EP4185281A1

EP4185281A1 - Compounds for the treatment of haemophilia

Info

Publication number: EP4185281A1
Application number: EP21742857.2A
Authority: EP
Inventors: Aline Thomas; Marie-Claire DAGHER; Muriel JOURDAN; Romain NAVARRO; Benoît POLACK; Raphael Marlu; Landry SEYVE; Renaud ZELLI
Original assignee: Centre National de la Recherche Scientifique CNRS; Institut Polytechnique de Grenoble; Universite Grenoble Alpes; Centre Hospitalier Universitaire Grenoble Alpes
Current assignee: Centre National de la Recherche Scientifique CNRS; Institut Polytechnique de Grenoble; Universite Grenoble Alpes; Centre Hospitalier Universitaire Grenoble Alpes
Priority date: 2020-07-24
Filing date: 2021-07-23
Publication date: 2023-05-31
Also published as: US20230346727A1; CN116710080A; FR3112684A1; WO2022018256A1; JP2024511910A; FR3112684B1; CA3186258A1

Abstract

The invention relates to a compound of general formula (III'), or one of the pharmaceutically acceptable salts thereof, for use of same in the treatment of haemophilia in a patient, in particular for restoring coagulation in the plasma of a patient suffering from haemophilia, this compound being advantageously orally administrable.

Description

COMPOUNDS FOR THE TREATMENT OF HEMOPHILIA

The present invention falls within the therapeutic field, more specifically in the field of the treatment of hemophilia.

More specifically, the present invention relates to a compound of particular chemical structure, for its use for the treatment of haemophilia. Hemophilia is a rare genetic disease resulting in an impossibility for the blood to clot, and whose symptoms are spontaneous and repetitive post-traumatic bleeding in the joints and muscles. This bleeding can result in severe bleeding, the consequences of which can be particularly serious.

There are two types of hemophilia: hemophilia type A, due to a deficiency of the coagulation factor FVIII, which is the most common type of hemophilia, and hemophilia type B, due to a deficiency of the factor coagulation FIX. These deficiencies in coagulation factor FVIII or FIX lead to a direct blockage of the intrinsic tenase complex, so that, in order to produce factor FXa, which generates thrombin and which is essential for the formation of blood clots and therefore for coagulation, patients haemophiliacs depend solely on the extrinsic pathway of coagulation, and therefore on the extrinsic tenase complex. This complex, composed of tissue factor (TF) and coagulation factor FVIIa, allows the activation of the FX factor to FXa. FXa can then associate with factor Va to form prothrombinase, which accelerates the transformation of prothrombin into thrombin necessary for coagulation. However, the extrinsic tenase complex is also inhibited in hemophiliacs by the binding of a protein, called Tissue Factor Pathway Inhibitor (TFPI), to the FXa factor and to the TF-FVIIa-FXa complex. TFPI is a protein that exists in two isoforms, alpha and beta. The alpha isoform contains an N-terminus of 22 residues, followed by three Kunitz domains (K1, K2, K3) and then a long negatively charged C-terminus. The beta isoform lacks a K3 domain and is terminated with a different C-terminus. The three-dimensional structure of each Kunitz domain is experimentally known. In the TFPI-TF-FVIIa-FXa complex, the generally accepted hypothesis is that the K2 domain of TFPI binds to the active site of FXa and the K1 domain of TFPI binds to the active site of FVIIa, as described in particular in the publication by Girard et al., 1989, Nature 338(6215), 518-20.

At present, hemophilia is systematically treated by replacement therapies, consisting of intravenous injections, in the subject affected by the disease, of the missing factors FVIII or FIX. These treatments, in addition to their binding mode of administration, have the disadvantage of generating antibodies.

New therapeutic strategies currently under development, such as that described in the publication by Franchini et al., 2018, Blood transfusion, 16, 457-461, are based on the use of proteins which either increase coagulation, such as emicizumab, a bispecific monoclonal antibody, restoring coagulation equivalently to 10 to 20 IU/dL (10 to 20%) of factor VIII, but which can under certain conditions be responsible for thrombotic accidents, or block the main anticoagulants of the coagulation cascade, in particular TFPI. Concizumab, an anti-TFPI monoclonal antibody, has in particular been proposed as an inhibitor of TFPI.

The present invention aims to provide a treatment for hemophilia not having in particular the disadvantages of antibody/protein-based treatments, this treatment making it possible to effectively restore coagulation in patients affected by the disease, preferably being administered by oral route.

Additional objects of the invention are that this treatment be inexpensive and easy to produce and administer, and that it causes few or no undesirable side effects.

The present inventors have now discovered that these objectives can be achieved by particular chemical molecules, derived from adamantane, and defined by a particular general formula.

Thus, the present invention relates to a compound of formula (III') below, or one of its pharmaceutically acceptable salts, for its use, as an active agent, for the treatment of hemophilia in a subject suffering from by illness:

in which

Y ₁ 'represents a covalent bond or an amide group,

R ₄ 'represents a hydrogen atom, a hydroxyl group, a halogen atom, an amine group or a linear or branched, saturated or unsaturated carbon radical, optionally interrupted and/or substituted by one or more heteroatoms and/or a or more groups comprising at least one heteroatom,

Y ₂ 'represents a covalent bond or an amide group, A ₂ ' represents an optionally substituted cyclic or heterocyclic group comprising two fused rings, at least one of said rings being aromatic.

When Y ₁ 'represents an amide group, the nitrogen atom of this group can just as easily be linked to the adamantyl unit as to the phenyl radical. Similarly, when Y ₂ 'represents an amide group, the nitrogen atom of this group may just as well be bonded to the phenyl radical as to the group A ₂ '. In the present description, the term treatment is understood to mean a curative treatment of the bleeding episodes linked to the disease, and in particular the reduction and/or inhibition of the development of at least one of the associated symptoms, in particular the improvement of clotting and decrease in the amount and/or frequency of bleeding.

The subject treated according to the invention is in particular a mammal, for example a non-human mammal. It is preferably a human being.

The compound used according to the invention advantageously makes it possible to restore coagulation, by restoring the generation of thrombin, in the plasma of a subject with haemophilia, type A as well as type B, including for subjects affected by severe forms of the disease.

In particular, it has been discovered by the present inventors that the compound according to the invention, subjected to an ex vivo test for the generation of fluorimetric thrombin, on the plasma of subjects suffering from severe hemophilia A, allows, at a dose of 50 μM, to restore the generation of thrombin equivalent to FVIII and even higher depending on the conditions.

The mechanisms underlying such an advantageous effect of the compound used according to the invention will not be prejudged here. It may however be thought that this effect could be due, at least in part, to an inhibition, by the compound according to the invention, in particular the compound of general formula (III') or one of its salts, of the binding of the factor pathway inhibitor (TFPI) to coagulation factor FXa.

The compound used according to the invention does not present any toxicity for mammals. It can advantageously be administered orally, much more simply than the proteins used by the prior art, which must in turn be administered by injection.

The compound according to the invention, and its pharmaceutically acceptable salts, by their chemical nature and their low molecular weight, generally less than 5 kDa and even, for certain combinations of substituents, less than 1 kDa, or even less than 500 Da, are in particular much easier, and less expensive, to prepare than the protein/antibody compounds proposed by the prior art for the treatment of haemophilia. In this respect, the compound according to the invention can be prepared by any method of synthesis conventional in itself for those skilled in the art.

In the present description, the term “pharmaceutically acceptable salt” means any salt of the compound that does not cause any adverse, allergic or other undesirable reaction when it is administered to the subject, in particular to a human subject.

Any non-toxic conventional salt of the compound of general formula (III') can be used according to the invention, for example a metallic salt such as a sodium, potassium, magnesium, calcium, lithium salt, etc. Alternatively, a salt formed from organic or inorganic acids may be used, for example salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids, etc., and salts derived from organic acids such as acetic, trifluoroacetic, propionic, maleic, benzoic, stearic acids, etc. The salt can be synthesized, starting from the compound of general formula (III'), according to any conventional chemical method in itself.

All the properties described in the present description for the compound of general formula (III') also apply to its pharmaceutically acceptable salts. The general formula (III') above further encompasses all possible combinations of isomeric forms at the level of the asymmetric carbons, and all mixtures of such isomeric forms. From a mixture of isomers, each particular isomer can be obtained by conventional purification methods per se for those skilled in the art. Preferably, in the general formula (III'), R ₄ 'represents an -OR ₈ group or an -O-CO-R _{8 group} , where R ₈ represents a linear or branched, saturated or unsaturated hydrocarbon radical, in particular alkyl, comprising from 1 to 10 carbon atoms, optionally substituted by one or two R ₁₄ , R _14' substituents, identical or different, each chosen from -F, -CO ₂ H, -SO ₃ H, - represents a hydrogen atom or a methyl group.

R ₈ can in particular represent a group of general formula (XVIII): in which y is an integer between 1 and 10 and R ₁₄ is as defined above.

In particular embodiments of the invention, in the general formula (III '), R ₄ 'is attached to the phenyl radical in the ortho or para position with respect to to the adamantyl unit, and Y ₂ 'is attached to the phenyl radical in the meta position with respect to the adamantyl unit.

