Deuterated derivatives of 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane

Abstract

The present invention relates to deuterated derivatives compound of 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane, or a stereoisomer, crystal form, or pharmaceutically acceptable salt thereof. The present invention also relates to said deuterated derivatives for use in a method for treating cancer and / or in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer. The present invention also relates to said deuterated derivatives for use in a method for treating fibrotic diseases.

Description

[0001]Deuterated derivatives of 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2- oxo-2λ5-[1,2]oxaphosphinane Field of the invention The present invention relates to deuterated derivatives compounds of 3-Hydroxy-4,5-bis- benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane and their use as drugs, in particular for use in methods for treating cancers and / or for reducing or preventing the appearance of metastases in a patient afflicted with a cancer, and / or for treating fibrotic diseases. Background of the invention 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane (additional name: 4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxy-2-phenyl-1,2- oxaphosphinane 2-oxide) is referred to as “Compound A” in the present disclosure: O Compound A Compound A is a or in previous documents) that has been proven to be an efficient anti-cancer agent, in particular for reducing or preventing the appearance of metastases, as described by PCT applications WO2009 / 004096 and WO2014 / 128429, respectively. Compound A and its use against glioblastoma is more specifically disclosed in J. Med. Chem.2012, 55, 2196-2211. A crystalline polymorphic form of Compound A was described by PCT application WO 2018 / 054925. Compound A has also been proven to be efficient for treating fibrotic diseases, as described by PCT application WO 2022 / 152795. This makes Compound A very promising. There is therefore a need to develop derivatives compounds of compound A that have improved ADME properties (Absorption, Distribution, Metabolism, and Excretion). Derivatives compounds of Compound A having improved stability and solubility would also be of great interest. Summary of the invention The inventors discovered and developed deuterated derivative compounds of 3-Hydroxy-4,5- bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane (Compound A) that have improved metabolic stability and improved solubility in biological fluids. More generally, these deuterated derivative compounds have surprisingly improved ADME properties. As shown in the Example section, the deuterated derivative compounds of the invention have also an improved efficacy for treating cancer in comparison to compound A, in particular through a stronger decrease of the GnT-V protein quantity in cancer cells after only 48h of treatment at 0.33µM, an increased concentration of Galectin-1 protein in cancer cell supernatant after 48h of treatment at 0.33µM, and an greater inhibition of 3T3 cell migration at 3µM. The preparation methods of the deuterated derivative compounds of the invention have the advantages to be simple and affordable, starting from the existing Compound A, or similar to the method for preparing Compound A. Accordingly, the invention relates to a deuterated derivative compound of 3-Hydroxy-4,5-bis- benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane (also called herein “Compound A”), or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof. In particular, the invention relates to a deuterated derivative compound of compound A, being of the general formula (I): B1A1wherein, A1 to A3 are independently of each other -CH2- or -CD2-; and B1to B4are independently of each other a phenyl or a phenyl-d5; with the proviso that at least one of A1 to A3 is -CD2- or at least one of B1 to B4 is phenyl-d5, or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof. The invention also relates to a pharmaceutical composition comprising at least one deuterated derivative compound of the invention, and one or more pharmaceutically acceptable excipients. The invention further relates to a deuterated derivative compound of the invention or a pharmaceutical composition of the invention, for use as a medicament. The invention further relates to a deuterated derivative compound of the invention or a pharmaceutical composition of the invention, for use in a method for treating cancer and / or in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer. The invention further relates to a deuterated derivative compound of the invention or a pharmaceutical composition of the invention, for use in a method for treating fibrotic diseases. Brief description of the figures Figure 1 shows the quantification of GnT-V protein in cell lysate samples after 48h of treatment with compounds PST3.1a, IIa, IIe or IIf, at 0.33µM. Results are expressed in ppm (pg / mg) of cell lysate proteins. Figure 2 shows the quantification of Galectin-1 proteins in supernatant cell culture samples after 48h of treatment with compounds PST3.1a, IIa, IIe or IIf, at 0.33µM. Results are expressed in pg / ml of culture medium. Figure 3 shows the quantification of complex secreted N-glycans motifs in supernatant samples after 48h of treatment with compounds PST3.1a, IIa, IIe or IIf, at 0.33µM using PHA-L staining. Results expressed equivalent glycoproteins in µg / ml. Detailed description of the invention Definitions As used herein, the term “ambient temperature” or “room temperature” refers to a temperature of between about 15° C to about 30° C, including between about 18°C to about In the present disclosure, the singular forms “a”, “an” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a solvent” is a reference to one or more of such solvents and equivalents thereof to those skilled in the art, and so forth. As used herein, the term “about” or “around” will be understood by a person of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” or “around” will mean up to plus or minus 10% of the particular term. The percentages are herein expressed by weight, unless otherwise specified. According to the invention, the term “comprise(s)” or “comprising” (and other comparable terms, e.g., “containing,” and “including”) is “open-ended” and can be generally interpreted such that all of the specifically mentioned features and any optional, additional and unspecified features are included. It can also be interpreted as the phrase “consisting essentially of” where the specified features and any optional, additional and unspecified features that do not materially affect the basic and novel characteristic(s) of the claimed invention are included or the phrase “consisting of” where only the specified features are included, unless otherwise stated. As used herein, the term “compound of the invention” refers to the deuterated derivative compounds of 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5- [1,2]oxaphosphinane as defined in the present description, or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof For the purpose of the invention, the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use. In particular, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio. The term “pharmaceutically acceptable salt” is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound. The pharmaceutically acceptable salts comprise: (1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2- hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2- naphtalenesulfonic, propionic, succinic, dibenzoyl-L- tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and (2) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine. N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers. In a preferred aspect of the disclosure, the stereoisomers include diastereoisomers and enantiomers. The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons. The “solvates” of the present disclosure include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. It can be for example an hydrate or an alcoholate such as an ethanolate. As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, chickens, amphibians, reptiles, etc. Within the context of the present disclosure, the term treatment denotes curative, symptomatic, and preventive treatment. Pharmaceutical compositions, kits, products and combined preparations of the invention can be used in humans with a disease or disorder. The pharmaceutical compositions, kits, products and combined preparations of the invention will not necessarily cure the patient but will delay or slow the progression or prevent further progression of the disease or disorder, and / or