R １ represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical having 1 to 6 carbon atoms, and R ２ represents a C1-C18 linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or a plurality of optionally fused rings, and when R １ represents a hydrogen atom, the hydrocarbon radical contains at least 2 carbon atoms, - or R １ and R ２ together with the atoms of the piperidine ring to which each is attached form a 3- to 6-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, or a linear, branched, and / or cyclic carbon radical, and which is saturated or unsaturated, aromatic or non-aromatic, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a single ring or a plurality of optionally fused rings Pharmaceutical composition.

2. In the general formula (I), R １ represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical having 1 to 6 carbon atoms, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ represents a -CH(R ３ )-R ４ group, wherein R ３ and R ４ are the same or different and each represents a hydrogen atom or a C1-C12 linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or optionally fused polycyclic ring, and when R １ represents a hydrogen atom, R ３ and R ４ do not simultaneously represent a hydrogen atom The pharmaceutical composition according to claim 1.

3. In the general formula (I), R １ represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical having 1 to 6 carbon atoms, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ is -(CHR ７ )-SO ２ -Ar １ group, wherein Ar １ represents an aryl radical or a heteroaryl radical, and R ７ represents a hydrogen atom, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic The pharmaceutical composition according to claim 1 or 2.

4. In the general formula (I), R １ represents a hydrogen atom, or a linear, branched, and / or cyclic hydrocarbon radical having 1 to 6 carbon atoms, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ represents a triazole group, The pharmaceutical composition according to claim 1 or 2.

5. In the general formula (I), R １ represents a hydrogen atom or a linear, branched, and / or cyclic hydrocarbon radical having 1 to 6 carbon atoms, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ is -(CH ２ ) ２ -R ８ group, wherein R ８ represents the following: - A hydrogen atom; - A C1-C12 alkyl group or cycloalkyl group, optionally containing a single ring or a plurality of fused rings; - -(CH ２ ) ａ -OH group, wherein a is an integer from 0 to 6; --(CH ２ ) ｂ -Ar ２ group, wherein Ar ２ represents an aryl radical or a heteroaryl radical, and b is an integer from 0 to 6; --(CH ２ ) ｃ -Si(R ９ ) ３ -group, wherein R ９ represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical, and c is an integer from 0 to 6; - or -(CH ２ ) ｄ -Z-R １０ group, wherein Z is a heteroatom selected from oxygen, nitrogen, and sulfur, and R １０ represents a hydrogen atom, or a C1-C12 alkyl radical, cycloalkyl radical, alkylaryl radical, aryl radical, or acyl radical, said radicals being optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, and d is an integer from 0 to 6, The pharmaceutical composition according to claim 1 or 2.

6. In the general formula (I), R １ represents a C1-C3 linear, branched, and / or cyclic alkyl group, The pharmaceutical composition according to any one of claims 1 to 5.

7. In the general formula (I'a), [Chemical 2] wherein, R １ represents a hydrogen atom or a linear, branched, and / or cyclic alkyl group having 1 to 6 carbon atoms, R ８ represents the following: a hydrogen atom; a methyl radical, an ethyl radical, a propyl radical, a butyl radical, a pentyl radical, a hexyl radical, a cycloalkyl radical, an adamantyl radical, a C1-C12 alkyl cycloalkyl radical, a C1-C12 alkyl aryl radical, or a C1-C12 aryl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms; a hydroxyl group; an Si(R １２ ) ３ group, wherein R １２ represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical; a -(CH ２ ) ｆ -Y-R １３ 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-C6 alkyl radical or a C1-C6 aryl radical or heteroaryl radical; a -(CH ２ ) ｇ -CO-R １３ group, wherein g is an integer from 0 to 6; or a -(CH ２ ) ｈ -SO ｅ -R １３ group, wherein h is an integer from 0 to 6, and e is equal to 1 or 2. R １ When R does not represent a propyl group, ８ R does not represent a hydrogen atom, The pharmaceutical composition according to claim 1 or 2.

8. In the general formula (I''a), [Chemical 3] wherein, R １ represents a hydrogen atom or a linear, branched, and / or cyclic alkyl group having 1 to 6 carbon atoms, R １８ represents a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, contains 4 to 12 carbon atoms, optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or a plurality of optionally fused rings, The pharmaceutical composition according to claim 1 or 2.

