Pyrazole derivatives as PD-1 / PD-L1 interaction inhibitors

Abstract

The present application relates to pyrazole derivatives as inhibitors of the PD-1 / PD-L1 interaction. The applicants have designed compounds of general formula (I) wherein R ', R2, y3, R3, R4, R5, R6 and R7 are as defined herein, which are effective in blocking PD-1 / PD-L1 interactions to restore an anti-tumor immune response in a subject and eradicate any tumors in which dormant tumor cells and PD-L1 participate in immune escape. The inventor verifies that these compounds block the PD-1 / PD-L1 interaction by performing physical and chemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Pralomig block assay, T cell assay). These compounds have affinity (Kd) in the order of pM, which Kd is higher than the Kd of the antibody Atezumab used in clinical use, and have IC50 comparable to or higher than that observed using Atezumab. Therefore, the invention also relates to a pharmaceutical composition containing the compound and application of the pharmaceutical composition in treatment of PD-1-PD-L1 interaction related diseases (cancers, chronic inflammatory diseases, neurological diseases and chronic infections).

Description

Technical Field

[0001] This invention relates to novel pyrazole derivatives that advantageously act as inhibitors of PD-1 / PD-L1 interaction. The invention also relates to a compound of general formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or 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 As defined in the description. The present invention also relates to a pharmaceutical composition comprising at least one of the said compounds, and the use of said compounds or pharmaceutical compositions, particularly as PD-1 / PD-L1 interaction inhibitors, preferably for the prevention and / or treatment of PD-1-PD-L1 interaction-related diseases, such as cancer, chronic inflammatory diseases, neurological diseases, and chronic infections. Background Technology

[0002] In recent years, immunotherapy has become a powerful strategy for treating cancer, so much so that in 2018, Allison and Honjo were awarded the Nobel Prize in Physiology or Medicine "for their discovery of cancer therapy through inhibition of negative immune regulation." Currently available immunotherapies are monoclonal antibodies that interfere with specific regulatory systems known as immune checkpoints, acting at the interface between tumor cells and immune system cells, particularly T cells. Immune checkpoint receptors (ICRs) are constitutively expressed on the surface of T cells to counteract an overactive adaptive response to self-antigens, thereby preventing autoimmune reactions.

[0003] Among 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 exhaustion in many types of cancer, including melanoma, breast cancer, pancreatic cancer, kidney cancer, and non-small cell lung cancer (NSCLC). The PD-L1 (CD274 / B7-H1) transmembrane molecule belongs to the B7 family of immunomodulatory proteins and was initially described as mediating tumor immune escape 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, which are currently considered innovative drugs for many cancers (Nishino et al.). Aberrant PD-L1 expression has been observed in hematologic malignancies and various solid tumor types. Tumor cells evade antitumor immunity in part by utilizing immune checkpoints such as the PD-1 / PD-L1 axis, which induce T cell dysfunction or non-responsiveness.

[0004] Over 1,000 clinical trials have evaluated the antitumor properties of anti-PD-1 / anti-PD-L1 mAbs. Consequently, several anti-PD1 mAbs (e.g., nivolumab and pembrolizumab) and anti-PD-L1 mAbs (e.g., atezolizumab, avelumab, and durvalumab) have entered the market, revolutionizing the treatment landscape for the aforementioned cancers, including their effectiveness against other malignancies. To overcome the limitations of mAbs (e.g., high production costs and side effects) while improving patient adherence (e.g., oral administration), macrocyclic peptides, peptide mimics, and small non-peptide molecules are being developed as anti-PD-L1 agents, ushering in a new era of drug discovery in the field of immunotherapy. However, the clinical development of anti-PD-L1 small molecules is still in its early stages; in fact, only one organic small molecule, INCB086550, is currently in a Phase II clinical trial for the treatment of advanced solid tumors.

[0005] Patent application WO2021 / 009384 discloses pyrazolone derivatives as inhibitors of PD-1 / PD-L1 interaction, and the use of said pyrazolone derivatives or pharmaceutical compositions containing said pyrazolone derivatives in the prevention and / or treatment of PD-1-PD-L1 interaction-related diseases.

[0006] Therefore, there is a need for novel small molecules that can efficiently block PD-1 / PD-L1 interactions, have high bioavailability, high tumor penetration, low production cost, and are non-toxic. Summary of the Invention

[0007] The inventors have successfully developed a novel pyrazole derivative that can efficiently block PD-1 / PD-L1 interaction to restore the anti-tumor immune response in subjects and ultimately eradicate dormant tumor cells and any tumors involved in PD-L1 immune evasion.

[0008] Therefore, this invention relates to a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: (I) in: -R 1 The aryl group represents a C1-C6 alkyl group, a C(O)OC1-C6 alkyl group, or an aryl group optionally substituted with one or two substituents selected from the group consisting of the following, particularly phenyl: halogen, C1-C6 alkoxy and C1-C6 alkyl; -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3, preferably 1 or 2; -Y 3 Let C represent the sum of C and R. 3 Indicates H or halogen; or Y 3 Let N be an integer, and R be a variable. 3 It does not exist; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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-C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10Heterocyclic -C(O)-C1-C6 alkyl, wherein m represents an integer between 1 and 3, preferably 1 or 2, and n represents an integer between 1 and 3, preferably 1 or 2.

[0009] As defined in this article, the term " tautomer "Tautomers" refers to structural isomers that differ only in the positions of hydrogen atoms and electrons. Examples of tautomers include, but are not limited to, keto-enols, enamine-imines, amide-imines, lactam-lactamimides, nitroso-oximes, enone-alkynols, amino acids, or phosphites-phosphonates.

[0010] As defined in this article, the term " mesosome "or" Meso compounds "" refers to a stereoisomer that has two or more chiral centers but is optically inactive.

[0011] As defined in this article, the term " racemic "or" racemic mixture "" refers to a mixture of two enantiomers in equal proportions.

[0012] As defined in this article, the term " Enantiomers "" refers to a stereoisomer that is a mirror image, i.e., a mirror isomer.

[0013] As defined in this article, the term " diastereomers "" refers to isomers of compounds having more than one chiral center, and the isomers are not mirror images of each other.

[0014] The compounds of the present invention containing basic functional groups can be in the form of pharmaceutically acceptable salts. As defined herein, the term "..." Pharmaceutically acceptable salts "" refers to a pharmaceutically acceptable salt of the compounds of the present invention, which contains one or more basic functional groups, and the pharmaceutically acceptable salt particularly includes its acid addition salt. Suitable acid addition salts are formed by acids that form non-toxic salts. Examples include acetates, adipic acid salts, aspartic acid salts, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, cinnamates, citrates, cyclohexylaminosulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, gluconate, gluconate, and glucuronide. Glucuronates, hexafluorophosphates, hydroxybenzoates, hydrochlorides / chlorides, hydrobromides / bromines, hydroiodides / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, p-toluenesulfonates, trifluoroacetates, and sinetes.

[0015] As defined in this article, the term "C1-C6" alkyl "" represents any monovalent group comprising a straight-chain or branched hydrocarbon chain containing one to six carbon atoms. Examples of suitable C1-C6 alkyl groups include, but are not limited to, 1-C4 alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), C6-C8 alkyl groups (such as n-hexyl, n-heptyl, or n-octyl), and n-pentyl, 2-ethylhexyl, 3,5,5-trimethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, or n-octadecyl.

[0016] As defined in this article, the term " Aryl "" indicates a polyunsaturated aromatic hydrocarbon group having a single ring (e.g., phenyl) or multiple aromatic rings (e.g., naphthyl) fused together, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, 1-naphthyl (or naphth-1-yl), 2-naphthyl (or naphth-2-yl), anthracene, indanyl, indenyl, and 1,2,3,4-tetrahydronaphthyl.

[0017] As defined in this article, the term " halogen "" indicates an atom of F, Cl, Br or I.

[0018] As defined in this article, the term " C 1- C 6 Alkoxy " represents a group of the formula -OR', where R' is a C1-C6 alkyl group. Examples of suitable C1-C6 alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), tert-butoxy (-OC(CH3)3) or -O(CH2)5CH3.

[0019] As defined in this article, the term " C 5 -C 10 heterocyclic group "" refers to any monovalent group of a 5- to 10-membered ring, whether monocyclic or bicyclic, containing one or more heteroatoms (such as O, N, or S). Examples of suitable heterocyclic groups include, but are not limited to, piperidinyl, piperazineyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, heptyl, aziridinyl, butyl, or pyrrolidinyl.

[0020] As defined in this article, the term " Between "The range between two numerical values ​​should be interpreted to include both the start and end points of the range. For example, the term ' Integers between 1 and 3 "Including values ​​1 and 3."

[0021] Unless otherwise specified, the groups and radicals defined above may be unsubstituted or substituted with one or more substituents (e.g., halogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkanoyl, aryl, formyl, nitrile, nitro, amide, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, amino, alkylamino, arylamino, dialkylamino, and diarylamino).

[0022] In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is wherein R 1 This indicates a phenyl group optionally substituted with one or two substituents selected from the group consisting of: halogens, C1-C6 alkoxy groups, and C1-C6 alkyl groups, preferably R. 1 express Compounds. More preferably, R 1 express .

[0023] In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is wherein R 2 This indicates a C1-C6 alkyl compound, preferably CH3.

[0024] In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is wherein Y 3 Let C represent the sum of C and R. 3 It represents halogens, more preferably compounds of Cl.

[0025] In a preferred embodiment of the invention, compounds of general formula (I) as defined herein are wherein the R can be the same or different. 4 R 5 R 6 and R 7 Compounds that represent H or halogens (such as Cl).

[0026] In another preferred embodiment of the invention, the compound of general formula (I) as defined herein is wherein R 4 R 5 and R 6 The same, and represents H; and R 7 Indicates halogen, preferably R 7 Compounds representing Cl.

[0027] In another preferred embodiment of the invention, the compound of general formula (I) as defined herein is wherein R 4 R 5 and R 7The same, and represents H; and R 6 Indicates halogen, preferably R 6 Compounds representing Cl.

[0028] In a particular embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein: -R 1 This represents a phenyl group consisting of CH3, C(O)OCH2CH3, or optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; preferably R. 1 express More preferably R 1 express ; and / or -R 2 Represents H, C1-C6 alkyl, CH2-C(O)OC1-C6 alkyl, or CH2C(O)OH; preferably R 2 Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; more preferably R 2 Indicates CH3; and / or -Y 3 Let C represent the sum of C and R. 3 This indicates H or a halogen, preferably a halogen, more preferably Cl; and / or - Can be the same or different R 4 R 5 R 6 and R 7 Represents H, Cl, CN, OCH3, C(O)NH2, C(O)OH, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, CH2NHC(O) CH2C(O)OH, CH2NHC(O)CH2C(O)OCH2CH3, Preferably, the R can be the same or different. 4 R 5 R 6 and R 7 Represents H, Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; more preferably, it can be the same or different R. 4 R 5 R 6 and R 7 It represents H or Cl.

