EP4735113A1 - Pyrazole derivatives as pd-1/pd-l1 interaction inhibitors - Google Patents

Abstract

The present application relates to pyrazole derivatives as PD-1/PD-L1 interaction inhibitors. The applicants designed compounds of general formula (I), wherein R', R², y³, R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein, that are able to efficiently block PD-1/PD-L1 interactions in order to restore anti-tumor immune responses of subjects and eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion. The applicants confirmed that these compounds blocked the PD-1/PD-L1 interactions by carrying out physicochemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Promega Blockade assay, T cell assay). These compounds had an affinity (Kd) of the order of pM that was higher than that of the antibody atezolizumab used in clinical use, and had a comparable or better IC50 than that observed with atezolizumab. Thus, the present invention also relates to a pharmaceutical composition comprising said compound(s) and their uses in the treatment of PD-1-PD-L1 interactions-related diseases (cancer, chronic inflammatory diseases, neurological diseases and chronic infections).

Description

PYRAZOLE DERIVATIVES AS PD-1/PD-L1 INTERACTION INHIBITORS

The present invention relates to novel pyrazole derivatives which act advantageously as PD-1/PD-L1 interaction inhibitors. The present invention is directed to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹, R², Y³, R³, R⁴, R⁵, R⁶and R⁷ are as defined in the description. The present invention also relates to a pharmaceutical composition comprising at least one of said compound, and uses of said compound or pharmaceutical composition, in particular as a PD-1/PD-L1 interaction inhibitor, preferably in the prevention and/or the treatment of PD-1-PD-L1 interactions-related diseases such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections.

In recent years, immunotherapy has emerged as a powerful strategy for treating cancer, so much so that in 2018 the Nobel Prize in Physiology or Medicine was awarded to Allison and Honjo "for their discovery of cancer therapy by inhibiting negative immune regulation". The immunotherapeutic drugs currently on the market are monoclonal antibodies that interfere with specific modulatory systems, called immune checkpoints, acting at the interface between the tumour and cells of the immune system, particularly T cells. Immune checkpoint receptors (ICRs) are constitutively expressed on the surface of T cells to counteract hyperactive adaptive responses to self-antigens, thereby preventing autoimmune reactions.

Among the immune checkpoints, programmed cell death protein 1 (PD-1 , also known as CD279) and its ligand, programmed death ligand 1 (PD-L1 , also known as CD274 or B7-H1 ) play a major role in T-cell depletion in many types of cancer, including melanoma, breast, pancreatic, kidney and non-small cell lung cancer (NSCLC). The PD-L1 (CD274/B7-H1 ) transmembrane molecule belongs to the B7 family of immunoregulatory proteins and was originally described as mediating tumor immunoescape through interaction with the PD-1 receptor on T cells (Schildberg, et al.-, Saudemont, et al.). This role has been well documented and has led to the development of several clinical grade blocking antibodies that are currently considered innovative drugs in many cancers (Nishino, et al.). Aberrant PD-L1 expression has been observed in hematologic malignancies and in a variety of solid tumor types. Tumor cells evade antitumor immunity, in part by exploiting immune checkpoints, such as the PD-1/PD-L1 axis, that induce T cell dysfunction or unresponsiveness. More than 1 ,000 clinical trials have evaluated the antitumour properties of anti-PD-1/anti- PD-L1 mAbs. As a result, some anti-PD1 (e.g., nivolumab and pembrolizumab) and anti-PD-L1 (e.g., atezolizumab, avelumab and durvalumab) mAbs have entered the market, revolutionising the treatment landscape for the above-mentioned tumours, including agents effective against other malignancies. In order to overcome the limitations of mAbs (e.g., high production costs and side effects), while improving patient compliance (e.g., oral administration), macrocyclic peptides, peptidomimetics and small non-peptidic molecules are being developed as anti-PD-L1 agents, opening a new era for drug discovery in the field of immunotherapy. However, clinical development of anti-PD-L1 small molecules is still in its infancy; in fact, there is only one organic small molecule, INCB086550, currently in phase II clinical trials for the treatment of advanced solid tumors.

The patent application W02021/009384 discloses pyrazolone derivatives as PD-1/PD-L1 interaction inhibitors, and uses of said pyrazolone derivatives or a pharmaceutical composition comprising said pyrazolone derivatives in the prevention and/or treatment of PD-1-PD-L1 interactions-related diseases.

There is thus a need for novel small molecules that are able to efficiently block PD-1/PD- L1 interactions, have high bioavailability, high tumor penetration, low production costs and are non-toxic.

The inventors have succeeded in developing novel pyrazole derivatives that are able to efficiently block PD-1/PD-L1 interactions in order to restore anti-tumor immune responses of subjects and ultimately eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion.

Thus, the present invention relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl, in particular a phenyl, optionally substituted with one or two substituents selected from the group consisting of halogen, Ci- Ce alkoxy and Ci-Ce alkyl;

R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3, preferably 1 or 2;

Y³ represents C and R³ represents H or halogen; or Y³ represents N and R³ is absent;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-C1-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci- Ce alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3, preferably 1 or 2, and n representing an integer between 1 and 3, preferably 1 or 2.

As defined herein, the term “tautomer¹’ refers to structural isomers differing only in the positions of hydrogen atoms and electrons. Examples of tautomers include, but are not limited to, ketone-enol, enamine-imine, amide-imidic acid, lactam-lactim, nitroso-oxime, ketene-ynol, amino acid, or phosphite-phosphonate.

As defined herein, the term “mesomer¹’ or “meso compound’ refers to a stereoisomer that has two or more chiral centers but is optically inactive.

As defined herein, the term “racemate" or “racemic mixtures" refers to a mixture of two enantiomers in equal proportions.

As defined herein, the term “enantiomer¹’ refers stereoisomers that are mirror images, i.e., mirror image isomers. As defined herein, the term “diastereomer¹’ refers to isomers of compounds with more than one chiral center that are not mirror images of one another.

The compounds of the invention containing a basic functional group may be in the form of pharmaceutically acceptable salts. As defined herein, the term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of the compounds of the invention containing one or more basic functional groups which include in particular the acid addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, cinnamate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

As defined herein, the term “CrCe alkyl’ represents any monovalent radical of a linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of suitable CrCe alkyl groups include, but are not limited to, C1-C4 alkyl groups such as methyl, ethyl, n-propyl, /'-propyl, n-butyl, /'-butyl, s-butyl or t-butyl, Ce-Cs alkyl groups such as n-hexyl, n-heptyl or n-octyl, as well as n-pentyl, 2-ethylhexyl, 3,5,5-trimethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl or n- octadecyl.

As defined herein, the term “aryl” represents a polyunsaturated, aromatic hydrocarbyl group having a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. Examples of aryl groups include but are not limited to phenyl, biphenyl, 1 -naphthyl (or naphthalene-1 -yl), 2-naphthyl (or naphthalene-2-yl), anthracenyl, indanyl, indenyl, 1 , 2,3,4- tetrahydronaphthyl.

As defined herein, the term “halogen" represents an atom of F, Cl, Br or I.

As defined herein, the term “C Ce alkoxy” represents a radical of formula -OR’, wherein R’ is a CrCe alkyl. Examples of suitable Ci-Ce alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), t-butoxy (-OC(CH₃)₃), or -O(CH₂)5CH₃.

As defined herein, the term “C5-C10 heterocyclyf’ refers to any monovalent radical of a monocyclic or bicyclic 5 to 10 membered ring containing one or more heteroatoms such as O, N, or S. Examples of suitable heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, aziridinyl, azetidinyl, or pyrrolidinyl.

As defined herein, the term “between" two numerical values of a range should be interpreted to be inclusive of the beginning point and the endpoint of the range. For example, the term “an integer between 1 and 3’ includes the values 1 and 3.

Unless mentioned otherwise, the groups and radicals defined hereinabove may be unsubstituted or substituted by one or more substituents such as, for example, halogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkanoyl, aroyl, formyl, nitrile, nitro, amido, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, amino, alkylamino, arylamino, dialkylamino and diarylamino.

In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein R¹ represents a phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl, preferably R¹

In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein R² represents Ci-Ce alkyl, preferably CH₃.

In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein Y³ represents C and R³ represents halogen, more preferably Cl. In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H or halogen such as Cl.

In another preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein R⁴, R⁵ and R⁶ are identical and represent H; and R⁷ represents halogen, preferably R⁷ represents Cl.

In another preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein R⁴, R⁵ and R⁷ are identical and represent H; and R⁶ represents halogen, preferably R⁶ represents Cl.

In a particular embodiment of the invention, the compound of general formula (I) as defined herein is one wherein:

- R¹ represents CH₃, C(O)OCH₂CH₃, or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; preferably R¹ represents

- R² represents H, Ci-Ce alkyl, CH₂-C(O)OCI-C6 alkyl, or CH₂C(O)OH; preferably R² represents H, CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; more preferably R² represents CH₃; and/or

- Y³ represents C and R³ represents H or halogen, preferably halogen, more preferably Cl; and/or

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, OCH₃, C(O)NH₂,

C(O)OH, CH₂NH₂, CH₂NH(CH₂)₂C(O)OH, CH₂NH(CH₂)₂C(O)OCH₂CH_3J CH₂NHC(O)CH₂C(O)OCH₂CH₃, preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; more preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H or Cl.

In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is one wherein: Y³ represents C and R³ represents halogen, preferably Cl; and:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; preferably R⁵ represents Cl; or

(ii) - R⁴, R⁵ and R⁶ are identical and represent H; and

R⁷ represents halogen, preferably R⁷ represents Cl; or

(iii) - R⁴, R⁵ and R⁷ are identical and represent H; and

R⁶ represents halogen, preferably R⁶ represents Cl.

In a particular embodiment of the invention, the compound of general formula (I) as defined herein is one wherein:

- Y³ represents C and R³ represents H or halogen, preferably H or Cl;

- R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R¹ represents CH₃, C(O)OCH₂CH₃, or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; more preferably R¹ represents

; even more preferably R¹ represents

- R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3, preferably 1 or 2; preferably R² represents H, CH₃,

CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; and

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy,

C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl,

C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-Cs-Cio heterocyclyl-C(O)-Ci-C6 alkyl, with m representing an integer between 1 and 3, preferably 1 or 2, and n representing an integer between 1 and 3, preferably 1 or 2; preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or which may be identical or different, represent H, Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; even more preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H or Cl.

In another particular embodiment of the invention, the compound of general formula (I) as defined herein is one wherein:

- R¹ represents aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; more preferably R¹ represents

R² represents CrCe alkyl, preferably CH₃;

Y³ represents N and R³ is absent; and

R⁴, R⁵, R⁶ and R⁷ represent H.

In a particular embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds:

In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396.

The present invention is also directed to a pharmaceutical composition comprising (i) at least one compound of general formula (I) as defined herein, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient. As defined herein, the term “pharmaceutically acceptable” means that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the subject thereof.

As defined herein, the term “excipient’ means a substance formulated alongside the active agent or active ingredient in a pharmaceutical composition or medicament. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 21 ^st Edition 2011 . The choice of excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. The at least one pharmaceutically acceptable excipient may be for example, a binder, a diluent, a carrier, a lubricant, a disintegrator, a wetting agent, a dispersing agent, a suspending agent, and the like.

By means of non-limiting examples, said pharmaceutical composition may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), cerebral administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the person skilled in the art; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

For example, the compound of general formula (I) as defined herein or the pharmaceutical composition according to the invention can be administered orally in the form of tablets, coated tablets, pills, capsules, soft gelatin capsules, oral powders, granules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, a disintegrant such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, a binder such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia, a lubricant such as magnesium stearate, stearic acid, glyceryl behenate. Solid compositions of a similar type may also be employed as fillers in hard gelatin capsules. Preferred excipients in this regard include lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Hard gelatin capsules may contain granules of the compound of the invention.