ameliorating thereby the patients’ condition. In treating the disease or disorder, the pharmaceutical composition of the invention is administered in a therapeutically effective amount. Whenever within this whole specification "treatment of a disease or disorder" or the like is mentioned with reference to the pharmaceutical composition of the invention, there is meant: a) a method for treating a disease or disorder, said method comprising administering a therapeutically effective amount of a compound of the invention or of a pharmaceutical composition comprising said compound to a subject in need of such treatment; b) the use of a compound of the invention or of a pharmaceutical composition comprising said compound for the treatment of a disease or disorder; c) the use of a compound of the invention or of a pharmaceutical composition comprising said compound for the manufacture of a medicament for the treatment of a disease or disorder; and / or d) a compound of the invention or of a pharmaceutical composition comprising said compound for use in the treatment a disease or disorder. As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder. By "therapeutically effective amount", it is meant the quantity of the pharmaceutical composition of the invention which prevents, removes or reduces the deleterious effects of a disease or disorder in mammals, including humans, alone or in combination with the other active ingredients of the pharmaceutical composition, kit, product or combined preparation. It is understood that the administered dose may be lower for each compound in the composition to the “therapeutic effective amount” define for each compound used alone or in combination with other treatments than the combination described here. The “therapeutic effective amount” of the composition will be adapted by those skilled in the art according to the patient, the pathology, the mode of administration, etc. As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients. Each particular / preferred / specific embodiment specified herein may be combined with each other, unless incompatible. Deuterated derivative compounds The present invention relates to a deuterated derivative compound of 3-Hydroxy-4,5-bis- benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane (also called Compound A), or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof. In the context of the invention, a “deuterated derivative compound of Compound A” differs from Compound A only by the substitution of at least one hydrogen atom by a deuterium atom. Therefore, in the context of the invention, a deuterated derivative compound is a compound comprising at least one specified position in the molecule enriched with deuterium above the naturally occurring distribution of deuterium. In particular, deuterium enrichment is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% (e.g., at least about 50%) of deuterium at the at least one specified position. In certain embodiments, deuterium enrichment is at least about 90%, 95% or 98% of deuterium at the at least one specified position. In other words, at least one of the available positions of the deuterated derivative compound has deuterium enrichment above the naturally occurring distribution of deuterium, such as at least about 10%, 25%, 50%, 75%, 90%, 95% or 98%. In certain embodiments, at least one of the available positions of the deuterated derivative compound has deuterium enrichment of at least about 90%, 95% or 98%. The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in place of hydrogen. For example, deuterium enrichment of 10% at a given position means that 10% of molecules in a given sample contain deuterium at that position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a molecule synthesized using non- deuterium-enriched starting materials or reagents is about 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In some embodiments, the present invention relates to a deuterated derivative compound of Compound A having deuterium enrichment above the naturally occurring distribution of deuterium, such as at least about 10%, 25%, 50%, 75%, 90%, 95% or 98%. Advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (I): B1A1wherein, A1 to A3 are independently of each other -CH2- or -CD2-; and B1to B4are independently of each other a phenyl or a phenyl-d5; with the proviso that at least one of A1to A3is -CD2- or at least one of B1to B4is phenyl-d5, or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof. In a first embodiment, in the compound of formula (I), at least one of A1to A3is -CD2-. For example, A1 is -CD2-, and A2 and A3 are -CH2-. As another example, A1 is -CH2-, and A2 and A3 are -CD2-. As a further example, A1 to A3 are -CD2-. In this first embodiment, B1to B4are, independently of each other, phenyl or phenyl-d5, preferably phenyl. In particular, at least one of A1 to A3 is -CD2-, and B1 to B4 are phenyl. For example, A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl. As another example, A1 is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl. As a further example, A1to A3are -CD2- , and B1to B4are phenyl. In a second embodiment, in the compound of formula (I), at least one of B1to B4is phenyl-d5. For example B4is a phenyl-d5 and B1to B3are phenyl. As another example, B1is a phenyl-d5 and B2 to B4 are phenyl. As a further example, B2 and B3 are phenyl-d5 and, B1 and B4 are phenyl. In this second embodiment A1to A3are, independently of each other, -CH2- or -CD2-, preferably -CH2-. In particular, at least one of B1 to B4 is a phenyl-d5, and A1 to A3 are -CH2-. For example B4 is a phenyl-d5, B1 to B3 are phenyl, and A1 to A3 are -CH2-. As another example, B1is a phenyl-d5, B2to B4are phenyl, and A1to A3are -CH2-. As a further example, B2and B3are phenyl-d5, B1 and B4 are phenyl, and A1 to A3 are -CH2-. Advantageously, the compound of formula (I) are deuterated on the benzyl group. Therefore, in a preferred embodiment of the invention, at least one of A1to A3is -CD2- and B1to B4are, independently of each other, phenyl or phenyl-d5, preferably phenyl. The present invention advantageously relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (I) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A2is -CD2-, A1and A3are -CH2-, and B1to B4are phenyl; or - A3 is -CD2-, A1 and A2 are -CH2-, and B1 to B4 are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1is -CD2-, A2and A3are -CH2-, B1to B3are phenyl, and B4is phenyl-d5; or - A2is -CD2-, A1and A3are -CH2-, B1to B3are phenyl, and B4is phenyl-d5; or - A3 is -CD2-, A1 and A2 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A1is -CH2-, A2and A3are -CD2-, B1to B3are phenyl, and B4is phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1 to A3 are -CD2-, B1 is phenyl-d5, and B2, B3 and B4 are phenyl; or - A1to A3are -CD2-, B2is phenyl-d5, and B1, B3and B4are phenyl; or - A1 to A3 are -CD2-, B3 is phenyl-d5, and B1, B2 and B4 are phenyl; or - A1 to A3 are -CD2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1to A3are -CD2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1to A3are -CH2-, B1is phenyl-d5, and B2, B3and B4are phenyl; or - A1 to A3 are -CH2-, B2 is phenyl-d5, and B1, B3 and B4 are phenyl; or - A1to A3are -CH2-, B3is phenyl-d5, and B1, B2and B4are phenyl; or - A1to A3are -CH2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1 to A3 are -CH2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1 to A3 are -CH2-, B1 to B3 are phenyl-d5, and B4 is phenyl; or - A1to A3are -CH2-, and B1to B4are phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (I) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A2is -CD2-, A1and A3are -CH2-, and B1to B4are phenyl; or - A3is -CD2-, A1and A2are -CH2-, and B1to B4are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1 is -CD2-, A2 and A3 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A1is -CH2-, A2and A3are -CD2-, B1to B3are phenyl, and B4is phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CD2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1 to A3 are -CH2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1 to A3 are -CH2-, B1 to B3 are phenyl-d5, and B4 is phenyl; or - A1to A3are -CH2-, and B1to B4are phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (I) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A1is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CH2-, B1is phenyl-d5, and B2, B3and B4are phenyl; or - A1to A3are -CH2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1 to A3 are -CH2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1to A3are -CH2-, and B1to B4are phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (I) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A2is -CD2-, A1and