[0029] In a preferred embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein: Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 Represents Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; preferably R 5 Represents Cl; or (ii)-R 4 R 5 and R 6 They are the same, and represent H; and -R 7 Represents halogen, preferably R 7 Represents Cl; or (iii)-R 4 R 5 and R 7 They are the same, and represent H; and -R 6 Represents halogen, preferably R 6 It represents Cl.

[0030] In a particular embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein: -Y 3 Let C represent the sum of C and R. 3 This indicates H or halogen, preferably H or Cl; -R 1 This refers to an aryl group, which is C1-C6 alkyl, C(O)OC1-C6 alkyl, or optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl; preferably R 1 This refers to a phenyl group consisting of CH3, C(O)OCH2CH3, or optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; more preferably R 1 express Even more preferably R 1 express ; -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2)m -C(O)OH, where m represents an integer between 1 and 3, preferably 1 or 2; preferably R 2 Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; and - Can be the same or different R 4 R 5 R 6 and R 7 , representing H, halogen, CN, C1-C6 alkoxy group, 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- C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, wherein m represents an integer between 1 and 3, preferably 1 or 2, and n represents an integer between 1 and 3, preferably 1 or 2; preferably, it can be the same or different R 4 R 5 R 6 and R 7 Represents H, Cl, CN, OCH3, C(O)NH2, C(O)OH, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, CH2NHC(O)CH2C(O)OH, CH2NHC(O)CH2C(O)OCH2CH3, More preferably, it can be the same or different R. 4 R 5 R 6 and R 7 It can represent H, Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; or even more preferably, it can be the same or different R. 4 R 5 R 6 and R 7It represents H or Cl.

[0031] In another specific embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein: -R 1 The aryl group is optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl; more preferably R 1 This indicates a phenyl group optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; more preferably R 1 express Even more preferably R 1 express ; -R 2 It represents a C1-C6 alkyl group, preferably CH3; -Y 3 Let N be an integer, and R be a variable. 3 It does not exist; and -R 4 R 5 R 6 and R 7 H represents H.

[0032] In a particular embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] 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.

[0039] The present invention also relates to a pharmaceutical composition comprising (i) at least one compound of general formula (I) as defined herein, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

[0040] As defined in this article, the term " Pharmaceutically acceptable This means that the components of the drug composition are compatible with each other and are harmless to the subjects.

[0041] As defined in this article, the term " excipient "Excipients" refers to substances formulated together with active agents or active ingredients in a pharmaceutical composition or drug. Acceptable excipients for therapeutic use are well-known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, 21st edition, 2011. The selection of excipients can be based on the intended route of administration and standard pharmaceutical practice. Excipients must be acceptable, meaning harmless to the recipient. At least one pharmaceutically acceptable excipient can be, for example, a binder, diluent, carrier, lubricant, disintegrant, wetting agent, dispersant, suspending agent, etc.

[0042] By way of non-limiting examples, the pharmaceutical composition may be in forms suitable for oral administration, parenteral administration (e.g., by intravenous, intramuscular, or subcutaneous injection or intravenous infusion), topical administration (including ocular), brain administration, and administration by inhalation, by skin patch, by implant, by suppository, etc. Such suitable forms of administration (which may be solid, semi-solid, or liquid depending on the manner of administration) and the methods and carriers, diluents, and excipients used to prepare them will be apparent to those skilled in the art; please refer to the latest edition of Remington's Pharmaceutical Sciences.

[0043] For example, compounds of formula (I) as defined herein or pharmaceutical compositions according to the invention may be administered orally in the form of tablets, coated tablets, pills, capsules, soft gelatin capsules, oral powders, granules, ovules, elixirs, solutions or suspensions, wherein the compounds of formula (I) as defined herein or pharmaceutical compositions according to the invention may contain flavoring agents or coloring agents for immediate, delayed, modified, sustained, pulsatile or controlled-release applications.

[0044] The tablets may contain: excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine; disintegrants such as starch (preferably corn starch, potato starch, or cassava starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates; binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic; and lubricants such as magnesium stearate, stearic acid, and glyceryl behenate. Similar solid compositions may also be used as fillers in hard gelatin capsules. In this regard, preferred excipients include lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. Hard gelatin capsules may contain particles of the compounds of the present invention.

[0045] Soft gelatin capsules can be prepared using capsules containing the compounds of the present invention, vegetable oils, waxes, fats, or other suitable mediators for soft gelatin capsules. For example, an acceptable mediator may be an oily mediator, such as a long-chain triglyceride vegetable oil (e.g., corn oil).

[0046] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water may contain active ingredients in mixtures with dispersants, wetting agents, suspending agents, and one or more preservatives. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present. These compositions may be preserved by adding antioxidants such as ascorbic acid.

[0047] 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 oily mediators. Liquid dosage forms may be presented as dry products prior to use, to be formulated with water or other suitable mediators. Such compositions may also contain: adjuvants, such as wetting agents; emulsifiers and suspending agents; complexing agents, such as 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin; and sweeteners; flavoring agents; aroma agents; coloring substances or dyes; and diluents, such as water, ethanol, propylene glycol, and glycerin; and combinations thereof. These compositions may be preserved by adding antioxidants, such as butylated hydroxyanisole or α-tocopherol.

[0048] The fine powder of the compounds of the present invention can be prepared, for example, by micronization or by processes known in the art. The compounds of the present invention can be ground using known grinding procedures (such as wet milling) to obtain particle sizes suitable for tablet formation and other formulation types.

[0049] If the compounds of the present invention are administered parenterally, examples of such administration include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, or subcutaneous administration of the agent; and / or administration by means of infusion techniques.

[0050] The compounds of the present invention can be administered via a parenteral route, together with readily available or reservoir-type formulations.

[0051] Pharmaceutical compositions for parenteral administration of readily available formulations may be in the form of sterile injectable aqueous or oily solutions or suspensions in nontoxic, parenteral-acceptable diluents or solvents, and may contain modifiers such as suspending agents, stabilizing dispersants, wetting agents, and / or complexing agents (such as cyclodextrins, for example 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin).

[0052] Reservoir formulations for parenteral administration can be prepared using conventional techniques with pharmaceutically acceptable excipients (including but not limited to biocompatible and biodegradable polymers such as poly(β-caprolactone), poly(ethylene oxide), poly(glycolic acid), poly[(lactic acid)-co-(glycolic acid)...], poly(lactic acid)...), non-biodegradable polymers such as ethylene vinyl acetate copolymer, polyurethane, polyester(amide), polyvinyl chloride...), and aqueous and non-aqueous mediators such as water, sesame oil, cottonseed oil, soybean oil, castor oil, almond oil, oily esters, ethanol or fractionated vegetable oil, propylene glycol, DMSO, THF, 2-pyrrolidone, N-methylpyrrolidone, N-vinylpyrrolidone...)).

[0053] Alternatively, the active ingredient may be in a dry form, such as powder, crystals, or lyophilized solid, to be formulated together with a suitable mediator. The preparation of suitable parenteral formulations under aseptic conditions can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art.

[0054] As indicated, the compounds of the present invention can be administered intranasally or by inhalation and can be conveniently delivered from a pressurized container, pump, nebulizer, or nebulizer in the form of a dry powder inhaler or aerosol spray using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane (e.g., from Ineos Fluor), carbon dioxide, or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver the measured amount. The pressurized container, pump, nebulizer, or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges for inhalers or blow-throughs (e.g., made of gelatin) can be formulated into powder mixtures containing the compound and a suitable powder matrix (e.g., lactose or starch). For compositions suitable for and / or applicable for inhalation use, it is preferred that the compounds or salts of the present invention are in a reduced particle size form, and more preferably, said reduced particle size form is obtained or available through micronization. The preferred particle size of the reduced-size (e.g., micronized) compound, salt, or solvate is defined by a D50 value of about 0.5 micrometers to about 50 micrometers (e.g., as measured using laser diffraction).

[0055] Alternatively, the compounds of the present invention can be administered in the form of suppositories or pessaries, or topically in the form of gels, hydrogels, lotions, solutions, creams, ointments, or powders. The compounds of the present invention can also be administered skin-on or transdermally, for example, by using skin patches. They can also be administered via the lungs or rectum. They can also be administered via the eye. For ophthalmic use, the compounds can be formulated as microparticle 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 benzalkonium chloride). Alternatively, they can be formulated as ointments, such as petrolatum.

[0056] For topical application to the skin, the pharmaceutical agent of the present invention can be formulated into a suitable ointment containing an 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 compounds, emulsified wax, and water. Alternatively, it can be formulated into a suitable lotion or cream suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecanool, benzyl alcohol, and water.

[0057] At least one compound of general formula (I) as defined herein may be used in pharmaceutical compositions in doses ranging from 0.01 mg to 1000 mg per day, administered once daily, or administered several times daily, such as twice daily at equal doses. Daily doses advantageously include those between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, doses outside these ranges may be necessary, as will be noted by those skilled in the art.

[0058] In a particular embodiment of the invention, the pharmaceutical composition comprises (i) a compound, for example, a single compound of general formula (I) as defined herein, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

[0059] In a particular embodiment of the invention, a method of using a compound of formula (I) as defined herein or a composition according to the invention for the prevention and / or treatment of a subject's disease is preferably as an inhibitor of PD-1 / PD-L1 interaction in the subject, particularly in humans. In particular, compounds of formula (I) as defined herein or compositions according to the invention are capable of restoring the subject's antitumor immune response and ultimately eradicating dormant tumor cells and any tumors involved in PD-L1 immune evasion.

[0060] In a preferred embodiment of the invention, the disease is a PD-1-PD-L1 interaction-related disease of the subject, particularly a human PD-1-PD-L1 interaction disease, such as cancer, chronic inflammatory diseases, neurological diseases, and chronic infections.

[0061] As defined in this article, the term " people "" refers to subjects of both sexes at any developmental stage (i.e., newborn, infant, minor, adolescent, adult). In one embodiment, the person is an adolescent or an adult, preferably an adult.

[0062] As defined in this article, the term " prevention "Protection" refers to primary, secondary, and tertiary prevention. Preventing PD-1-PD-L1 interaction-related diseases means minimizing, i.e., blocking or delaying, the disease and its associated risk factors. Specifically, the disease can be prevented before it occurs or identified early to alleviate its symptoms.

[0063] As defined in this article, the term " treat This means including alleviating or eliminating PD-1-PD-L1 interaction-related diseases and / or their accompanying symptoms.

[0064] As defined in this article, the term " PD-1-PD-L1 interaction-related diseases "This includes any disease caused by the suppression of T cell activation, particularly by the interaction between PD-L1 and PD-1, and the treatment or prevention of said disease would benefit from the use of an inhibitor of said interaction. Non-limiting examples of diseases related to the PD-1-PD-L1 interaction include cancer, chronic inflammatory diseases, neurological diseases, and chronic infections."