Soft gelatin capsules may be prepared with capsules containing the compound of the invention, vegetable oil, waxes, fat, or other suitable vehicle for soft gelatin capsules. As an example, the acceptable vehicle can be an oleaginous vehicle, such as a long chain triglyceride vegetable oil (e.g. corn oil).

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may contain the active ingredient in a mixture with dispersing agents, wetting agents, and suspending agents and one or more preservatives. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Liquid dosage forms for oral administration may include pharmaceutically acceptable, solutions, emulsions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or an oleaginous vehicle. Liquid dosage form may be presented as a dry product for constitution with water or other suitable vehicle before use. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, complexing agents such as 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cylodextrin, and sweetening, flavouring, perfuming agents, colouring matter or dyes with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Finely divided powder of the compound of the invention may be prepared for example by micronisation or by processes known in the art. The compound of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.

If the compound of the invention is administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.

The compound of the invention can be administered via the parenteral route with a readily available or a depot-type formulation. The pharmaceutical composition for the parenteral administration of a readily available formulation may be in the form of a sterile injectable aqueous or oleagenous solution or suspension in a non-toxic parenterally-acceptable diluent or solvent and may contain formulatory agents such as suspending, stabilising dispersing, wetting and/or complexing agents such as cyclodextrin e.g. 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cylodextrin.

The depot-type formulation for the parenteral administration may be prepared by conventional techniques with pharmaceutically acceptable excipient including without being limited to, biocompatible and biodegradable polymers (e.g. poly(p-caprolactone), polyethylene oxide), poly(glycolic acid), poly[(lactic acid)-co-(glycolic acid)...)], poly(lactic acid)...), non- biodegradable polymers (e.g. ethylene vinylacetate copolymer, polyurethane, polyester(amide), polyvinyl chloride...) aqueous and non-aqueous vehicles (e.g. water, sesame oil, cottonseed oil, soybean oil, castor oil, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils, propylene glycol, DMSO, THF, 2-pyrrolidone, N-methylpyrrolidinone, N-vinylpyrrolidinone... ).

Alternatively, the active ingredient may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

As indicated, the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch. For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of the invention is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 50 microns (for example as measured using laser diffraction). Alternatively, the compound of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compound of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. It may also be administered by the ocular route. For ophthalmic use, the compound can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, it may be formulated in an ointment such as petrolatum.

For topical application to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.

The at least one compound of general formula (I) as defined herein can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day in equal doses. The daily administered dose is advantageously comprised between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.

In a particular embodiment of the invention, the pharmaceutical composition comprises (i) one compound, e.g., a single compound, of general formula (I) as defined herein, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

In a particular embodiment of the invention, the compound of general formula (I) as defined herein, or the composition according to the invention are for use in a method of prevention and/or treatment of a disease in a subject, preferably as a PD-1/PD-L1 interaction inhibitor in a subject, in particular a human. In particular the compound of general formula (I) as defined herein, or the composition according to the invention is able to restore the anti-tumor immune response of the subject and ultimately eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion.

In a preferred embodiment of the invention, the disease is a PD-1 -PD-L1 interactions- related disease such as cancer, chronic inflammatory disease, neurological disease and chronic infection in a subject, in particular a human.

As defined herein, the term “human" refers to subjects of both genders and at any stage of development (/.e., neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.

As defined herein, the term “prevention" refers to primary, secondary and tertiary preventions. Prevention of a PD-1-PD-L1 interactions-related disease means that said disease and associated risk factors are minimized, i.e., are obstructed or delayed. In particular, said disease may be prevented before it occurs or identified at an early stage so that the symptoms of said disease may be reduced.

As defined herein, the term “treatment’ is meant to include alleviating or abrogating a PD- 1 -PD-L1 interactions-related disease and/or their attendant symptoms.

As defined herein, the term “PD-1-PD-L1 interactions-related disease" includes any disease due to the inhibition of T-cell activation, in particular caused by the interaction between PD-L1 and PD-1 , and the treatment or prevention of which would benefit from the use of an inhibitor of said interaction. Non-limiting examples of PD-1 -PD-L1 interactions-related diseases include cancer, chronic inflammatory disease, neurological diseases and chronic infections.

In a preferred embodiment of the invention, the cancer is selected from the group consisting of lung carcinoma (Non small cell and Small cell), head and neck carcinoma, bladder carcinoma, kidney carcinoma, triple negative breast cancer, pancreatic carcinoma, melanoma, gastric carcinoma, oesophagus carcinoma, Hodgkin’s lymphoma, non Hodgkin lymphoma, glioblastoma, multiple myeloma, acute myeloide leukemia, Cholangiocarcinoma (gallbladder carcinoma), Merkel carcinoma, squamous cell carcinoma and endometrial carcinoma; the neurological disease is Alzheimer disease; the chronic inflammatory disease is psoriasis; and/or the chronic infections are selected from the group consisting of Human immunodeficiency virus (HIV), malaria, tuberculosis and B hepatitis.

In a particular embodiment of the invention, the pharmaceutical composition further comprises at least one other active ingredient, such as an anticancer agent. In particular, the anticancer agent may be an anti-CTLA4 antibody such as Ipilimumab, a CAR-T compound such as axicabtagene ciloleucel, an anti-LAG3 antibody such as BMS-986016, an anti-TIM3 antibody such as MBG453, an antiCD47 antibody such as Hu5F9-G4, a small molecule blocking SIRP1 a , an anti-VISTA antibody, an anti-TIGIT antibody, an anti CD200 antibody such as samalizumab, an anti-CD38 antibody such as daratumumab, an anti-TNF a inhibitor such as Etanercept, and an anti-200R inhibitor such as 0X2 inhibitory peptide. Said particular pharmaceutical composition may be for use, e.g., simultaneous, separate or sequential use, in the prevention and/or the treatment of a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections as previously defined.

In particular embodiment of the invention, the compound of general formula (I) as defined herein, or the composition according to the invention is for use in the prevention and/or the treatment of a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections, in association with radiotherapy and/or virotherapy.

The invention also relates to a method for the preparation of the compound of general formula (I) as defined herein, said method comprising: i) reacting a (3-ketonitrile having the formula (II): o

R¹ A /^CN (II), in which R¹ is as defined herein, with an aryl-hydrazine having the formula (III): which Y³, R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein, preferably in the presence of p-toluenesulfonic acid (PTSA) in a polar solvent such as ethanol; or ii) conducting a one-pot reaction from an ethyl ester derivative having the formula (IV): o

R A OEt (IV), in which R¹ is as defined herein, a polar solvent such as acetonitrile and with an aryl-hydrazine having the formula (III): which Y³, R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein, followed by an acylation step.

According to an aspect, the invention relates to the following items:

Item 1. A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: wherein:

R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3;

Y³ represents C and R³ represents H or halogen; or Y³ represents N and R³ is absent;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-Ci-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci- Ce alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3. Item 2. The compound according to item 1 , wherein:

R¹ represents CH₃, C(O)OCH₂CH₃, or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; preferably R¹ represents y

- R² represents H, Ci-Ce alkyl, CH₂-C(O)OCi-Ce alkyl, or CH₂C(O)OH; preferably R² represents H, CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; more preferably R² represents CH₃; and/or

- Y³ represents C and R³ represents H or halogen, preferably halogen, more preferably Cl; and/or

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, OCH₃, C(O)NH₂, represent H, Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; more preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H or Cl. Item 3. The compound according to item 1 or 2, wherein Y³ represents C and R³ represents halogen, preferably Cl; and wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; preferably R⁵ represents Cl; or

(ii) - R⁴, R⁵ and R⁶ are identical and represent H; and

R⁷ represents halogen, preferably R⁷ represents Cl; or

(iii) - R⁴, R⁵ and R⁷ are identical and represent H; and

R⁶ represents halogen, preferably R⁶ represents Cl.

Item 4. The compound according to any one of items 1 to 3, wherein:

- Y³ represents C and R³ represents H or halogen, preferably H or Cl;

- R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R¹ represents CH₃, C(O)OCH₂CH₃, or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; more preferably R¹

; even more preferably R¹ represents

- R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3; preferably R² represents H, CH₃, CH₂C(O)OCH₂CH₃, or

CH₂C(O)OH; and R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl,

C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-Cs-Cio heterocyclyl-C(O)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, OCH₃, represent H, Cl, C(O)OH, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; even more preferably R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H or Cl.

Item 5. The compound according to any one of items 1 to 3, wherein:

- R¹ represents aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and

CH₃; more R¹ represents

- R² represents CrCe alkyl, preferably CH₃;

- Y³ represents N and R³ is absent; and

- R⁴, R⁵, R⁶ and R⁷ represent H.

Item 6. The compound according to any one of items 1 to 5, which is selected from the group consisting of the following compounds ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321. ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD372, ALIPD373, ALIPD376, ALIPD381 , ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396.

Item 7. The compound according to any one of items 1 to 6, which is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396.

Item 8. A pharmaceutical composition comprising at least one compound according to any one of items 1 to 7, and at least one pharmaceutically acceptable excipient.

Item 9. The compound according to any one of items 1 to 7, or the composition according to item 8, for use in a method of prevention and/or treatment of a disease in a subject, preferably for use as a PD-1/PD-L1 interaction inhibitor in a subject, in particular a human.

Item 10. The compound or the composition for use according to item 9, wherein the disease is a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory disease, neurological disease and chronic infection in a subject, in particular a human. Item 11. The compound or the composition for use according to item 10, wherein: the cancer is selected from the group consisting of lung carcinoma (Non small cell and Small cell), head and neck carcinoma, bladder carcinoma, kidney carcinoma, triple negative breast cancer, pancreatic carcinoma, melanoma, gastric carcinoma, oesophagus carcinoma, Hodgkin’s lymphoma, non Hodgkin lymphoma, glioblastoma, multiple myeloma, acute myeloide leukemia, Cholangiocarcinoma (gallbladder carcinoma), Merkel carcinoma, squamous cell carcinoma and endometrial carcinoma; the neurological disease is Alzheimer disease; the chronic inflammatory disease is psoriasis; and/or the chronic infections are selected from the group consisting of Human immunodeficiency virus (HIV), malaria, tuberculosis and B hepatitis.

In one embodiment of the invention, the compound of general formula (I) as defined herein or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or the pharmaceutically acceptable salt thereof is one wherein:

- (a) Wherein Y³ represents C and R³ represents H; and

R¹ represents phenyl substituted with one Cl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or

- (b) Wherein Y³ represents C and R³ represents halogen, preferably Cl; and R¹ represents C(O)OCi-Ce alkyl, or phenyl substituted with one Cl;

R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl,

C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-Cs-Cio heterocyclyl-C(O)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or is the following compound ALIPD347 ; or

- (c) Wherein Y³ represents N and R³ is absent; and

R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷ are identical and represent H.

In one embodiment of the invention, the compound of general formula (I) as defined herein is one wherein (a) Y³ represents C and R³ represents H; and wherein:

- R¹ represents

- R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, OCH₃, CH₂NH₂, CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃; preferably wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents Cl, CN, OCH₃, CH₂NH₂, CH₂NH(CH₂)₂C(O)OH, CH₂NH(CH₂)₂C(O)OCH₂CH₃; preferably R⁵ represents Cl, or CH₂NH(CH₂)₂C(O)OH; more preferably R⁵ represents Cl; or (ii) - R⁵, R⁶ and R⁷ are identical and represent H; and

R⁴ represents Cl.