Preferably, in general formula (III'), A ₂ 'is at least substituted by one substituent R ₁₁ chosen from fluorine, carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole groups, and linear, branched and /or cyclic, saturated or unsaturated, aromatic or not, optionally interrupted and/or substituted by one or more heteroatoms, in particular fluorine, and/or one or more groups comprising at least one heteroatom, in particular carboxyl -CO ₂ H, sulfonyl - SO ₃ H and/or phosphonyl -P(O)(OH) ₂ . R ₁₁ can in particular be chosen from tetrazole or keto-oxadiazole groups of respective formulas:

In particular embodiments of the invention, the compound used for the treatment of hemophilia corresponds to the general formula (IX): in which Y ₁ ', Y ₂ ' and R ₄ ' are as defined above,

A ₃ represents a 3 to 8-membered cyclic or heterocyclic hydrocarbon, saturated or unsaturated, aromatic or not, fused to the adjacent six-membered aromatic ring,

B ₁ and B ₂ , identical or different, each represent a -CH- or a nitrogen atom, R ₉ and R ₁₀ , which are identical or different, each represent a hydrogen atom, a hydroxyl group or an -OR ₁₂ or -CO-OR _{12 group} where R ₁₂ represents a linear or branched hydrocarbon radical, saturated or unsaturated, in particular alkyl, containing from 1 to 10 carbon atoms, optionally substituted by one or two substituents R ₁₆ , R _{16 '} , identical or different, each chosen from -F, -CO2H, -SO ₃ H, -P (O)(OH) ₂ , -P(O)(OCH ₃ )2, -P(O)(OCH ₂ CH ₃ ) ₂ , methyl, and R ₁₁ represents a substituent chosen from fluorine, carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole groups, and linear, branched and/or cyclic, saturated or unsaturated, aromatic or non-aromatic, optionally interrupted and / or substituted by one or more heteroatoms, in particular fluorine, and/or one or more groups comprising at least one heteroatom, in particular carboxyl, sulfonyl and/or phosphonyl. R ₁₁ may in particular represent a -(CH ₂ ) _X -R _{13 group} where x is an integer between 0 and 4 and R ₁₃ represents a fluorine atom or a carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole group , in particular a tetrazole or keto-oxadiazole group of respective formulas:

In general formula (IX), R ₉ and R ₁₀ , which are identical or different, may also each represent a group of general formula (XVI II'): in which y' is an integer between 1 and 10 and R ₁₈ is chosen from where R ₁₉ represents a hydrogen atom or a methyl group.

The compound used according to the invention may in particular correspond to the general formula (X): in which Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , B ₂ , R ₉ , R ₁₀ , R ₁₃ and x are as defined above.

It can in particular correspond to the general formula (XI): in which Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , R ₉ , R ₁₀ , R ₁₃ and x are as defined above. It can otherwise respond to the general formula (XII): in which Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , B ₂ , R ₉ , R ₁₀ , R ₁₃ and x are as defined above. In particular embodiments of the invention, the compound used corresponds to the general formula (XIII): in which Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , R ₉ , R ₁₀ , R ₁₃ and x are as defined above. In particular, it can respond to the general formula (XIV):

in which Y ₁ ', Y ₂ ', R ₄ ', R ₉ , B ₁ , R ₁₀ , R ₁₃ and x are as defined above. In particular, it can respond to the general formula (XV): in which Y ₁ ', Y ₂ ', R ₄ ', R ₉ , B ₁ , R ₁₀ , R ₁₃ and x are as defined above.

A particularly preferred sub-family of the general formula (XV) in the context of the invention corresponds to the general formula (XVI):

in which Y ₁ ', Y ₂ ', R ₄ ', R ₁₃ and x are as defined above.

More generally, the present invention relates to a compound of formula (I) below, or one of its pharmaceutically acceptable salts, for its use, as an active agent, for said treatment of hemophilia in a subject suffering from by illness: in which

W ₁ , W ₂ , W ₃ and W ₄ , which are identical or different, each represent an oxygen atom or a bivalent radical chosen from the groups -CH ₂ -, carbonyl -CO-, amine, in particular secondary amine -NH-, and sulfonyl -SO ₂ -, R ₁ and R ₂ , identical or different, each represent a hydrogen atom, a hydroxyl group or a hydrocarbon radical, preferably C1-C8 and in particular C1-C4, linear, branched and/or cyclic, saturated or unsaturated, aromatic or not, optionally substituted, possibly comprising one or more heteroatoms and/or one or more groups comprising at least one heteroatom and possibly comprising a single cycle or several cycles, fused cycles where appropriate ,

R ₃ represents a hydrogen atom, a halogen atom, a group alkyl, preferably C1-C8 and preferably C1-C4, or a hydroxyl group, and R represents a hydrogen atom, a hydroxyl group, an -NH ₂ group or a linear, branched and/or cyclic hydrocarbon radical, saturated or unsaturated, aromatic or not, optionally substituted, possibly comprising one or more heteroatoms and/or one or more groups comprising at least one heteroatom and possibly comprising a single cycle or several cycles, where appropriate fused cycles.

The compound used according to the invention is adamantane, or tricyclo[3.3.1.1(3.7)]decane, of chemical formula: or one of its derivatives or analogues corresponding to the general formula (I).

Any non-toxic conventional salt of the compound of general formula (I) can be used according to the invention, for example a metallic salt such as a sodium, potassium, magnesium, calcium, lithium salt, etc. Alternatively, a salt formed from organic or inorganic acids may be used, for example salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids, etc., and salts derived from organic acids such as as acetic, trifluoroacetic, propionic, maleic, benzoic, stearic, etc. The salt can be synthesized, starting from the compound of general formula (I), according to any conventional chemical method in itself.

All the properties described in the present description for the compound of general formula (I) also apply to its pharmaceutically acceptable salts.

The general formula (I) above further encompasses all possible combinations of isomeric forms at the asymmetric carbons, and all mixtures of such isomeric forms. From a mixture of isomers, each particular isomer can be obtained by conventional purification methods per se for those skilled in the art. A particularly preferred isomer according to the invention corresponds to the general formula (I'):

In particular embodiments, the compound used according to the invention meets one or more of the characteristics below, implemented alone or according to any technically relevant combination. Preferably, at least one, preferably at least two, preferably at least three and preferably all four, among W ₁ , W ₂ , W ₃ and W ₄ , represent(s) a methylene bridge -CH ₂ -. R ₁ and R ₂ , which are identical or different, also preferably each represent a hydrogen atom, a hydroxyl group, a C1-C8 alkyl group, preferably a C1-C4 alkyl group or an optionally substituted phenyl radical. R ₁ and R ₂ can for example be identical, and each represent a hydrogen atom or a methyl group. They can otherwise be different, and for example represent for one, a hydrogen atom, and for the other, a hydroxyl group.

Particular compounds according to the invention correspond to the following combinations of characteristics:

- W ₁ , W ₂ , W ₃ and W ₄ each represent a methylene bridge, R ₃ represents a hydrogen atom, R ₁ represents a hydrogen atom and R ₂ represents a hydroxyl group;

- W1, W2, W3 and W4 each represent a methylene bridge, R ₃ represents a hydrogen atom and R ₁ and R ₂ each represent a methyl group;

- W1, W3 and W4 each represent a methylene bridge, W ₂ represents a carbonyl group, R ₃ represents a hydrogen atom, and R ₁ and R ₂ each represent a methyl group.

W ₂ can otherwise represent a group of formula:

In this respect, the compound of general formula (I) may be bromantane, in which W ₁ , W ₃ and W ₄ each represent a methylene bridge -CH ₂ -, and R ₁ , R ₂ , R ₃ and R each represent a hydrogen atom. In particular embodiments of the invention, R ₂ is chosen from the groups of chemical formulas:

The compound used according to the invention can thus in particular be saxagliptin, of chemical formula: or vildagliptin, with the chemical formula:

In the general formula (I), R can represent a primary amine group. The 4th compound used according to the invention can then in particular be amantadine or memantine, in which W ₁ , W ₂ , W ₃ and W ₄ each represent a methylene bridge -CH ₂ -, R ₃ represents a hydrogen atom, and R ₁ and R ₂ each represent a hydrogen atom for the first, and a methyl group for the second.

R may otherwise, for example, represent a group chosen from the following groups:

The compound used according to the invention can then in particular be adapromine, rimantadine or tromantadine, in which W ₁ , W ₂ , W ₃ and W ₄ each represent a methylene bridge -CH ₂ -, and R ₁ , R ₂ and R ₃ each represent a hydrogen atom.

In particularly preferred embodiments of the invention, R represents a group of formula -Y ₁ -A ₁ , in which: Y ₁ represents a covalent bond, an amine group or a linear or branched, saturated or unsaturated, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups comprising at least one heteroatom, said carbon radical preferably comprising 1 to 4 carbon atoms, in particular an -NH-CO-, -CO group -NH-, -NH-CS- or -CS-NH-, and A ₁ represents a cyclic or heterocyclic, saturated or unsaturated, optionally substituted hydrocarbon, which may comprise a single ring, aromatic or not, or several fused rings, each of said rings which may or may not be aromatic. The compound then corresponds to the general formula (II):

in which W ₁ , W ₂ , W ₃ , W ₄ , R ₁ , R ₂ , R ₃ , Y ₁ and A1 are as defined above. A ₁ can in particular be of the monocyclic, bicyclic or tricyclic type. Preferably, A ₁ represents a monocyclic unit, preferably aromatic, comprising from 4 to 6 atoms, one or more of these atoms possibly being a heteroatom, and substituted on at least one, preferably at least two (this being understood in addition bond to Y ₁ ), ring atoms. A ₁ may in particular represent a phenyl radical, substituted on at least two of the ring atoms (this being understood in addition to the bond to Y ₁ ), the substituents preferably being located in the para position with respect to the the other, one of the substituents also preferably being located in the ortho position with respect to the bond to Y ₁ .

Preferably, A ₁ is substituted, in the ortho position with respect to the bond to Y ₁ , by a group R ₄ representing a hydrogen atom, a hydroxyl group, a halogen atom, an amine group or a linear, branched carbon radical and/or cyclic, saturated or unsaturated, aromatic or not, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups comprising at least one heteroatom.

In particularly preferred embodiments according to the invention, in particular when A ₁ represents an aromatic carbocyclic or heterocyclic group, in particular with 6 atoms, A ₁ is substituted by at least one group of general formula (II'): in which Y ₂ represents a covalent bond, an amine group, or a linear or branched, saturated or unsaturated, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups comprising at least one heteroatom, preferably C1-C4, in particular an -NH-CO-, -CO-NH-, -NH-CS- or -CS- group NH-, and A ₂ represents an optionally substituted cyclic or heterocyclic group, which may comprise a single ring, which may or may not be aromatic, or several fused rings, each of said rings may or may not be aromatic. A ₂ can in particular be of the monocyclic, bicyclic or tricyclic type. Preferably, A ₂ represents a cyclic or heterocyclic group, optionally substituted, comprising two fused rings, at least one of said rings being aromatic, each of said rings preferably comprising between 4 and 6 atoms, one or more of these atoms possibly being a heteroatom.