[0065] In a preferred embodiment of the invention, the cancer is selected from the group consisting of: lung cancer (non-small cell and small cell), head and neck cancer, bladder cancer, kidney cancer, triple-negative breast cancer, pancreatic cancer, melanoma, gastric cancer, colon cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioblastoma, multiple myeloma, acute myeloid leukemia, cholangiocarcinoma (gallbladder cancer), Merkelcarcinoma, squamous cell carcinoma, and endometrial cancer; the neurological disease is Alzheimer's disease; the chronic inflammatory disease is psoriasis; and / or the chronic infection is selected from the group consisting of: human immunodeficiency virus (HIV), malaria, tuberculosis, and hepatitis B.

[0066] In a specific embodiment of the invention, the pharmaceutical composition further comprises at least one other active ingredient, such as an anticancer agent. Specifically, 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 anti-CD47 antibody (such as Hu5F9-G4), a small molecule blocking SIRP1a, an anti-VISTA antibody, an anti-TIGIT antibody, an anti-CD200 antibody (such as samalizumab), an anti-CD38 antibody (such as daratumumab), an anti-TNFa inhibitor (such as etanercept), and an anti-200R inhibitor (such as OX2 inhibitory peptide). The specific pharmaceutical composition may be used, for example, simultaneously, alone or sequentially, for the prevention and / or treatment of PD-1-PD-L1 interaction-related diseases, such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections as previously defined.

[0067] In specific embodiments of the invention, compounds of general formula (I) as defined herein or compositions according to the invention are used for the prevention and / or treatment of PD-1-PD-L1 interaction-related diseases, such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections, in combination with radiotherapy and / or viral therapy.

[0068] The present invention also relates to a method for preparing compounds of general formula (I) as defined herein, the method comprising: i) To make β-ketonitriles having formula (II): (II), where R 1 As defined in this article, Reaction with aryl-hydrazine having formula (III): (III), where Y 3 R 3 R 4 R 5 R 6 and R 7 As defined in this article, Preferably in the presence of p-toluenesulfonic acid (PTSA) in a polar solvent (such as ethanol); or ii) From ethyl ester derivatives having formula (IV): (IV), where R 1 As defined in this article, Polar solvents, such as acetonitrile and One-pot reaction with aryl-hydrazine having formula (III): (III), where Y 3 R 3 R 4 R 5 R 6 and R 7 As defined in this paper, an acylation step is then performed.

[0069] According to one aspect, the present invention relates to the following items: Project 1. A compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: (I) in: -R 1 The aryl group represents a C1-C6 alkyl group, a C(O)OC1-C6 alkyl group, or an aryl group optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl. -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3; -Y 3 Let C represent the sum of C and R. 3 Indicates H or halogen; or Y 3 Let N be an integer, and R be a variable. 3 It does not exist; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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-C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3.

[0070] Project 2. The compound according to Project 1, wherein: -R 1 This represents a phenyl group consisting of CH3, C(O)OCH2CH3, or optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; preferably R. 1 express More preferably R 1 express ; and / or -R 2 Represents H, C1-C6 alkyl, CH2-C(O)OC1-C6 alkyl, or CH2C(O)OH; preferably R 2Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; more preferably R 2 Indicates CH3; and / or -Y 3 Let C represent the sum of C and R. 3 This indicates H or a halogen, preferably a halogen, more preferably Cl; and / or - Can be the same or different R 4 R 5 R 6 and R 7 Represents H, Cl, CN, OCH3, C(O)NH2, C(O)OH, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, CH2NHC(O)CH2C(O)OH, CH2NHC(O)CH2C(O)OCH2CH3 or Preferably, the R can be the same or different. 4 R 5 R 6 and R 7 Represents H, Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; more preferably, it can be the same or different R. 4 R 5 R 6 and R 7 It represents H or Cl.

[0071] Project 3. The compound according to Project 1 or 2, wherein Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and wherein: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 Represents Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; preferably R 5 Represents Cl; or (ii)-R 4 R 5 and R 6 They are the same, and represent H; and -R 7 Represents halogen, preferably R 7 Represents Cl; or (iii)-R4 R 5 and R 7 They are the same, and represent H; and -R 6 Represents halogen, preferably R 6 It represents Cl.

[0072] Item 4. The compound according to any one of Items 1 to 3, wherein: -Y 3 Let C represent the sum of C and R. 3 This indicates H or halogen, preferably H or Cl; -R 1 This refers to an aryl group, which is C1-C6 alkyl, C(O)OC1-C6 alkyl, or optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl; preferably R 1 This refers to a phenyl group consisting of CH3, C(O)OCH2CH3, or optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; more preferably R 1 express Even more preferably R 1 express ; -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3; preferably R 2 Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; and - Can be the same or different R 4 R 5 R 6 and R 7 , representing H, halogen, CN, C1-C6 alkoxy group, 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-C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; preferably, they can be the same or different R. 4 R 5 R 6 and R 7 Represents H, Cl, CN, OCH3, C(O)NH2, C(O)OH, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, CH2NHC(O)CH2C(O)OH, CH2NHC(O)CH2C(O)OCH2CH3 or More preferably, it can be the same or different R. 4 R 5 R 6 and R 7 It can represent H, Cl, C(O)OH, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; or even more preferably, it can be the same or different R. 4 R 5 R 6 and R 7 It represents H or Cl.

[0073] Item 5. The compound according to any one of Items 1 to 3, wherein: -R 1 The aryl group is optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl; more preferably R 1 This indicates a phenyl group optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; more preferably R 1 express Even more preferably R 1 express ; -R 2 It represents a C1-C6 alkyl group, preferably CH3; -Y 3 Let N be an integer, and R be a variable. 3 It does not exist; and -R 4 R 5 R6 and R 7 H represents H.

[0074] Project 6. A compound according to any one of Projects 1 to 5, said compound being selected from the group consisting of: ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321, ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD339, ALIPD330 ... IPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD 372, ALIPD373, ALIPD376, ALIPD381, ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396.

[0075] Item 7. The compound according to any one of Items 1 to 6, wherein the compound is selected from the group consisting of: ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381, ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396.

[0076] 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.

[0077] Item 9. A method for preventing and / or treating a disease in a subject using a compound according to any one of Items 1 to 7 or a composition according to Item 8, preferably as a PD-1 / PD-L1 interaction inhibitor in a subject, particularly a human.

[0078] Item 10. The compound or composition for use according to Item 9, wherein the disease is a PD-1-PD-L1 interaction-related disease of the subject, particularly a human, such as cancer, chronic inflammatory disease, neurological disease, and chronic infection.

[0079] Item 11. The compound or composition for use according to Item 10, wherein: - The cancers mentioned are selected from the group consisting of: lung cancer (non-small cell and small cell), head and neck cancer, bladder cancer, kidney cancer, triple-negative breast cancer, pancreatic cancer, melanoma, gastric cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioblastoma, multiple myeloma, acute myeloid leukemia, cholangiocarcinoma (gallbladder cancer), Merkel's cancer, squamous cell carcinoma, and endometrial cancer; - The neurological disease mentioned is Alzheimer's disease; - The chronic inflammatory disease mentioned is psoriasis; and / or - The chronic infection is selected from the group consisting of: human immunodeficiency virus (HIV), malaria, tuberculosis and hepatitis B.

[0080] In one embodiment of the invention, a compound of general formula (I) as defined herein, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound wherein: (I) -(a)where Y 3 Let C represent the sum of C and R. 3 Represents H; and -R 1 This indicates a phenyl group that has been substituted by one Cl group; -R 2 Indicates C1-C6 alkyl; - Can be the same or different R 4 R 5 R 6 and R 7 This indicates H, halogen, CN, C1-C6 alkoxy group, or (CH2). m -NH2、(CH2) m -NH-(CH2) n -C(O)OH、(CH2) m -NH-(CH2) n -C(O)O-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; or -(b)where Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and -R 1 It represents a C(O)OC1-C6 alkyl group or a phenyl group substituted with one Cl group; -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m-C(O)OH, where m represents an integer between 1 and 3; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C(O)NH2, C(O)OH, and (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-C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; Or the following compound ALIPD347 ;or -(c)where Y 3 Let N be an integer, and R be a variable. 3 It does not exist; and -R 1 The phenyl group is optionally substituted with one or two substituents selected from the group consisting of: halogens, C1-C6 alkoxy groups, and C1-C6 alkyl groups. -R 2 Indicates C1-C6 alkyl; -R 4 R 5 R 6 and R 7 They are the same, and represent H.

[0081] In one embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein (a) Y 3 Let C represent the sum of C and R. 3 H represents H; and where: -R 1 express ; -R 2 It represents CH3; and - Can be the same or different R 4 R 5 R 6 and R 7 It represents H, Cl, CN, OCH3, CH2NH2, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3; Preferably, wherein: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 Represents Cl, CN, OCH3, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3; preferably R 5 Represents Cl or CH2NH(CH2)2C(O)OH; more preferably R 5 Represents Cl; or (ii)-R 5 R 6 and R 7 They are the same, and represent H; and -R 4 It represents Cl.

[0082] In one embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein (b) Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and wherein: -R 1 It represents C(O)OCH2CH3 or More preferably R 1 express ; -R 2 Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; preferably R 2 Represents CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; more preferably R 2 It represents CH3 or CH2C(O)OCH2CH3; or even more preferably R 2 It represents CH3; and - Can be the same or different R 4 R 5 R 6 and R 7Represents 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, or ; Preferably, wherein: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 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, Preferably R 5 This represents Cl, C(O)OH, CH2-NH-C(O)-CH2-C(O)OH, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, ;or (ii)-R 4 R 5 and R 6 They are the same, and represent H; and -R 7 Represents Cl; or (iii)-R 4 R 5 and R 7 They are the same, and represent H; and -R 6 Represents Cl; More preferably, of which: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 express Or Cl; preferably R 5 It represents Cl.

[0083] In one embodiment of the invention, the compound of general formula (I) as defined herein is the following compound, wherein (c) Y 3Let N be an integer, and R be a variable. 3 It does not exist; and among them: -R 1 This indicates a phenyl group optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; preferably R 1 express More preferably R 1 express ; -R 2 It represents CH3; and -R 4 R 5 R 6 and R 7 H represents H.

[0084] In one embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of: ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321, ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD32 ... IPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD 372, ALIPD373, ALIPD376, ALIPD381, ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396.

[0085] In one embodiment of the invention, the compound of general formula (I) as defined herein is selected from the group consisting of: ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381, ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, and even more preferably ALIPD304, ALIPD395 and ALIPD396.