In one embodiment of the invention, the compound of general formula (I) as defined herein is one wherein (b) Y³ represents C and R³ represents halogen, preferably Cl; and wherein:

R² represents H, CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; preferably R² represents CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; more preferably R² represents CH₃, or CH₂C(O)OCH₂CH₃; even more preferably R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, C(O)NH₂, preferably wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents H, Cl, CN, C(O)NH₂, C(O)OH, CH₂-NH₂, CH₂-NH-(CH₂)₂-C(O)OH, CH₂-NH- (CH₂)₂-C(O)O- CH₂CH₃, CH₂-NH-C(O)-CH₂-C(O)OH, CH₂-NH-C(O)-CH₂-C(O)O-CH₂CH₃,

(ii) - R⁴, R⁵ and R⁶ are identical and represent H; and - R⁷ represents Cl; or

(iii) - R⁴, R⁵ and R⁷ are identical and represent H; and

R⁶ represents Cl; more preferably wherein:

(I) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents preferably R⁵ represents Cl.

In one embodiment of the invention, the compound of general formula (I) as defined herein is one wherein (c) Y³ represents N and R³ is absent; and wherein:

- R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; preferably R¹ represents

- R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷ represent H.

In one embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds ALIPD290, ALIPD304, ALIPD307, ALIPD314. ALIPD319, ALIPD321 , ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD372, ALIPD373, ALIPD376, ALIPD381. ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396.

In one embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.

In one embodiment of the invention, the pharmaceutical composition comprises (i) at least one compound of general formula (I) as defined herein, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

In one embodiment of the invention, the compound of the following general formula (I) or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or the pharmaceutically acceptable salt thereof; or the pharmaceutical composition comprising at least one of said compound of the following general formula (I), and at least one pharmaceutically acceptable excipient, is for use in a method of prevention and/or treatment of a disease in a subject, in particular a human:

- Wherein (a) Y³ represents C and R³ represents H; and wherein:

R¹ represents aryl substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and CrCe alkyl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-C1-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci- Ce alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or

- Wherein (b) Y³ represents C and R³ represents halogen, preferably Cl; or (c) Y³ represents N and R³ is absent; and wherein:

R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3;

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-C1-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; preferably R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as previously defined in all the above-mentioned embodiments described throughout the description; or the compound is selected from the group of the following compounds ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321. ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD372, ALIPD373, ALIPD376, ALIPD381 , ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396; preferably is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, more preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.

In one embodiment of the invention, the compound of general formula (I) as defined herein, or the composition according to the invention is for use as a PD-1/PD-L1 interaction inhibitor in a subject, in particular a human.

In one embodiment of the invention, the disease is a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory disease, neurological disease and chronic infection in a subject, in particular a human.

In one embodiment of the invention, the cancer is selected from the group consisting of lung carcinoma (Non small cell and Small cell), head and neck carcinoma, bladder carcinoma, kidney carcinoma, triple negative breast cancer, pancreatic carcinoma, melanoma, gastric carcinoma, colon carcinoma, oesophagus carcinoma, Hodgkin’s lymphoma, non Hodgkin lymphoma, glioblastoma, multiple myeloma, acute myeloide leukemia, Cholangiocarcinoma (gallbladder carcinoma), Merkel carcinoma, squamous cell carcinoma and endometrial carcinoma; the neurological disease is Alzheimer disease; the chronic inflammatory disease is psoriasis; and/or the chronic infections are selected from the group consisting of Human immunodeficiency virus (HIV), malaria, tuberculosis and B hepatitis.

All the particular and preferred embodiments in relation to the definition of the compound of general formula (I) as defined herein apply to said method.

Unless otherwise stated, all the above-mentioned embodiments may be combined together. Thus, features which are described in the context of separate embodiments may be combined in a single embodiment. Other features and advantages of the invention will be apparent from the examples which follow and will also be illustrated in the figures.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Chemical structure of a compound of general formula (I).

Figure 2. Schematic representation of the FRET principle. Without FRET phenomenon, the excited fluorochrome emits its own fluorescence (left). Since there is a second fluorochrome close to the first, energy transfer can be made, which results in an excitation of the first fluorochrome (donor, named CFP) and an emission of the second fluorochrome (acceptor, named YFP) (right).

Figure 3. MST assays for compounds ALIPD304 (Figure 3A), ALIPD307 (Figure 3B), ALIPD395 (Figure 3C), ALIPD381 (Figure 3D), ALIPD396 (Figure 3E) and ALIPD382 (Figure 3F).

EXPERIMENTAL SECTION

Material and Methods

Immune Checkpoint Blocking. Promega Blockade Bioassay was used according to the manufacturer’s instructions to monitor immune blocking. APC cells were seeded on 96-well at 10 000 cells/well, 16 h prior to the experiment. A 2-fold dilution of the small molecules was prepared in 0.1% DMSO. Atezolizumab was used as positive control. The next day Jurkat cells were seeded at the density of 20 000 cells per well in the same assay plate. After 6 h of incubation assay plates were equilibrated at room temperature for 15 min, followed by a 30 min incubation with the Bio Gio reagent. The luminescence was detected using a Spectramax i3 (Molecular Devices). Half maximal effective concentrations (EC50 values) were fitted to a 4PL using Graphpad.

Microscale thermophoresis (MST). MST was conducted using a NT.115 Pico MST instrument (Nano Temper Technologies GmbH) equipped with red and blue filter sets. His-PD-L1 protein (Biotechne # 9049-B7-100), was diluted to 200 nM in PBS-T buffer (supplied by vendor) was labeled with Monolith His-Tag Labeling Kit RED-tris-NTA (Nano Temper). The RED-tris-NTA dye was diluted in PBS-T to 100 nM. The mix was incubated at room temperature in the dark for 30 min. Ligands (50 pM) were diluted with a serial 1 :1 ratio of 16 gradients. Then the labeled protein and ligands were mix with 1 :1 ratio and incubated at room temperature in the dark for 15 min. Capillaries are then filled individually and loaded into instrument. Data were acquired using medium MST power and 20 % LED. Data were analyzed using MO Control Software (Nano Temper). MST figures (see Figures 3A, 3B, 3C, 3D, 3E and 3F) were rendered using MO Affinity Analysis (Nano Temper).

FRET assay. Energy transfer between fluorescent molecules (FRET) is a technique that allows visualizing interactions between 2 fluorescent molecules (see Figure 2). A model was developed using CHO-K1 cells involving overexpression of proteins of interest. It involves the expression of a PD-1 -YFP fluorescent protein and a second fluorescent protein SHP-2-CFP (phosphatase recruited during the interaction between PD-1 and PD-L1 ). During excitation at a given length (ACFP 445-485 nm, AYFP 485-535 nm), an energy transfer takes place when the proximity is sufficient between the two proteins resulting in a FRET phenomenon. Using a blocking compound, the interaction is inhibited. Therefore, the recruitment of phosphatase no longer intervenes. The FRET phenomenon is therefore no longer observed.

A Spectramax i3 (Molecular Devices) was configured according to the selected fluorochromes with their excitation and emission spectra. Endpoint reading was performed, at the center of the well; the reading time was 2 minutes for a 96-well plate. For this test, a 96-well flat-bottomed white plate was required. All mixes introduced into the plate were made of triplicate. The negative control was provided by the CHO transfected by the void plasmid, the positive control was provided by CHO transfected with a plasmid containing the YFP-CFP fusion protein making it possible to mimic the FRET phenomenon. To check that the two fluorochromes did not emit in the FRET channel separately, the PD1-YFP and SHP2-CFP constructs were checked separately. It was also necessary to remove the background noise, that was to say the FRET without activation with PD- L1. After the addition of PD-L1 (10 pM) to the co-transfected PD1-SHP2 cells of the inventors, dose-response curved were performed to determine the IC50 of the molecule under study. The IC50 values were obtained using Graphpad and the results were listed above. Nivolumab was taken as positive control of interaction’s inhibitions. T-cell assay. Human CD4+ T lymphocytes were expanded and activated as described above. T cell response assays were conducted by ELISA in coculture system. CHO PD-L1 promega cells (J 1250) were plated in 96- well plates at a density of 10,000 cells per well and allowed to adhere for 24 h. Afterward, preactivated CD4+ T lymphocytes (2 x 104) were added to selected wells at a ratio of 2:1 effector to target (E:T), in the presence or absence of additives (Atezolizumab or

PD290) in 200 pL complete RPMI1640 medium, followed by coculturing at 37°C, 5% CO2 incubator for 48 h. Prestimulated T cells alone (2 x 104), in the presence or absence of additives in medium was also cultured at 37°C, 5% CO2 incubator for 48 h. Culture supernatants were harvested, and the levels of IFN-y and TNF-a were detected by the Human IFN-y ELISA kit (Cat. 88-7316-22, Invitrogen) and Human TNF-a ELISA kit (Cat. 88-7346-88, Invitrogen), respectively

( I means no expression, + to ++++ means low expression to high expression).

EXAMPLES

Example 1. Synthesis of intermediate products and pyrazole derivatives according to the invention

Scheme 1. General synthetic route of ALIPD277, ALIPD308, ALIPD362, ALIPD375, ALIPD325, ALIPD290, ALIPD314, ALIPD304, ALIPD321 , ALIPD370, ALIPD381, ALIPD328 and ALIPD307

General procedure for the preparation of 1-3-(aryl)-5-amino-arylpyrazole ALIPD277,

ALIPD308, ALIPD362, ALIPD375, ALIPD325

R: 2,4-diCI-phenyl (ALIPD277)

2-CI-4-CN-phenyl (ALIPD308)

2-CI-phenyl (ALIPD362)

4-CI-phenyl (ALIPD375)

4-CN-phenyl (ALIPD325) To a solution of (3-ketonitrile (1 eq, 1 mmol) in ethanol (20 mL) were added p-toluenesulfonic acid (0.5 eq) and hydrazine (1.1 eq). The reaction mixture was stirred and heated to reflux for 4h. After cooling, the solvent was evaporated under reduced pressure. The residue was taken up in the water and adjusted to pH 10 using aqueous NaHCOs. The solid was filtered and washed to water and crystallized.

• Synthesis of 3-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 /-/-pyrazol-5-amine (ALIPD277)

The product was recrystallized with heptane. Beige powder. Yield: 88 %. mp: 104 ± 1°C. Rf (cyclohexane I ethyl acetate 1 -1 ): 0.7. LC-MS (ES⁺): m/z = 338, t_r = 2,28 min. ¹H NMR(DMSO) 5 (ppm): 5,41 (s, 2H, NH₂); 5,82 (s, 1 H); 7,41 (d, 2H, J = 8,6 Hz); 7,56 (s, 1 H); 7,57 (d, 1 H, J= 2.0 Hz); 7,72 (dd, 1 H, J= 8,6 Hz); 7,85 (dd, 1 H, J= 1 ,9Hz, J= 0,5 Hz). IR v (cm'¹): 3407,4 and 3340,7 (NH); 3092,6 and 2920,1 (C-H); 1612,9 (C=N); 1548,6 (C=C); 827,7 and 764,5(C-CI).

• Synthesis of 4-[5-Amino-3-(4-chlorophenyl)-1 /-/-pyrazol-1-yll-3-chlorobenzonitrile

The product was recrystallized with isopropanol. Beige powder. Yield: 89 %. mp: 157 ± 1 °C. Rf (cyclohexane I ethyl acetate 2-3):0.6. LC-MS (ES⁺): m/z = 329, t_r = 2,95 min. ¹H NMR (DMSO) 5 (ppm): 5,55 (s, 2H, NH₂); 5,87 (s, 1 H); 7,44 (d, 2H, J = 8,5 Hz); 7,75 (d, 3H, J= 8,5 Hz); 8,00 (dd, 1 H, J= 8,2 Hz, J = 1 ,7 Hz); 8,33 (d, 1 H, J= 1 ,7 Hz). IR v (cm'¹): 3408,9 and 3341 ,7 (NH); 2236,0 (C=N); 1615,3 (C=N); 1503,4 (C=C); 843,7 and 766,3 (C-CI).