9. In the general formula (I'b), 【Chemical Formula 4】 wherein, R １４ represents a hydrogen atom, a carbonyl radical, or a C1-C12 alkyl radical, alkenyl radical, alkynyl radical, alkylaryl radical, or aryl radical, and the radical is optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of the heteroatoms, and R １５ represents a hydrogen atom, a hydroxyl radical, an amino radical, or a C1-C12 alkyl radical, alkenyl radical, or aryl radical, optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, The pharmaceutical composition according to claim 1.

10. In the general formula (I), R １ and R ２ together with the atoms of the piperidine ring to which each is attached form a 3-membered heterocyclic ring fused to the piperidine ring and are optionally substituted by a -X-R ５ group, wherein - X is -C(=O)- or -CH(OR ６ )- radical, in the formula, R ６ represents a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ５ represents a hydrogen atom, an amino group, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or optionally fused multiple rings, - or X represents a -CH(OH)- radical, and R ５ represents a hydrogen atom, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or a plurality of optionally fused rings, The pharmaceutical composition according to claim 1.

11. The pharmaceutical composition according to any one of claims 1 to 10 for stabilizing human acidic α-glucosidase.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition has a form suitable for oral administration.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound of formula (I) is present in a pharmaceutically acceptable excipient.

14. A compound of the general formula (I') or one of pharmaceutically acceptable salts thereof, 【Chemical Formula 5】 wherein, -R １ represents a hydrogen atom or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ represents a -CH(R ３ )-R ４ group, wherein R ３ and R ４ are the same or different and each represents a hydrogen atom or a linear, branched and / or cyclic C1-C12 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or optionally fused polycyclic ring, and R ３ and R ４ are such that when R １ and R ３ each represent a hydrogen atom, R ４ does not represent a hydrogen atom or a phenyl radical, and R １ and R ２ shall not represent a propyl radical and an ethyl radical simultaneously, respectively, - or R １ and R ２ together with the atoms of the piperidine ring to which each is attached form a 4-membered heterocyclic ring fused to the piperidine ring, optionally substituted by one or more radicals, which may be the same or different, each selected from a hydroxyl group, an amino group, or a linear, branched, and / or cyclic C1-C12 carbon radical, and which is saturated or unsaturated, aromatic or non-aromatic, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or optionally fused plurality of rings, - or R １ and R ２ together with the atoms of the piperidine ring to which each is attached form a 3-membered heterocyclic ring fused to the piperidine ring, optionally substituted with a -X-R ５ group, wherein - X represents a -C(=O)- or -CH(OR ６ )- radical, wherein R ６ represents a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ５ represents a hydrogen atom, an amino group, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, optionally containing one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally containing a monocyclic or optionally fused plurality of rings; ・ or X represents a —CH(OH)— radical, and R ５ represents a hydrogen atom, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or optionally fused plurality of rings, and R ５ represents a compound or one of these pharmaceutically acceptable salts that does not represent an n-propyl radical, a cyclohexyl radical, or a phenyl radical.

15. In the general formula (I'), R １ represents a hydrogen atom or a linear, branched and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ is -(CHR ７ )-SO ２ -Ar １ represents a group, in which Ar １ represents an aryl radical or a heteroaryl radical, and R ７ represents a hydrogen atom, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic The compound according to claim 14 or one of pharmaceutically acceptable salts thereof.

16. In the general formula (I'), R １ represents a hydrogen atom, or a linear, branched and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ represents a triazole group, The compound according to claim 14 or one of pharmaceutically acceptable salts thereof.

17. In the general formula (I'), R １ represents a hydrogen atom, or a linear, branched, and / or cyclic C1-C6 hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, and R ２ is -(CH ２ ) ２ -R ８ group, where R ８ represents the following: - A hydrogen atom; - A C1-C12 alkyl group or cycloalkyl group, optionally containing a single ring or a plurality of fused rings; - -(CH ２ ) ａ -OH group, wherein a is an integer from 0 to 6; - -(CH ２ ) ｂ -Ar ２ group, wherein Ar ２ represents an aryl radical or a heteroaryl radical, and b is an integer from 0 to 6; --(CH ２ ) ｃ -Si(R ９ ) ３ -group, wherein R ９ represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical, and c is an integer from 0 to 6, - or -(CH ２ ) ｄ -Z-R １０ group, wherein Z is a heteroatom selected from oxygen, nitrogen, and sulfur, and R １０ represents a C1-C12 alkyl radical, cycloalkyl radical, alkylaryl radical, aryl radical, or acyl radical, said radicals being optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, and d is an integer from 0 to 6, The compound according to claim 14 or one of pharmaceutically acceptable salts thereof.