[0086] 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, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

[0087] In one embodiment of the invention, a compound of the following general formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising at least one compound of the following general formula (I) and at least one pharmaceutically acceptable excipient is used in a method of preventing and / or treating a disease in a subject, particularly a human: (I) -where (a)Y 3 Let C represent the sum of C and R. 3 H represents H; and where: -R 1 aryl group substituted by one or two substituents selected from the group consisting of: halogens, C1-C6 alkoxy groups and C1-C6 alkyl groups; -R 2 Indicates C1-C6 alkyl; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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- C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; or -where (b)Y 3 Let C represent the sum of C and R.3 The halogen is represented, preferably Cl; or (c)Y. 3 Let N be an integer, and R be a variable. 3 It does not exist; and among them: -R 1 The aryl group represents a C1-C6 alkyl group, a C(O)OC1-C6 alkyl group, or an aryl group optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl. -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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- C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; Preferably R 1 R 2 R 3 R 4 R 5 R 6 and R 7As defined in all the examples mentioned above as described throughout this description; or the compound is selected from the group consisting of: 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, ALI PD381, ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396; preferably 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, and even more preferably ALIPD304, ALIPD395 and ALIPD396.

[0088] In one embodiment of the invention, a compound of general formula (I) as defined herein or a composition according to the invention is used as a subject, particularly a human, PD-1 / PD-L1 interaction inhibitor.

[0089] In one embodiment of the invention, the disease is a PD-1-PD-L1 interaction-related disease in the subject, particularly in humans, such as cancer, chronic inflammatory diseases, neurological diseases, and chronic infections.

[0090] In one embodiment of the invention, the cancer is selected from the group consisting of: lung cancer (non-small cell and small cell), head and neck cancer, bladder cancer, kidney cancer, triple-negative breast cancer, pancreatic cancer, melanoma, gastric cancer, colon cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioblastoma, multiple myeloma, acute myeloid leukemia, cholangiocarcinoma (gallbladder cancer), Merkel's cancer, squamous cell carcinoma, and endometrial cancer; - The neurological disease mentioned is Alzheimer's disease; - The chronic inflammatory disease mentioned is psoriasis; and / or - The chronic infection is selected from the group consisting of: human immunodeficiency virus (HIV), malaria, tuberculosis and hepatitis B.

[0091] All specific and preferred embodiments relating to the definition of compounds of general formula (I) as defined herein are applicable to the method.

[0092] Unless otherwise stated, all the embodiments mentioned above can be combined together. Therefore, features described in the context of individual embodiments can be combined in a single embodiment.

[0093] Other features and advantages of the invention will be apparent from the following examples and will also be shown in the accompanying drawings. Attached Figure Description

[0094] Figure 1 Chemical structure of compounds of general formula (I).

[0095] Figure 2 A schematic representation of the FRET principle. Without the FRET phenomenon, the excited fluorescent dye would emit its own fluorescence (left). Due to the presence of a second fluorescent dye near the first fluorescent dye, energy transfer can occur, causing excitation of the first fluorescent dye (donor, called CFP) and emission of the second fluorescent dye (acceptor, called YFP) (right).

[0096] Figure 3. Compound ALIPD304 ( Figure 3A ), ALIPD307 ( Figure 3B ), ALIPD395 ( Figure 3C ), ALIPD381 ( Figure 3D ), ALIPD396 ( Figure 3E ) and ALIPD382 ( Figure 3F MST determination of ). Detailed Implementation

[0097] Experimental Section Materials and Methods Immune checkpoint blockade.Immunoblockade was monitored using the PromegaBlockade Bioassay according to the manufacturer's instructions. Sixteen hours prior to the experiment, APC cells were seeded into 96 wells at a rate of 10,000 cells / well. A two-fold dilution of the small molecule was prepared in 0.1% DMSO. Atezolizumab was used as a positive control. The following day, Jurkat cells were seeded into the same assay plate at a density of 20,000 cells / well. After incubation for 6 hours, the assay plate was equilibrated at room temperature for 15 minutes, followed by incubation with Bio-Gio reagent for 30 minutes. Luminescence was detected using a Spectramax i3 (Molecular Devices). The half-maximum effective concentration (EC50 value) was fitted to 4PL using Graphpad.

[0098] Micro-thermophoresis (MST). MST was performed using an NT.115 Pico MST instrument (Nano Temper Technologies GmbH) equipped with red and blue filter kits. His-PD-L1 protein (Biotechne No. 9049-B7-100) was diluted to 200 nM in PBS-T buffer (supplied by the vendor) and labeled with the Monolith His-Tag Labeling Kit RED-tris-NTA (Nano Temper Technologies GmbH). The RED-tris-NTA dye was diluted to 100 nM in PBS-T. The mixture was incubated in the dark at room temperature for 30 min. The ligand (50 pM) was diluted sequentially at 1:1 ratios in 16 gradients. The labeled protein and ligand were then mixed at a 1:1 ratio and incubated in the dark at room temperature for 15 min. Capillaries were then individually filled and loaded into the instrument. Data were acquired using medium MST power and 20% LED. Data were analyzed using MO control software (Nano Temper Technologies GmbH). MST plot (see [link]). Figure 3A , 3B (3C, 3D, 3E, and 3F) were rendered using MO affinity analysis (Nano Temperature Technology Co., Ltd.).

[0099] FRET determination. Fluorescent molecule-to-fluorescent energy transfer (FRET) is a technique that allows visualization of the interaction between two fluorescent molecules (see [link to technical documentation]). Figure 2A model for the overexpression of the proteins of interest was developed using CHO-K1 cells. It involved the expression of the PD-1-YFP fluorescent protein and the second fluorescent protein SHP-2-CFP (a phosphatase recruited during the interaction between PD-1 and PD-L1). During excitation at a given length (λCFP 445–485 nm, λYFP 485–535 nm), energy transfer occurs when the two proteins are sufficiently close, resulting in the FRET phenomenon. Using a blocking compound, the interaction was inhibited. Therefore, the recruitment of the phosphatase was no longer interfered with. Consequently, the FRET phenomenon was no longer observed.

[0100] Spectramax i3 (Molecular Devices, Inc.) was configured according to the selected fluorescent dye and its excitation and emission spectra. Endpoint readings were taken at the center of the wells; for 96-well plates, the reading time was 2 minutes. A 96-well flat-bottomed white plate was required for this assay. All mixtures introduced into the plate were in triplicate. A negative control was provided by CHO transfected with a gap plasmid, and a positive control was provided by CHO transfected with a plasmid containing the YFP-CFP fusion protein, which allowed for the simulation of the FRET phenomenon. To examine whether the two fluorescent dyes emitted independently in the FRET channel, the PD1-YFP construct and the SHP2-CFP construct were examined separately. Background noise removal was also required, i.e., FRET was not activated by PD-L1. Dose-response curves were performed after adding PD-L1 (10 μM) to the inventors' co-transfected PD1-SHP2 cells to determine the IC50 of the molecule under investigation. 50 Obtain IC using Graphpad 50 The values ​​are shown above, and the results are listed. Nivolumab served as a positive control for the inhibition of the interaction.

[0101] T cell assay.As described above, human CD4+ T lymphocytes were expanded and activated. T cell responses were measured by ELISA in a co-culture system. CHO PD-L1 promega cells (J 1250) were seeded at a density of 10,000 cells / well in 96-well plates and allowed to adhere for 24 hours. Then, pre-activated CD4+ T lymphocytes (2 × 10⁴ cells) were added to selected wells in 200 μL of complete RPMI 1640 medium, with or without additives (atezolizumab or PD290), and subsequently co-cultured at 37°C in a 5% CO₂ incubator for 48 hours. Pre-stimulated T cells alone (2 × 10⁴ cells) were also cultured in the medium at 37°C in a 5% CO₂ incubator for 48 hours, with or without additives. Culture supernatant was collected and the levels of IFN-γ and TNF-α were detected using the human IFN-γ ELISA kit (catalog number 88-7316-22, Invitrogen) and the human TNF-α ELISA kit (catalog number 88-7346-88, Invitrogen), respectively ( / means no expression, + to ++++ means low to high expression).

[0102] Example Example 1. Synthesis of intermediate products and pyrazole derivatives according to the present invention. ● Option 1. ALIPD277, ALIPD308, ALIPD362, ALIPD375, ALIPD325, ALIPD290 General synthetic routes for ALIPD314, ALIPD304, ALIPD321, ALIPD370, ALIPD381, ALIPD328 and ALIPD307

[0103] Used to prepare 1,3-(aryl)-5-amino-arylpyrazoles ALIPD277, ALIPD308, and ALIPD362. General procedures for ALIPD375 and ALIPD325

[0104] R: 2,4-DiCl-phenyl (ALIPD277) 2-Cl-4-CN-phenyl (ALIPD308) 2-Cl-phenyl (ALIPD362) 4-Cl-phenyl (ALIPD375) 4-CN-phenyl (ALIPD325) Add p-toluenesulfonic acid (0.5 equivalents) and hydrazine (1.1 equivalents) to a solution of β-ketonitriles (1 equivalent, 1 mmol) in ethanol (20 mL). Stir the reaction mixture and heat to reflux for 4 hours. After cooling, evaporate the solvent under reduced pressure. Dissolve the residue in water and adjust the pH to 10 using an aqueous solution of NaHCO3. Filter the solid, wash with water, and crystallize.

[0105] ● 3-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H Synthesis of pyrazole-5-amine (ALIPD277)

[0106] The product was recrystallized from heptane. It was a beige powder. Yield: 88%. mp: 104 ± 1℃. Rf (cyclohexane / ethyl acetate 1-1): 0.7. LC-MS (ES) + ): m / z = 338, t r = 2.28 minutes. 1 H NMR(DMSO) δ (ppm):5,41 (s, 2H,NH2); 5,82 (s, 1H); 7,41 (d, 2H, J = 8,6 Hz); 7,56 (s, 1H); 7,57 (d, 1H, J = 2.0 Hz); 7,72 (dd, 1H, J = 8.6 Hz); 7.85 (dd, 1H, J = 1.9 Hz J = 0.5 Hz). IR v (cm) -1 ): 3407,4 and 3340,7 (NH); 3092,6 and 2920,1 (CH); 1612,9 (C=N); 1548,6 (C=C); 827,7 and 764,5 (C-Cl).

[0107] ● 4-[5-amino-3-(4-chlorophenyl)-l H Synthesis of 4-[5-amino-3-(4-chlorophenyl)-l

[0108] The product was recrystallized from isopropanol. It was a beige powder. Yield: 89%. mp: 157 ± 1℃. Rf (cyclohexane / ethyl acetate 2-3): 0.6. LC-MS (ES) + ): m / z = 329, t r = 2.95 minutes. 1 H NMR (DMSO) δ (ppm):5,55 (s,2H, NH2); 5,87 (s, 1H); 7,44 (d, 2H, J = 8.5 Hz); 7.75 (d, 3H, J = 8.5 Hz); 8.00 (dd, 1H, J = 8.2 Hz J = 1,7 Hz); 8,33 (d, 1H, 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-Cl).