A3are -CH2-, and B1to B4are phenyl; or - A3is -CD2-, A1and A2are -CH2-, and B1to B4are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl. In a preferred embodiment, the present invention relates to a deuterated derivative compound of Compound A, wherein said deuterated derivative compound is selected in the group consisting of: D or The compounds of formula (I) as defined in the specification can be in the form of a stereoisomer of formula (II) or (III) below, or a mixture thereof: B1A1B1A1wherein In a particular embodiment, the deuterated derivative compounds of Compound A of the invention are compounds of formula (II), in particular, isolated compounds of formula (II). In another particular embodiment, the deuterated derivative compounds of Compound A of the invention are compounds of formula (III) , in particular, isolated compounds of formula (III). In a particular embodiment, the deuterated derivative compounds of Compound A of the invention are in the form of a mixture of compounds of formula (II) and (III). Preferably, the deuterated derivative compounds of Compound A of the invention are compounds of formula (II), more preferably isolated compounds of formula (II). Therefore, the present invention advantageously relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (II) as defined above wherein: - A1is -CD2-, A2and A3are -CH2-, and B1to B4are phenyl; or - A2 is -CD2-, A1 and A3 are -CH2-, and B1 to B4 are phenyl; or - A3 is -CD2-, A1 and A2 are -CH2-, and B1 to B4 are phenyl; or - A1is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl; or - A1 is -CD2-, A2 and A3 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A2 is -CD2-, A1 and A3 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A3is -CD2-, A1and A2are -CH2-, B1to B3are phenyl, and B4is phenyl-d5; or - A1 is -CH2-, A2 and A3 are -CD2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CD2-, B1is phenyl-d5, and B2, B3and B4are phenyl; or - A1to A3are -CD2-, B2is phenyl-d5, and B1, B3and B4are phenyl; or - A1 to A3 are -CD2-, B3 is phenyl-d5, and B1, B2 and B4 are phenyl; or - A1 to A3 are -CD2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1to A3are -CD2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1 to A3 are -CH2-, B1 is phenyl-d5, and B2, B3 and B4 are phenyl; or - A1 to A3 are -CH2-, B2 is phenyl-d5, and B1, B3 and B4 are phenyl; or - A1to A3are -CH2-, B3is phenyl-d5, and B1, B2and B4are phenyl; or - A1 to A3 are -CH2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1 to A3 are -CH2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1to A3are -CH2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1to A3are -CH2-, and B1to B4are phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (II) as defined above wherein: - A1is -CD2-, A2and A3are -CH2-, and B1to B4are phenyl; or - A2 is -CD2-, A1 and A3 are -CH2-, and B1 to B4 are phenyl; or - A3 is -CD2-, A1 and A2 are -CH2-, and B1 to B4 are phenyl; or - A1is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl; or - A1is -CD2-, A2and A3are -CH2-, B1to B3are phenyl, and B4is phenyl-d5; or - A1 is -CH2-, A2 and A3 are -CD2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl; or - A1to A3are -CD2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1 to A3 are -CD2-, B1 to B3 are phenyl-d5, and B4 is phenyl; or - A1 to A3 are -CH2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CH2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1 to A3 are -CH2-, and B1 to B4 are phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (II) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1to A3are -CD2-, and B1to B4are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1 to A3 are -CH2-, B1 is phenyl-d5, and B2, B3 and B4 are phenyl; or - A1to A3are -CH2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1 to A3 are -CH2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or - A1 to A3 are -CH2-, and B1 to B4 are phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl-d5. More advantageously, the present invention relates to a deuterated derivative compound of Compound A, said deuterated derivative compound being of the general formula (II) as defined above wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A2 is -CD2-, A1 and A3 are -CH2-, and B1 to B4 are phenyl; or - A3is -CD2-, A1and A2are -CH2-, and B1to B4are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl. In a most preferred embodiment, the present invention relates to a deuterated derivative compound of Compound A, wherein said deuterated derivative compound is selected in the group consisting of: D D OBn OBn OBn OBn or a acceptable salt or solvate thereof. The deuterated derivative compound of the invention is preferably of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ik), preferably (Ia), (Id), (Ie), (If) or (Ig), more preferably (Ia), (Id) or (Ie), as defined above. In a particular embodiment, the deuterated derivative compound of the invention is preferably of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIk), preferably (IIa), (IId), (IIe), (IIf) or (IIg), more preferably (IIa), (IId) or (IIe), as defined above. The invention also relates to a deuterated derivative compound of compound A as defined above, especially one of those selected from compounds (Ia) to (Ik) and (IIa) to (IIk), or a pharmaceutical composition comprising it, for use as a drug. The invention also relates to the use of a deuterated derivative compound of compound A as defined above, especially one of those selected from compounds (Ia) to (Ik) and (IIa) to (IIk), or a pharmaceutical composition comprising it, for the manufacture of a medicament. The invention further relates to a method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a a deuterated derivative compound of compound A as defined above, especially one of those selected from compounds (Ia) to (Ik) and (IIa) to (IIk), to said subject. The method for preparing compound A is known in the art, in particular some methods can be found in international applications WO2009 / 004096, WO2014 / 128429 and WO 2018 / 054925. A method for preparing the deuterated derivative compounds of compound A can be conducted, for example, by using the corresponding deuterated starting compound, and synthetizing by the same route. Some other methods for preparing the deuterated derivative compounds of compound A according to the invention are disclosed hereinbelow in the examples section. Pharmaceutical compositions The present invention further relates to pharmaceutical composition comprising a deuterated derivative compound according to the invention, and one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" is meant to encompass any carrier (e.g., support, substance, solvent, etc.) which does not interfere with effectiveness of the biological activity of the active ingredient(s) and that is not toxic to the host to which it is administered. For example, for parental administration, the active compounds(s) may be formulated in a unit dosage form for injection in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution. The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicle, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations suitable for parental administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. The pharmaceutical or veterinary composition as disclosed herein may further comprise an additional active ingredient or drug. Deuterated derivative compounds for use for treating cancer The present invention further relates to a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it, for use as a medicament, in particular for use in a method for treating cancer and / or for a use in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer. The present invention further provides for a use of a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it, for the manufacture of a pharmaceutical composition for use in a method for treating cancers and / or in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer. The present invention further provides for a method for the treatment of cancers and / or for reducing or preventing the appearance of metastases in a patient afflicted with a cancer by administering in a patient in need of such treatment an effective amount of a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it. In particular, the deuterated derivative compounds described herein are useful as active principles in pharmaceutical compositions for human or veterinary use, intended for treating cancers (metastatic or primary), i.e. cancer cells, or for preventing the appearance of cancers, especially for reducing or preventing the appearance of metastases in a patient afflicted by a cancer. In the case where the patient