Preferably, in such a configuration, each of the rings of A ₂ is aromatic. Each of the rings also preferably comprises 6 carbon atoms. A ₂ is preferably substituted on at least one, preferably at least two, of the atoms of at least one ring. A ₂ is preferentially substituted on at least one, preferably at least two, ring atoms not carrying the bond to Y ₂ . Preferably, A ₂ represents a naphthalene unit, optionally substituted, and preferentially substituted on at least the ring not bearing the bond to Y ₂ .

In particular embodiments of the invention, A ₂ is substituted by at least one group chosen from the group consisting of halogen atoms, in particular chlorine, bromine or iodine atoms, hydroxyl, amine or amine oxide groups , and linear, branched and/or cyclic, saturated or unsaturated, aromatic or non-aromatic carbon radicals, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups comprising at least one heteroatom. As examples of such radicals, mention may be made of the amide, ketoxime, carbonyl, carboxyl, ester, alkyl, in particular C1-C8, in particular C1-C4, aryl, etc. radicals.

In particular embodiments of the invention, the compound corresponds to the general formula (III): in which W ₁ , W ₂ , W ₃ , W ₄ , R ₁ , R ₂ , R ₃ , Y ₁ , Y ₂ and A ₂ are as defined above, and R ₄ represents a hydrogen atom, a hydroxyl group, a halogen atom, an amine group or a linear, branched and/or cyclic, saturated or unsaturated, aromatic or non-aromatic carbon radical, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups containing at least one heteroatom. In particular, in the general formula (III), R ₄ can represent a hydrogen atom or an -OR ₅ group, where R ₅ represents a C1-C8 alkyl group, preferably C1-C4, and in particular a methyl group.

The compound used according to the invention may, for example, correspond to one of the general formulas (IIIa), (IIIb), (IIIc) or (IIId) below:

in which R ₄ , Y ₂ and A ₂ are as defined above.

In particularly preferred embodiments of the invention, the compound corresponds to the general formula (IV): in which W ₁ , W ₂ , W ₃ , W ₄ , R ₁ , R ₂ , R ₃ , Y ₁ and Y ₂ are as defined above,

R5 represents a hydrogen atom or a C1-C8, preferably C1-C4, alkyl group, for example a methyl group, and R ₆ represents a halogen atom, in particular a chlorine, bromine and iodine atom , a hydroxyl, amine or amineoxide group, or a linear, branched and/or cyclic, saturated or unsaturated, aromatic or non-aromatic carbon radical, optionally interrupted and/or substituted by one or more heteroatoms and/or one or more groups comprising at least a heteroatom. R ₆ can for example represent an amide, ketoxime, carbonyl, carboxyl, ester, alkyl, in particular C1-C8, in particular C1-C4, aryl, etc

In particular embodiments of the invention, R ₆ represents a -CO-OR _{7 group} , where R ₇ represents a hydrogen atom, a C1-C8, preferably C1-C4, alkyl group, a aryl group or a C6-C14 arylalkyl group.

The compound used according to the invention may in particular correspond to one of the general formulas (IVa), (IVb), (IVc) and (IVd) below:

in which W ₁ , W ₂ , W ₃ , W ₄ , R ₁ , R ₂ , R ₃ , R ₅ and R ₆ are as defined above

A particularly preferred compound according to the invention is adapalene, name given to 6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid, of formula (V): Adapalene is particularly effective in restoring coagulation in the plasma of patients with severe hemophilia A.

Other particularly preferred compounds according to the invention, corresponding in particular to the general formula (III'), have the formulas (XVII) and (XIX):

Other compounds which can be used in accordance with the invention, corresponding in particular to the general formula (III'), have the formulas (XX), (XXI), (XXII) and (XXIII):

Other examples of compounds which can be used according to the invention have the formulas (VI), (VII) and (VIII) below:

The compound according to the invention can be administered to the subject in need thereof, that is to say suffering from hemophilia, in a therapeutically effective quantity, by any route, in particular by the enteral route, in particular oral, buccal or rectal, parenterally, including subcutaneous, intramuscular, intravenous, intradermal, etc. The administration of the compound to the treated subject is preferably carried out orally.

The term “therapeutically effective amount” is understood to mean the amount of the compound which makes it possible, when it is administered to the subject, to obtain the desired level of therapeutic response, in particular, for the particular case of hemophilia, the level of restoration of the desired clotting. The therapeutically effective dose level of each specific compound for a particular subject varies depending on many factors such as, for example, the exact pathology and its severity, body weight, age and general health of the subject, duration of treatment, any drugs used in parallel, the sensitivity of the individual to be treated, etc. Accordingly, the optimal dosage is determined by the doctor based on the parameters that he considers relevant. The administration dosage of the compound used according to the invention can for example be taken once or twice a day.

In preferred embodiments of the invention, the compound is contained in a pharmaceutical composition, within which it constitutes an active principle, and is contained in a pharmaceutically acceptable vehicle.

This pharmaceutical composition may be in any form suitable for enteral or parenteral administration. It is preferably presented in a form suitable for administration to the subject by the oral route.

All of the constituents of this pharmaceutical composition are of course chosen to be pharmaceutically compatible, that is to say that they do not produce any adverse, allergic or other undesirable reaction when they are administered to the subject, in particular to a mammal and in particular to a human.

The pharmaceutical composition may contain any conventional excipient by itself. Such an excipient may be a diluent, an adjuvant or any other conventional substance in itself for the constitution of medicaments, such as a preservative, filler, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agent, etc., or any of their mixtures It may also contain one or more other active principles, acting or not acting in synergy with the compound used according to the invention,

The pharmaceutical composition can be formulated according to any pharmaceutical form suitable for oral administration in mammals, and in particular in humans. It may in particular be in the form of a powder, of tablets, of capsules, of granules, of a syrup, or of an oral solution or suspension, prepared in a conventional manner by itself.

It is preferably packaged in the form of unit doses, each dose containing a therapeutically effective quantity of the compound according to the invention. The concentration of the compound in each dose of the pharmaceutical composition is thus preferably chosen to deliver to the subject, at each administration, an amount of compound which is effective to obtain the desired therapeutic response. The pharmaceutical composition is for example packaged in the form of unit doses, which may in particular each comprise a quantity of between 1 and 10 g of the compound according to the invention.

The present invention is also expressed in terms of a method of treating hemophilia in a subject, and in particular a method of restoring coagulation in the plasma of a subject afflicted with hemophilia. The subject can in particular be a mammal, and preferentially a human being. This method comprises the administration, to said subject in need, of a therapeutically effective amount of the compound as defined above, or one of its pharmaceutically acceptable salts. This method can meet one or more of the characteristics described above with reference to the use of the compound according to the invention for the treatment of haemophilia.

The present invention is also expressed in terms of the use of a compound according to the invention, or of one of its pharmaceutically acceptable salts, for the manufacture of a medicament for the treatment of haemophilia. This use may correspond to one or more of the characteristics described above with reference to the use of the compound according to the invention for the treatment of haemophilia.

The characteristics and advantages of the invention will appear more clearly in the light of the examples of implementation below, provided purely by way of illustration and in no way limiting of the invention, with the support of figures 1 to 4, in which:

FIG. 1 shows a graph representing the results (amount of thrombin as a function of time) of an ex vivo thrombin generation test for the plasma of a subject suffering from severe hemophilia A, in the presence of plasma factor FVIII (100 % VIII, positive control), dilution buffer (0% VIII, negative control), and a compound according to the invention, adapalene, at respective concentrations of 0.5 mM, 5 mM and 50 mM.

FIG. 2 represents the chemical structure of comparative compounds C1 to C9 implemented in an example, not corresponding to the general formula (I).

FIG. 3 shows a histogram representing the amount of thrombin measured at the peak during an ex vivo thrombin generation test (TGT) in the plasma of an individual suffering from severe hemophilia A, in the presence of plasma factor FVIII (100 % VIII, positive control), dilution buffer (0 % VIII, control negative) and in the presence of adapalene at 50 mM (Ad) or of a comparative compound C1 to C9 not corresponding to the general formula (I).

Figure 4 shows a histogram representing the total amount of thrombin generated (endogenous thrombin potential) during an ex vivo thrombin generation test (TGT) in the plasma of an individual with severe hemophilia A, in the presence of plasma FVIII factor (100% VIII, positive control), dilution buffer (0% VIII, negative control) and in the presence of 50 mM adapalene (Ad) or a comparative compound C1 to C9 not responding to the general formula (I).

Example 1 - ex vivo thrombin generation test

During the activation of coagulation, a chain of enzymatic reactions, called the coagulation cascade, occurs. It results in the production of thrombin (factor IIa), the last enzymatic “link” in this coagulation cascade.

The thrombin generation test consists of measuring the kinetics of appearance of this key coagulation factor in the plasma over time. After activation of coagulation by calcium, the amount of thrombin changes over time. It is measured using a synthetic thrombin substrate coupled to a fluorescent molecule (ZGGR-AMC). The main parameters determined are the latency time before observing an increase in thrombin generation, the thrombin peak corresponding to the maximum amount of thrombin generated and IΈTR (endogenous thrombin potential) corresponding to the total amount of thrombin generated. in the plasma during the test. In the case of a haemophilia A patient, the generation of thrombin is low or even almost zero for some patients. Adding the missing coagulation factor (factor VIII) to its physiological level (1 IU/mL or 100%) restores coagulation in patients and recovers “normal” thrombin generation. Thus the thrombin generation test makes it possible to globally evaluate the coagulation rate of a given plasma and in the present case, it makes it possible to evaluate the capacity of a molecule to restore or not restore coagulation in a hemophiliac patient.

For this example, several ex vivo thrombin generation assays were carried out on a plasma of a patient suffering from severe hemophilia A, therefore lacking factor FVIII, in order to evaluate the effect on coagulation of a compound of general formula (I), more particularly adapalene, of formula (V) above, on the kinetics and the amount of thrombin generated.