[0109] ● 1-(2-chlorophenyl)-3-(4-chlorophenyl)-1 H Synthesis of pyrazole-5-amine (ALIPD362)

[0110] The product was recrystallized from heptane. It was a beige powder. Yield: 83%. mp: 110 ± 1℃. Rf (cyclohexane / ethyl acetate, 1-1): 0, 6. LC-MS (ES) + ): m / z = 304.1, t r = 2.13 minutes. 1 H NMR (DMSO) δ (ppm):5,31 (s,2H, NH2); 5,85 (s, 1H); 7,43 (d, 2H, J = 8,6 Hz); 7,52 (m, 3H); 7,68 (m, 1H); 7,74 (d, 1H, J = 8,6 Hz). IR v(cm -1 ): 3387,1 and 3310,8 (NH); 3094,1 (CH); 1559,7 (C=N); 1504,5 (C=C); 836,2 and 755,0 (C-Cl).

[0111] ● 1,3-bis(4-chlorophenyl)-1 H Synthesis of pyrazole-5-amine (ALIPD375)

[0112] The product was recrystallized from heptane. It was a brown powder. Yield: 80%. mp: 139 ± 1℃. Rf (cyclohexane / ethyl acetate, 1-1): 0, 7. LC-MS (ES) + ): m / z = 304.1, t r = 2.33 minutes. 1 H NMR (DMSO) δ (ppm):5,57 (s,2H, NH2); 5,94 (s, 1H); 7,44 (d, 2H, J = 8.5 Hz); 7.56 (d, 2H, J = 8,9 Hz); 7,71 (d, 1H, J = 8,9 Hz); 7,78 (d, 1H, J = 8.5 Hz). IR v (cm) -1): 3410,9 and 3287,8 (NH); 3171,6 (CH aromatics); 1556,8 (C=N); 1497,0 (C=C); 834,6 (C-Cl).

[0113] ● 4-[5-amino-3-(4-chlorophenyl)-l H Synthesis of 4-[5-amino-3-(4-chlorophenyl)-l

[0114] The product was recrystallized from acetonitrile. It was a beige powder. Yield: 62%. mp: 201 ± 1℃. Rf (cyclohexane / ethyl acetate, 6-4): 0.6. LC-MS (ES) + ): m / z = 295.2, t r = 3.45 minutes. 1 H NMR (DMSO) δ (ppm):5,78 (s,2H, NH2); 6.01 (s, 1H); 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 (C≡N); 1602,4 (C=N); 1503,8 (C=C); 762,0 (C-Cl).

[0115] ● 5-amino-1-(2,4-dichlorophenyl)-1 H Synthesis of ethyl pyrazole-3-carboxylate (ALIPD353)

[0116] 2,4-Dichlorophenylhydrazine hydrochloride (2.79 mmol) was added to a suspension of 1-cyano-3-ethoxy-3-oxoprop-1-en-2-ol potassium (2.79 mmol) in EtOH (10 mL) containing APTS (2.79 mmol). The reaction mixture was refluxed for 2 hours. After cooling, water was added, and the solution was neutralized with K₂CO₃ and extracted with AE. The organic phase was washed with a solution of brine, dried over MgSO₄, filtered, and concentrated under reduced pressure.

[0117] The product was recrystallized from ethanol. Solid, brown. Yield: 26%. mp: 88℃ ± 1℃. Rf (cyclohexane / ethyl acetate 6-4): 0.42. LC-MS (ES) + ): m / z = 300, t r = 1.85 minutes. RMN 1 H (DMSO) δ (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, 1H) ; 7,19 (s, 2H) ; 7,20 (d, 1H, J = 2.1 Hz); 7,30 (d, 1H, J = 2.1 Hz). IR v (cm) -1 ): 1708 (C=O); 1577 (C=N); 1492 (C=C); 866 and 807 (C-Cl).

[0118] ● 3-(methyl)-1-(2,4-dichlorophenyl)-1 H Synthesis of pyrazole-5-amine (ALIPD346)

[0119] A mixture of 2,4-dichlorophenylhydrazine hydrochloride (6 mmol) and 3-aminocrotonitrile (6 mmol) was heated in HCl (1 N, 15 mL) for 10 min at 150 °C (150 W) in a microwave oven. The reaction medium was cooled to room temperature, and the mixture was washed with ethyl acetate in a separatory funnel. The aqueous phase was neutralized with K₂CO₃. 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 minutes. RMN 1 H (DMSO) δ (ppm):2.04 (s;3H), 5,13 (s, 2H, NH2); 5,20 (s, 1H); 7,44(d, 2H, J = 8.5 Hz); 7,52 (dd, 1H, J = 8.5 Hz, J = 2.3 Hz); 7,80 (d, 1H, J = 2.3 Hz). IRv (cm) -1 ): 3420 and 3301 (NH); 3196 and 2170 (CH aromatics); 1622 (C=N); 1558 (C=C); 838 and 746 (C-Cl).

[0120] Used for preparation N -[3-(4-chlorophenyl)-1-aryl-1 H pyrazol-5-yl]acetamides General procedures for ALIPD304, ALIPD321, ALIPD370, ALIPD381, and ALIPD328

[0121] A suspension of 1,3-(aryl)-5-amino-arylpyrazole (1 equivalent) and Ac₂O (2 equivalents) in AcOH (8 equivalents) was stirred at room temperature for 18 hours. NaHCO₃ solution was added to the reaction medium. The solid was filtered, washed with water, and recrystallized.

[0122] ● N - [3-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-l H - pyrazol-5-yl] acetamide (ALIPD304) become

[0123] The product was recrystallized from isopropanol. White powder. Yield: 79%. mp: 186 ± 1℃. Rf (cyclohexane / ethyl acetate, 6-4): 0.35. LC-MS (ES) + ): m / z = 380.0, t r = 2.26 minutes. 1 H NMR (DMSO) δ (ppm):1,99(s, 3H); 6,99 (s, 1H); 7,47 (d, 2H, J = 8,5 Hz); 7,62 (m, 2H); 7,84 (d, 2H, J = 8.5 Hz); 7.92 (d, 1H, J = 1,5 Hz); 10,00 (s, 1H, NH). IR v(cm -1 ): 3158.5 (NH); 3005,9 (CH aromatics); 2932,7 (CH); 1709,5 (C=O); 1542,1 (C=N); 1482,8 (C=C); 1247,3 (CN); 834,6 and 788,7 (C-Cl).

[0124] ● N - [1 -(2-chloro-4-chlorophenyl)-3-(4-chlorophenyl)-1 H - pyrazol-5-yl]acetamide (ALIPD321) become

[0125] The product was recrystallized from acetonitrile. White powder. Yield: 76%. mp: 264 ± 1℃. Rf (cyclohexane / ethyl acetate, 1-1): 0.7. LC-MS (ES) + ): m / z = 371.2, t r = 2.11 minutes. 1 H NMR (DMSO) δ (ppm):1,98 (s,3H); 7,01 (s, 1H); 7,48 (d, 2H, J = 8.5 Hz); 7.80 (d, 1H, J =8,2 Hz); 7,85 (d,2H, J = 8.5 Hz); 8,05 (dd, 1H, J = 8,2 Hz, J = 1,7 Hz); 8,38 (d, 1H, J = 1,7Hz); 10,09 (s, 1H, NH). IR v(cm -1 ): 3314,1 (NH); 3065,8 (CH aromatics); 2244,1 (C≡N); 1700,5 (C=O); 1543,9 (C=N); 1494,0 (C=C); 1243,0 (CN); 837,0 and 776,0 (C-Cl).

[0126] ● N - [1 -(2-chlorophenyl)-3-(4-chlorophenyl)-1 H - pyrazol-5-yl]acetamide (ALIPD370)

[0127] The product was recrystallized from isopropanol. White powder. Yield: 41%. mp: 150 ± 1℃. Rf (cyclohexane / ethyl acetate, 1-1): 0, 3. LC-MS (ES) + ): m / z = 346.1, t r = 2.14 minutes. 1 H NMR (DMSO) δ (ppm):1,97(s, 3H); 6,97 (s, 1H); 7,48 (d, 2H, J = 8,5 Hz); 7,53- 7,62 (m, 3H); 7,70 (d,1H, J = 7.3 Hz); 7.84 (d, 2H, J = 8,5 Hz); 9,97 (s, 1H, NH). IR v(cm -1 ): 3139,2 (NH); 2941,2 (CH); 1691,6 (C=O); 1555,7 (C=N); 1490,4 (C=C); 1264,0 (CN); 760,0 and 730,5 (C-Cl).

[0128] ● N - [1,3-bis(4-chlorophenyl)-1 H Synthesis of 1 -(4-chlorophenyl)-3-(4-iodophenyl)-urea (ALIPD381)

[0129] The product was recrystallized from acetonitrile. It was a beige powder. Yield: 57%. mp: 220 ± 1℃. Rf (cyclohexane / ethyl acetate, 1-1): 0, 4. LC-MS (ES) + ): m / z = 346.1, t r = 2.27 minutes. 1H NMR (DMSO) δ (ppm):2,02 (s,3H); 6,93 (s, 1H); 7,50 (d, 2H, J = 8,5 Hz); 7,61 (s, 4H); 7,88 (d, 2H, J = 8,5Hz); 10.08 (s, 1H, NH). IR v(cm -1 ): 3242,7 and 3197,3 (NH); 3050,6 (CH aromatics); 1669,7 (C=O); 1534,6 (C=N); 1495,8 (C=C); 1272,0 (CN); 838,9 and 775,4 (C-Cl).

[0130] ● N - [3-(4-chlorophenyl)-l-(4-cyanophenyl)-l H - Synthesis of pyrazol-5-yl]acetamide (ALIPD328)

[0131] The product was recrystallized from ethanol. White solid. Yield: 68%. mp: 258 ± 1℃. Rf (cyclohexane / ethyl acetate 1-1): 0, 3. LC-MS (ES) + ): m / z = 337.1, t r = 2.03 minutes. 1 H NMR (DMSO) δ (ppm):2,05 (s,3H); 6,99 (s, 1H); 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, 1H, NH). IR v(cm -1 ): 3196,8 (NH); 2224,1 (C=N); 1678,3 (C=O); 1505,7 (C=C); 1275,7 (CN); 792,4 (C-Cl).

[0132] ●5-Acetamido-1-(2,4-Dichlorophenyl)-1 H ethyl pyrazole-3-carboxylate Synthesis of (ALIPD357)

[0133] 5-amino-1-(2,4-dichlorophenyl)-1 HA suspension of ethyl pyrazole-3-carboxylate (ALIPD353) (1 equivalent) and Ac2O (2 equivalents) in AcOH (8 equivalents) was stirred at room temperature for 18 hours. NaHCO3 solution was added to the reaction medium. The solid was filtered and washed with water.