• Synthesis of 1 -(2-ChloroDhenyl)-3-(4-chloroDhenyl)-1 /-/-pyrazol-5-amine (ALIPD362)

The product was recrystallized with heptane. Beige powder. Yield: 83 %. mp: 110 ± 1°C. Rf (cyclohexane I ethyl acetate, 1-1 ): 0,6. LC-MS (ES⁺): m/z = 304.1 , t_r = 2,13 min. ¹H NMR (DMSO) 5 (ppm): 5,31 (s, 2H, NH₂); 5,85 (s, 1 H); 7,43 (d, 2H, J = 8,6 Hz); 7,52 (m, 3H); 7,68 (m, 1 H); 7,74 (d, 1 H, J = 8,6 Hz). IR v (cm'¹): 3387,1 and 3310,8 (NH); 3094,1 (C-H); 1559,7 (C=N); 1504,5 (C=C); 836,2 and 755,0 (C-CI). Synthesis of 1 ,3-bis(4-Chlorophenyl)-1 /-/-pyrazol-5-amine (ALIPD375)

The product was recrystallized with heptane. Brown powder. Yield: 80 %. mp: 139 ± 1 °C. Rf (cyclohexane I ethyl acetate, 1-1 ): 0,7. LC-MS (ES⁺): m/z = 304.1 , t_r = 2,33 min. ¹H NMR (DMSO) 5 (ppm): 5,57 (s, 2H, NH₂); 5,94 (s, 1 H); 7,44 (d, 2H, J= 8,5 Hz); 7,56 (d, 2H, J = 8,9 Hz); 7,71 (d, 1 H, J = 8,9 Hz); 7,78 (d, 1 H, J = 8,5 Hz). IR v (cm ¹): 3410,9 and 3287,8 (NH); 3171 ,6 (CH aromatic); 1556,8 (C=N); 1497,0 (C=C); 834,6 (C-CI).

• Synthesis of 4-[5-Amino-3-(4-chlorophenyl)-1 /-/-pyrazol-1 -yllbenzonitrile (ALIPD325)

The product was recrystallized with acetonitrile. Beige powder. Yield: 62 %. mp: 201 ± 1°C. Rf (cyclohexane I ethyl acetate, 6-4): 0.6. LC-MS (ES⁺): m/z = 295.2, t_r = 3,45 min. ¹H NMR (DMSO) 5 (ppm): 5,78 (s, 2H, NH₂); 6.01 (s, 1 H); 7,47 (d, 2H, J = 8,6 Hz); 7,81 (d, 2H, J = 8,6 Hz); 7,96 (m, 4H). IR v (cm'¹): 3420,9 and 3328,1 (NH); 2224,8 (CEN); 1602,4 (C=N); 1503,8 (C=C); 762,0 (C-CI).

• Synthesis of ethyl 5-Amino-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylate

(ALIPD353)

2,4-dichlorophenylhydrazine hydrochloride (2.79 mmol) was added to a suspension of potassium1 -cyano-3-ethoxy-3-oxoprop-1-en-2-olate (2.79 mmol) in EtOH (10 mL) with APTS (2.79 mmol). The reaction mixture was refluxed for 2h. After cooling, water was added, and solution was neutralized with K₂COs and extracted with AE. The organic phase was washed with a solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure.

The product was recrystallized with ethanol. Solid brown. Yield: 26 %. mp: 88°C ± 1 °C. Rf (cyclohexane / ethyl acetate 6-4): 0.42. LC-MS (ES⁺): m/z = 300, t_r = 1 .85 min. RMN ¹H (DMSO) 8 (ppm): 1 .27 (3H, t, J= 7.1 Hz), 4.23 (2H, q, J= 7.1 Hz) 5,53 (s, 2H, NH₂) ; 5,79 (s, 1 H) ; 7,19 (s, 2H) ; 7,20 (d, 1 H, J = 2.1 Hz) ; 7,30 (d, 1 H, J= 2.1 Hz). IR v (cm ¹) : 1708 (C=O) ; 1577 (C=N) ; 1492 (C=C) ; 866 et 807 (C-CI).

• Synthesis of 3-(methyl)-1-(2,4-dichlorophenyl)-1 /-/-pyrazol-5-amine (ALIPD346)

A mixture of 2,4-dichlorophenylhydrazine hydrochloride (6 mmol) and 3-aminocrotononitrile (6 mmol) was heated in a microwave at 150°C (150 W) for 10 min in HCI (1 N,15 mL). The reaction media was cooled to room tremperature and in a separatory funnel, the mixture was washed with ethyl acetate. The aqueous phase was neutralized with K₂COs. The white precipitate was filtered, washed with water and dried. Yield: 74 %. Rf (cyclohexane / ethyl acetate 1-1 ): 0.38. mp: 135°C. LC-MS (ES⁺): m/z = 242, t_r = 1 .61 min. RMN ¹H (DMSO) 8 (ppm) : 2.04 (s ;3H), 5,13 (s, 2H, NH₂) ; 5,20 (s, 1 H) ; 7,44 (d, 2H, J=8.5 Hz ) ; 7,52 (dd, 1 H, J= 8.5 Hz, J= 2.3 Hz ) ; 7,80 (d, 1 H, J= 2.3 Hz). IR v (cm'¹) : 3420 et 3301 (N-H) ; 3196 et 2170 (C-H aromatique) ; 1622 (C=N) ; 1558 (C=C) ; 838 et 746 (C-CI).

General procedure for the preparation of A/-[3-(4-Chlorophenyl)-1 -Aryl-1 /-/-pyrazol-5- yllacetamide ALIPD304, ALIPD321 , ALIPD370, ALIPD381 , ALIPD328

R : 2,4-diCI-phenyl (ALIPD304) 2-CI-4-CN-phenyl (ALIPD321) 2-CI-phenyl (ALIPD370) 4-CI-phenyl (ALIPD381) 4-CN-phenyl (ALIPD328)

A suspension of 1 -3-(aryl)-5-amino-arylpyrazole (1 eq) and Ac₂O (2 eq) in AcOH (8 eq) was stirred 18h at room temperature. A NaHCOs solution was added to the reaction medium. The solid was filtered and washed with water and recrystallized. • Synthesis of /V-[3-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 /-/-pyrazol-5-yl]acetamide

(ALIPD304)

.ci

O CH₃

The product was recrystallized with isopropanol. White powder. Yield: 79 %. mp: 186 ± 1 °C. Rf (cyclohexane / ethyl acetate, 6-4): 0.35. LC-MS (ES⁺): m/z = 380.0, t_r = 2,26 min. ¹H NMR (DMSO) 5 (ppm): 1 ,99 (s, 3H); 6,99 (s, 1 H); 7,47 (d, 2H, J= 8,5 Hz); 7,62 (m, 2H); 7,84 (d, 2H, J = 8.5 Hz); 7,92 (d, 1 H, J= 1 ,5 Hz); 10,00 (s, 1 H, NH). IR v (cm'¹): 3158,5 (NH); 3005,9 (CH aromatic); 2932,7 (CH); 1709,5 (C=O); 1542,1 (C=N); 1482,8 (C=C); 1247,3 (C-N); 834,6 et 788,7 (C-CI).

• Synthesis of /\/-[1 -(2-Chloro-4-cvanophenyl)-3-(4-chlorophenyl)-1 /-/-pyrazol-5- yllacetamide (ALIPD321)

The product was recrystallized with acetonitrile. White powder. Yield: 76 %. mp: 264 ± 1°C. Rf (cyclohexane I ethyl acetate, 1-1 ): 0.7. LC-MS (ES⁺): m/z = 371.2, t_r = 2,11 min. ¹H NMR (DMSO) 5 (ppm): 1 ,98 (s, 3H); 7,01 (s, 1 H); 7,48 (d, 2H, J= 8,5 Hz); 7,80 (d, 1 H, J = 8,2 Hz); 7,85 (d, 2H, J= 8.5 Hz); 8,05 (dd, 1 H, J = 8,2 Hz, J = 1 ,7 Hz); 8,38 (d, 1 H, J= 1 ,7 Hz); 10,09 (s, 1 H, NH). IR v (cm'¹): 3314,1 (NH); 3065,8 (CH aromatic); 2244,1 (CEN); 1700,5 (C=O); 1543,9 (C=N); 1494,0 (C=C); 1243,0 (C-N); 837,0 and 776,0 (C-CI).

• Synthesis of /V-[1 -(2-Chlorophenyl)-3-(4-chlorophenyl)-1 H-pyrazol-5-yllacetamide

The product was recrystallized with isopropanol. White powder. Yield: 41 %. mp: 150 ± 1 °C. Rf (cyclohexane I ethyl acetate, 1-1 ): 0,3. LC-MS (ES⁺): m/z = 346.1 , t_r = 2,14 min. ¹H NMR (DMSO) 5 (ppm): 1 ,97 (s, 3H); 6,97 (s, 1 H); 7,48 (d, 2H, J = 8,5 Hz); 7,53- 7,62 (m, 3H); 7,70 (d, 1 H, J = 7,3 Hz); 7,84 (d, 2H, J= 8,5 Hz); 9,97 (s, 1 H, NH). IR v (cm'¹): 3139,2 (NH); 2941 ,2 (CH); 1691 ,6 (C=0); 1555,7 (C=N); 1490,4 (C=C); 1264,0 (C-N); 760,0 and 730,5 (C-CI).

• Synthesis of /V-[1 ,3-bis(4-Chlorophenyl)-1 /-/-pyrazol-5-yllacetamide (ALIPD381)

The product was recrystallized with acetonitrile. Beige powder. Yield: 57 %. mp: 220 ± 1°C. Rf (cyclohexane I ethyl acetate, 1-1 ): 0,4. LC-MS (ES⁺): m/z = 346.1 , t_r = 2,27 min. ¹H NMR (DMSO) 5 (ppm): 2,02 (s, 3H); 6,93 (s, 1 H); 7,50 (d, 2H, J = 8,5 Hz); 7,61 (s, 4H); 7,88 (d, 2H, J = 8,5 Hz); 10.08 (s, 1 H, NH). IR v (cm'¹): 3242,7 and 3197,3 (NH); 3050,6 (CH aromatic); 1669,7 (C=O); 1534,6 (C=N); 1495,8 (C=C); 1272,0 (C-N); 838,9 and 775,4 (C-CI).

• Synthesis of /V-[3-(4-Chlorophenyl)-1-(4-cyanophenyl)-1 /-/-pyrazol-5-yl]acetamide

The product was recrystallized with ethanol. White solid. Yield: 68 %. mp: 258 ± 1 °C. Rf (cyclohexane I ethyl acetate 1 -1 ): 0,3. LC-MS (ES⁺): m/z = 337.1 , t_r = 2,03 min. ¹H NMR (DMSO) 5 (ppm): 2,05 (s, 3H); 6,99 (s, 1 H); 7,51 (d, 2H, J= 8,5 Hz); 7,83 (d, 2H, J = 8,6 Hz); 7,91 (d, 2H, J= 8,5 Hz); 8,03 (d, 2H, J= 8,6 Hz); 10.24 (s, 1 H, NH). IR v (cm ¹): 3196,8 (NH); 2224,1 (CEN); 1678,3 (C=O); 1505,7 (C=C); 1275,7 (C-N); 792,4 (C-CI).