is afflicted by a metastatic cancer, the deuterated derivative compounds as described herein are especially directed in particular toward reducing or preventing the appearance of additional metastases. In the present description, a patient denotes both an animal, in particular a non-human mammal, and a person. The term “patient afflicted by a cancer” means both a patient afflicted by a declared cancer (primary or metastatic) and a hidden cancer, i.e. invisible, the existence of which has been revealed, for example, by the discovery of metastases. In the present description, cancer cells denote cells having typical characteristics of cells that cause cancer, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and high speed of proliferation, and certain specific morphological characteristics. Cancer cells are often in the form of a tumor, but such cells may exist alone in the body, or may be non- tumor-forming cancer cells, such as leukemic cells. Cancer cells may be associated with numerous types of cancers, comprising, without limitation, leukemia, a lymphoma, a melanoma, a neuroblastoma, liver cancer, ovarian cancer, brain cancer, lung cancer, bowel cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, esophageal cancer, uterine cancer, cervical cancer, kidney cancer, stomach cancer, bladder cancer, a cerebrospinal cancer or a colorectal cancer. The deuterated derivative compounds or the pharmaceutical compositions of the invention may be used for the therapeutic treatment of at least one of the cancers mentioned above. When a deuterated derivative compound according to the invention is used in the context of an antimetastatic treatment, the patient is afflicted with a “primary” cancer. This cancer is a cancer that is capable of metastatizing, which may be, without limitation, a melanoma, a glioblastoma multiform, a lung cancer, especially non-small-cell lung cancer, bowel cancer or colorectal cancer, breast cancer, prostate cancer, testicular cancer, cervical cancer, kidney cancer, preferably a glioblastoma multiform, breast cancer or non-small-cell lung cancer. The deuterated derivative compounds of the invention are particularly suited for treating the risk of metastasis in a patient afflicted with a glioblastoma multiform. It is now recognized that glioblastoma multiform (GBM), commonly known as glioblastoma, may be a cancer with metastatic potential giving rise to a generalized pathology (Schönsteiner, S. S. et al., Journal of Clinical Oncology 2011, 29, 23, 668-671). Cancer cells originating from glioblastomas may effectively cross the blood-brain barrier and establish extraneural metastases. The reported sites of extraneural metastases are the lungs, the pleura, the liver, cervical lymphatic nodules, bones and bone marrow. The cancer is more particularly selected from glioblastoma multiform, breast cancer and non- small-cell lung cancer, preferably glioblastoma multiform. Deuterated derivative compounds for use for treating fibrotic disease The present invention further relates to a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it, for use as a medicament, in particular for use in a method for treating fibrotic diseases. The present invention further provides for a use of a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it, for the manufacture of a pharmaceutical composition for use in a method for treating fibrotic diseases. The present invention further provides for a method for the treatment of fibrotic diseases by administering in a patient in need of such treatment an effective amount of a deuterated derivative compound as described herein, or a pharmaceutical composition comprising it. According to the present invention, the term "fibrosis" includes in particular a lung, kidney, liver, heart, muscle, skin, soft tissue (e.g. mediastinum or retroperitoneum), bone marrow, intestinal, aortic and joint (e.g. knee, shoulder or other joints) fibrosis. In particular, the term "fibrotic disease" resulting from fibrosis includes, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers’ pneumoconiosis), nephrogenic systemic fibrosis, Crohn’s disease, keloid, old myocardial infarction, scleroderma, systemic sclerosis, arthrofibrosis and some forms of adhesive capsulitis. In a particular aspect, the fibrotic disease is liver, kidney or skin fibrosis, more specifically in the treatment of kidney or skin fibrosis, including keloids or scleroderma. In a particular aspect, the fibrotic disease is aortic fibrosis. In a particular aspect, the treatment of fibrosis is by inhibition of GnT-V activity. In a further particular aspect, the treatment of fibrosis is by inhibition of the production of collagen fibers, more specifically collagen of types 1, 3 and / or 4, and / or by inhibition of mechanisms implicated in cell matrix and / or cell / cell interactions, including inhibition of fibroblast migration. In one embodiment the treatment of a fibrotic disease is a therapeutic treatment. In therapeutic applications, compounds are administered to a subject already suffering from a disorder or condition as described above, in an amount sufficient to cure, alleviate or partially arrest the condition or one or more of its symptoms. Such therapeutic treatment may result in a decrease in severity of disease symptoms, or an increase in frequency or duration of symptom-free periods. An amount adequate to accomplish this is defined as a "therapeutically effective amount". In one embodiment the treatment of a fibrotic disease is a prophylactic treatment. In prophylactic applications, formulations are administered to a subject at risk of a disorder or condition as described above, in an amount sufficient to prevent or reduce the subsequent effects of the condition or one or more of its symptoms. An amount adequate to accomplish this is defined as a "prophylactically effective amount". The treatment involves the administration of the compound or a pharmaceutical composition containing the same to a patient having a declared disorder to cure, delay, or slow down the progress, thus improving the condition of the patient or to a healthy subject, in particular a subject who is at risk of developing a fibrotic disease. The subjects to be treated according to the invention can be selected on the basis of several criteria associated to fibrotic diseases such as previous drug treatments, associated pathologies, genotype, exposure to risk factors, viral infection, as well as any other relevant biomarker that can be evaluated by means of imaging methods and immunological, biochemical, enzymatic, chemical, or nucleic acid detection method. Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting. Examples Example 1: Synthesis of di-deuterated derivative compounds according to the invention 1- Synthesis of 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5- [1,2]oxaphosphinane (also named PST3.1a) The synthesis of PST3.1a was performed starting from commercially available 2,3,5-tri-O- benzylarabinofuranose 3 and ethyl phenylphosphinate 4 (Scheme 1). Scheme 1: synthesis of PST3.1a Treatment of an equimolar mixture of 3 and 4 in THF by potassium tert-butoxide (tBuOK) provided a mixture of 4 diastereoisomers (scheme 2). Scheme 2 PST3.1b was the main impurity (the ratio PST3.1a / PST3.1b / other diastereoisomers obtained was: 29 / 31 / 39 (by31P NMR). The overall process was the following (scheme 3): Scheme 3 Ethyl acetate was thus added to the quenched mixture to allow decantation of the organic layer. After aqueous washings and without drying, solvents were switched to methyl tert-butylether (MTBE) under vacuum until precipitation occurred. MTBE was added and the resulting yellow suspension was filtered to afford crude PST3.1a in 20-25% yield (% by weight) and 75 / 25 to 78 / 22 PST3.1a / PST3.1b ratio (measured by31P NMR). Both other diastereoisomers were removed from the mixture by MTBE. PST3.1a is then purified from this mixture by successive recrystallization in ethanol and acetone. 2- Synthesis of di-deuterated derivatives of PST3.1a OO a) ZnCl2, Ac2O / AcOH, rt, 5 h First step: O-Protection In a tricol flask (equipped with a bubbler) previously heated under vacuum and placed under N2 is introduced the compound PST 3.1a (6.16g, 11.3mmol, 1eq.) in anhydrous THF (60mL). The medium is placed at 0°C and NaH (60% dispersion in mineral oil, 678.7mg, 1.5eq) is added per portion. After stirring from 0°C to RT until the off-gassing disappears (approx. 2h), TBDMSCl (2.11g, 1.2eq.) is added and the mixture is stirred at RT until completion of the reaction monitored by TLC. THF is removed under vacuum, the residue diluted in AcOEt (30mL), washed with water (2x10mL) and brine (2x10mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude yellow oil is directly used without purification. 