[0134] The product was purified by rapid chromatography (cyclohexane-AE; 1-1). Solid, white. Yield: 55%. mp: 195 ± 1℃. Rf (cyclohexane / ethyl acetate 1-1): 0.14. LC-MS (ES) + ): m / z = 342.0, t r = 1.87 minutes. RMN 1 H(CDCl3) δ(ppm): 1,42 (t, 3H, J = 7,1 Hz); 2,11 (s, 3H); 4,45 (q, 2H, J = 7,1Hz); 6,70 (s, 1H); 7,13 (s, 1H, NH); 7,42-7,50 (m, 2H); 7,60 (d, 1H, J = 2, 1Hz). IR v (cm) -1 ): 3304 (NH); 2982 (CH); 1707 (C=O); 1541 (C=N); 1455 (C=C); 1230 (CN); 870 and 778 (C-Cl).

[0135] ● N-[1-(2,4-dichlorophenyl)-3-methyl-1 H Synthesis of N-[(1 -carbamimidoyl-1 H-indol-3-yl)thio]-4-methylbenzamide (ALIPD348)

[0136] 3-(methyl)-1-(2,4-dichlorophenyl)-1 H A suspension of pyrazole-5-amine (ALIPD346) (1 equivalent) and Ac2O (2 equivalents) in AcOH (8 equivalents) was stirred at room temperature for 18 hours. NaHCO3 solution was added to the reaction medium. The solid was filtered, washed with water, and recrystallized from cyclohexane. Solid, white. Yield: 90%. mp: 161 ± 1℃. Rf (cyclohexane / ethyl acetate 1-1): 0.30. LC-MS (ES) + ): m / z = 284, t r = 1.64 minutes. RMN 1 H (DMSO) δ(ppm):1,93 (s, 3H); 2,17 (s, 3H); 6,30 (s, 1H); 7,47 (d, 2H, J =8,5 Hz); 7,58 (dd, 1H, J = 8.5 Hz, J = 2.3 Hz ) 7.92 (d, 1H, J = 1,5 Hz); 9,81 (s, 1H,NH). .IR v (cm -1 ): 3178 (NH); 2969 and 2923 (CH); 1706 (C=O); 1550 (C=N); 1491 (C=C); 1254 (CN); 831 and 783 (C-Cl).

[0137] Preparation of N-(1H-pyrazol-5-yl)formamide derivatives ALIPD290 and ALIPD314: ● N-[3-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H The synthesis of N-[3-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 become

[0138] A solution of ALIPD277 (0.47 g, 1.3 mmol) in formic acid (6 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature, and an aqueous solution of NaHCO3 was added. The resulting solid was filtered off and purified by rapid chromatography (cyclohexane-AE, 6-4). The product was recrystallized from heptane-EtOH (7-3). White solid. Yield: 42%. mp: 173 ± 1 °C. Rf (cyclohexane / ethyl acetate, 6-4): 0.5. LC-MS (ES) + ): m / z = 366.0, t r = 3,20 minutes. 1 H NMR (DMSO)δ (ppm):7,07 (s, 1H); 7,48 (d, 2H, J = 8,5 Hz); 7,67 (m, 2H); 7,85 (d, 2H, J = 8.5 Hz); 7.96 (d, 1H, J = 1,4 Hz); 8,17 (s, 1H); 10,45 (s, 1H, NH). IR v(cm -1 ): 3199,1 (NH); 3087,1 and 3053,9 (CH aromatics); 1661,3 (C=O); 1707,5 (C=O); 1555,5 (C=N); 1489,8 (C=C); 809,6 and 775,7 (C-Cl).

[0139] ● N-[1-(2-chloro-4-cyanophenyl)-3-(4-chlorophenyl)-1 H - pyrazol-5-yl]formamide (ALIPD314) synthesis

[0140] Ac₂O (2 equivalents) and HCO₂H (2.1 equivalents) were stirred at 50 °C for 15 min and immediately cooled to 0 °C. ALIPD 308 dissolved in THF (1 equivalent) was added to the solution. The mixture was heated at 68 °C for 3 h. The reaction mixture 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 10% NaHCO₃ and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The product was recrystallized from 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 minutes. 1 H NMR(DMSO) δ (ppm):7,10 (s, 1H); 7,50 (d, 2H, J = 8,4 Hz); 7,86 (m, 3H); 8,08 (dd,1H, J = 8.2 Hz, J = 1,6 Hz); 8,18 (s, 1H); 8,39 (s, 1H); 10,54 (s, 1H, NH). IRv(cm -1 ): 3299,3 (NH); 2244,4 (C≡N); 1707,5 (C=O); 1551,3 (C=N); 1494,2 (C=C); 833,2 and 772,1 (C-Cl).

[0141] ● 3-{[3-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H ethyl 3-{[3-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 Synthesis of (ALIPD307)

[0142] In a nitrogen-filled flask, ALIPD 277 was dissolved in DCM. TEA and ethylmalonyl chloride were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction medium was washed with water in a separatory funnel. The organic phase was dried over CaCl2, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (cyclohexane-AE, 8-2). The product was recrystallized from ethanol. White powder. Yield: 42%. mp: 131 ± 1℃. Rf (cyclohexane / ethyl acetate, 8-2): 0.2. LC-MS (ES) + ): m / z = 452.0, t r = 3.35 minutes. 1 H NMR (DMSO) δ (ppm):1,17 (t, 3H, J = 7,1 Hz); 3.43 (s,2H); 4.08 (q, 2H, J =7,1 Hz); 7,03 (s, 1H); 7,48 (d, 2H, J = 8.6 Hz); 7,63(m, 2H); 7,85 (d, 2H, J = 8.6 Hz); 7,94 (s, 1H); 10,24 (s, 1H, 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 (CO); 825,6 and 805,8 (C-Cl).

[0143] ● Scheme 2. Synthesis of 3-chloro-4-hydrazinonitrile (ALIPD129)

[0144] A mixture of 2-chloro-4-fluorobenzonitrile (2.0 g, 12.9 mmol), hydrazine monohydrate (2 equivalents), and NMP (10 mL) was stirred at 65 °C for 4 hours. The reaction mixture was cooled to room temperature and water was added. The mixture was alkalized with K₂CO₃, and the resulting precipitate 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 minutes. 1 H NMR (DMSO) δ(ppm):4,41 (s, 2H);7,22 (d, 1H, J = 8,7 Hz); 7.55 (dd, 1H, J = 8,7 Hz, J' = 1,8Hz); 7,62 (s, 1H); 7,67 (d, 1H, 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).

[0145] ● Scheme 3. Synthesis of ALIPD318, ALIPD319 and ALIPD322

[0146] ● 1 -[4-(aminomethyl)-2-chlorophenyl]-3-(4-chlorophenyl)-1 H Synthesis of pyrazole-5-amine (ALIPD318)

[0147] Under nitrogen atmosphere and in an ice bath, ALIPD 308 (1 equivalent) was added to a solution of nickel chloride hexahydrate (0.4 equivalents) in 10 mL of anhydrous methanol. Sodium borohydride (6 equivalents) was added. The reaction medium was stirred at room temperature for 2 hours. The reaction mixture was quenched at 0 °C by adding NH4Cl solution. The mixture was concentrated to remove most of the methanol, and the residue was placed in a separatory funnel separate from the solution of ethyl acetate and hydrochloric acid (10%). K2CO3 was added to the aqueous phase and the amine was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow powder. The product was recrystallized from 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 minutes. 1 H NMR (DMSO) δ (ppm):3,82 (s, 2H, CH2); 5,24 (s, 2H, NH2); 5,84 (s,1H); 7,39-7,46 (m, 4H); 7,66 (d, 1H, 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-Cl); 744,0 (C-Cl).

[0148] ● 3-((1-(2-chloro-4-((3-ethoxy-3-oxopropionamido)methyl)phenyl)-3-(4- chlorophenyl)-1 -hydroxy-1 -methyl-3-oxobutan-2-yl)amino)propanoic acid H - Synthesis of ethyl pyrazol-5-yl)amino)-3-oxopropionate (ALIPD319)

[0149] ALIPD318 (1 equivalent) was dissolved in DCM. TEA (2.2 equivalents) and ethylmalonyl chloride (2.5 equivalents) were added at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction medium was washed with water in a separatory funnel. The organic phase was dried over CaCl2, filtered, and concentrated under reduced pressure. The product was purified by rapid 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 minutes. 1H NMR (DMSO) δ(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, 1H, H) 烯醇 ) ;7,43 (dd, 1H, J = 1.7 Hz J' = 8.2 Hz); 7.47 (d, 2H, J = 8.6 Hz); 7.54 Hz (d, 1H, J = 8,1 Hz); 7.59 (d, 1H, J = 1.5 Hz), 7.85 (d, 2H, J = 8,6 Hz), 8,79(t, 1H, J = 6.0 Hz, NH); 10,25 (s, 1H, 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 (CN); 1153,9 (CO); 834,8 and 785,4 (C-Cl).

[0150] ● 3-((4-(5-(2-carboxyacetamido)-3-(4-chlorophenyl)-1 H - pyrazol-1-yl)-3-chlorobenzyl)amino Synthesis of 3-oxopropionic acid (ALIPD322)

[0151] At 0 °C, a solution of NaOH (10 N, 2 equivalents) was added to a solution of ALIPD319 (1 equivalent) in ethanol (10 equivalents). The mixture was stirred at room temperature for 24 hours. The ethanol was evaporated under vacuum, and water was added to the residue. The resulting aqueous phase was washed with AE. After acidifying the aqueous phase with a solution of HCl 1 N (pH = 3), the obtained precipitate was filtered, washed with water, and dried to give a white powder. The product was purified by rapid 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 minutes. 1H NMR(DMSO) δ(ppm): 3,27 (s, 2H, CH2); 3,35 (s, 2H, CH2); 4,42 (d, 2H, J = 5,6Hz, CH2), 7,02 (s, 1H); 7,42 (d, 1H, J m = 8.1 Hz) ;7.48 (d, 2H, J = 8,5 Hz) ;7,54 (d, 1H, J = 8,1 Hz); 7,62 (s, 1H), 7.85 (d, 2H, J = 8.5 Hz), 8.73 (t, 1H, J = 6.0 Hz, NH); 10,22 (s, 1H); 12,63 (s, 1H). 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 (CN); 826,0 and 783,0 (C-Cl).