• Synthesis of ethyl 5-acetamido-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylate A suspension of ethyl 5-Amino-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylate (ALIPD353) (1 eq) and AC2O (2 eq) in AcOH (8 eq) was stirred 18h at room temperature. A NaHCOs solution was added to the reaction medium. The solid was filtered and washed with water.

The product was purified by flash chromatography (cyclohexane- AE; 1-1 ). Solid white. Yield: 55 %. mp: 195 ± 1 °C. Rf (cyclohexane I ethyl acetate 1-1 ): 0.14. LC-MS (ES⁺): m/z = 342.0, t_r = 1.87 min. RMN ¹H (CDCI3) 5 (ppm) : 1 ,42 (t, 3H, J= 7,1 Hz); 2,11 (s, 3H); 4,45 (q, 2H, J= 7,1 Hz); 6,70 (s, 1 H); 7,13 (s, 1 H, NH); 7,42-7,50 (m, 2H) ; 7,60 (d, 1 H, J=2, 1 Hz). IR v (cm'¹) : 3304 (N-H) ; 2982 (C-H) ; 1707 (C=O) ; 1541 (C=N) ; 1455 (C=C) ; 1230 (C-N) ; 870 et 778 (C-CI).

• Synthesis of N-[1 -(2,4-dichlorophenyl)-3-methyl-1 H-pyrazol-5-yllacetamide

A suspension of 3-(methyl)-1 -(2,4-dichlorophenyl)-1 /-/-pyrazol-5-amine (ALIPD346) (1eq) and AC2O (2 eq) in AcOH (8 eq) was stirred for 18h at room temperature. A NaHCOs solution was added to the reaction medium. The solid was filtered and washed with water and recrystallized with cyclohexane. Solid white. Yield: 90%. mp: 161 ± 1 °C. Rf (cyclohexane / ethyl acetate 1 -1): 0.30. LC-MS (ES⁺): m/z = 284, t_r = 1.64 min. RMN ¹H (DMSO) 5 (ppm) : 1 ,93 (s, 3H); 2,17 (s, 3H) ; 6,30 (s, 1 H) ; 7,47 (d, 2H, J= 8,5 Hz); 7,58 (dd, 1 H, J=8.5 Hz, J=2.3 Hz ) 7,92 (d, 1 H, J= 1 ,5 Hz) ; 9,81 (s, 1 H, NH). .IR v (cm ¹) : 3178 (N-H) ; 2969 and 2923 (C-H) ; 1706 (C=O) ; 1550 (C=N) ; 1491 (C=C) ; 1254 (C-N) ; 831 et 783 (C-CI). of l-5-vl)formamide derivatives ALIPD290 and ALIPD314:

Synthesis of /V-[3-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 /-/-pyrazol-5-yl]formamide

(ALIPD290)

.ci

A solution of ALIPD277 (0.47 g, 1 .3 mmol) in formic acid (6 mL) was refluxed for 4h. The reaction mixture was cooled to room temperature and an aqueous solution of NaHCOs was added. The solid obtained was filtered off and purified by flash chromatography (cyclohexane-AE, 6-4). The product was recrystallized with heptane-EtOH (7-3). White solid. Yield: 42 %. mp: 173 ± 1°C. Rf (cyclohexane I ethyl acetate, 6-4): 0.5. LC-MS (ES⁺): m/z = 366.0, t_r = 3,20 min. ¹H NMR (DMSO) 5 (ppm): 7,07 (s, 1 H); 7,48 (d, 2H, J = 8,5 Hz); 7,67 (m, 2H); 7,85 (d, 2H, J = 8.5 Hz); 7,96 (d, 1 H, J = 1 ,4 Hz); 8,17 (s, 1 H); 10,45 (s, 1 H, NH). IR v (cm ¹): 3199,1 (NH); 3087,1 and 3053,9 (CH aromatic); 1661 ,3 (C=O); 1707,5 (C=O); 1555,5 (C=N); 1489,8 (C=C); 809,6 and 775,7 (C-CI).

• Synthesis of /\/-[1 -(2-Chloro-4-cvanophenyl)-3-(4-chlorophenyl)-1 /-/-pyrazol-5- yllformamide (ALIPD314)

AC2O (2 eq) and HCO2H (2.1 eq) was stirred at 50°C for 15 min and cooled immediately to 0°C. To this solution was added ALIPD308 (1 eq) dissolved in THF. The mixture was heated at 68 °C for 3 h. The reaction was cooled to room temperature and stirred for 12 h. Water was added and the mixture was extracted with AE. The organic phase was washed with a solution of NaHCOs 10% and brine, dried over MgSC , filtered and concentrated under reduced pressure. The product was recrystallized with acetonitrile. White solid. Yield: 85 %. mp: 228 ± 1 °C. Rf (cyclohexane / ethyl acetate, 1 -1): 0.6. LC-MS (ES⁺): m/z = 357.0, t_r = 2,98 min. ¹H NMR (DMSO) 5 (ppm): 7,10 (s, 1 H); 7,50 (d, 2H, J= 8,4 Hz); 7,86 (m, 3H); 8,08 (dd, 1 H, J = 8.2 Hz, J=1 ,6 Hz); 8,18 (s, 1 H); 8,39 (s, 1 H); 10,54 (s, 1 H, NH). IR v (cm ¹): 3299,3 (NH); 2244,4 (CEN); 1707,5 (C=O); 1551 ,3 (C=N); 1494,2 (C=C); 833,2 and 772,1 (C-CI).

Synthesis of Ethyl 3-{[3-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 /-/-pyrazol-5-yl]amino}-3- oxopropanoate (ALIPD307)

In a flask under nitrogen, ALIPD277 was dissolved in DCM. TEA and ethylmalonylchloride were added. The reaction was stirred at room temperature for 18 h. In a separatory funnel, the reaction medium was washed with water. The organic phase was dried over CaCh, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane-AE, 8-2). The product was recrystallized with ethanol. White powder. Yield: 42 %. mp: 131 ± 1°C. Rf (cyclohexane I ethyl acetate, 8-2): 0.2. LC-MS (ES⁺): m/z = 452.0, t_r = 3,35 min. ¹H NMR (DMSO) 5 (ppm): 1 ,17 (t, 3H, J = 7,1 Hz); 3.43 (s, 2H); 4.08 (q, 2H, J= 7,1 Hz); 7,03 (s, 1 H); 7,48 (d, 2H, J= 8.6 Hz); 7,63 (m, 2H); 7,85 (d, 2H, J= 8.6 Hz); 7,94 (s, 1 H); 10,24 (s, 1 H, NH). IR v (cm'¹): 3342,3 (NH); 3159,6 (CH aromatic); 2987,4 and 2903,6 (CH aliphatic); 1728,9 (C=O, ester); 1687,5 (C=O; amide); 1551 ,4 (C=N); 1487,6 (C=C); 1201 ,0 (C-O); 825,6 and 805,8 (C-CI).

A mixture of 2-chloro-4-fluorobenzonitrile (2.0 g, 12.9 mmol), hydrazine monohydrate (2 eq), and NMP (10 mL) was stirred at 65 °C for 4 h. The reaction mixture was cooled to room temperature and water was added. The mixture was alkalized with K2CO3 and the precipitate obtained was filtered, washed with water, and dried to give a beige powder. Yield: 80 %. mp: 128 ± 1 °C. Rf (cyclohexane / ethyl acetate, 7-3): 0.2. LC-MS (ES⁺): m/z = 168.1 , t_r = 2,05 min. ¹H NMR (DMSO) 5 (ppm): 4,41 (s, 2H); 7,22 (d, 1 H, J = 8,7 Hz); 7,55 (dd, 1 H, J = 8,7 Hz, J’= 1 ,8 Hz); 7,62 (s, 1 H); 7,67 (d, 1 H, J = 1 ,8 Hz). IR v (cm'¹): 3363,8 (NH); 3331 ,5 (NH); 3270,2 (NH); 2213,0 (C=N); 1595,6 and 1515,6 (C=C). • Synthesis of 1 -[4-(Aminomethyl)-2-chlorophenyl]-3-(4-chlorophenyl)-1 /-/-pyrazol-5-amine

ALIPD308 (1 eq) was added to solution of nickel chloride hexahydrate (0.4 eq), in 10 mL anhydrous methanol, under nitrogen, in an ice bath. Sodium borohydride (6 eq) was added. The reaction medium was stirred for 2h at room temperature. At 0°C, the reaction was quenched by adding a NH₄CI solution. The mixture was concentrated to remove most methanol, and the residue was placed in a separated funnel with ethyl acetate and a solution of hydrochloric acid (10%). K2CO3 was added to the aqueous phase and the amine was extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give pale yellow powder. The product was recrystallized with cyclohexane. Yellow powder. Yield: 69 %. mp: 127 ± 1 °C. Rf (EtOH - AE, 1 - 9): 0.56. LC-MS (ES⁺): m/z: 333, tr = 1 ,75 min. ¹H NMR (DMSO) 5 (ppm): 3,82 (s, 2H, CH₂); 5,24 (s, 2H, NH₂); 5,84 (s, 1 H); 7,39-7,46 (m, 4H); 7,66 (d, 1 H, J= 3,42); 7,72-7,76 (m, 2H). IR v (cm ¹): 3312,3 and 3169,2 (NH); 2865,6 (CH aliphatic); 1557,5 (C=N); 1506,4 (C=C); 832,2 (C-CI); 744,0 (C-CI).

• Synthesis of Ethyl 3-((1 -(2-chloro-4-((3-ethoxy-3-oxopropanamido)methyl)phenyl)-3-(4- chlorophenylM /-/-pyrazol-5-yl)amino)-3-oxopropanoate (ALIPD319)

ALIPD318 (1 eq) was solubilized in DCM. At 0°C, TEA (2.2 eq) and ethyl malonyl chloride (2,5 eq) was added and the mixture was stirred at room temperature for 4 h. In a separatory funnel, the reaction medium was washed with water. The organic phase was dried over CaCI₂, filtered and concentrated under reduced pressure. The product was purified by flash chromatography (cyclohexane-AE, 1 -1). Yellow powder. Yield: 48 %. mp: 109 ± 1°C. Rf (EtOH - AE, 1 - 9): 0.8. LC/MS (ES⁺): m/z = 561 , tr = 2,15 min. ¹H NMR (DMSO) 8 (ppm): 1 ,20 (2t, 6H, CH₃); 3,34 (s, 2H, CH₂) ; 3,36 (s, 2H, CH₂) ; 4,10 (2q, 4H, CH₂) ; 4,43 (d, 2H, J = 5,94 Hz, CH₂), 7,02 (s, 1 H, H_enoi) ; 7,43 (dd, 1 H, J = 1 ,7 Hz, J’= 8,2 Hz) ;7.47 (d, 2H, J = 8,6 Hz) ; 7,54 (d, 1 H, J= 8,1 Hz); 7,59 (d, 1 H, J = 1 ,5 Hz), 7.85 (d, 2H, J = 8,6 Hz), 8,79 (t, 1 H, J = 6.0 Hz, NH) ; 10,25 (s, 1 H, NH). IR v (cm'¹): 3268,9 and 3201 ,0 (NH); 3069,7 (CH aromatic); 2977,9 and 2927,5 (CH aliphatic); 1731 ,5 (C=O, ester); 1656,7 (C=O, amide); 1550,1 (C=N); 1502,4 (C=C); 1201 ,1 (C-N); 1153,9 (C-O); 834,8 and 785,4 (C-CI).