7 1 O - bis -6- -3- Internal reference PPL-010 (purified)31P NMR (162 MHz, CDCl3) δ 35.17.1H NMR (400 MHz, CDCl3) δ 7.97 – 7.77 (m, 2H, CHAr), 7.71 – 7.56 (m, 1H, CHAr), 7.51 (td, J = 7.6, 3.6 Hz, 2H, CHAr), 7.38 – 7.25 (m, 10H, CHAr), 7.28 – 7.19 (m, 3H, CHAr), 7.09 – 7.01 (m, 2H, CHAr), 4.97 (d, J = 11.7 Hz, 1H, PhCH2), 4.90 (d, J = 11.7 Hz, 1H, PhCH2), 4.83 (d, J = 10.6 Hz, 1H, PhCH2), 4.65 (d, J = 10.6 Hz, 1H, PhCH2), 4.62 (d, J = 12.0 Hz, 1H, PhCH2), 4.56 – 4.53 (m, 1H,6CH), 4.53 (d, J = 12 Hz, 1H, PhCH2), 4.21 (td,3JHH =3JHH = 9.7,3JHP = 3.5 Hz, 1H,4CH), 4.07 (dd,3JHH = 10.1,2JHP = 1.0 Hz, 1H,3CH), 4.03 (t,3JHH=3JHH= 9.7 Hz, 1H,5CH), 3.97 (dt,2JHH= 11.2,3JHH=4JHP= 2.4Hz, 1H,7CH2), 3.74 (dd,2JHH = 11.2,3JHH = 1.9 Hz, 1H,7CH2), 0.72 (s, 9H, tBuSi-), -0.17 (s, 3H, CH3Si-), -0.64 (s, 3H, CH3Si-). LCMS (ES+): m / z 659.7 [M+H]+Second step: Acetolysis In a bicol flask previously heated under vacuum and then placed under N2 is introduced crude 2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)- 2-phenyl-1,2-oxaphosphinane 2-oxide (1 eq.) and dissolved in Ac2O / AcOH (2 / 1 v / v, 80mL). Anhydrous ZnCl2 (9eq.) is then introduced and the mixture stirred at RT for 5h. The reaction is quenched with water, stirred for 10min and carefully neutralized with sat. aqueous K2CO3 at 0°C until gas evolution stopped. The aqueous phase is then extracted with AcOEt (3x20mL). The resulting organic phase is washed with water (2x10mL), brine (2x10mL), dried over MgSO4, filtered and concentrated under vacuum. The residue is then co-evaporated (5-6 times) with cyclohexane to yield the crude product as a pale yellow waxy solid which is directly used without purification. Third step: Deacetylation In a bicol flask previously heated under vacuum and placed under Ar is introduced the crude ((2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2-oxido-2-phenyl-1,2- oxaphosphinan-6-yl)methyl acetate (1 eq.) in dry MeOH (30mL) and then tBuOK (0.6eq.) is added. The mixture is stirred at RT for 2h. TLC showed completion of the reaction. The mixture is concentrated under vacuum and the yellow oily crude residue is purified by normal-phase flash chromatography (eluant AcOEt / PE 50:50) to yield the desired product as a white powder (m=3.88g, 60.3% over 3 steps). 7 1 O 10 (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-((tert- butyldimethylsilyl)oxy)-6-(hydroxymethyl)-2-phenyl-1,2- oxaphosphinane 2-oxide / Exact Mass: 568,2410 / Internal reference PPL-01131P NMR (162 MHz, CDCl3) δ 35.46.1H NMR (400 MHz, CDCl3) δ 7.91 – 7.81 (m, 2H, CHAr), 7.66 – 7.57 (m, 1H, CHAr), 7.51 (td, J = 7.6, 3.6 Hz, 2H, CHAr), 7.36 – 7.20 (m, 7H, CHAr), 7.26 – 7.14 (m, 3H, CHAr), 4.99 (d, J = 11.7 Hz, 1H, PhCH2), 4.91 (d, J = 11.7 Hz, 1H, PhCH2), 4.87 (d J =, 10.8 Hz, 1H, PhCH2), 4.71 (d, J = 10.8 Hz, 1H, PhCH2), 4.47 (ddt,3JHH = 9.7,3JHH = 3.1,3JHH = 2.9,3JHP = 2.9Hz, 1H,6CH), 4.24 (td,3JHH =3JHH = 9.6,3JHP =3.5 Hz, 1H,4CH), 4.08 (dd,3JHH= 10.0,2JHP=1.4 Hz, 1H,3CH), 3.97 – 3.85 (m, 3H,7CH2,7CH2,5CH), 0.72 (s, 9H, tBu), -0.15 (s, 3H, CH3), -0.62 (s, 3H, CH3). HRMS (ESI) m / z [M+H]+calcd for C31H42O6PSi, 569.2483; found, 569.2478 (PPL-106) Fourth step: Di-benzylation (first protocol) A flame-dried 25mL bicol flask, topped with a refrigerator and placed under Ar is charged with (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6-(hydroxymethyl)-2- phenyl-1,2-oxaphosphinane 2-oxide (129.6mg, 0.22mmol, 1 eq.), PhCD2Br (46.9mg, 1.2eq.) DD vacuum. The residue is diluted with AcOEt (20mL), washed with sat. aq. NaHCO3 (1x10mL), distilled water (3x5mL) and brine (1x5mL), dried over Na2SO4, filtered and concentrated under vacuum. The yellow-orange solid crude is directly used without purification. (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2-phenyl-6- ((phenylmethoxy-d2)methyl)-1,2-oxaphosphinane 2-oxide Chemical Formula: C38H45D2O6PSi / Exact Mass: 660,3005 / Internal reference PPL-00731P NMR (162 MHz, CDCl3) δ 35.51.1H NMR (400 MHz, Chloroform-d) δ 7.91-7.86 (m, 2H, CHAr), 7.64 – 7.59 (m, 1H, CHAr), 7.54 – 7.49 (m, 2H, CHAr), 7.36 – 7.22 (m, 13H, CHAr), 7.05 – 7.03 (m, 2H, CHAr), 4.98 (d, J = 11.7 Hz, 1H, PhCH2), 4.90 (d, J = 11.7 Hz, 1H, PhCH2), 4.83 (d, J = 10.6 Hz, 1H, PhCH2), 4.64 (d, J = 10.6 Hz, 1H, PhCH2), 4.53 (ddt, 3JHH = 10.1, 3JHH = 4.3, 3JHH = 2.2, , 3JHP = 2.2 Hz, 1H, 6CH), 4.21 (td, 3JHH = 3JHH =9.7, 3JHP =3.5 Hz, 1H, 4CH), 4.06 (dd, 3JHH = 10.1, 2JHP =1.2 Hz, 1H, 3CH), 4.02 (t, 3JHH = 3JHH = 9.7 Hz, 1H, 5CH), 3.97 (dt, 2JHH = 11.1, 3JHH = 2.4 Hz, 4JHP = 2.4 Hz, 1H, 7CH2), 3.74 (dd, 2JHH = 11.2, 3JHH = 2.0 Hz, 1H, 7CH2), 0.72 (s, 9H, tBu), -0.16 (s, 3H, CH3), -0.64 (s, 3H, CH3). LCMS (ES+): m / z 661.7 [M+H]+Fifth-step: O-deprotection A monocol flask is charged with crude (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-((tert- butyldimethylsilyl)oxy)-2-phenyl-6-((phenyl methoxy-d2)methyl)-1,2-oxaphosphinane 2- oxide in MeOH (1mL). The flask is placed under Ar and HCl (4M in dioxane, 4mL) is introduced. The mixture is stirred at RT for 5h and concentrated under vacuum. The crude residue is purified twice by normal-phase flash chromatography (eluant AcOEt / cyclohexane) to yield the desired product as a white powder (m=64.4mg, 51.7% over 2 steps). DD1 (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-hydroxy-2-phenyl-6- ((phenylmethoxy-d2)methyl)-1,2-oxaphosphinane 2-oxide (=compound IIa) Chemical Formula: C32H31D2O6P / Exact Mass: 546,2140 / Internal reference PPL-01331P NMR (162 MHz, CDCl3) δ 36.17.1H NMR (400 MHz, CDCl3) δ 7.91 – 7.79 (m, 2H), 7.69 – 7.55 (m, 1H), 7.54 – 7.44 (m, 2H), 7.38 – 7.24 (m, 12H), 7.27 – 7.16 (m, 3H), 4.96 (d, J = 11.0 Hz, 1H), 4.93 (d, J = 10.8 Hz, 1H), 4.91 (d, J = 11.0 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 4.54 (ddt, J = 10.1, 4.5, 2.5 Hz, 1H), 4.18 (td, J = 9.5, 2.6 Hz, 1H), 4.01 (dd, J = 9.8, 1.9 Hz, 1H), 3.96 (t, J = 9.6 Hz, 1H), 3.94 (dt, J = 11.1, 2.5 Hz, 1H), 3.76 (dd, J = 11.2, 2.0 Hz, 1H). LCMS (ES+): m / z 547.6 [M+H]+ 3- Synthesis of hexa-deuterated derivatives of PST3.1a To a stirred solution of methyl D-arabinofuranoside (300mg, 1.83mmol, 1 eq.) in dry DMF (18mL) at 0°C is added NaH (60% dispersion in mineral oil, 255.9mg, 3.5eq.) under dry nitrogen. After stirring for 45min at 0-5°C, PhCD2Br (1g, 3.2eq.) is added and the medium is allowed to warm up to room temperature. After completion of the reaction monitored by TLC (thin layer chromatography), the medium is diluted with water (100mL) and extracted with AcOEt (3x10mL). The resulting organic phase is washed with brine (10x5mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue is purified by normal- phase flash chromatography (eluant 10-25% AcOEt / PE) to yield desired product as a yellow syrup (m=826.7mg, 97.3%). Ph (3S,4R,5R)-2-methoxy-3,4-bis(phenylmethoxy-d2)-5- ((phenylmethoxy-d2)methyl)tetrahydrofuran Chemical Formula: C27H24D6O5 / Exact Mass: 440,2470 / Internal reference PPL-X’’ 1H NMR (400 MHz, CDCl3) δ 7.62 – 6.94 (m, 15H), 4.95 (s, 1H), 4.21 (ddd, J = 6.4, 5.2, 4.1 Hz, 1H), 3.99 (dd, J = 2.8, 1.0 Hz, 1H), 3.90 (ddd, J = 6.4, 2.9, 0.5 Hz, 1H), 3.73 – 3.51 (m, 2H), 3.40 (s, 3H). HRMS (ESI) m / z [M+Na]+calcd for C27H24D6O5Na, 463.2362; found, 463.2361. Second step: Demethylation A round-bottom flask is charged with (3S,4R,5R)-2-methoxy-3,4-bis(phenylmethoxy-d2)-5- ((phenylmethoxy-d2)methyl)tetrahydrofuran (826.7mg, 1.88mmol, 1eq.), H2SO4(3M aq. solution, 4.7mL, 7.5eq.), AcOH (14.1mL) and topped with a refrigerant. The mixture is heated at 100°C for 30min, cooled down to room temperature and carefully neutralized with sat. aqueous K2CO3at 0°C until gas evolution stopped. The aqueous phase is then extracted with DCM (3x10mL), the resulting organic phase washed with water (10mL) and brine (10mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue is purified by normal-phase flash chromatography (eluant 20-30% AcOEt / PE) to yield desired product as a yellow syrup which crystallized upon standing (m=572.6mg, 69%). Ph (3S,4R,5R)-3,4-bis(phenylmethoxy-d2)-5-((phenylmethoxy- d2)methyl)tetrahydrofuran-2-ol (mixture of two anomers ratio 54:46) Chemical Formula: C26H22D6O5 / Exact Mass: 426,2313 / Internal reference PPL-X4 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.24 (m, 30H), 5.40 (s, 1H), 5.33 (d, J = 3.5 Hz, 1H), 4.46 (td, J = 6.0, 3.8 Hz, 1H), 4.19 – 4.10 (m, 2H), 4.02 (dd, J = 4.8, 4.4 Hz, 1H), 3.98 (dd, J = 1.9, 0.7 Hz, 1H), 3.94 (ddd, J = 3.7, 1.9, 0.8 Hz, 1H), 3.65 – 3.46 (m, 4H). HRMS (ESI) m / z [M+Na]+calcd for C26H22D6O5Na, 449.2206; found, 449.2203. Third step: Introduction of P To a stirred solution of (3S,4R,5R)-3,4-bis(phenylmethoxy-d2)-5-((phenylmethoxy- d2)methyl)tetrahydrofuran-2-ol (262.7mg, 0.62mmol, 1eq.) and ethylphenylphosphinate (107.5mg, 1eq.) in dry THF (1mL) was added freshly sublimated tBuOK (21.1mg, 30mol%). The mixture was stirred at room temperature overnight.31P NMR revealed no completion of the reaction. Additional freshly sublimated tBuok (50mol%) and dry THF (1mL) was added and the mixture stirred overnight.31P NMR indicated completion of the reaction. Chloroform (5mL) was added to the crude oil. The organic solution was washed with a saturated aqueous solution of ammonium chloride (3 × 5mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under vacuum. The crude product was purified in three steps: a) First purification by preparative TLC (eluant CHCl3 / ethyl acetate 9:1) to isolate a mixture of 3 diastereoisomers, b) Precipitation of diastereoisomers 3.1a-d6 and 3.1b-d6 with ether and c) final purification by preparative TLC (eluant CHCl3 / Et2O / toluene 6:3:1) to separate 3.1a-d6and 3.1b-d6. 