Hemophilia patient plasma was obtained from Cryopep (Montpellier, France).

Adapalene is commercially available, in particular from Prestwick. It was dissolved in an 8% solution of dimethylsulfoxide (DMSO) then diluted to a concentration of 1 mM and then tested at the following concentrations: 50 mM, 5 mM, 0.5 mM (final concentrations in plasma).

The thrombin generation test was performed at 37°C using a fully automated STA-Genesia analyzer (Diagnostica Stago) with STG®- Bleedscreen reagent (Diagnostica Stago) according to the manufacturer's instructions and according to the method established by Pr. Hemker in 2003. The STG®- Bleedscreen reagent is a mixture of tissue factor (TF) at low concentration with phospholipid vesicles (PL). The test is triggered by the addition of a mixture of calcium + fluorescent substrate (ZGGR-AMC) (STG®-FluoStart mixture).

From a technical point of view, 4 volumes of spiked plasma sample are added to 1 volume of “initiator complex” (STG®-Bleedscreen) and incubated for 10 min at 37°C. Then, the reaction is triggered by adding 1 volume of STG®-FluoStart (mixture of CaCl ₂ and ZGGR-AMC substrate) and the fluorescence signal is measured over time. Each test is carried out in duplicate For each molecule tested, 475 μL of plasma from the hemophiliac patient were spiked with 25 μL of a solution containing different amounts of compound (molecule to be tested, factor VIII or dilution buffer) to obtain the concentration final desired (systematic dilution of the molecule to be tested in the plasma at 1/20). For example, to obtain the final concentration of 50 mM in plasma, 25 μL of a 1 mM solution was added to 475 μL of plasma. The preparation of 500 μL of spiked plasma enables the 2 thrombin generation tests (duplicate), the 2 calibration tests (duplicate) to be carried out and takes into account the dead volume of the automaton. In parallel with the tests on the different chemical compounds, the plasma of a hemophiliac patient is spiked with the same buffer for diluting the compound, an 8% solution of dimethylsulfoxide (DMSO), as a negative control (0.4% of final DMSO ) in order to obtain the basal level of thrombin generation of the plasma used. The positive control is the same plasma spiked with plasma factor VIII (Factane, LFB, France) at a concentration of 1 IU/mL (or 100% factor VIII) in order to obtain the expected “normal” level of thrombin generation plasma used.

The results obtained in thrombin generation, for each of the adapalene concentrations tested, are shown in Figure 1.

The negative control (plasma from a hemophilia A patient overloaded with the dilution buffer) shows weak thrombin generation with a peak at 25 nM of thrombin and an ETP at 360 nM.min. The positive control (plasma from a hemophilia A patient spiked with 1 IU/mL of factor VIII) shows a “normal” generation of thrombin with a peak at 51 nM and an ETP at 599 nM.min. For the different concentrations of adapalene, an increase in the generation of thrombin is observed depending on the concentration of adapalene: the higher the concentration, the greater the generation of thrombin. At 0.5 mM, adapalene already has an effect on increasing thrombin generation with a peak at 29.7 nM and an ETP at 455 nM.min. At 5 mM, the increase in thrombin generation is greater with a peak at 39 nM and an ETP at 504 nM.min. At a concentration of 50 mM, adapalene restores thrombin generation to the same level as the positive control (100% FVIII) with a peak at 55 nM and an ETP at 588 nM.min.

By way of comparison, several compounds with a close structure, but not corresponding to the general formula (I) (compounds C1 to C9), were also subjected to the same test. These compounds are shown in Figure 2. Each of these compounds was spiked into the plasma of the hemophiliac patient under the same conditions as adapalene, up to 50 mM.

The results obtained, for adapalene (Ad) at 50 mM and for the comparative compounds C1 to C9, are shown in figure 3 and figure 4.

It is observed that among the various compounds tested, only adapalene (Ad) at 50 mM makes it possible to obtain an increase in the generation of thrombin compared to the negative control, with a peak of thrombin generated and an ETP at the same level as the positive control.

Example 2 - Effect on FXa inhibition by TFPI

The ability of adapalene to remove FXa inhibition by TFPI was assessed using a low TFPI concentration FXa activity assay. For this test, a truncated human TFPI (TFPI-K1 K2) was used, which is common to both TFPI isoforms a and b, having the amino acid sequence SEQ ID No 1: DSEEDEEHTIITDTELPPLKLMHSGCAFKADDGPCKAIMKRFFFNIFTRQCEEF IYGGCEGNQNRFESLEECKKMCTRDNANRIIKTTLQEKPDFCFLEEDPGICR GYITRYFYKNNGPNICCLGNTGFGKYFGFTKY. Adapalene was tested for its ability to release FXa inhibition by TFPI-K1 K2 using a colorimetric assay in a 96-well plate format. All steps were performed at room temperature. FXa inhibition by increasing TFPI-K1 K2 concentrations was first analyzed to determine the best detection conditions. Concentrations of TFPI-K1 K2 and of FXa (New England Biolabs) of 30 nM and 0.5 nM respectively, were chosen to ensure complete inhibition of FXa, without a significant excess of TFPI-K1 K2. Each protein was diluted using the same buffer: 20 mM Hepes, 135 mM NaCl, 1% BSA, _{2 mM CaCl 2} , pH 7.3. The test was performed manually in 96-well plates (Nunc Maxisorp®). The experiment was performed in duplicate at a final adapalene concentration of 50 mM.

Briefly, 14.5 μL of 350 µM adapalene, prediluted in the buffer described above, was added to 62.5 μL 50 nM TFPI-K1 K2 and mixed together by aspiration/dispensing. After 10 min of incubation at room temperature, 6.25 μL of 8 nM FXa was added, the mixture was mixed again, and the activity of uninhibited FXa was quantified by the addition of 18 μL of PNAPEP-1025 (Cryopep), an FXa substrate, diluted to 2 mM in H ₂ O.

For the negative control, 14.5 µl of 0.25% DMSO was added to 62.5 µl of TFPI-K1 K2, and for the positive control, 14.5 µl of 0.25% DMSO was added to 62 .5 µl buffer. Then, after 10 min incubation at temperature ambient temperature, 6.25 μI of 8 nM FXa and 18 mI of PNAPEP-1025 were added as previously described.

The plates were centrifuged to remove any bubbles and the optical density (OD) at 405 nm, corresponding to the hydrolysis of the PNAPEP-1025 substrate, was measured for 1 h at room temperature. The absorbance value at tO, corresponding to an absorbance of 0.05, was subtracted and the thrombin generation restoration value was reported as a percentage of the positive control.

The following results were obtained: negative control: OD=0.048; positive control: OD = 0.406; 50 mM adapalene: OD = 0.105. The percentage of coagulation restoration measured is about 14%. This result demonstrates that adapalene exhibits a lifting effect of FXa inhibition by TFPI. Example 3 - Synthesis of compounds according to the invention Compound H27 Compound H27 (HEMO-027) of formula: is prepared according to the following reaction scheme:

Methyl 2-(3-(adamantan-1-yl)-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (7)

Pd2(dba)2 (1.7 mg, 0.0016 mmol, 1 mol%) was added to a flame-dried reactor followed by SPHOS (2.6 mg, 0.0064 mmol, 4 mol%), 1 -(5-bromo-2-methoxyphenyl)adamantane (5) (50 mg, 0.16 mmol, 1 eq.), methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (6) (43 mg , 0.19 mmol, 1.2 eq.) and NaOfBu (36.5 mg, 0.38 mmol, 2.4 eq.). Anhydrous toluene (600mI, 267mM) was added and the reactor was sealed. The resulting mixture was stirred at 100°C for 16 hours. After reaching room temperature, H ₂ O and AcOEt were added. The aqueous phase was extracted 3 times with AcOEt, and the combined organic phases were evaporated over MgSO4, filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 4:1 cyclohexane-AcOEt to obtain (7) (66 mg, 96%) as a yellow solid. ¹ H NMR (CDCI ₃ , 400 MHz): d 7.85 (s, 1 H, H-ar), 7.84 (d, 1 H, J = 7.9 Hz, H-ar), 7.20 (d, 1 H, J = 7.9 Hz, H-ar), 6.99 (s, 1 H, H-ar), 6.85-6.80 (m, 2H, 2 H-ar), 4.32 (s, 2H, NCH ₂ ), 3.91 (s, 3H, OCH ₃ ), 3.81 (s, 3H, OCH ₃ ), 3.45 (t, 2H, J = 5.8 Hz, NCH ₂ CH ₂ ), 3.05 (t, 2H, J = 5.8 Hz, NCH ₂ CH ₂ ), 2.11 ( db, 6H), 2.07 (db, 3H), 1.78 (db, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) D 167.3, 153.5, 145.0, 140.4, 139.6, 135.0, 130.2, 128.3, 127.1, 126.8, 117.4, 114.7, 53, 52.1, 48.8, 40.8, 37.4, 37.3 , 29.5, 29.3.

2-(3-(adamantan-1-yl)-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (HEMO-027)

To a solution of (7) (22 mg, 0.051 mmol) in 2:1 THF:H2O (2 mL) at room temperature was added LiOH (3.5 mg, 0.13 mmol, 2.5 eq.) . After stirring for 16 h, 1 M HCl was added to reach a pH=1. The precipitate formed was filtered off and washed with H ₂ O then with cold MeOH. The resulting solid was dried in vacuo to obtain (HEMO-027) (8mg, 38%) as a light yellow solid. ¹ H NMR (DMSO -d ₆ , 400 MHz): δ 12.79 (bs, 1 H, OH), 7.75 (s, 1 H, H-ar), 7.73 (d, 1 H, J = 8.0 Hz, H- ar), 7.32 (d, 1H, J = 8.0 Hz, H-ar), 6.88- 6.81 (m, 3H, 3H-ar), 4.29 (s, 2H, NCH ₂ ), 3.73 (s, 3H, OCH ₃ ), 3.39 (t, 2H, J = 5.8 Hz, NCH ₂ CH ₂ ), 2.97 (t, 2H, J = 5.8 Hz, NCH ₂ CH ₂ ), 2.04 (bs, 9H), 1.73 (bs, 6H ). ¹³ C NMR (DMSO -D ₆ , 125.7 MHz) Δ 167.3, 152.3, 144.5, 140.0, 138.2, 134.7, 130.2, 129.6, 126.6, 115.6, 114.2, 113.0, 55.6, 51.6, 28.5, 28.5 , 28.4. HRMS (ESI/Q-TDE) m/z wedge, for C27H31NO3 [M+H] ⁺ 418.2377, obtained 418.2369.