• Synthesis of 3-((4-(5-(2-carboxyacetamido)-3-(4-chlorophenyl)-1 /-/-pyrazol-1 -yl)-3- chlorobenzyl)amino)-3-oxopropanoic acid (ALIPD322)

To a solution of ALIPD319 (1 eq) in ethanol (10 eq) was added a solution of NaOH (10N, 2 eq) at 0°C. The mixture was stirred at room temperature for 24 hours. Ethanol was evaporated under vacuum and water was added to the residue. The resulting aqueous phase was washed with AE. After acidification of aqueous phase with a solution of HCI 1 N (pH = 3), the precipitate obtained was filtered, washed with water, and dried to give a white powder. The product was purified by flash chromatography (DCM-MeOH, 9-1 ). Yield: 52 %. mp: 190 ± 1°C. Rf (MeOH - DCM, 1 - 9): 0.3. LC/MS (ES⁺) : m/z = 505,1 , tr =1 .53 min. ¹H NMR (DMSO) 8 (ppm) : 3,27 (s, 2H, CH₂) ; 3,35 (s, 2H, CH₂) ; 4,42 (d, 2H, J=5,6 Hz, CH₂), 7,02 (s, 1 H) ; 7,42 (d, 1 H, J_m = 8.1 Hz) ;7.48 (d, 2H, J=8,5 Hz) ; 7,54 (d, 1 H, J= 8,1 Hz) ; 7,62 (s, 1 H), 7.85 (d, 2H, J = 8,5 Hz), 8,73 (t, 1 H, J= 6.0 Hz, NH) ; 10,22 (s, 1 H); 12,63 (s, 1 H). IR v (cm ¹): 3282,0 (NH); 3093,3 (CH aromatic); 1728,3 (C=O, acid); 1706,7 (C=O, amide); 1651 ,2 (C=N); 1554,6 (C=C); 1201 ,1 (C-N); 826,0 and 783,0 (C-CI).

• Scheme 4. Syntheses of AUPD324, ALIPD350, ALIPD384, ALIPD382, AUPD323,

AUPD342 and ALIPD356 • Synthesis of 4-[5-Acetamido-3-(4-chlorophenyl)-1 H-pyrazol-1 -yl]-3-chlorobenzamide

A stirred solution of ALIPD321 (1 eq), 6 N NaOH (0.25 eq), and 28% H2O2 (3.4 eq) in 95% EtOH was heated at 55°C for 3h and 18h at room temperature. Water was added to the reaction mixture, and acidified by HCI 1 N. The precipitate obtained was filtered, washed with water, and dried to give a white solid. The product was recrystallized with acetonitrile. White powder. Yield: 88 %. mp: 278 ± 1 °C. Rf (AE-EtOH, 9-1): 0.60. LC-MS (ES⁺): m/z = 389,1 , t_r = 1 ,82 min. ¹H NMR (DMSO) 5 (ppm): 1 ,98 (s, 3H); 7,00 (s, 1 H); 7,48 (d, 2H, J = 8,5 Hz); 7,67 (d, 1 H, J = 8,2 Hz) ; 7,70 (s, 1 H); 7,85 (d, 2H, J= 8.5 Hz); 8,01 (dd, 1 H, J = 8,2 Hz, J = 1 ,8 Hz ); 8,15 (d, 2H, J = 1 ,8 Hz); 8,26 (s, 1 H) 10,03 (s, 1 H). IR v (cm^-1): 3341 ,3 and 3195,2 (NH); 3063,9 (CH aromatic); 1699,9 and 1677,9 (C=O); 1548,2 (C=N); 1503,6 (C=C); 1253,6 (C-N); 833,1 and 782,5 (C-CI).

• Synthesis of 4-[5-Acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1-yl]-3-chlorobenzoic acid

To a solution of ALIPD324 (1 eq) in TFA (170 eq) and DCM (20 mL) at 0 °C was added NaN02 (11 eq). The reaction mixture was stirred at 0 °C for 30 min. Water was added. The precipitate obtained was filtered, washed with water and dried. The product was recrystallized with acetonitrile-ethanol. White powder. Yield: 96 %. mp: 278 ± 1°C. Rf (DCM-MeOH, 9-1): 0.52. LC-MS (ES⁺): m/z = 390,1 , t_r = 1 .72 min. ¹H NMR (DMSO) 5 (ppm): 1 ,98 (s, 3H); 7,00 (s, 1 H); 7,47 (d, 2H, J = 8,6 Hz); 7,71 (d, 1 H, J= 8,2 Hz); 7,85 (d, 2H, J= 8.6 Hz); 8,05 (dd, 1 H, J= 8,2 Hz, J = 1 ,8 Hz); 8,13 (d, 1 H, J = 1 ,8 Hz); 10.04 (s, 1 H) 13.54 (s, 1 H). IR v (cm ¹): 3288,7 (O-H); 2786,6 (CH aliphatic); 1720,3 (C=O, acid); 1688,2 (C=O, amide); 1532,4 (C=C); 1265,7 (C-O); 799,9 and 764,9 (C-CI). General procedure for preparation of ALIPD382 and ALIPD384 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 1.3 eq), 4-(dimethylamino)pyridine (DMAP, 1.2 eq) and TEA (1.3 eq) were dissolved in THF and cooled to 0 °C. ALIPD350 (1 eq) and amine (1 .2 eq) were added sequentially. The reaction mixture was stirred for 2h at reflux after slowly warming to ambient temperature.

• Synthesis of 4-(5-acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1-yl)-3-chloro-/\/-(2- morpholinoethvDbenzamide (ALIPD382)

The solution was diluted with ethyl acetate, the organic phase was washed with aqueous K2CO3 10% after by saturated water with NaCI and separated. The organic phase was dried over MgSC . The solvent was removed in vacuum and the residue was purified by column chromatography (DCM-MeOH saturated with NH₃ 9 :1). The product was recrystallized with cyclohexane. Beige powder. Yield: 47 %. mp: 192 ± 1°C. Rf (DCM-MeOH NH₃, 9-1): 0.3. LC-MS (ES⁺): m/z = 502,2, t_r = 1 .78 min. ¹H NMR (DMSO) 5 (ppm): 1 ,97 (s, 3H); 2,45 (t, 2H); 3.44 (q, 2H); 3,59 (t, 4H); 6,99 (s, 1 H); 7,48 (d, 2H, J= 8,5 Hz); 7,67 (d, 1 H, J= 8,2 Hz); 7,85 (d, 2H, J= 8.5 Hz); 7.97 (dd, 1 H, J = 8,2 Hz, J= 1 ,8 Hz); 8,11 (d, 1 H, J= 1 ,8 Hz);8.71 (t, 1 H) 10.02 (s, 1 H). IR v (cm ¹): 3262,5 and 3204,3 (NH); 2951 ,2 (CH aromatic); 2844,2 and 2817,8 (CH aliphatic); 1642,8 (C=O, amide); 1546,0 (C=N); 1496,2 (C=C); 1265,2 (C-O); 836,0 and 763,8 (C-CI).

• Synthesis of /V-(1-(4-(4-acetylpiperazine-1 -carbonyl)-2-chlorophenyl)-3-(4-chlorophenyl)-

1 /-/-pyrazol-5-yl)acetamide (ALIPD384)

The solution was diluted with ethyl acetate, the organic phase was washed with HCI 1 N, H2O saturated with NaCI and with a solution of NaHCOs (5%). The organic phase was dried over MgSC The solvent was removed in vacuum. The product was recrystallized with EtOH-H₂O, 1- 1. White powder. Yield: 86 %. mp: 296 ± 1 °C. Rf (DCM-MeOH, 9-1): 0,7. LC-MS (ES⁺): m/z = 500,3, t_r = 1 .89 min. ¹H NMR (DMSO) 5 (ppm): 1 ,99 (s, 3H); 2.04 (s, 3H); 3.53 (m, 8H); 7,00 (s, 1 H); 7,48 (d, 2H, J= 8,6 Hz); 7,57 (dd, 1 H, J= 8,0 Hz, J= 1 ,7 Hz); 7,65 (d, 1 H, J= 8.0 Hz); 7.77 (d, 1 H, J = 1 ,5 Hz); 7,85 (d, 2H, J = 8,6 Hz); 10.06 (s, 1 H). IR v (cm'¹): 3432,3 (NH); 3195,9 (CH aromatic); 2920,1 (CH aliphatic); 1682,1 and 1610,8 (C=O, amide); 1547,5 (C=N); 1504,1 (C=C); 1255,4 (C-N); 833,1 and 785,0 (C-CI).

• Synthesis of /V-(1-[4-(Aminomethyl)-2-chloroDhenyll-3-(4-chloroDhenyl)-1 /-/-pyrazol-5- vDacetamide (ALIPD323)

To a stirred mixture of ALIPD308 (1 eq) in MeOH with a solution of HCI 12N (1 ,5 eq) was added PtO₂ (0.45 eq) in portions at room temperature. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 2h. The mixture was filtered and washed with HCI 1 N. In a separatory funnel, the aqueous phase was washed with ethyl acetate. The aqueous phase was alkalinized with K₂COs. The precipitate was filtered, washed with water and dried. Beige powder. Yield: 70 %. mp: 193 ± 1 °C. Rf (DCM- MeOH, 9-1 ): 0.1. LC-MS (ES⁺): m/z = 375,1 , t_r = 1 ,67 min. ¹H NMR (DMSO) 5 (ppm): 1 ,96 (s, 3H); 3,82 (s, 2H); 5,24 (s, 1 H); 6,95 (s, 1 H); 7,40- 7,49 (m, 4H); 7,66 (s, 1 H); 7,83 (d, 2H, J = 8.5 Hz); 9,98 (s, 1 H). IR v (cm'¹): 3362,5 (NH); 2911 ,1 and 2802,9 (CH aliphatic); 1697,2 (C=O); 1549,8 (C=N); 1502,9 (C=C); 1260,6 (C-N); 836,5 and 786,0 (C-CI). • Synthesis of Ethyl 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1 -yl)-3- chlorobenzyl)amino)propanoate (ALIPD342)

To a solution of ethyl acrylate (2 eq) in ethanol, ALIPD323 (1 eq) was added at room temperature, and the resulting solution was stirred at room temperature for 18h. The solution was concentrated under reduced pressure, and the residue obtained was purified by flash chromatography. Yellow powder. Yield: 40 %. mp: 87 ± 1 °C. Rf (DCM-MeOH, 9-1): 0,5. LC-MS (ES⁺): m/z = 475,2, t_r = 1.84 min. ¹H NMR (DMSO) 5 (ppm): 1 ,18 (t, 3H); 1 ,96 (s, 3H); 2,00 (s, 1 H); 2.50 (t, 2H); 2.77 (t, 2H); 3.80 (s, 2H); 4,05 (q, 2H); 6,95 (s, 1 H); 7,45- 7,51 (m, 4H); 7,63 (s, 1 H); 7,83 (d, 2H, J = 8.5 Hz); 9,94 (s, 1 H). IR v (cm'¹): 2923,5 and 2851 ,1 (CH aliphatic); 1720,1 (C=O, ester); 1686,6 (C=O, amide); 1545,3 (C=N); 1500,1 (C=C); 833,5 and 781 ,7 (C-CI).