3.1a-d6(compound (IIe): White powder (m=12.6mg),31P NMR purity= 100%, HPLC purity = 97.5% Ph (2S,3S,4S,5S,6R)-3-hydroxy-2-phenyl-4,5-bis(phenylmethoxy-d2)-6- ((phenylmethoxy-d2)methyl)-1,2-oxaphosphinane 2-oxide Chemical Formula: C32H27D6O6P / Exact Mass: 550,2391 / Internal reference PPL-S2-P1 31P NMR (162 MHz, CDCl3) δ 35.88. 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.79 (m, 2H, CHAr), 7.67 – 7.56 (m, 1H, CHAr), 7.55 – 7.44 (m, 2H, CHAr), 7.40 – 7.26 (m, 13H, CHAr), 7.25 – 7.17 (m, 2H, CHAr), 4.61 – 4.47 (m, 1H,6CH), 4.17 (td, J = 9.5, 2.4 Hz, 1H,4CH), 4.05 – 3.92 (m, 3H,3CH +5CH +7CH2), 3.76 (dd, J = 11.1, 1.8 Hz, 1H,7CH2). HRMS (ESI) m / z [M+H]+calcd for C32H28D6O6, 551.24641; found, 551.24652. 3.1b-d6: White powder (m=9.9mg),31P NMR purity= 100%, HPLC purity = 98% (2S,3R,4S,5S,6R)-3-hydroxy-2-phenyl-4,5-bis(phenylmethoxy-d2)-6- D O ((phenylmethoxy-d2)methyl)-1,2-oxaphosphinane 2-oxide 7 1 O O D D 6 2 P 2 P0h Chemical Formula: C32H27D6O6P / Exact Mass: 550,2391 / Internal 5 3 4 Ph O OH reference PPL-S2-P2 D O D Ph 31P NMR (162 MHz, CDCl3) δ 36.51. 1H NMR (400 MHz, CDCl3) δ 8.07 – 7.89 (m, 2H, CHAr), 7.76 – 7.57 (m, 1H, CHAr), 7.56 – 7.46 (m, 2H, CHAr), 7.42 – 7.27 (m, 13H, CHAr), 7.24 – 7.19 (m, 2H, CHAr), 4.54 (dtd,3JHH,trans = 9.8,3JHH =3JHP = 3.2,3JHH = 2.0 Hz, 1H,6CH), 4.42 (t,3JHH,cis =3JHP = 3.1 Hz, 1H,3CH), 4.35 (dd,3JHH,trans= 9.5,3JHH,cis= 2.8 Hz, 1H,4CH), 4.26 (t,3JHH,trans=3JHH,trans= 9.7 Hz, 1H, 5CH), 3.98 (dt,2JHH = 11.3,3JHH =4JHP = 2.9 Hz, 1H,7CH2), 3.77 (dd,2JHH = 11.3,3JHH = 1.9 Hz, 1H,7CH2). C13 n°30420 / 02 4- Synthesis of deuterated derivatives of PST3.1a: Phenyl-d5-H phosphinate OEtH OEt Under dry nitrogen, a solution of bromobenzene-d5(0,062 mol) in THF (100 mL) was added dropwise to Mg turnings (0,062 mol, 1,5 g) over a period of 1h. The reaction mixture was stirred vigorously and heated at reflux temperature for 1h. A solution of P(OEt)3(0,041 mol, 7,12 mL) in THF (120 mL) was then added rapidly over 5-10 min and the mixture heated at reflux temperature for 5h. The solvent was evaporated under vacuum after which Celite (previously dried in an oven at 100°C, 5 g) and n-heptane (50 mL) were added to the residue under N2 atm. The resulting gum was filtered and washed with n-heptane, under N2atm. After removal of the solvent under vacuum, the resulting oil was dissolved in THF (120 mL) at room temperature. Next, an aqueous solution of HCl (0,8 mL, 1M) was added. The mixture was stirred for 20 min, dried over Na2SO4, filtered and concentrated under vaccuum to give a pure oil wich was used without any purification (2,9 g, 41%)31P RMN (162 MHz, CDCl3): δ 24.71H RMN (400.13 MHz, CDCl3): δ 1.41 (t, J= 7.05 Hz, 3H), 4,18 (m, 2H), 7,61 (d, J= 562.7 Hz, 1H) 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-d5-2-oxo-2λ5- [1,2]oxaphosphinane synthesis Under dry nitrogen, 2,3,5-tri-O-benzyl-D-arabinofuranose (1 equiv, 0,017 mol) was added to a solution of ethyl phenyl-d5-phosphinates (1 equiv, 0,017 mol) in THF (35 mL) and then sublimated potassium tert-butoxide (0,2 equiv) was added to the solution. The reaction mixture was stirred at room temperature for 15h. After evaporation of the solvant under vacuum, chloroform was added to the crude oil. The organic solution was washed with a saturated aqueous solution of ammonium chloride (3 times). The organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under vacuum. The residue taken up in diethyl ether resulted in the selective precipitation of 2 diastereoisomers. The filtration product was dried, and then purified by 4 successive recrystallisations in acetone to give the pure diastereoisomer 3.1a-d5(200 mg, 2%) 31P RMN (162 MHz, CDCl3): δ 35,81H RMN (400,13 MHz, CDCl3): δ 3,80 (dd, 1H, J = 1.9 Hz, J= 11.1 Hz), 3,97-4,06 (m, 3H), 4,18 (dd, 1H, J= 9.7, 9.4, 2.5 Hz), 4,54-4,73 (m, 4H), 4,92-4,99 (m, 3H), 7,20-7,42 (m, 15H). LCMS (ES+): m / z 551.1 [M+H]+Example 2: Biological activity Materials and methods • Metabolic stability: Intrinsic Clearance Liver S9 fraction plus cofactors - experimental protocol Compounds have been tested at a final concentration of 0.5 µM with 0.01% DMSO, 0.25 % acetonitrile and 0.25 % methanol by default. Final S9 protein concentration: 0.1 mg / mL. The test compound is pre-incubated with pooled liver S9 and cofactors UDPGA (1 mM), glutathione (1 mM), and PAPS (1 mM), in phosphate buffer (pH 7.4) for 5 min in a 37ºC shaking waterbath. The reaction is initiated by adding NADPH-generating system and incubated for 0, 15, 30, 60, and 90 min. The reaction is stopped by transferring the incubation mixture to acetonitrile / methanol. Samples are then mixed and centrifuged. Supernatants are used for HPLC-MS / MS analysis. Samples are then analyzed by HPLC-MS / MS using selected reaction monitoring. The HPLC system consists of a binary LC pump with autosampler, a C-18 column, and a gradient. Data analysis Peak areas corresponding to the test compound are recorded. The compound remaining is calculated by comparing the peak area at each time point to time zero. The half-life is calculated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first order kinetics. In addition, the intrinsic clearance (Clint) is calculated from the half-life using the following equation: • Metabolic stability: Intrinsic Clearance liver microsomes Human - Experimental protocol Compounds have been tested at a final concentration of 0.1 µM with 0.01% DMSO, 0.25 % acetonitrile and 0.25 % methanol by default. Final microsomal protein concentration: 0.1 mg / mL The test compound is pre-incubated with pooled liver microsomes in phosphate buffer (pH 7.4) for 5 min in a 37ºC shaking waterbath. The reaction is initiated by adding NADPH-generating system and incubated for 0, 15, 30, 45, and 60 min. The reaction is stopped by transferring the incubation mixture to acetonitrile / methanol. Samples are then mixed and centrifuged. Supernatants are used for HPLC-MS / MS analysis. Samples are analyzed by HPLC-MS / MS using selected reaction monitoring. The HPLC system consists of a binary LC pump with autosampler, a C-18 column, and a gradient. Peak areas corresponding to the test compound are recorded. The compound remaining is calculated by comparing the peak area at each time point to time zero. The half-life is calculated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first order kinetics. In addition, the intrinsic clearance (Clint) is calculated from the half-life using the following equation: • Aqueous Solubility - experimental protocol - Assay buffers Dulbecco’s PBS NaCl 137 mM, KCl 2.7 mM, Na2HPO48.1 mM, KH2PO41.5 mM, pH 7.4 - Simulated gastric fluid (per USP) NaCl 34.2 mM, HCl 84.7 mM, pepsin 3.2 g / L, pH ~2 - Simulated intestinal fluid (per USP) KH2PO450 mM, NaOH 38 mM, pancreatin 10 g / L, pH 7.5 The test compound is prepared at 200 µM in the corresponding buffer from a 10 mM DMSO stock solution. The final DMSO concentration is 2 %. The buffer samples are mixed thoroughly followed by incubation at room temperature for 24 h. At the end of the incubation, the buffer samples are centrifuged and supernatants are then injected for the HPLC analysis. A calibration standard of the test compound is prepared at 200 µM in methanol / water (3 / 2, v / v) from a 10 mM DMSO stock solution on the day of HPLC analysis. Analytical method HPLC-UV / VIS with photodiode array detection, with monitoring at 205, 230, 260, and 300 nm wavelengths. The HPLC system consists of a C18 column, and the following gradient program: The aqueous solubility (µM) of the test compound is determined by comparing the peak area of the principal peak in the calibration standard (200 µM) with the peak area of the corresponding peak in each of the buffer samples. The range of the assay is approximately 