WO2025003429A1 - Dérivés de pyrazole en tant qu'inhibiteurs d'interaction pd-1/pd-l1 - Google Patents

Dérivés de pyrazole en tant qu'inhibiteurs d'interaction pd-1/pd-l1 Download PDF

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Publication number
WO2025003429A1
WO2025003429A1 PCT/EP2024/068292 EP2024068292W WO2025003429A1 WO 2025003429 A1 WO2025003429 A1 WO 2025003429A1 EP 2024068292 W EP2024068292 W EP 2024068292W WO 2025003429 A1 WO2025003429 A1 WO 2025003429A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
represent
carcinoma
halogen
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PCT/EP2024/068292
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English (en)
Inventor
Xavier THURU
Christian Bailly
Bruno QUESNEL
Frédérique Klupsch
Raphaël LE BIANNIC
Régis MILLET
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Hospitalier Universitaire de Lille
Universite de Lille
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Hospitalier Universitaire de Lille
Universite de Lille
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Priority to KR1020267001350A priority Critical patent/KR20260035902A/ko
Priority to AU2024310722A priority patent/AU2024310722A1/en
Priority to CN202480043861.XA priority patent/CN121752548A/zh
Priority to EP24737945.6A priority patent/EP4735113A1/fr
Publication of WO2025003429A1 publication Critical patent/WO2025003429A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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 R 1 , R 2 , Y 3 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the description.
  • the present invention also relates to a pharmaceutical composition
  • 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.
  • 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.
  • programmed cell death protein 1 also known as CD279
  • PD-L1 programmed death ligand 1
  • CD274 or B7-H1 programmed death ligand 1
  • 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.).
  • anti-PD1 e.g., nivolumab and pembrolizumab
  • anti-PD-L1 e.g., atezolizumab, avelumab and durvalumab
  • 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.
  • 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.
  • 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.
  • 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:
  • R 1 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;
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3, preferably 1 or 2;
  • Y 3 represents C and R 3 represents H or halogen; or Y 3 represents N and R 3 is absent;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-C1-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci- Ce alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an
  • tautomer 1 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.
  • the term “mesomer 1 ’ or “meso compound’ refers to a stereoisomer that has two or more chiral centers but is optically inactive.
  • racemate or “racemic mixtures” refers to a mixture of two enantiomers in equal proportions.
  • the term “enantiomer 1 ’ refers stereoisomers that are mirror images, i.e., mirror image isomers. As defined herein, the term “diastereomer 1 ’ 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.
  • 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,
  • CrCe alkyl represents any monovalent radical of a linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms.
  • 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.
  • 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.
  • 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.
  • halogen represents an atom of F, Cl, Br or I.
  • Ci-Ce alkoxy represents a radical of formula -OR’, wherein R’ is a CrCe alkyl.
  • suitable Ci-Ce alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), t-butoxy (-OC(CH 3 ) 3 ), or -O(CH 2 )5CH 3 .
  • 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.
  • suitable heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, aziridinyl, azetidinyl, or pyrrolidinyl.
  • 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.
  • the term “an integer between 1 and 3’ includes the values 1 and 3.
  • 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.
  • substituents such as, for example, halogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkanoyl, aroyl, formyl, nitrile, nitro, amid
  • the compound of general formula (I) as defined herein is one wherein R 1 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 R 1
  • the compound of general formula (I) as defined herein is one wherein R 2 represents Ci-Ce alkyl, preferably CH 3 .
  • the compound of general formula (I) as defined herein is one wherein Y 3 represents C and R 3 represents halogen, more preferably Cl.
  • the compound of general formula (I) as defined herein is one wherein R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H or halogen such as Cl.
  • the compound of general formula (I) as defined herein is one wherein R 4 , R 5 and R 6 are identical and represent H; and R 7 represents halogen, preferably R 7 represents Cl.
  • the compound of general formula (I) as defined herein is one wherein R 4 , R 5 and R 7 are identical and represent H; and R 6 represents halogen, preferably R 6 represents Cl.
  • the compound of general formula (I) as defined herein is one wherein:
  • R 1 represents CH 3 , C(O)OCH 2 CH 3 , or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; preferably R 1 represents
  • R 2 represents H, Ci-Ce alkyl, CH 2 -C(O)OCI-C6 alkyl, or CH 2 C(O)OH; preferably R 2 represents H, CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; more preferably R 2 represents CH 3 ; and/or
  • R 3 represents H or halogen, preferably halogen, more preferably Cl;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, CN, OCH 3 , C(O)NH 2 ,
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; more preferably R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H or Cl.
  • the compound of general formula (I) as defined herein is one wherein: Y 3 represents C and R 3 represents halogen, preferably Cl; and:
  • R 5 represents Cl, C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; preferably R 5 represents Cl; or
  • R 7 represents halogen, preferably R 7 represents Cl; or
  • R 6 represents halogen, preferably R 6 represents Cl.
  • the compound of general formula (I) as defined herein is one wherein:
  • R 3 represents H or halogen, preferably H or Cl;
  • R 1 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 R 1 represents CH 3 , C(O)OCH 2 CH 3 , or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; more preferably R 1 represents
  • R 1 represents
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3, preferably 1 or 2; preferably R 2 represents H, CH 3 ,
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy,
  • the compound of general formula (I) as defined herein is one wherein:
  • R 1 represents aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; more preferably R 1 represents
  • R 2 represents CrCe alkyl, preferably CH 3 ;
  • Y 3 represents N and R 3 is absent
  • R 4 , R 5 , R 6 and R 7 represent H.
  • the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds:
  • the compound of general formula (I) as defined herein is selected from the group consisting of the following compounds
  • 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
  • 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.
  • pharmaceutically acceptable means that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the subject thereof.
  • 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.
  • 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.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • cerebral administration for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an anti-oxidant such as butylated hydroxyani
  • 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.
  • 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.
  • 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
  • the active ingredient may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • 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.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas
  • Capsules and cartridges 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.