• Synthesis of 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1 -yl)-3- chlorobenzyl)amino)propanoic acid (ALIPD356)

To a solution of ALIPD342 (1 eq) in EtOH was added at room temperature a solution of NaOH (10%, 15 eq). After 12h, the reaction medium was concentrated to remove EtOH. An aqueous solution of citric acid was added to the mixture and the white precipitate obtained was filtered, washed with water and dried. White powder. Yield: 53 %. mp: 213 ± 1 °C. Rf (DCM-MeOH, 9-1): 0,4. LC-MS (ES⁺): m/z = 447,2, t_r = 1 .66 min. ¹H NMR (DMSO) 5 (ppm): 1 ,97 (s, 3H); 2.40 (t, 2H); 3.78 (t, 2H); 3.85 (s, 2H); 6,95 (s, 1 H); 7,45- 7,50 (m, 4H); 7,66 (s, 1 H); 7,83 (d, 2H, J= 7,9 Hz); 9,96 (s, 1 H). IR v (cm-¹): 3237,5 (O-H); 2921 ,4 and 2798,5 (CH aliphatic); 1679,6 (C=O, acid); 1632,0 (C=O, amide); 1534,1 (C=C); 1256,8 (C-O); 830,3 and 785,7 (C-CI). Scheme 5. Syntheses of ALIPD330, ALIPD340, ALIPD349

- Synthesis of /\/-{1-[4-(Aminomethyl)phenyl1-3-(4-chlorophenyl)-1 /-/-pyrazol-5-yl}acetamide

(ALIPD330)

To a stirred mixture of ALIPD328 (1 eq) in a mixture of MeOH/THF (1 :1) and HCI 12N (1 ,5 eq) was added PtC>2 (0.45 eq) in portions at room temperature. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The mixture was filtered, washed with HCI 1 N. The aqueous phase was washed with ethyl acetate and neutralized with K2CO3. The white precipitate was filtered, washed with water and dried. White powder. Yield: 79 %. mp: 213 ± 1°C. Rf (DCM-MeOH, 9-1): 0,5. LC-MS (ES⁺): m/z = 341 ,2, t_r = 1.56 min. ¹H NMR (DMSO) 5 (ppm): 2,00 (s, 3H); 3,79 (s, 2H); 6,90 (s, 1 H); 7,49 (m, 6H); 7,87 (d, 2H, J = 8.25 Hz); 10,01 (s, 1 H). IR v (cm'¹): 3354,6 (NH); 2897,7 and 2793,5 (CH aliphatic); 1703,2 (C=O); 1541 ,2 (C=N); 1506,9 (C=C); 1263,6 (C-N); 815,4 (C-CI). - Synthesis of ethyl 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1 - yl)benzyl)amino)propanoate (ALIPD340)

To a solution of ethyl acrylate (2 eq) in ethanol at room temperature, ALIPD330 (1 eq) was added and was stirred at room temperature for 18h. The resulting solution was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography. Purification by flash chromatography eluted by DCM-MeOH, 95-5. Yellow oil. Yield: 41 %. Rf (DCM-MeOH, 9-1): 0.48. LC-MS (ES⁺): m/z = 441 ,2, t_r = 1.77 min. ¹H NMR (DMSO) 5 (ppm): 1 ,18 (t, 3H); 1 ,99 (s, 3H); 2,00 (s, 1 H); 2.50 (t, 2H); 2.77 (t, 2H); 3.77 (s, 2H); 4,05 (q, 2H); 6,90 (s, 1 H); 7,41 - 7,55 (m, 6H); 7,86 (d, 2H, J=8.5 Hz); 10,01 (s, 1 H). IR v (cm'¹): 2923,0 (CH aliphatic); 1724,6 (C=O, ester); 1703,9 (C=O, amide); 1600,6 (C=N); 1508,5 (C=C); 834,6 (C-CI).

- Synthesis of 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 /-/-pyrazol-1 - yl)benzyl)amino)propanoic acid (ALIPD349)

To a solution of ALIPD340 (1 eq) in EtOH was added a solution of NaOH (10%, 15 eq) at room temperature. After 12h, the mixture was concentrated to remove EtOH. The residue was dissolved in a solution of citric acid. The white precipitate obtained was filtered, washed with water and dried. Brown powder. Yield: 75 %. mp: 189 ± 1 °C. Rf (DCM-MeOH, 9-1 ): 0,5. LC-MS (ES⁺): m/z = 413,2, t_r = 1 .61 min. ¹H NMR (DMSO) 5 (ppm): 2,01 (s, 3H); 2.68-2,68 (m, 3H); 3.12 (t, 2H); 4,20 (s, 2H); 6,93 (s, 1 H); 7,50 (d, 2H, J= 8.5 Hz); 7,66 (m, 4H); 7,89 (d, 2H, J = 8.5 Hz); 10,11 (s, 1 H). IR v (cm'¹): 2954,5- 2923,1 and 2852,6 (CH aliphatic); 1710,1 (C=O, acid); 1679,2 (C=O, amide); 1600,6 (C=N); 1460,4 (C=C); 789,8 (C-CI). • The synthesis of ALIPD337, ALIPD338, ALIPD339, ALIPD363, ALIPD372, ALIPD373, ALIPD376, ALIPD390, ALIPD394, ALIPD395 and ALIPD396 was carried out according to Scheme 6 below. In this procedure, the inventors prepared compounds by a one-pot reaction. Then, the procedure resulted of the successive condensation of an ester with an acetonitrile, followed the condensation the resulting (3-keto nitrile formed and a hydrazine, and finally an acylation step by anhydride acetic.

Scheme 6. of AUPD337, ALIPD338, ALIPD339, ALIPD363, AUPD372, ALIPD373,

AUPD376, ALIPD390, AUPD394, ALIPD395 and ALIPD396.

1. THF, ACN, t-BuOK, rt, 5 min

General procedure for the preparation of compounds ALIPD337, ALIPD338, ALIPD339, ALIPD363, ALIPD372, ALIPD373, ALIPD376, ALIPD390, ALIPD394, ALIPD395 and ALIPD396 Ethyl ester (1 eq.) was dissolved in a solution of t-BuOK in THF (1 N), then acetonitrile (1.1 eq) was added. The mixture was stirred at room temperature for 5 min. The medium was cooled down to 0°C. Acetic acid (30 eq) and the corresponding hydrazine (1.5 eq) were slowly added. The mixture was stirred under microwave irradiation at 100W, 85°C for 20 minutes. The medium was then cooled down to room temperature and acetic anhydride (5 eq) was added. The mixture was stirred under microwave irradiation at 100W, 120°C for 20 minutes. The mixture was cooled down to room temperature and a saturated solution of NaHCOs was added. The mixture was extracted 3 times with ethyl acetate. The organic layers were collected, washed with brine, dried with MgSO4, and concentrated under reduced pressure.

- Synthesis of /V-(3-phenyl-1 -(pyridin-2-yl)-1 H-pyrazol-5-yl)acetamide (ALIPD337) The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Orange powder, mp: 167 ± 1 °C. Yield: 72%. LC-MS (ES⁺): 279 (MH⁺), t_r= 2.23 min. ¹H NMR (CDCI₃) 8 (ppm): 12.17 (s, 1 H); 8.38 (ddd, 1 H, J= 5.1 Hz, J = 1.7 Hz, J” = 0.6 Hz); 8.22 (1 H, ddd, J = 8.5 Hz, J = 1.1 Hz, 0.6 Hz); 7.96 (2H, m); 7.89 (1 H, ddd, J= 8.5 Hz, J = 7.4 Hz, J’ = 1.7 Hz); 7.44 (m, 2H); 7.38 (td, 1 H, J= 6.1 Hz, J’ = 1.4 Hz); 7,30 (1 H, s); 7.20 (1 H, ddd, J= 7.4 Hz, J = 5.1 Hz, J” = 1.1 Hz); 2.31 (3H, s).

- Synthesis of /V-(3-(4-chlorophenyl)-1-(pyridin-2-yl)-1 H-Dyrazol-5-yl)acetamide (ALIPD338)

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). White powder, mp: 144 ± 1°C. Yield: 60%. LC-MS (ES⁺): 313; t_r= 2.44 min. ¹H NMR (CDCI₃) 8 (ppm): 12.15 (s, 1 H); 8.38 (ddd, 1 H, J= 5.1 Hz, J’ = 1.7 Hz, J” = 0.6 Hz); 8.19 (ddd, 1 H, J = 8.5 Hz, J’ = 1.1 Hz, J” = 0.6 Hz); 7.92-7.85 (m, 3H); 7.41 (d, 2H, J = 8.7 Hz); 7,26 (s, 1 H); 7.21 (ddd, 1 H, J= 7.4 Hz, J’ = 5.1 Hz, J” = 1.1 Hz); 2.31 (s, 3H).

- Synthesis of /V-(3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Yellow powder, mp: 160 ± 1 °C. Yield: 59%. LC-MS (ES⁺): 309, t_r = 2.15 min. ¹H NMR (CDC ) 8 (ppm): 12.17 (s, 1 H); 8.38 (ddd, 1 H, J = 5.1 Hz, J = 1.7 Hz, J” = 0.6 Hz); 8.22 (ddd, 1 H, J = 8.5 Hz, J = 1.1 Hz, J’ = 0.6 Hz); 7.91-7.85 (m, 3H); 7,24 (s, 1 H); 7.18 (ddd, 1 H, J = 7.4 Hz, J = 5.1 Hz, J’ = 1 .1 Hz); 6.98 (d, 2H, J = 8.9 Hz); 3.88 (s, 3H); 2.31 (s, 3H).

- Synthesis of /V-(3-(2-methoxyphenyl)-1-(pyridin-2-yl)-1 H-pyrazol-5-yl)acetamide

(ALIPD363)

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Yellow powder, mp: 142 ± 1 °C. Yield: 67%. LC-MS (ES⁺): 309, t_r = 2.19 min. ¹H NMR (CDCI₃) 8 (ppm): 12.11 (s, 1 H); 8.38 (ddd, 1 H, J = 5.1 Hz, J’ = 1.7 Hz, J” = 0.6 Hz); 8.22 (ddd, 1 H, J= 8.5 Hz, J’ = 1.1 Hz, J" = 0.6 Hz); 8.04 (dd, 1 H, J = 7.7 Hz, J’ = 1.8 Hz); 7.87 (ddd, 1 H, J= 8.5 Hz, J’ = 7.4 Hz, J” = 1.7 Hz); 7,45 (s, 1 H); 7.36 (ddd, 1 H, J = 9.2Hz, J’ = 7.4 Hz, J" = 1.8 Hz); 7.18 (ddd, 1 H, J= 7.4 Hz, J’= 5.1 Hz, J”= 1.1 Hz); 7.08-7.00 (m, 2H); 3.95 (s, 3H); 2.31 (s, 3H).

- Synthesis of /V-(3-(3,4-dimethoxyphenyl)-1 -(pyridin-2-yl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Yellow powder, mp: 155 ± 1 °C. Yield: 46%. LC-MS (ES⁺): 339, t_r = 2.05 min. ¹H NMR (CDC ) 8 (ppm): 12.19 (s, 1 H); 8.38 (ddd, 1 H, J = 5.1 Hz, J = 1.7 Hz, J” = 0.6 Hz); 8.22 (ddd, 1 H, J= 8.5 Hz, J’= 1 .1 Hz, J”= 0.6 Hz); 7.89 (ddd, 1 H, J= 8.5 Hz, J’= 7.4 Hz, J”= 1 .7 Hz); 7.49 (m, 2H); 7,25 (s, 1 H); 7.20 (ddd, 1 H, J= 7.4 Hz, J’= 5.1 Hz, J”= 1.1 Hz); 6.95 (d, 1 H, = 8.0 Hz); 4.01 (s, 3H); 3,95 (s, 3H); 2.31 (s, 3H).

- Synthesis of /V-(3-(3,4-dichlorophenyl)-1 -(pyridin-2-yl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Yellow Powder, mp: 190 ± 1 °C. Yield: 81%. LC-MS (ES⁺): 293, t_r = 2.34 min. ¹H NMR (CDCI₃) 5 (ppm): 12.13 (s, 1 H); 8.38 (ddd, 1 H, J = 5.1 Hz, J’ = 1.7 Hz, J” = 0.6 Hz); 8.19 (ddd, 1 H, <7= 8.5 Hz, J’= 1.1 Hz, J”= 0.6 Hz); 8.04 (d, 1 H, J = 2.0 Hz); 7.90 (ddd, 1 H, J = 8.5 Hz, J’ = 7.4 Hz, J” = 1.7 Hz); 7.72 (dd, 1 H, J= 8.4 Hz, J’ = 2.0 Hz); 7.50 (s, 1 H, J= 8.4 Hz); 7,30 (m, 2H); 2.31 (s, 3H).