0.5 µM to 200 µM. The chromatographic purity (%) is determined as the peak area of the principal peak relative to the total integrated peak areas in the HPLC chromatogram of the calibration standard. • Cell culture and sample preparation 300000 cells Hs578t are seeded in T75 flasks containing 12ml of culture medium (DMEM, 10%FBS and Insulin) for 4 days to reach 70% confluency before treatment of 3 flasks per condition / product for triplicate supernatant and cell extract. Compounds stock solution are prepared at 100µM in pure DMSO. Then intermediate dilutions are performed at 1 / 50 in cell culture medium preheated and kept at 37C°, corresponding to compounds at 2µM and 2% DMSO. Medium culture is adjusted at 10ml before addition of 2ml of intermediate compounds dilution Final volume in flasks culture of 12ml, compounds at 0,33µM and 0.3% DMSO. After 48h, various samples are prepared. For supernatant, culture media is transferred in flacon 15 ml for centrifugation to remove cells fragments 5min 300g and then aliquoted in 2ml tubes before storage at -80°C. For cell lysate, T75 flasks are washed two time with 10ml of cold HBSS- / -. After aspiration of T75 cold HBSS- / -, cells lysis is directly performed in the flask by addition of 500µL of RIPA buffer including protease inhibitor on ice for 10 min. Scrap cells using a scrapper and transfer in Eppendorf on ice for centrifugation. The aliquots are then vortexed for 2*1min, crush using pestle and sonicate 1 min. Finally samples are centrifugated at 4°C for 20 min 18000g and aliquoted in different format, frozen at -80°C before for analysis. • ELISA kit protocol Galectin-1 is quantified on supernatant samples using the Human LGALS1 Picokine assay from Boster Bio according to their protocol (EK0762) in 96 well plate format. GnT-V is quantified on cell lysate samples using the Human MGAT5 ELISA kit from Biorbyt according to their protocol (orb779023) in 96 well plate format. Final analysis is performed by 450nm DO reading using a Perkin Elmer plate reader. • PHA-L quantification Analysis performed on supernatant samples by lectin assay and based on fluorescence intensity measurement on 96 well plate format. This type of assay is able to measure interaction profile of glycoproteins secreted with a range of lectins. The proteins and glycoproteins contained in the culture medium supernatants were preliminary biotinylated before analysis. The interaction profile of each cell culture medium supernatants were studied at three concentrations corresponding to a dilution of the culture medium by a factor respectively of 5, 10 and 20 and repeated twice independently. • 3T3 Scratch assay In a 24-well plates, 3T3 cells are seeded at 100000 cells per well in 600 µl of DMEM containing 10% FBS and incubate at 37°C for 48h before treatment. Compounds stock solution are prepared at 3 mM in pure DMSO. hTGF1 is diluted at 1 / 1000 (10 µg / ml -> 10 ng / ml) in DMEM 0% FBS preheated. Then compounds intermediate dilution is done on DMEM containing hTGF1. The scratch is performed using the SPL Scar tool. Then medium is aspirate carefully using a vacuum pump and cell layer is washed with DMEM 0%. After aspiration, wells are filled with the new culture medium, 0% FBS, hTGF and test item in 0.3% DMSO. The plate is placed at 37°C and follow up is achieved by taking picture at 24h and 48h. Picture analysis is performed using ImageJ software and healing rate is calculated. • Glycosyltransferase Inhibition Assay The glycosyltransferase activity assay was performed using the UDP-Glo Glycosyltransferase Assay kit (Promega, cat#V6972). The GnT-V enzymatic reaction was achivied in 384 well microplate, by incubating in each well 16ng of purified GnT-V luminal domain with 0,25 mM of Bianntennary N-linked core pentasaccharide acceptor substrate (Dextra Laboratories, cat#M592) and 0,3 mM ultrapure UDP-GlcNAc donor substrate (supplied in the kit), in the presence of tested compounds previously solubilized in DMSO at a final concentration of 1% DMSO. Control condition is achivied by addition of pure DMSO to reach final concentration of 1%. The reaction is performed in a final volume of 6 μL, in a buffer containing 125 mM MES (pH 6.25), 10 mM EDTA, 200 mM GlcNAc (Merck, cat# PHR1432), 0.5% (v / v) Triton X-100, and 1 mg / mL BSA (Euromedex cat#LG-B-1000-100). After 180 min of incubation at room temperature, the enzymatic reaction is stopped by adding 6µl of UDP-glo enzyme detection to each well according to the Promega protocol. Then, an additional incubation of 60 min is perfromed at room temperature, before the luminescence quantification using a PHERAstar microplate reader. After raw data processing, IC50 is estimated for each compound. RESULTS • Metabolic Stability and solubility in biological fluids The results of metabolic stability and solubility in biological fluids are summarized in Table 1 below. Table 1 Intrinsic Intrinsic Clearance Liver Clearance Solubility microsomes Liver S9 Human Human Compound PBS, Clearance Half- Clearance Half- Simulated Simulated pH (µl / min / m life (µl / min / m life gastric intestinal 7.4 g) (min) g) (min) fluid (µM) fluid (µM) (µM) Compound 1324,1 5,235 304,3 7,592 12,87 4,144 1.002 PST3.1a Compound IIa 939,3 7,373 201,4 11,48 12,52 5,834 0.513 Compound IIf 1351,4 5,128 308,6 7,488 11,9 4,086 1.160 Compound IIe 961,2 7,21 206,9 11,17 11,11 7,828 0.764 Table 1 : Metabolic stability and solubility determination in various mediums. It is shown that deuterated compounds (IIa) and (IIe) have a higher metabolic stability than non- deuterated compound PST3.1a, leading to a higher half-life. Equivalent metabolic stability and half-life are observed for deuterated compound (IIf) and compound PST3.1a. The results of Table 1 also show that the deuterated compounds have a higher solubility in gastric fluid than compound PST3.1a. Solubility in other biological fluids is equivalent for all compounds. It could be conclude, without any restriction, that deuteration on the benzyl groups has significant effects on the metabolic stability, while deuteration on the phenyl group leads to an equivalent metabolization as compound PST3.1a. • Effect on MGAT5 expression Results are summarized in Figure 1. Figure 1 demonstrates the impact of compounds deuteriation on MGAT5 expression. The results show a stronger decrease of the GnT-V protein quantity in cancer cells after only 48h of treatment at 0.33µM, in comparison to PST3.1a in the same experimental conditions. • Effect on Galectin-1 on cell culture supernatant Results are summarized in Figure 2. Figure 2 shows an increased concentration of Galectin-1 protein in cancer cell supernatant after 48h of treatment at 0.33µM with deuterated compounds, equivalent to the effect of PST3.1a. Due to the decreased quantity of GnT-V, the number of complex N-glycan motives are reduced at the cell surface, consequently the binding of Galectin protein to this type of glycan motives is no longer possible leading to an increase of their quantity as free fraction on the supernatant. • N-glycosylation / PHA-L binding on cell culture supernatant Results are summarized in Figure 3 and Table 2 below. Results presented in Figure 3 and Table 2 demonstrate the effect of deuterated compounds on the secreted N-glycans motives due to the direct effect on GnT-V expression. PHA-L is the specific lectin recognizing the N-glycan motif put in place by GnT-V. Table 2 Equivalent Control Compound Compound Compound Compound glycoprotein (µg / ml) DMSO PST3.1a IIa IIf IIe PHA-L 215 254 75 195 226 Table 2 : Quantification of complex secreted N-glycans motifs on supernatant samples after 48h of treatment with compounds at 0.33µM using PHA-L staining. Results expressed equivalent glycoproteins in µg / ml. • Effects on 3T3 migration scratch assay Results are summarized in Table 3 below. The table 3 shows the effect of deuterated compounds on 3T3 cell migration at 3µM. Inhibition observed at 3µM is increased compare to the one observed with PST3.1a. Table 3 Migration inhibition (%) 3µM Compound PST3.1a 3,65 Compound IIa 14,46 Compound IIf 6,81 Compound IIe 12,73 Table 3 : Inhibition of 3T3 migration after 48h of treatment with compounds at 3µM. Results expressed in percent of inhibition based on the control DMSO condition. • Glycosyltransferase Inhibition Assay Results obtained are summarized in Table 4, demonstrating the inhibitory effect of deuterated compound IIa, superior to the reference compound PST3.1a. Table 4 Estimated IC50 (M) Compound PST3.1a 8.80E-08 Compound IIa 5.50E-08 Table 4 : Estimation of the inihibitory concentration of PST3.1a and compound IIa on the Gnt- V enzymatic assay, leading to a 50% inhibition of enzymatic activity (IC50).