[0152] ● Option 4. ALIPD324, ALIPD350, ALIPD384, ALIPD382, ALIPD323, ALIPD342 and Synthesis of ALIPD356

[0153] ● 4-[5-acetamido-3-(4-chlorophenyl)-l H Synthesis of 4-[5-acetamido-3-(4-chlorophenyl)-l become

[0154] A stirred solution of ALIPD 321 (1 equivalent), 6 N NaOH (0.25 equivalent), and 28% H2O2 (3.4 equivalent) in 95% EtOH was heated at 55 °C for 3 h and then at room temperature for 18 h. Water was added to the reaction mixture and acidified with HCl (1 N). The resulting precipitate was filtered, washed with water, and dried to give a white solid. The product was recrystallized from 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 minutes. 1 H NMR (DMSO) δ (ppm):1,98 (s, 3H); 7,00 (s, 1H); 7,48(d, 2H, J =8.5 Hz); 7.67 (d, 1H, J = 8,2 Hz); 7,70 (s, 1H); 7,85 (d, 2H, J = 8.5 Hz); 8,01 (dd, 1H, J = 8.2 Hz J = 1,8 Hz); 8,15 (d, 2H, J = 1,8 Hz); 8,26 (s, 1H) 10,03 (s, 1H). IR v(cm -1 ): 3341,3 and 3195,2 (NH); 3063,9 (CH aromatics); 1699,9 and 1677,9 (C=O); 1548,2 (C=N); 1503,6 (C=C); 1253,6 (CN); 833,1 and 782,5 (C-Cl).

[0155] ● 4-[5-acetamido-3-(4-chlorophenyl)-l H Synthesis of 4-[5-acetamido-3-(4-chlorophenyl)-l

[0156] NaNO₂ (11 equivalents) was added to a solution of ALIPD 324 (1 equivalent) in TFA (170 equivalents) and DCM (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water was added. The resulting precipitate was filtered, washed with water, and dried. The product was recrystallized from 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 minutes. 1 H NMR (DMSO) δ (ppm):1,98 (s, 3H); 7,00 (s, 1H); 7,47 (d, 2H, J = 8,6 Hz); 7,71 (d, 1H, J = 8.2 Hz); 7.85 (d, 2H, J = 8.6 Hz); 8.05 (dd, 1H, J = 8.2 Hz J = 1,8 Hz); 8,13 (d, 1H, J = 1,8 Hz); 10.04(s, 1H) 13.54(s, 1H). IR v(cm -1): 3288,7 (OH); 2786,6 (CH aliphatic); 1720,3 (C=O, acid); 1688,2 (C=O, amide); 1532,4 (C=C); 1265,7 (CO); 799,9 and 764,9 (C-Cl).

[0157] General procedure for preparing compounds ALIPD382 and ALIPD384 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 1.3 equivalents), 4-(dimethylamine)pyridine (DMAP, 1.2 equivalents), and TEA (1.3 equivalents) were dissolved in THF and cooled to 0°C. ALIPD 350 (1 equivalent) and the amine (1.2 equivalent) were added sequentially. After slowly warming to ambient temperature, the reaction mixture was stirred under reflux for 2 hours.

[0158] ● 4-(5-acetamido-3-(4-chlorophenyl)-1 H -3- chloro-N-(2-morpholinoethyl)benzamide Synthesis of amide (ALIPD382)

[0159] The solution was diluted with ethyl acetate, and the organic phase was washed with a 10% K₂CO₃ aqueous solution, followed by washing and separation with saturated water containing NaCl. The organic phase was dried over MgSO₄. The solvent was removed under vacuum, and the residue was purified by column chromatography (DCM-MeOH saturated with NH₃ 9:1). The product was recrystallized from cyclohexane. It was a beige powder. Yield: 47%. mp: 192 ± 1℃. Rf (DCM-MeOH NH₃, 9-1): 0.3. LC-MS (ES) + ): m / z = 502,2, t r = 1.78 minutes. 1 H NMR(DMSO) δ (ppm):1,97 (s, 3H); 2,45 (t, 2H); 3.44 (q, 2H); 3,59 (t, 4H); 6,99(s, 1H); 7,48 (d, 2H, J = 8.5 Hz); 7.67 (d, 1H, J = 8.2 Hz); 7.85 (d, 2H, J =8.5 Hz); 7.97 (dd, 1H, J = 8.2 Hz, J = 1,8 Hz); 8,11 (d, 1H, J = 1,8 Hz);8.71 (t,1H) 10.02 (s, 1H). 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 (CO); 836,0 and 763,8 (C-Cl).

[0160] ● N-(1-(4-(4-acetylpiperazin-1-ylcarbonyl)-2-chlorophenyl)-3-(4-chlorophenyl)-1 H - pyrazol-5-yl) acetamide (ALIPD384) Synthesis

[0161] The solution was diluted with ethyl acetate, and the organic phase was washed with HCl (1 N, H2O, saturated with NaCl) and NaHCO3 (5%) solution. The organic phase was dried over MgSO4. The solvent was removed under vacuum. The product was recrystallized from EtOH-H2O, 1-1. White powder. Yield: 86%. mp: 296 ± 1℃. Rf (DCM-MeOH, 9-1): 0, 7. LC-MS (ES) + ): m / z = 500,3, t r =1.89 minutes. 1 H NMR (DMSO) δ (ppm):1,99 (s, 3H); 2.04 (s, 3H); 3.53 (m, 8H); 7,00(s, 1H); 7,48 (d, 2H, J = 8.6 Hz); 7.57 (dd, 1H, J = 8,0 Hz, J = 1.7 Hz); 7.65 (d, 1H, J = 8.0 Hz); 7.77 (d, 1H, J = 1.5 Hz); 7.85 (d, 2H, J = 8,6 Hz); 10.06 (s, 1H). 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 (CN); 833,1 and 785,0 (C-Cl).

[0162] ● N-{1-[4-(aminomethyl)-2-chlorophenyl]-3-(4-chlorophenyl)-1 H - pyrazol-5-yl}acetamide Synthesis of (ALIPD323)

[0163] PtO2 (0.45 equivalents) was added in portions to a stirred mixture of ALIPD308 (1 equivalent) and HCl 12 N (1.5 equivalents) in MeOH at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered and washed with HCl 1 N. The aqueous phase was washed with ethyl acetate in a separatory funnel. The aqueous phase was alkalized with K2CO3. The precipitate was filtered, washed with water, and dried. A beige powder was obtained. Yield: 70%. mp: 193 ± 1℃. Rf (DCM-MeOH, 9-1): 0.1. LC-MS (ES) + ): m / z = 375,1, t r = 1.67 minutes. 1 H NMR (DMSO) δ (ppm):1,96 (s, 3H); 3,82(s, 2H); 5,24 (s, 1H); 6,95 (s, 1H); 7,40- 7,49 (m, 4H); 7,66 (s, 1H); 7,83(d, 2H, J = 8.5 Hz); 9.98 (s, 1H). 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 (CN); 836,5 and 786,0 (C-Cl).

[0164] ● 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 H - pyrazol-1-yl)-3-chlorobenzyl)amino)propanoic acid ethyl ester Synthesis of (ALIPD342)

[0165] ALIPD 323 (1 equivalent) was added to a solution of ethyl acrylate (2 equivalents) in ethanol at room temperature, and the resulting solution was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure, and the residue obtained was purified by rapid chromatography. Yellow powder. Yield: 40%. mp: 87 ± 1℃. Rf (DCM-MeOH, 9-1): 0, 5. LC-MS (ES) + ):m / z = 475,2, t r = 1.84 minutes. 1H NMR (DMSO) δ (ppm):1,18 (t, 3H); 1,96 (s, 3H); 2,00 (s, 1H); 2.50 (t, 2H); 2.77 (t, 2H); 3.80 (s, 2H); 4,05 (q, 2H); 6,95 (s,1H); 7,45- 7,51 (m, 4H); 7,63 (s, 1H); 7,83 (d, 2H, J = 8.5 Hz); 9,94 (s, 1H). 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-Cl).

[0166] ● 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 H - pyrazol-1-yl)-3-chlorobenzyl)amino)propanoic acid Synthesis of (ALIPD356)

[0167] A solution of NaOH (10%, 15 equivalents) was added to a solution of ALIPD342 (1 equivalent) in EtOH at room temperature. After 12 hours, the reaction medium was concentrated to remove EtOH. An aqueous solution of citric acid was added to the mixture, and the resulting white precipitate was filtered, washed with water, and dried. White powder. Yield: 53%. mp: 213 ± 1℃. Rf (DCM-MeOH, 9-1): 0, 4. LC-MS (ES) + ): m / z = 447,2, t r = 1.66 minutes. 1 H NMR (DMSO) δ (ppm):1,97 (s,3H); 2.40 (t, 2H); 3.78 (t, 2H); 3.85 (s, 2H); 6,95 (s, 1H); 7,45- 7,50 (m,4H); 7,66 (s, 1H); 7,83 (d, 2H, J = 7,9 Hz); 9,96 (s, 1H). IRv (cm -1 ): 3237,5 (OH); 2921,4 and 2798,5 (CH aliphatic); 1679,6 (C=O, acid); 1632,0 (C=O, amide); 1534,1 (C=C); 1256,8 (CO); 830,3 and 785,7 (C-Cl).

[0168] ● Scheme 5. Synthesis of ALIPD330, ALIPD340, and ALIPD349

[0169] ● N - {1 -[4-(amino methyl)phenyl]-3-(4-chlorophenyl)-1 H pyrazol-5-yl} acetamide (ALIPD330) Synthesis

[0170] PtO2 (0.45 equivalents) was added in portions to a stirred mixture of ALIPD328 (1 equivalent) in a mixture of MeOH / THF (1:1) and HCl 12 N (1.5 equivalents) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered and washed with HCl 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℃. Rf (DCM-MeOH, 9-1): 0.5. LC-MS (ES) + ): m / z = 341,2, t r = 1.56 minutes. 1 H NMR (DMSO) δ (ppm):2,00 (s, 3H); 3,79 (s, 2H); 6,90 (s, 1H); 7,49 (m, 6H); 7,87 (d, 2H, J = 8.25 Hz); 10,01 (s, 1H). 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 (CN); 815,4 (C-Cl).

[0171] - 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 H - pyrazol-1-yl)benzyl)amino)propionic acid ethyl ester Synthesis of (ALIPD340)

[0172] ALIPD 330 (1 equivalent) was added to a solution of ethyl acrylate (2 equivalents) in ethanol at room temperature, and the mixture was stirred for 18 hours at room temperature. The resulting solution was concentrated under reduced pressure, and the residue was purified by rapid chromatography. Purification was achieved by rapid chromatography elution with DCM-MeOH, 95-5. A yellow oily substance was obtained. Yield: 41%. Rf (DCM-MeOH, 9-1): 0.48. LC-MS (ES) + ): m / z = 441,2, t r = 1.77 minutes. 1H NMR (DMSO) δ (ppm):1,18 (t,3H); 1,99 (s, 3H); 2,00 (s, 1H); 2.50 (t, 2H); 2.77 (t, 2H); 3.77 (s, 2H); 4,05 (q, 2H); 6,90 (s, 1H); 7,41- 7,55 (m, 6H); 7,86 (d, 2H, J = 8.5 Hz); 10,01(s, 1H). 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-Cl).