- Synthesis of /V-(1 -(pyridin-2-yl)-3-(p-tolyl)-1 H-pyrazol-5-yl)acetamide (ALIPD376)

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). Orange powder, mp: 168 ± 1 °C. Yield: 61%. LC-MS (ES⁺): 293, t_r = 2.34 min. ¹H NMR (DMSO) 5 (ppm): 11.82 (s, 1 H); 8.55 (m, 1 H); 8.07 (m, 2H); 7.80 (d, 2H, J = 8.1 Hz); 7.40 (m, 1 H); 7.27 (d, 2H, J= 8.1 Hz); 7.16 (s, 1 H); 2.36 (s, 3H); 2.24 (s, 3H).

- Synthesis of /V-(3-(4-chlorophenyl)-1-(4-methoxyphenyl)-1 H-Dyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). White powder, mp: 204 ± 1°C. Yield: 85%. LC-MS (ES⁺): 342, t_r= 2.13 min. ¹H NMR (DMSO) 5 (ppm): 9.97 (s, 1 H); 7.88 (d, 2H, J= 8.5 Hz); 7.48 (d, 2H, J= 8.5 Hz); 7.45 (d, 2H, J = 8.6 Hz); 7.33 (d, 2H, J = 8.6 Hz); 6.90 (s, 1 H); 2.38 (s, 3H); 2.00 (s, 3H).

- Synthesis of /V-(1-(3-chlorophenyl)-3-(4-chlorophenyl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). White powder, mp: 188 ± 1°C. Yield: 93%. LC-MS (ES⁺): 346, t_r= 2.30 min. ¹H NMR (DMSO) 5 (ppm): 9.97 (s, 1 H); 7.88 (d, 2H, J= 8.5 Hz); 7.67 (s, 1 H); 7.57 (m, 2H); 7.48 (m, 3H);

6.94 (s, 1 H); 2.02 (s, 3H).

Synthesis of /V-(3-(4-chlorophenyl)-1 -(2,6-dichlorophenyl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). White powder, mp: 224 ± 1°C. Yield: 82%. LC-MS (ES⁺): 382, t_r= 2.24 min. ¹H NMR (DMSO) 5 (ppm): 10.08 (s, 1 H); 7.83 (d, 2H, J = 8.5 Hz); 7.73 (m, 2H); 7.64 (dd, 1 H, J = 6.8 Hz, 9.3 Hz); 7.48 (d, 2H, J = 8.5 Hz); 7.04 (s, 1 H); 2.02 (s, 3H).

Synthesis of /V-(3-(4-chlorophenyl)-1 -(2,5-dichlorophenyl)-1 H-pyrazol-5-yl)acetamide

The product was purified by chromatography on silica gel with the eluent: cyclohexane I ethyl acetate (6:4). White powder. Yield: 68%. mp: 186 ± 1°C. LC-MS (ES⁺): 382, t_r= 2.34 min. ¹H NMR (DMSO) 5 (ppm): 10.06 (s, 1 H); 7.86 (d, 2H, J = 8.5 Hz); 7.76 (d, 1 H, J = 1.9 Hz); 7.75 (d, 1 H, J = 8.0 Hz); 7.69 (dd, 1 H, J = 8.0 Hz, J’ = 1.9 Hz); 7.48 (d, 2H, J = 8.5 Hz); 6.99 (1 H, s); 1.99 (s, 3H).

Results:

With the aim of identifying novel small molecules as PD-1/PD-L1 interaction inhibitors, the inventors carried out a screening of an in-house chemical library. Two relevant and complementary methodologies were used for the screening: (i) an in vitro microscale thermophoresis (MST) assay and (ii) a cell-based Forster resonance energy transfer (FRET) assay. MST is a powerful method for the quantitative analysis of protein-ligand interactions with low sample consumption based on the movement of molecules along local temperature gradients, useful for assessing the affinity of compounds for PD-L1 (KD) as described previously (Smith et al.). The FRET assay assessed the compounds' ability to effectively disrupt the PD-L1 :PD-1 interaction and inhibit recruitment of the Src homology region domain-containing phosphatase (SHP2, the downstream effector protein) to PD-1 . In particular, after screening, the inventors identified and synthesized several compounds based on the general formula (I) of the invention such as the compounds disclosed in Table 1 below. The inventors then confirmed that these compounds were capable of blocking the PD- 1/PD-L1 interactions by carrying out physicochemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Promega Blockade assay, T cell assay).

Table 1. Results of MST, FRET, Promega Blockade, NanoDSF and T-cell response assays in relation to the following compounds of the invention. N.B = No binding; T-cell response assay: / means no expression, + to ++++ means low expression to high expression.

Conclusion

In summary, the compounds of general formula (I) of the present invention, in particular compounds ALIPD304, ALIPD307, ALIPD381 , ALIPD382, ALIPD395 and ALIPD396, have a real therapeutic interest in the treatment of cancers. They have an affinity (Kd) of the order of pM, an affinity which is higher than that of atezolizumab, an antibody used in clinical use. Indeed, compounds ALIPD304, ALIPD307, ALIPD381 , ALIPD382, ALIPD395 and ALIPD396 have a respective Kd of 423 pM, 729 pM, 710 pM, 412 pM, 123 pM and 526 pM compared to atezolizumab which has a Kd of 6.7 nM. This affinity is correlated with in vitro activity for the compounds ALIPD304, ALIPD307, ALIPD381 , ALIPD395 and ALIPD396 resulting in a comparable or better IC50 (77 nM, 25 nM, 2.5 nM, 429 pM and 556 pM) than that observed with atezolizumab (15.3 nM) in the Promega Assay. The compounds of the present invention, in particular ALIPD304, ALIPD307, ALIPD381 , ALIPD395 and ALIPD396 therefore have the ability due to their affinity for PD-L1 and their ability to block the PD1/PD-L1 interaction to restore the anti-tumor immune response. For this reason, the compounds of the present invention represent a good therapeutic for the treatment of cancers.

References

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2. Saudemont A, Quesnel B. In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis. Blood 2004;104:2124-33.

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4. Smith WM, Purvis IJ, Bomstad CN, Labak CM, Velpula KK, Tsung AJ, Regan JN, Venkataraman S, Vibhakar R, Asuthkar S. Therapeutic targeting of immune checkpoints with small molecule inhibitors. Am J Transl Res. 2019; 11 :529-541 .

Claims

1 . A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

- (a) Wherein Y³ represents C and R³ represents H; and

R¹ represents phenyl substituted with one Cl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or

- (b) Wherein Y³ represents C and R³ represents halogen, preferably Cl; and

R¹ represents C(O)OCi-Ce alkyl, or phenyl substituted with one Cl;

R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n-C(O)O-Ci-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl,

C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-Cs-Cio heterocyclyl-C(O)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or is the following compound ALIPD347

- (c) Wherein Y³ represents N and R³ is absent; and

R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, CrCe alkoxy and Ci-Ce alkyl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷ are identical and represent H.

2. The compound according to claim 1 , wherein (a) Y³ represents C and R³ represents H; and wherein:

- R¹ represents

- R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, OCH₃, CH₂NH₂,

CH₂NH(CH₂)₂C(O)OH, or CH₂NH(CH₂)₂C(O)OCH₂CH₃.

3. The compound according to claim 2, wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents Cl, CN, OCH₃, CH₂NH₂, CH₂NH(CH₂)₂C(O)OH, CH₂NH(CH₂)₂C(O)OCH₂CH₃; preferably R⁵ represents Cl, or CH₂NH(CH₂)₂C(O)OH; more preferably R⁵ represents Cl; or

(ii) - R⁵, R⁶ and R⁷ are identical and represent H; and

R⁴ represents Cl.

4. The compound according to claim 1 , wherein (b) Y³ represents C and R³ represents halogen, preferably Cl; and wherein:

R² represents H, CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; preferably R² represents CH₃, CH₂C(O)OCH₂CH₃, or CH₂C(O)OH; more preferably R² represents CH₃, or CH₂C(O)OCH₂CH₃; even more preferably R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, Cl, CN, C(O)NH₂,

5. The compound according to claim 4, wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

-

(ii) - R⁴, R⁵ and R⁶ are identical and represent H; and R⁷ represents Cl; or (iii) - R⁴, R⁵ and R⁷ are identical and represent H; and R⁶ represents Cl.

6. The compound according to claim 5, wherein:

(i) - R⁴, R⁶ and R⁷ are identical and represent H; and

- R⁵ represents preferably R⁵ represents Cl.

7. The compound according to claim 1 , wherein (c) Y³ represents N and R³ is absent; and wherein:

R¹ represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH₃ and CH₃; preferably R¹ represents

- R² represents CH₃; and

- R⁴, R⁵, R⁶ and R⁷ represent H.

8. The compound according to any one of claims 1 to 7, which is selected from the group consisting of the following compounds:

9. The compound according to claim 8, which is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9, and at least one pharmaceutically acceptable excipient.

11. A compound of the following general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising at least one of said compound of the following general formula (I), and at least one pharmaceutically acceptable excipient; wherein said compound or said pharmaceutical composition is for use in a method of prevention and/or treatment of a disease in a subject, in particular a human:

- Wherein (a) Y³ represents C and R³ represents H; and wherein:

R¹ represents aryl substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl;

R² represents Ci-Ce alkyl;

R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-C1-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci- Ce alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or

- Wherein (b) Y³ represents C and R³ represents halogen, preferably Cl; or (c) Y³ represents N and R³ is absent; and wherein:

R¹ represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; R² represents H, Ci-Ce alkyl, (CH₂)_m-C(O)OCi-C6 alkyl, or (CH₂)_m-C(O)OH, with m representing an integer between 1 and 3;

- R⁴, R⁵, R⁶ and R⁷, which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH₂, C(O)OH, (CH₂)_m-NH₂, (CH₂)_m-NH-(CH₂)_n-C(O)OH, (CH₂)_m-NH-(CH₂)_n- C(O)O-C1-C₆ alkyl, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)OH, (CH₂)_m-NH-C(O)-(CH₂)_n-C(O)O-Ci-C₆ alkyl, C(0)NH(CH₂)_m-C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3.

12. The compound or the composition for use according to claim 11 , as a PD-1/PD-L1 interaction inhibitor in a subject, in particular a human.

13. The compound or the composition for use according to claim 11 or 12, wherein the disease is a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory disease, neurological disease and chronic infection in a subject, in particular a human.

14. The compound or the composition for use according to claim 13, wherein: the cancer is selected from the group consisting of lung carcinoma (Non small cell and Small cell), head and neck carcinoma, bladder carcinoma, kidney carcinoma, triple negative breast cancer, pancreatic carcinoma, melanoma, gastric carcinoma, colon carcinoma, oesophagus carcinoma, Hodgkin’s lymphoma, non Hodgkin lymphoma, glioblastoma, multiple myeloma, acute myeloide leukemia, Cholangiocarcinoma (gallbladder carcinoma), Merkel carcinoma, squamous cell carcinoma and endometrial carcinoma; the neurological disease is Alzheimer disease; the chronic inflammatory disease is psoriasis; and/or the chronic infections are selected from the group consisting of Human immunodeficiency virus (HIV), malaria, tuberculosis and B hepatitis.

15. The compound or the composition for use according to any one of claims 11 to 14, wherein:

- R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in any one of claims 2 to 7; or

- the compound is selected from the group of the following compounds ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321 , ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD372, ALIPD373, ALIPD376, ALIPD381 , ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396; preferably is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, more preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.