  • a suitable powder base such as lactose or starch.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • said disease may be prevented before it occurs or identified at an early stage so that the symptoms of said disease may be reduced.
  • treatment is meant to include alleviating or abrogating a PD- 1 -PD-L1 interactions-related disease and/or their attendant symptoms.
  • 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.
  • 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.
  • HIV Human immunodeficiency virus
  • the pharmaceutical composition further comprises at least one other active ingredient, such as an anticancer agent.
  • 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.
  • an anti-CTLA4 antibody such as Ipilimumab
  • a CAR-T compound such as axicabtagene ciloleucel
  • an anti-LAG3 antibody such as
  • 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.
  • a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections as previously defined.
  • 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.
  • 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
  • PTSA p-toluenesulfonic acid
  • 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:
  • R 1 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
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3;
  • Y 3 represents C and R 3 represents H or halogen; or Y 3 represents N and R 3 is absent;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-Ci-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci- Ce alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an
  • R 1 represents CH 3 , C(O)OCH 2 CH 3 , or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; preferably R 1 represents y
  • R 2 represents H, Ci-Ce alkyl, CH 2 -C(O)OCi-Ce alkyl, or CH 2 C(O)OH; preferably R 2 represents H, CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; more preferably R 2 represents CH 3 ; and/or
  • R 3 represents H or halogen, preferably halogen, more preferably Cl;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, CN, OCH 3 , C(O)NH 2 , represent H, Cl, C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; more preferably R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H or Cl.
  • Item 3 The compound according to item 1 or 2, wherein Y 3 represents C and R 3 represents halogen, preferably Cl; and wherein:
  • R 5 represents Cl, C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; preferably R 5 represents Cl; or
  • R 7 represents halogen, preferably R 7 represents Cl; or
  • R 6 represents halogen, preferably R 6 represents Cl.
  • R 3 represents H or halogen, preferably H or Cl;
  • R 1 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 R 1 represents CH 3 , C(O)OCH 2 CH 3 , or phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; more preferably R 1
  • R 1 represents
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3; preferably R 2 represents H, CH 3 , CH 2 C(O)OCH 2 CH 3 , or
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci-C 6 alkyl,
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, CN, OCH 3 , represent H, Cl, C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; even more preferably R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H or Cl.
  • R 1 represents aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; preferably R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and
  • R 2 represents CrCe alkyl, preferably CH 3 ;
  • R 4 , R 5 , R 6 and R 7 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 immuno
  • 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:
  • R 1 represents phenyl substituted with one Cl
  • R 2 represents Ci-Ce alkyl
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or
  • Y 3 represents C and R 3 represents halogen, preferably Cl; and R 1 represents C(O)OCi-Ce alkyl, or phenyl substituted with one Cl;
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci-C 6 alkyl,
  • R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl;
  • R 2 represents Ci-Ce alkyl
  • R 4 , R 5 , R 6 and R 7 are identical and represent H.
  • the compound of general formula (I) as defined herein is one wherein (a) Y 3 represents C and R 3 represents H; and wherein:
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, CN, OCH 3 , CH 2 NH 2 , CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; preferably wherein:
  • R 5 represents Cl, CN, OCH 3 , CH 2 NH 2 , CH 2 NH(CH 2 ) 2 C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; preferably R 5 represents Cl, or CH 2 NH(CH 2 ) 2 C(O)OH; more preferably R 5 represents Cl; or (ii) - R 5 , R 6 and R 7 are identical and represent H; and
  • R 4 represents Cl
  • the compound of general formula (I) as defined herein is one wherein (b) Y 3 represents C and R 3 represents halogen, preferably Cl; and wherein:
  • R 2 represents H, CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; preferably R 2 represents CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; more preferably R 2 represents CH 3 , or CH 2 C(O)OCH 2 CH 3 ; even more preferably R 2 represents CH 3 ; and
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, Cl, CN, C(O)NH 2 , preferably wherein:
  • R 5 represents H, Cl, CN, C(O)NH 2 , C(O)OH, CH 2 -NH 2 , CH 2 -NH-(CH 2 ) 2 -C(O)OH, CH 2 -NH- (CH 2 ) 2 -C(O)O- CH 2 CH 3 , CH 2 -NH-C(O)-CH 2 -C(O)OH, CH 2 -NH-C(O)-CH 2 -C(O)O-CH 2 CH 3 ,
  • R 6 represents Cl; more preferably wherein:
  • R 5 represents preferably R 5 represents Cl.
  • the compound of general formula (I) as defined herein is one wherein (c) Y 3 represents N and R 3 is absent; and wherein:
  • R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; preferably R 1 represents
  • R 4 , R 5 , R 6 and R 7 represent H.
  • 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.
  • 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.
  • 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.
  • 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:
  • R 1 represents aryl substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and CrCe alkyl;
  • R 2 represents Ci-Ce alkyl
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-C1-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci- Ce alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an
  • Y 3 represents C and R 3 represents halogen, preferably Cl; or (c) Y 3 represents N and R 3 is absent; and wherein:
  • R 1 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
  • R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3;
  • R 4 , R 5 , R 6 and R 7 which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-C1-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with
  • 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.
  • 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.
  • 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.
  • HIV Human immunodeficiency virus
  • FIG. 1 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).
  • CFP first fluorochrome
  • YFP emission of the second fluorochrome
  • MST Microscale thermophoresis
  • FRET Fluorescence Reactivation reaction
  • 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 ).
  • SHP-2-CFP phosphatase recruited during the interaction between PD-1 and PD-L1 .
  • 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.
  • 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.
  • 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 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.
  • 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
  • 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 K 2 COs and extracted with AE. The organic phase was washed with a solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure.
  • 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.
  • 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 NH 4 CI 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%).
  • 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 CaCI 2 , 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.
  • 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.
  • MST microscale thermophoresis
  • FRET FRET
  • 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 .
  • SHP2 the downstream effector protein
  • 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).
  • 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.
  • 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.
  • ALIPD304, ALIPD307, ALIPD381 , ALIPD395 and ALIPD396 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.