Compound H31

The compound H31 (HEMO-031) of formula: is prepared according to the following reaction scheme:

Methyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-2-carboxylate (10) Pd(OAc)2 (6.10 mg, 0.027 mmol, 5 mol%) and S-Phos (11 .2 mg, 0.027 mmol, 5 mol%) was added to a degassed solution of methyl 6-bromoquinoline-2-carboxylate (8) (144.5 mg, 0.54 mmol, 1 eq.), boronic ester (9 ) (200 mg, 0.54 mmol, 1 eq.) and Na ₂ CO ₃ (173 mg, 1.63 mmol, 3 eq.) in 10:1 Dioxane:H ₂ O. The yellow suspension obtained was stirred at 80°C for 16 hours. H ₂ O was then added and the aqueous phase was extracted 3 times with AcOEt. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was eluted on a silica gel column with 0 to 70% AcOEt in Cyclohexane to obtain (10) (95 mg, 41%) as a white solid. ¹ H NMR (CDCI ₃ , 400 MHz): d 8.46 (d, 1 H, J = 8.9 Hz, H-ar), 8.34 (d, 1 H, J = 8.5 Hz, H-ar), 8.17 (d, 1 H, J = 8.5 Hz, H-ar), 8.03 (dd, 1 H, J = 2.1 Hz,

J = 8.9 Hz, H-ar), 7.95 (d, 1 H, J = 2.1 Hz, H-ar), 7.54 (d, 1 H, J = 2.4 Hz, H-ar), 8.03 (dd, 1 H , J = 2.4 Hz, J = 8.4 Hz, H-ar), 6.94 (d, 1 H, J = 8.5 Hz, H-ar), 4.05 (s, 3H, CH ₃ ), 3.85 (s, 3H, CH ₃ ), 2.11 (db, 6H), 2.04 (db, 3H), 1.74 (db, 6H).

6-(3-(adamantan-1-yl)-4-m2thoxyph2nyl)quinoline-2-carboxylic acid (HEMO-031)

To a solution of ester (10) (30 mg, 0.07 mmol, 1eq.) in 4:1 THF:MeOH at room temperature was added 2M NaOH (105 μI, 0.21 mmol, 3 eq.) . The solution obtained was mixed for 16 h at 60°C. The reaction mixture was then poured into water and the aqueous phase was extracted with AcOEt. The resulting aqueous phase was acidified using 1 M HCl and extracted 3 times with AcOEt. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain (HEMO-031) (17 mg, 59%) in the form of a white solid. ¹ H NMR (DMSO -d ₆ , 500 MHz): δ 8.57 (d, 1 H, J = 8.6 Hz, H-ar), 8.30 (d, 1 H, J = 1.4 Hz, H-ar), 8.19 (d, 1H, J=8.9Hz, H-ar), 8.15 (dd, 1H, J=1.9Hz, J=9.0Hz, H-ar), 8.11 (d, 1H, J=8.5Hz , H-ar), 7.69 (dd, 1 H, J = 2.2 Hz, J = 8.4 Hz, H-ar), 7.61 (d, 1 H, J = 2.2 Hz, H-ar), 7.14 (d, 1 H, J = 8.6 Hz, H-ar), 3.88 (s, 3H, CH ₃ ), 2.14 (db, 6H), 2.08 (db, 3H), 1.77 (db, 6H). ¹³ C NMR (DMSO -D ₆ , 125.7 MHz) Δ 166.5, 158.8, 145.8, 140.0, 138.1, 137.4, 130.9, 130.1, 129.5, 129.2, 125.9, 125.2, 124.0, 121.1, 112.8, 55.4, 36.6, 36.5, 28.4 . HRMS (ESI/Q-TDE) m/z wedge for C27H28NO3 [M+H] ⁺ 414.2064, obtained 414.2060. Compound H32

The compound H32 (HEMO-032) of formula: is prepared according to the following reaction scheme:

Methyl 7-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-3-carboxylate (12) Pd(OAc) ₂ (16.9 mg, 0.075 mmol, 10 mol%) and S-Phos (15 .4 mg, 0.037 mmol, 5 mol%) was added to a degassed solution of methyl 7-bromoquinoline-3-carboxylate (11) (200 mg, 0.75 mmol, 1 eq.), boronic ester (9) ( 415 mg, 1.13 mmol, 1.5 eq.) and Na ₂ CO ₃ (239 mg, 02.25 mmol, 3 eq.) in 10:1 Dioxane:H20. The yellow suspension obtained was stirred at 80° C. for 16 h. H ₂ O then was added and the aqueous phase was extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 0 to 70% AcOEt in Cyclohexane to obtain (12) (40 mg, 13%) in the form of a white solid. ¹ H NMR (DMSO -d ₆ , 400 MHz): d 9.33 (d, 1 H, J = 2.2 Hz, H-ar), 9.02 (d, 1 H, J = 2.2 Hz, H-ar), 8.28- 8.26 (m, 2H, 2H-ar), 8.05 (dd, 1H, J=1.8Hz, J=8.7Hz, H-ar), 7.74 (dd, 1H, J=2.3Hz, J=8.5Hz , H-ar), 7.63 (d, 1H, J = 2.4 Hz, H-ar), 7.16 (d, 1H, J = 8.6 Hz, H-ar), 3.97 (s, 3H, CH ₃ ), 3.89 (s, 3H, CH ₃ ), 2.16 (dbs, 6H), 2.08 (dbs, 3H), 1.77 (dbs, 6H).

7-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-3-carboxylic acid

(HEMO-032)

To a solution of ester (12) (15 mg, 0.035 mmol, 1eq.) in 2:1 THF:MeOH at room temperature was added 2M NaOH (53 μl, 0.11 mmol, 3 eq.). The solution obtained was stirred for 2 hours at 60°C. The reaction mixture was poured into water and the aqueous phase was extracted with AcOEt. The resulting aqueous phase was acidified with 1 M HCl and extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to obtain (HEMO-032) (9mg, 62%) as a white solid. ¹ H NMR (DMSO -d ₆ , 500 MHz): d 13.45 (s, 1H, OH), 9.31 (d, 1H, J = 2.1 Hz, H-ar), 8.96 (d, 1 H, J = 1.8 Hz , H-ar), 8.25 (s, 1 H, H-ar), 8.23 (d, 1 H, J = 8.6 Hz, H-ar), 8.02 (dd, 1 H, J = 1.7 Hz, J = 8.5 Hz, H-ar), 7.73 (dd, 1H, J = 2.2 Hz, J = 8.5 Hz, H-ar), 7.61 (d, 1H, J = 2.3 Hz, H-ar), 7.14 (d, 1H , J = 8.6 Hz, H- ar), 3.88 (s, 3H, CH ₃ ), 2.14 (bs, 6H), 2.07 (bs, 3H), 1.76 (bs, 6H). ¹³ C NMR (DMSO -D ₆ , 125.7 MHz) D 166.4, 159.0, 150.3, 149.7, 143.9, 138.2, 138.1, 130.8, 130.1, 126.6, 126.1, 125.3, 124.8, 55.4, 36.6, 36.5, 28.4 . HRMS (ESI/Q-TDE) m/z wedge. C27H28NO3 [M+H] ⁺ 414.2064, obtained 414.2058.

Compound H35

The compound H35 (HEMO-035) of formula: is prepared according to the following reaction scheme:

Methyl 6-(3-(adamantan-1-yl)-4-((2-methoxyethoxy)methoxy)phenyl)-2- naphthoate (15)

Boronic acid (14) (500 mg, 1.39 mmol, 1 eq.) was added to the flame-dried reactor followed by methyl 6-bromo-2-naphthoate (13) (368 mg, 1.39 mmol,

1 eq.), Pd(PPh3) ₄ (80 mg, 0.070 mmol, 5 mol%), and K ₂ CO ₃ (383 mg, 2.78 mmol,

2 eq.). After addition of 10:1 MeOH:H ₂ O (11.5 ml, 120 mM) then the reactor was then sealed. The solution obtained was stirred at 80°C for 4 hours. After reaching room temperature, H ₂ O and CH ₂ CI ₂ were added. The aqueous phase was extracted 3 times with CH ₂ Cl2, and the combined organic phases were washed with a saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel containing 0 to 5% AcOEt in toluene to obtain (15) (610 mg, 88%) in the form of a white solid. ¹ H NMR (CDCI ₃ , 400 MHz): δ 8.61 (s, 1 H, H-ar), 8.07 (dd, 1 H, J = 1.4 Hz, J = 8.6 Hz, H-ar), 8.01 (s, 1 H, H-ar), 7.99 (d, 1 H, J = 8.6 Hz, H-ar), 7.92 (d, 1 H, J = 8.6 Hz, H-ar), 7.79 (dd, 1 H, J = 1 .6 Hz, J = 8.5 Hz, H-ar), 7.92 (d, 1 H, J = 2.2 Hz, H-ar), 7.51 (dd, 1 H, J = 2.2 Hz, J = 8.5 Hz, H-ar), 7.29 (d, 1H, J = 8.6 Hz, H-ar), 5.39 (s, 2H, OCH ₂ O), 3.99 (s, 3H, OCH ₃ ), 3.90

(dd, 1 H, J = 3.9 Hz, J = 5.4 Hz, OCH ₂ ), 3.62 (dd, 1 H, J = 3.9 Hz, J = 5.4 Hz, OCH ₂ ), 3.42 (s, 3H, OCH ₃ ) , 2.20 (sec, 6H), 2.11 (sec, 3H), 1.81 (sec, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) Δ 167.4, 156.7, 141.4, 139.1, 136.0, 133.8, 129.8, 128.4, 127.1, 126.6, 126.2, 126.0, 125.7, 125.0, 115.2, 93.5, 71.7, 68.0 , 59.2, 52.3, 40.9, 37.4, 37.2, 29.2. HRMS (ESI/Q-TDE) m/z wedge, for C32H40NO5 518.2901 , obtained 518.2890.