Claims

CLAIMS 1. A deuterated derivative compound of 3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl- 2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane, or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof.

2. The deuterated derivative compound according to claim 1, being of the general formula (I): B1A1wherein,A1to A3are independently of each other -CH2- or -CD2-; and B1 to B4 are independently of each other a phenyl or a phenyl-d5; with the proviso that at least one of A1 to A3 is -CD2- or at least one of B1 to B4 is a phenyl-d5, or a stereoisomer, crystal form, or pharmaceutically acceptable salt or solvate thereof.

3. The deuterated derivative compound according to claim 2, wherein at least one of A1 to A3 is -CD2-.

4. The deuterated derivative compound according to claim 2, wherein at least one of A1 to A3 is -CD2-, and B1 to B4 are phenyl.

5. The deuterated derivative compound according to claim 2, wherein at least one of B1 to B4 is a phenyl-d5.

6. The deuterated derivative compound according to claim 2, wherein at least one of B1to B4is phenyl-d5, and A1 to A3 are -CH2-.

7. The deuterated derivative compound according to claim 2, wherein: - A1is -CD2-, A2and A3are -CH2-, and B1to B4are phenyl; or - A2 is -CD2-, A1 and A3 are -CH2-, and B1 to B4 are phenyl; or - A3 is -CD2-, A1 and A2 are -CH2-, and B1 to B4 are phenyl; or - A1is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl; or - A1 is -CD2-, A2 and A3 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A2 is -CD2-, A1 and A3 are -CH2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A3is -CD2-, A1and A2are -CH2-, B1to B3are phenyl, and B4is phenyl-d5; or - A1 is -CH2-, A2 and A3 are -CD2-, B1 to B3 are phenyl, and B4 is phenyl-d5; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl; or - A1to A3are -CD2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1to A3are -CD2-, B1is phenyl-d5, and B2, B3and B4are phenyl; or - A1 to A3 are -CD2-, B2 is phenyl-d5, and B1, B3 and B4 are phenyl; or - A1to A3are -CD2-, B3is phenyl-d5, and B1, B2and B4are phenyl; or - A1to A3are -CD2-, B2and B3are phenyl-d5, and B1and B4are phenyl; or - A1 to A3 are -CD2-, B1 to B3 are phenyl-d5, and B4 is phenyl; or - A1 to A3 are -CH2-, B1 is phenyl-d5, and B2, B3 and B4 are phenyl; or - A1to A3are -CH2-, B2is phenyl-d5, and B1, B3and B4are phenyl; or - A1 to A3 are -CH2-, B3 is phenyl-d5, and B1, B2 and B4 are phenyl; or - A1 to A3 are -CH2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CH2-, B2and B3are phenyl-d5, and B1and B4are phenyl; or - A1to A3are -CH2-, B1to B3are phenyl-d5, and B4is phenyl; or - A1 to A3 are -CH2-, and B1 to B4 are phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl-d5.

8. The deuterated derivative compound according to claim 2, wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A1is -CH2-, A2and A3are -CD2-, and B1to B4are phenyl; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, B4 is phenyl-d5, and B1, B2 and B3 are phenyl; or - A1to A3are -CH2-, B1is phenyl-d5, and B2, B3and B4are phenyl; or - A1to A3are -CH2-, B4is phenyl-d5, and B1, B2and B3are phenyl; or - A1 to A3 are -CH2-, B2 and B3 are phenyl-d5, and B1 and B4 are phenyl; or- A1 to A3 are -CH2-, and B1 to B4 are phenyl-d5; or - A1to A3are -CD2-, and B1to B4are phenyl-d5, preferably wherein: - A1 is -CD2-, A2 and A3 are -CH2-, and B1 to B4 are phenyl; or - A2 is -CD2-, A1 and A3 are -CH2-, and B1 to B4 are phenyl; or - A3is -CD2-, A1and A2are -CH2-, and B1to B4are phenyl; or - A1 is -CH2-, A2 and A3 are -CD2-, and B1 to B4 are phenyl; or - A1 to A3 are -CD2-, and B1 to B4 are phenyl.

9. The deuterated derivative compound according to claim 2, wherein said compound is selected from the group consisting of: D D OBnD10. The deuterated derivative compound according to claim 2, wherein said compound is of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ik), preferably (Ia), (Id), (Ie), (If) or (Ig) as defined in claim 9.

11. A pharmaceutical composition comprising at least one deuterated derivative compound as defined in anyone of claims 1 to 10, and one or more pharmaceutically acceptable excipients.

12. A deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, for use as a medicament.

13. A deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, for use in a method for treating cancer and / or in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer.

14. A deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, for use in a method for treating fibrotic diseases.

15. A deuterated derivative compound or a pharmaceutical composition for use according to claim 14, wherein the fibrotic disease is selected from the group consisting of lung fibrosis, heart fibrosis, liver fibrosis, kidney fibrosis, muscle, skin fibrosis, soft tissue fibrosis, bone marrow fibrosis, intestinal, aortic fibrosis, joint fibrosis, a skin disease, kidney disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, old myocardial infarction, scleroderma, systemic sclerosis, arthrofibrosis, and an adhesive capsulitis.

16. Use of a deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, in the manufacture of a medicament for use in a method for treating cancer and / or in a method for reducing or preventing the appearance of metastases in a patient afflicted with a cancer.

17. Use of a deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, for the manufacture of a medicament for use in a method for treating fibrotic diseases, wherein the fibrotic disease is advantageously selected from the group consisting of lung fibrosis, heart fibrosis, liver fibrosis, kidney fibrosis,muscle, skin fibrosis, soft tissue fibrosis, bone marrow fibrosis, intestinal, aortic fibrosis, joint fibrosis, a skin disease, kidney disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, old myocardial infarction, scleroderma, systemic sclerosis, arthrofibrosis, and an adhesive capsulitis.

18. Method for treating cancer and / or for reducing or preventing the appearance of metastases in a patient afflicted with a cancer, comprising administering to the patient in need thereof a therapeutically effective amount of a deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11.

19. Method for treating fibrotic diseases in a patient in need thereof, comprising administering a therapeutically effective amount of a deuterated derivative compound as defined in anyone of claims 1 to 10 or a pharmaceutical composition as defined in claim 11, to said patient, wherein the fibrotic disease is advantageously selected from the group consisting of lung fibrosis, heart fibrosis, liver fibrosis, kidney fibrosis, muscle, skin fibrosis, soft tissue fibrosis, bone marrow fibrosis, intestinal, aortic fibrosis, joint fibrosis, a skin disease, kidney disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, old myocardial infarction, scleroderma, systemic sclerosis, arthrofibrosis, and an adhesive capsulitis.

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