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Abstract

La présente demande concerne des dérivés de pyrazole en tant qu'inhibiteurs d'interaction PD-1/PD-L1. Les demandeurs ont conçu des composés de formule générale (I), dans laquelle R', R2, y3, R3, R4, R5, R6 et R7 sont tels que définis dans la description, qui sont capables de bloquer efficacement des interactions PD-1/PD-L1 afin de restaurer des réponses immunitaires antitumorales de sujets et d'éradiquer des cellules tumorales dormantes et toutes tumeurs dans lesquelles PD-L1 est impliqué dans l'évasion immunitaire. Les demandeurs ont confirmé que ces composés bloquaient les interactions PD-1/PD-L1 en effectuant des tests physico-chimiques (MST, NanoDSF) et des tests biologiques in vitro (essai FRET, essai de blocage Promega, dosage des lymphocytes T). Ces composés ont une affinité (Kd) de l'ordre du pM qui était supérieure à celle de l'anticorps atézolizumab utilisé en utilisation clinique, et ont une CI50 comparable ou meilleure par rapport à celle observée avec l'atézolizumab. Ainsi, la présente invention concerne également une composition pharmaceutique comprenant ledit ou lesdits composés et leurs utilisations dans le traitement de maladies associées à des interactions PD-1/PD-L1 (cancer, maladies inflammatoires chroniques, maladies neurologiques et infections chroniques).
PCT/EP2024/068292 2023-06-30 2024-06-28 Dérivés de pyrazole en tant qu'inhibiteurs d'interaction pd-1/pd-l1 Ceased WO2025003429A1 (fr)

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KR1020267001350A KR20260035902A (ko) 2023-06-30 2024-06-28 Pd-1/pd-l1 상호작용 억제제로서의 신규 피라졸 유도체
AU2024310722A AU2024310722A1 (en) 2023-06-30 2024-06-28 Pyrazole derivatives as pd-1/pd-l1 interaction inhibitors
CN202480043861.XA CN121752548A (zh) 2023-06-30 2024-06-28 作为pd-1/pd-l1相互作用抑制剂的吡唑衍生物
EP24737945.6A EP4735113A1 (fr) 2023-06-30 2024-06-28 Dérivés de pyrazole en tant qu'inhibiteurs d'interaction pd-1/pd-l1

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CN121752548A (zh) 2026-03-27
AU2024310722A1 (en) 2026-01-15

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