Methyl 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-2-naphthoate (16)

A suspension of (15) (610 mg, 1.22 mmol, 1 eq.) in HCl (2M in Et20, 25 mL) was stirred at room temperature for 16 h. A saturated solution of NaHCO ₃ was added and the aqueous phase was extracted 3 times with AcOEt. The combined organic phases were washed with a saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 0 to 40% AcOEt in hexane to obtain (16) (440 mg, 87%) in the form of a white solid. ¹ H NMR (DMSO -d ₆ , 400 MHz): d 9.58 (s, 1 H, OH), 8.61 (s, 1 H, H-ar), 8.17 (s, 1 H, H-ar), 8.14 ( d, 1 H, J = 8.6 Hz, H-ar), 8.06 (d, 1 H, J = 8.7 Hz, H-ar), 7.97 (dd, 1 H, J = 1.1 Hz, J = 8.6 Hz, H -ar), 7.86 (dd, 1H, J=0.9Hz, J=8.6Hz, H-ar), 7.52-7.48 (m, 2H, 2H-ar), 6.92 (d, 1H, J=8.2 Hz, H-ar), 3.91 (s, 3H, OCH ₃ ), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H). 1 ³ C NMR (DMSO -d ₆ , 100.6 MHz) δ 166.4, 156.5, 140.9, 136.1, 135.6, 130.7,

130.2, 129.9, 129.8, 128.5, 126.0, 125.4, 125.2, 125.0, 123.6, 117.0, 52.1, 36.6, 36.4, 28.4.

Methyl 6-(3-(adamantan-1-yl)-4-(prop-2-yn-1-yloxy)phenyl)-2-naphthoate (17)

To a solution of naphthoate (16) (100 mg, 0.24 mmol, 1eq.) in anhydrous THF (2.4 ml, 0.1 M) under an argon atmosphere at 0° C. in a flask dried by flame was added NaH (60%, 12 mg, 0.29 mmol, 1.2 eq.). The mixture obtained was stirred for 5 min at 0° C. then propargyl bromide (33 μl, 0.29 mmol, 1.2 eq.) was then added. The solution, after reaching room temperature, was mixed for 3 hours. H ₂ O was added and the aqueous phase was extracted 3 times with CH ₂ Cl2 and the combined organic phases were washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 5:95 AcOEt:Cyclohexane to obtain (17) (102 mg, 94%) as a white solid. ¹ H NMR (CDCI ₃ , 400 MHz): d 8.62 (s, 1 H, H-ar), 8.07 (dd, 1 H, J = 1.6 Hz, J = 8.6 Hz, H-ar), 8.01 ( s, 1H, H-ar), 7.99 (d, 1H, J=8.6Hz, H-ar), 7.92 (d, 1H, J=8.6Hz, H-ar), 7.79 (dd, 1H , J = 1.7 Hz, J = 8.5 Hz, H-ar), 7.62 (d, 1 H, J = 2.3 Hz, H-ar), 7.54 (dd, 1 H, J = 2.3 Hz, J = 8.4 Hz, H-ar), 2.55 (t, 1 H, J = 2.3 Hz, CHCCH ₂ ), 2.20 (s, 6H), 2.12 (s, 3H), 1.81 (s, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) d 167.4, 157.0, 141.4,

139.6, 136.1, 133.7, 131.5, 131.0, 129.9, 128.4, 127.2, 126.6, 126.4, 125.8,

125.7, 125.0, 113.5, 78.9, 75.5, 55.9, 52.3, 40.9, 37.4, 37.2, 29.2.

6-(3-(adamantan-1-yl)-4-(prop-2-yn-1-yloxy)phenyl)-2-naphthoic acid (HEMO-035)

To a solution of (17) (100 mg, 0.22 mmol) in 2:1 THF:H2O (3 mL) at room temperature was added LiOH (13 mg, 0.55 mmol, 2.5 eq.) . After mixing for 16 h, 1 M HCl was added to reach pH = 1. The precipitate formed was filtered, washed with H ₂ O and dried in vacuo to obtain (HEMO-035) (36 mg, 38%) under form a white solid. ¹ H NMR (DMSO -d ₆ , 500 MHz): d 13.03 (s, 1 H, OH), 8.62 (s, 1 H, H-ar), 8.23 (s, 1 H, H-ar), 8.16 ( d, 1 H, J = 8.6 Hz, H-ar), 8.08 (s, 1 H, H-ar), 7.98 (d, 1 H, J = 8.6 Hz, H-ar), 7.90 (d, 1 H , J = 8.6 Hz, H-ar), 7.66 (dd, 1 H, J = 1 .3 Hz, J = 8.4 Hz, H-ar), 7.60 (s, 1 H, H-ar), 7.18 (d , 1 H, 8.5 Hz, H-ar), 4.91 (d, J = 1.6 Hz, H-ar), 3.60 (t, 1 H, J = 1.6 Hz, CHCCH ₂ ), 2.16 (s, 6H), 2.08 (sec, 3H), 1.77 (sec, 6H). ¹³ C NMR (DMSO -d ₆ , 125.7 MHz) δ 167.5,

156.5, 140.1, 138.5, 135.5, 132.3, 131.0, 130.3, 129.8, 128.4, 127.7, 126.0,

125.6, 125.5, 125.3, 124.3, 114.0, 79.3, 78.1, 67.0, 56.6, 40.1, 36.6, 36.5, 28.4. HRMS (ESI/Q-TDE) m/z wedge, for C30H27O3 [MH]- 435.1966, obtained 435.1962. Compound H38 Compound H38 (HEMO-038) of formula: is prepared according to the following reaction scheme: Ethyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-4-hydroxy-2-naphthoate (19)

Boronic acid (2) (150 mg, 0.53 mmol, 1 eq.) was added to a flame-dried reactor followed by bromoester (18) (179 mg, 0.53 mmol, 1 eq. ), Pd(PPh3)4 (31 mg, 0.027 mmol, 5 mol%), and K ₂ CO ₃ (146 mg, 1.06 mmol, 2 eq.). 10:1 EtOH:H ₂ O (4.4 mL, 120 mM) was added and the reactor was sealed. The resulting mixture was stirred at 80°C for 5 hours. After reaching room temperature, H ₂ O and CH ₂ Cl2 were added. The aqueous phase was extracted 3 times with CH ₂ Cl2, and the combined organic phases were washed with a saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated in _{cold CH 2} Cl2 and the resulting precipitate was filtered and dried in vacuo to obtain (19) (142 mg, 59%) as a white solid. ¹ H NMR (DMSO -d ₆ , 500 MHz): d 10.55 (s, 1 H, OH), 8.31 (s, 1 H, H-ar), 8.08 (s, 1 H, H-ar), 8.06 ( d, 2H, J = 8.4 Hz, H-ar), 7.85 (d, 1 H, J = 8.4 Hz, H-ar), 7.60 (d, 1 H, J = 8.1 Hz, H-ar), 7.53 ( s, 1H, H-ar), 7.41 (s, 1H, H-ar), 7.10 (d, 1H, J = 8.4 Hz, H-ar), 4.35 (q, 2H, J = 6.9 Hz, OCH ₂ ), 3.85 (s, 3H, OCH ₃ ), 2.12 (bs, 6H), 2.05 (bs, 3H), 1.74 (bs, 6H), 4.35 (t, 2H, J = 7.1 Hz, CH ₃ ). ¹³ C NMR (DMSO -D ₆ , 125.7 MHz) D 166.0, 158.5, 153.5, 139.3, 138.0, 132.2, 121.9, 129.8, 127.2, 127.1, 126.2, 125.0, 118.3, 112.8, 106.9, 60.7, 55.3 , 40.1 , 36.6, 36.5, 28.4, 14.3.

6-(3-(adamantan-1-yl)-4-methoxyphenyl)-4-hydroxy-2-naphthoic acid (HEMO-038)

To a suspension of ester (19) (25 mg, 0.055 mmol) in 2:1 THF:H ₂ O (1.5 ml) was added LiOH (3 mg, 0.11 mmol, 2.5 eq. ). After mixing for 4h at 60°C, 1M HCl was added to reach pH=1. The precipitate obtained was filtered, washed with H ₂ O and dried in vacuo to obtain (HEMO-038) (12.3 mg, 52%) in the form of a light yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz): d 12.86 (bs, 1 H, OH), 10.47 (s, 1 H, OH), 8.29 (s, 1 H, H-ar), 8.06 (s, 1 H, H-ar), 8.05 (d, 2H, J = 7.8 Hz, H-ar), 7.84 (d, 1 H, J = 8.7 Hz, H-ar), 7.61 (d, 1 H, J = 8.0 Hz, H-ar), 7.54 (s, 1 H, H-ar), 7.38 (s, 1 H, H-ar), 7.13 (d, 1 H, J = 8.6 Hz, H-ar), 3.87 (s, 3H, OCH ₃ ), 2.13 (db, 6H), 2.07 (db, 3H), 1.76 (db, 6H). ¹³ C NMR (DMSO -D ₆ , 100.6 MHz) D 167.6, 158.5, 153.4, 139.0, 138.1, 132.2, 132.0, 129.7, 128.2, 127.0, 126.9, 125.6, 124.9, 121.1, 118.3, 112.4, 107.4, 53.4, 40.1 , 36.6, 36.5, 28.4. HRMS (ESI/Q-TDE) m/z wedge, for 427.1915, obtained 427.1911.