18. A compound of the general formula (I'a), 【Chemical Formula 6】 wherein, R １ represents a hydrogen atom or a linear, branched, and / or cyclic alkyl group having 1 to 6 carbon atoms, R ８ represents the following: a hydrogen atom; a hydroxyl group; a methyl radical, an ethyl radical, a propyl radical, a butyl radical, a pentyl radical, a hexyl radical, a cyclohexyl radical, an adamantyl radical, a C1-C12 alkylcycloalkyl radical, a C1-C12 alkylaryl radical, or a C1-C12 aryl radical, said radical being optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms; -Si(R １２ ), where R ３ represents a hydroxyl radical, a C1-C4 alkyl radical, a C1-C4 alkoxyl radical, or a phenyl radical; -(CH １２ ), where f is an integer from 0 to 6, Y is a heteroatom selected from oxygen, nitrogen, and sulfur, and R ２ ), where g is an integer from 0 to 6; or -(CH ｆ -Y-R １３ group, where f is an integer from 0 to 6, Y is a heteroatom selected from oxygen, nitrogen, and sulfur, and R １３ represents a C1-C6 alkyl radical, or a C1-C6 aryl radical or heteroaryl radical; -(CH ２ ), where h is an integer from 0 to 6, e is equal to 1 or 2, and ｇ -CO-R １３ group, where g is an integer from 0 to 6; or -(CH ２ ), where h is an integer from 0 to 6, e is equal to 1 or 2, and ｈ -SO ｅ -R １３ group, where h is an integer from 0 to 6, e is equal to 1 or 2, R １ When R represents a propyl radical, ８ R does not represent a hydrogen atom, The compound according to claim 14 or one of pharmaceutically acceptable salts thereof.

19. A compound of the general formula (I''a), 【Chemical Formula 7】 wherein, R １ represents a hydrogen atom, or a linear, branched, and / or cyclic alkyl group having 1 to 6 carbon atoms, R １８ represents a linear, branched, and / or cyclic hydrocarbon radical, which is saturated or unsaturated, aromatic or non-aromatic, contains 4 to 12 carbon atoms, optionally contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and silicon and / or one or more groups containing at least one of said heteroatoms, and optionally contains a monocyclic or a plurality of optionally fused rings. One of the compounds according to claim 14 or a pharmaceutically acceptable salt thereof.

20. A compound of general formula (I'b), wherein 【Chemical Formula 8】 In the formula, R １４ is a hydrogen atom, a carbonyl radical, or a C1-C12 alkyl radical, alkenyl radical, alkynyl radical, alkylaryl radical, or aryl radical, said radical optionally being interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, and R １５ represents a hydrogen atom, a hydroxyl radical, an amino radical, or a C1-C12 alkyl radical, alkenyl radical, or aryl radical, optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, One of the compounds according to claim 14 or a pharmaceutically acceptable salt thereof.

21. A compound of general formula (I'c), 【Chemical Formula 9】 In the formula, R １６ represents a hydrogen atom or a C1-C6 alkyl radical, which radical is optionally interrupted and / or substituted by one or more heteroatoms selected from oxygen, nitrogen, sulfur and silicon and / or one or more groups containing at least one of said heteroatoms, and R １６ does not represent an n-propyl radical, a cyclohexyl radical or a phenyl radical. One of the compounds according to claim 16 or a pharmaceutically acceptable salt thereof.

22. A method for preparing one of the compounds according to any one of claims 17 to 19 or a pharmaceutically acceptable salt thereof, comprising the following consecutive steps: a / A reaction of a compound of general formula (III) or (IV) with a compound of general formula (V), 【Chemical Formula 10】 In the formula, Bn represents a benzyl radical, and R ８ is defined in claim 17 or 18, and when an organometallic compound is present, R ８ does not represent a hydrogen atom, a hydroxyl group, or an amino group. b / Optionally, reduction of the hydroxylamine functional group to an amine, c / Optionally, alkylation of the nitrogen atom of the piperidine ring, d / And hydrocracking of the product obtained at the end of step a / , and if applicable, at the end of step b / or step c / . A method comprising.

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