Compound H39

The compound H39 (HEMO-039) of formula: is prepared according to the following reaction scheme:

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methanol (21)

Boronic acid (2) (150 mg, 0.53 mmol, 1 eq.) was added to a flame-dried microwave reactor followed by bromonaphthol (20) (126 mg, 0.53 mmol, 1 eq.), Pd(PPh3)4 (31 mg, 0.027 mmol, 5 mol%), and K ₂ CO ₃ (146 mg, 1.06 mmol, 2 eq.). 10:1 MeOH:H ₂ O (4.4 mL, 120 mM) was added and the reactor was sealed. The resulting mixture was stirred at 120°C for 1 hour in the microwave. After reaching room temperature, H ₂ O and CH ₂ CI ₂ were added. The aqueous phase was extracted 3 times with CH ₂ Cl ₂ , and the combined organic phases were washed with a saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 100% CH ₂ Cl ₂ to obtain (21) (167 mg, 80%) in the form of a white solid. ¹ H NMR (CDCI ₃ , 400 MHz): d 7.98 (s, 1 H, H-ar), 7.90-7.82 (m, 4H, 4 H-ar), 7.74 (d, 1 H, J = 8.5 Hz, H-ar), 7.60 (d, 1H, J=1.7Hz, H-ar), 7.55-7.48 (m, 2H, 2H-ar),

6.99 (d, 1H, J = 8.4 Hz, H-ar), 4.87 (s, 2H, OCH ₂ ), 3.90 (s, 3H, OCH ₃ ), 2.20 (bs, 6H), 2.11 (bs, 3H) , 1.81 (bs, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 158.7, 139.2, 139.0, 138.1 , 133.4, 133.2, 132.3, 128.6, 128.4, 126.2, 126.0, 125.7, 125.6, 125.4, 125.0, 112.2, 65.7, 55.3, 40.8, 37.3, 29.3. HRMS (ESI/Q-TDE) m/z calc. for C ₂₈ H _3O O ₂ K[M+K] ⁺ 437.1877, obtained 437.1869.

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methyl)ethanethioate

(22)

Di-tert-butyl azodicarboxylate (60 mg, 0. 26 mmol, 2 eq.) and the resulting solution was stirred for 30 min at 0°C. A solution of alcohol (21) (50 mg, 0.13 mmol, 1 eq.) in THF (500 μl) was then added and the mixture obtained was stirred for 1 hour at 0°C then for 1 hour at ambient temperature. After dilution with CH ₂ Cl2, the organic phase was washed with 1 M HCl. The aqueous phase was extracted 3 times with CH ₂ Cl2 and the combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 3:1 CH ₂ Cl2:Cyclohexane to obtain (22) (43 mg, 72%) in the form of a white solid. ¹ H NMR (CDCI ₃ , 400 MHz): d 7.95 (d, 1 H, J = 0.6 Hz, H-ar), 7.83 (d, 1 H, J = 8.4 Hz, H-ar), 7.76 (s, 1 H, H-ar), 7.72 (dd, 1 H, J = 1 .6 Hz, J = 8.5 Hz, H-ar), 7.58 (d, 1 H, J = 2.3 Hz, H-ar), 7.52 (dd, 1 H, J = 2.3 Hz, J = 8.4 Hz, H-ar), 7.39 (dd, 1 H, J = 1.6 Hz, J = 8.4 Hz, H-ar), 6.99 (d, 1 H, J = 8.4 Hz, H-ar), 4.30 (s, 2H, SCH ₂ ), 3.90 (s, 3H, OCH ₃ ), 2.38 (s, 3H, SAc), 2.19 (bs, 6H), 2.10 ( db, 3H), 1.81 (db, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 195.3, 158.8, 139.2, 139.0, 134.7,

133.2, 133.1, 132.3, 128.8, 128.2, 127.4, 127.3, 126.2, 126.0, 125.7, 124.9,

112.3, 55.3, 40.8, 37.3, 34.0, 30.5, 29.3.

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methanesulfonic acid (HEMO-039)

Thioacetate (22) (43 mg, 0.094 mmol, 1eq.) was suspended in AcOH (1.07 ml, 87.5 mM). AcONa (77 mg, 0.94 mmol, 10 eq.) was added, followed by potassium hydrogen persulfate (74 mg, 0.24 mmol, 2.5 eq.) and the mixture obtained was stirred vigorously for 16 h. AcOEt was added and the precipitate obtained was filtered and washed with AcOEt then the organic phases were concentrated in vacuo. The residue was eluted on a silica gel column with 0 to 20% MeOH in CH ₂ Cl ₂ to obtain (HEMO-039) (14.5 mg, 33%) in the form of a white solid. ¹ H NMR (DMSO -d ₆ , 400 MHz): d 8.08 (s, 1 H, H- ar), 7.89 (d, 1 H, J = 8.7 Hz, H-ar), 7.86 (d, 1 H, J = 8.4 Hz, H-ar), 7.77 -7.74 (m, 2H, 2 H-ar) , 7.62 (dd, 1 H, J = 2.2 Hz, J = 8.4 Hz, H-ar), 7.56 (d, 1 H, J = 2.3 Hz, H-ar), 7.52 (dd, 1 H, J = 1 .5 Hz, J = 8.4 Hz, H-ar), 7.10 (d, 1 H, J = 8.6 Hz, H-ar), 3.88 (s, 2H, SCH ₂ ), 3.86 (s, 3H, OCH ₃ ) , 2.14 (db, 6H), 2.07 (db, 3H), 1.76 (db, 6H). ¹³ C NMR (DMSO-D ₆ , 100.6 MHz) Δ 158.2, 137.9, 137.1, 133.1, 132.3, 129.4, 128.1, 128.0, 126.9, 123.9, 112.7, 57.7, 28.4, 28.4 . HRMS (ESI/Q-TDE) m/z wedge for C28H29O4S [MH]- 461.1792, obtained 461.1784.

Example 4 - Synthesis of Compound H24 Compound H24 of formula: is prepared according to the following reaction scheme:

Methyl 3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylate (3) Boronic acid (2) (242 mg, 0.85 mmol, 1 eq .) was added to a flame-dried reactor followed by methyl 4-bromobenzoate (1) (183 mg, 0.85 mmol, 1 eq.), Pd(PPh3)4 (54 mg, 0.047 mmol, 5 mol% ), and K2CO3 (257 mg, 1.86 mmol, 2 eq.). After addition of 10:1 MeOH:H ₂ O (7.75 ml, 120 mM) the reactor was sealed. The solution was then stirred at 80°C for 16 h. After reaching room temperature, H ₂ O and CH ₂ Cl2 were added. The aqueous phase was extracted 3 times with CH ₂ Cl ₂ , and the combined organic phases were washed with a saturated solution of NaCl, evaporated on MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 1:2 CH ₂ Cl ₂ :Cyclohexane to give (3) (260 mg, 85%) in the form of a solid White. ¹ H NMR (CDCI ₃ , 400 MHz): d 8.07 (d, 2H, J = 8.4 Hz, 2 H-ar), 7.63 (d, 2H, J = 8.4 Hz, 2 H-ar), 7.50 (d, 1 H, J = 2.3 Hz, H-ar), 7.45 (dd, 1 H, J = 2.3 Hz, J = 8.4 Hz, 2 H-ar), 6.96 (d, 1 H, J = 8.4 Hz, H- ar), 3.93 (s, 3H, CH ₃ ), 3.89 (s, 3H, CH ₃ ), 2.15 (bs, 6H), 2.09 (bs, 3H), 1.79 (bs, 6H). ¹³ C NMR (CDCI ₃ , 100.6 MHz) d 167.3, 159.3, 146.2, 139.1 , 132.1 , 130.2, 128.1 , 126.7, 125.9, 125.7, 112.2, 55.3, 52.2, 40.7, 277.2, 391.2, 391.2, 391.2 HRMS (ESI/Q-TDE) m/z wedge, for C25H29O3 [M+H] ⁺ 377.2111 , found 377.2111 .

2-(3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-4-ylcarboxamido) methyl acetate (4)

To a suspension of ester (3) (112 mg, 0.31 mmol) in 2:1 THF:H2O (4.3 mL) was added LiOH (19 mg, 0.78 mmol, 2.5 eq.) . After mixing for 18 h, 1 M HCl was added to reach pH = 1. The precipitate formed was filtered, washed with H ₂ O and evaporated in vacuo before being suspended in _{anhydrous CH 2} Cl ₂ (7 .5ml). EDC.HCI (140 mg, 0.73 mmol, 2.5 eq.), HOBt (120 mg, 0.87 mmol, 3 eq.) and DIPEA (200 μl, 1.15 mmol, 4 eq.) were then added and the mixture obtained was stirred for 5 min at room temperature before the addition of glycine methyl ester (74 mg, 0.58 mmol, 2 eq.). After stirring for 16 h, 1M HCl was added and the aqueous phase was extracted 3 times with CH ₂ Cl2. The combined organic phases were washed with H ₂ O and a saturated NaCl solution, evaporated over MgSO ₄ , filtered and concentrated in vacuo. The residue was eluted on a column of silica gel with 30 to 50% AcOEt in Cyclohexane to obtain (4) (97 mg, 74%) in the form of a white solid. ¹ H NMR (CDCI ₃ , 500 MHz): d 7.87 (d, 2H, J = 8.3 Hz, 2 H-ar), 7.64 (d, 2H, J = 8.3 Hz, 2 H-ar), 7.48 (d, 1 H, J = 2.2 Hz, H-ar), 7.44 (dd, 1 H, J = 2.3 Hz, J = 8.4 Hz, 2 H-ar), 6.96 (d, 1 H, J = 8.4 Hz, H- ar), 6.68 (bs, 1H, NH), 4.28 (d, 2H, J = 4.9 Hz, NCH ₂ ) 3.89 (s, 3H, CH ₃ ), 3.82 (s, 3H, CH ₃ ), 2.15 (bs , 6H), 2.09 (db, 3H), 1.79 (db, 6H). ¹³ C NMR (CDCI ₃ , 125.7 MHz) D 170.8, 167.5, 159.2, 145.2, 139.1, 127.7, 126.9, 125.8, 125.6, 112.2, 55.3, 52.6, 37.2, 29.2, 37.3, 37.2, 29.2. HRMS (ESI/Q-TDE) m/z wedge, for C ₂₇ H ₃₂ NO ₄ [M+H] ⁺ 434.2326, obtained 434.2322.

2-(3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-4-ylcarboxamido)acetic acid (HEMO-024, or H24) To a suspension of ester (4) (25 mg, 0.058 mmol) in 2:1 THF:H ₂ O (1.5 ml) was added LiOH (4 mg, 0.15 mmol, 2.5 eq.) . After stirring for 18 h, 1 M HCl was added to reach a pH=1. The precipitate formed was filtered, washed with H ₂ O and evaporated in vacuo to obtain (HEMO-024) (13 mg, 54%) in the form of a white solid. ¹ H NMR (DMSO -d ₆ , 400 MHz): d 12.57 (bs, 1 H, OH), 8.84 (t, 1 H, J = 5.9 Hz, NH), 7.93 (d, 2H, J = 8.4 Hz, 2 H-ar), 7.72 (d, 2H, J = 8.4 Hz, 2 H-ar), 7.55 (dd, 1 H, J = 1 .9 Hz, J = 8.4 Hz, H-ar), 7.46 (d , 1 H, J = 1 .9 Hz, H-ar), 7.08 (d, 1 H, J = 8.6 Hz, H-ar), 3.94 (d, 2H, J = 5.8 Hz, NCH ₂ ), 3.85 ( s, 3H, OCH ₃ ), 2.11 (dbs, 6H), 2.06 (dbs, 3H), 1.75 (dbs, 6H). ¹³ C NMR (DMSO -d ₆ , 125.7 MHz) d 171.4, 166.3, 158.7, 143.4, 138.0, 131.7, 131.1 , 127.9, 126.0, 125.5, 124.8, 112.7, 55.4, 41.2, 28.4.6, 36.4.6 HRMS (ESI/Q-TDE) m/z wedge, for C ₂₆ H ₂₈ NO ₄ [M-H]- 418.2024, obtained 418.2016.

Example 5 - Ex Vivo Thrombin Generation Assay

A second thrombin generation test is carried out, for compounds H27, H31, H32, H35, H38, H39 and compound H24.

The thrombin generation test was carried out at 37°C using a CAT analyzer (Diagnostica Stago) with the PPP Reagent LOW reagent (Diagnostica Stago) in accordance with the manufacturer's instructions and according to the method established by Pr. Hemker in 2003. PPP Reagent LOW is a mixture of tissue factor (TF) 1pM with phospholipid vesicles (PL, 4mM). The test is triggered by the addition of a mixture of calcium + fluorescent substrate (ZGGR-AMC) (FluCa mixture).

From a technical point of view, 80 μL of spiked plasma sample are added to 20 μL of “initiator complex” (PPP Reagent LOW) and incubated for 10 min at 37°C. Then, the reaction is triggered by the addition of 20 μL of FluCa (mixture of CaCl ₂ and ZGGR-AMC substrate) and the fluorescence signal is measured over time. Each test is performed in triplicate.

For each molecule tested, 247 μL of plasma from the hemophiliac patient were spiked with 13 μL of a solution containing different amounts of compound (molecule to be tested, factor VIII or dilution buffer) to obtain the desired final concentration (systematic dilution of the molecule to be tested in plasma at 1/20). For example, to obtain the final concentration of 50 mM in plasma, 13 μL of a 1 mM solution was added to 247 μL of plasma. In parallel with the tests on the different chemical compounds, the plasma of a hemophiliac patient is spiked with the same buffer for diluting the compound, an 8% solution of dimethylsulfoxide (DMSO), as a negative control (0.4% of final DMSO ) in order to obtain the basal level of thrombin generation of the plasma used. The positive control is the same plasma spiked with plasma factor VIII (Factane, LFB, France) at a concentration of 1 IU/mL (or 100% factor VIII) in order to obtain the expected “normal” level of thrombin generation plasma used. For this example, solutions of adapalene and 1 mM compounds were prepared with buffer (18 mM HEPES, 135 mM NaCl, pH 7.35) instead of water as in Example 1. This modification has made it possible to increase the quantity of thrombin generated by the plasma of the hemophiliac patient A in the presence of 50 μM of adapalene. The compounds were tested at a final concentration of 50 μM in plasma, and the signal was measured over time. The results obtained, expressed as the amount of thrombin measured at the maximum of the peak obtained and normalized to the thrombin peak obtained with adapalene, are shown in Table 1 below: Table 1

All the compounds according to the invention tested make it possible to obtain a significant increase in the generation of thrombin compared to the negative control, with, for all of them except compound H24, a peak of thrombin generated higher than that of the control positive, and in particular much higher for compounds Ad, H38 and H39.

Claims

1. Compound of general formula (III'): in which

Y ₁ 'represents a covalent bond or an amide group, R ₄ 'represents a hydrogen atom, a hydroxyl group, a halogen atom, an amine group or a linear or branched, saturated or unsaturated, optionally interrupted carbon radical and /or substituted by one or more heteroatoms and/or one or more groups comprising at least one heteroatom, Y ₂ 'represents a covalent bond or an amide group, A ₂ ' represents a cyclic or heterocyclic group, optionally substituted, comprising two fused rings , at least one of said rings being aromatic, or a pharmaceutically acceptable salt thereof, for use as an active agent for the treatment of hemophilia in a subject.

2. Compound for its use according to claim 1, for the restoration of coagulation in the plasma of a subject suffering from haemophilia.

3. Compound for its use according to claim 2, for the restoration of the generation of thrombin in the plasma of a subject suffering from hemophilia.

4. Compound for its use according to any one of claims 1 to 3, according to which, in the general formula (III '), R ₄ 'represents an -ORs group or an -O-CO-R _{8 group} , where Rs represents a linear or branched, saturated or unsaturated hydrocarbon radical containing from 1 to 10 carbon atoms, optionally substituted by one or two substituents R ₁₄ , R _14' , identical or different, each chosen from F, -CO ₂ H, -SO ₃ H, -P(O)(OH)2, -P(O)(OCH ₃ ) ₂ , hydrogen or a methyl group.

5. Compound for its use according to claim 4, according to which Rs represents a group of general formula (XVIII): wherein y is an integer between 1 and 10 and R ₁₄ is as defined in claim 4.

6. Compound for its use according to any one of claims 1 to 5, according to which, in the general formula (III '), R ₄ 'is attached to the phenyl radical in the ortho or para position with respect to the adamantyl unit, and Y ₂ ' is attached to the phenyl radical in the meta position relative to the adamantyl unit.

7. Compound for its use according to any one of claims 1 to 6, according to which, in the general formula (III '), A2' is at least substituted by one substituent R ₁₁ chosen from fluorine, carboxyl groups, sulfonyl , phosphonyl, tetrazole or keto-oxadiazole, and linear, branched and/or cyclic, saturated or unsaturated, aromatic or unaromatic carbon radicals, optionally interrupted and/or substituted by one or more heteroatoms, and/or one or more groups comprising at least one heteroatom.

8. Compound for its use according to claim 7, according to which R ₁₁ is chosen from the groups of formulas:

9. Compound for its use according to any one of claims 1 to 8, said compound corresponding to the general formula (IX): in which Y ₁ ', Y ₂ ' and R ₄ ' are as defined in one of claims 1 to 8, A ₃ represents a cyclic or heterocyclic hydrocarbon with 3 to 8 members, saturated or unsaturated, aromatic or not,

B ₁ and B ₂ , identical or different, each represent a -CH- group or a nitrogen atom, R ₉ and R ₁₀ , identical or different, each represent a hydrogen atom, a hydroxyl group or an -OR group ₁₂ or -O-CO-R ₁₂ where R ₁₂ represents a linear or branched hydrocarbon radical, saturated or unsaturated, containing from 1 to 10 carbon atoms, optionally substituted by one or two substituents R ₁₆ , R _{16 '} , identical or different , each chosen from where R17 represents a hydrogen atom or a methyl group, and R ₁₁ represents a substituent chosen from fluorine, carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole groups, and linear, branched and/or cyclic carbon radicals, saturated or unsaturated, aromatic or not, optionally interrupted and/or substituted by one or more heteroatoms, and/or one or more groups comprising at least one heteroatom.

10. A compound for its use according to claim 9, in which R ₁₁ represents a -(CH ₂ ) _x -R _{13 group} where x is an integer between 0 and 4 and R ₁₃ represents a fluorine atom or a carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole group.

11. Compound for its use according to claim 10, said compound corresponding to the general formula (X): wherein Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , B2, R ₉ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

12. Compound for its use according to one of claims 10 or 11, said compound corresponding to the general formula (XI): wherein Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , R ₉ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

13. Compound for its use according to any one of claims 10 to 11, said compound corresponding to the general formula (XII):

wherein Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , B ₂ , R ₉ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

14. Compound for its use according to any one of claims 10 to 13, said compound corresponding to the general formula (XIII): wherein Y ₁ ', Y ₂ ', R ₄ ', A ₃ , B ₁ , R ₉ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

15. Compound for its use according to any one of claims 10 to 14, said compound corresponding to the general formula (XIV):

wherein Y ₁ ', Y ₂ ', R ₄ ', R ₉ , B ₁ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

16. Compound for its use according to any one of claims 10 to 15, said compound corresponding to the general formula (XV): wherein Y ₁ ', Y ₂ ', R ₄ ', R ₉ , B ₁ , R ₁₀ , R ₁₃ and x are as defined in claim 9.

17. Compound for its use according to any one of claims 10 to 16, said compound corresponding to formula (XVI):

wherein Y ₁ ', Y ₂ ', R ₄ ', R ₁₃ and x are as defined in claim 9.

18. Compound for its use according to any one of claims 1 to 17, said compound corresponding to formula (V):

19. Compound for its use according to any one of claims 1 to 17, said compound corresponding to formula (XVII):

at 19, wherein said subject is a mammal, in particular a human being.

21. A compound for its use according to any one of claims 1 to 20, wherein said compound is contained in a pharmaceutical composition, in a pharmaceutically acceptable vehicle.

22. A compound for use according to claim 21, wherein said composition is in a form suitable for administration to said subject orally.