[0173] - 3-((4-(5-acetamido-3-(4-chlorophenyl)-1 H - pyrazol-1-yl)benzyl)amino)propanoic acid (ALIPD349) Synthesis

[0174] A solution of NaOH (10%, 15 equivalents) was added to a solution of ALIPD 340 (1 equivalent) in EtOH at room temperature. After 12 hours, the mixture was concentrated to remove EtOH. The residue was dissolved in a solution of citric acid. The resulting white precipitate was filtered, washed with water, and dried. Brown powder. Yield: 75%. mp: 189 ± 1℃. Rf (DCM-MeOH, 9-1): 0.5. LC-MS (ES) + ): m / z = 413,2, t r = 1.61 minutes. 1 H NMR (DMSO) δ (ppm):2,01 (s, 3H); 2.68-2,68 (m, 3H); 3.12 (t, 2H); 4,20 (s, 2H); 6,93 (s, 1H); 7,50 (d, 2H, J = 8.5 Hz); 7,66 (m, 4H); 7,89 (d, 2H, J = 8.5 Hz); 10,11 (s, 1H). 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-Cl).

[0175] 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 the compounds by a one-pot reaction. The procedure then involves the continuous condensation of the ester with acetonitrile, followed by the condensation of the resulting β-ketonitrile and hydrazine, and finally the acylation step with acetic anhydride.

[0176] Option 6. ALIPD337, ALIPD338, ALIPD339, ALIPD363, ALIPD372, ALIPD373 Synthesis of ALIPD376, ALIPD390, ALIPD394, ALIPD395 and ALIPD396.

[0177]

[0178] The general procedure for preparing compounds ALIPD337, ALIPD338, ALIPD339, ALIPD363, ALIPD372, ALIPD373, ALIPD376, ALIPD390, ALIPD394, ALIPD395, and ALIPD396 was as follows: Ethyl ester (1 equivalent) was dissolved in a solution of t-BuOK in THF (1 N), followed by the addition of acetonitrile (1.1 equivalent). The mixture was stirred at room temperature for 5 minutes. The medium was cooled to 0 °C. Acetic acid (30 equivalent) and the corresponding hydrazine (1.5 equivalent) were slowly added. The mixture was stirred under microwave irradiation at 100 W and 85 °C for 20 minutes. The medium was then cooled to room temperature and acetic anhydride (5 equivalent) was added. The mixture was stirred under microwave irradiation at 100 W and 120 °C for 20 minutes. The mixture was cooled to room temperature and a saturated solution of NaHCO3 was added. The mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with brine, dried with MgSO4, and concentrated under reduced pressure.

[0179] - N-(3-phenyl-1-(pyridin-2-yl)-1 H Synthesis of N-(3-phenyl-1-(pyridin-2-yl)-1

[0180] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. It was an orange powder, mp: 167 ± 1 °C. Yield: 72%. LC-MS (ES) + : 279 (MH + ), t r = 2.23 minutes. 1 H NMR(CDCl3) δ(ppm):12.17 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J =1.7 Hz, J'' = 0.6 Hz);8.22 (1H, ddd, J = 8.5 Hz, J = 1.1 Hz, 0.6 Hz); 7.96 (2H, m); 7.89 (1H, ddd, J = 8.5 Hz, J = 7.4 Hz, J' = 1.7 Hz); 7.44 (m, 2H); 7.38 (td, 1H, J = 6.1 Hz, J' = 1.4 Hz); 7,30 (1H, s); 7.20 (1H, ddd, J = 7.4 Hz, J = 5.1 Hz, J'' = 1.1 Hz);2.31 (3H, s).

[0181] - N-(3-(4-chlorophenyl)-l-(pyridin-2-yl)-l H Synthesis of N-(3-(4-chlorophenyl)-l-(pyridin-2-yl)-l

[0182] The product was purified by silica gel chromatography with cyclohexane / ethyl acetate (6:4) as the eluent. It was a white powder, mp: 144 ± 1℃. Yield: 60%. LC-MS (ES) + ): 313; t r = 2.44 minutes. 1 H NMR (CDCl3) δ(ppm):12.15 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J' = 1.7 Hz, J'' = 0.6 Hz); 8.19(ddd, 1H, 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, 1H); 7.21 (ddd, 1H, J = 7.4 Hz, J' = 5.1 Hz, J'' = 1.1 Hz); 2.31 (s, 3H).

[0183] - N-(3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1 H Synthesis of N-(3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1 become

[0184] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. It was a yellow powder, mp: 160 ± 1℃. Yield: 59%. LC-MS (ES) + ): 309, t r = 2.15 minutes. 1 H NMR (CDCl3) δ(ppm):12.17 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J = 1.7 Hz, J'' = 0.6 Hz); 8.22(ddd, 1H, J = 8.5 Hz, J = 1.1 Hz, J' = 0.6 Hz); 7.91-7.85 (m, 3H); 7,24 (s,1H); 7.18 (ddd, 1H, J = 7.4 Hz, J = 5.1 Hz, J' = 1.1 Hz); 6.98 (d, 2H, J = 8.9Hz); 3.88 (s, 3H); 2.31 (s, 3H).

[0185] - N-(3-(2-methoxyphenyl)-1-(pyridin-2-yl)-1 H Synthesis of N-(3-(2-methoxyphenyl)-1-(pyridin-2-yl)-1 become

[0186] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. Yellow powder, mp: 142 ± 1℃. Yield: 67%. LC-MS (ES) + ): 309, t r = 2.19 minutes. 1 H NMR (CDCl3) δ(ppm):12.11 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J' = 1.7 Hz, J'' = 0.6 Hz); 8.22(ddd, 1H, J = 8.5 Hz, J' = 1.1 Hz, J'' = 0.6 Hz); 8.04 (dd, 1H, J = 7.7 Hz, J' =1.8 Hz); 7.87 (ddd, 1H, J =8.5 Hz, J' = 7.4 Hz, J'' = 1.7 Hz); 7,45 (s, 1H); 7.36 (ddd, 1H, J = 9.2 Hz, J' = 7.4 Hz, J'' = 1.8 Hz); 7.18 (ddd, 1H, 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).

[0187] - N-(3-(3,4-dimethoxyphenyl)-1-(pyridin-2-yl)-1 H - pyrazol-5-yl)acetamide (ALIPD372) Synthesis

[0188] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. Yellow powder, mp: 155 ± 1℃. Yield: 46% LC-MS (ES). + ): 339, t r = 2.05 minutes. 1 H NMR (CDCl3) δ (ppm):12.19 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J = 1.7 Hz, J'' = 0.6 Hz); 8.22 (ddd,1H, J = 8.5 Hz, J' = 1.1 Hz, J'' = 0.6 Hz); 7.89 (ddd, 1H, J = 8.5 Hz, J' = 7.4Hz, J'' = 1.7 Hz); 7.49 (m, 2H); 7,25 (s, 1H); 7.20 (ddd, 1H, J = 7.4 Hz, J' = 5.1 Hz, J'' = 1.1 Hz); 6.95 (d, 1H, J = 8.0 Hz); 4.01 (s, 3H); 3,95 (s, 3H); 2.31 (s, 3H).

[0189] - N-(3-(3,4-dichlorophenyl)-1-(pyridin-2-yl)-1 H 5-pyrazole-5-yl)acetamide (ALIPD373) become

[0190] The product was purified by silica gel chromatography with cyclohexane / ethyl acetate (6:4) as the eluent. Yellow powder, mp: 190 ± 1℃. Yield: 81%. LC-MS (ES) + ): 293, t r = 2.34 minutes. 1 H NMR (CDCl3) δ(ppm):12.13 (s, 1H); 8.38 (ddd, 1H, J = 5.1 Hz, J' = 1.7 Hz, J'' = 0.6 Hz); 8.19(ddd, 1H, J = 8.5 Hz, J' = 1.1 Hz, J'' = 0.6 Hz); 8.04 (d, 1H, J = 2.0 Hz);7.90 (ddd, 1H, J = 8.5 Hz, J' = 7.4 Hz, J'' = 1.7 Hz); 7.72 (dd, 1H, J = 8.4 Hz,J' = 2.0 Hz); 7.50 (s, 1H, J = 8.4 Hz); 7,30 (m, 2H); 2.31 (s, 3H).

[0191] - N-(1-(pyridin-2-yl)-3-(p-tolyl)-1 H Synthesis of 5-pyrazole-5-yl)acetamide (ALIPD376)

[0192] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. It was an orange powder, mp: 168 ± 1 °C. Yield: 61%. LC-MS (ES) + ): 293, t r = 2.34 minutes. 1 H NMR (DMSO) δ (ppm):11.82 (s, 1H); 8.55 (m, 1H); 8.07 (m, 2H); 7.80 (d, 2H, J = 8.1 Hz); 7.40 (m,1H); 7.27 (d, 2H, J = 8.1 Hz); 7.16 (s, 1H); 2.36 (s, 3H); 2.24 (s, 3H).

[0193] - N-(3-(4-chlorophenyl)-1-(4-methoxyphenyl)-1 H Synthesis of 5-pyrazole-5-yl)acetamide (ALIPD390)

[0194] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. It was a white powder, mp: 204 ± 1℃. Yield: 85%. LC-MS (ES) + ): 342, t r = 2.13 minutes. 1 H NMR (DMSO) δ (ppm):9.97 (s, 1H); 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, 1H); 2.38 (s, 3H); 2.00 (s, 3H).

[0195] - N-(1-(3-chlorophenyl)-3-(4-chlorophenyl)-1 H Synthesis of 5-pyrazole-5-yl)acetamide (ALIPD394)

[0196] The product was purified by silica gel chromatography with cyclohexane / ethyl acetate (6:4) as the eluent. It was a white powder, mp: 188 ± 1℃. Yield: 93%. LC-MS (ES) + ): 346, t r = 2.30 minutes. 1 H NMR (DMSO) δ (ppm):9.97 (s, 1H); 7.88 (d, 2H, J = 8.5 Hz); 7.67 (s, 1H); 7.57 (m, 2H); 7.48 (m, 3H); 6.94 (s, 1H); 2.02 (s, 3H).

[0197] - N-(3-(4-chlorophenyl)-1-(2,6-dichlorophenyl)-1 H Synthesis of 5-pyrazole-5-yl)acetamide (ALIPD395)

[0198] The product was purified by silica gel chromatography with cyclohexane / ethyl acetate (6:4) as the eluent. It was a white powder, mp: 224 ± 1℃. Yield: 82%. LC-MS (ES) + ): 382, ​​t r = 2.24 minutes. 1 H NMR (DMSO) δ (ppm):10.08 (s, 1H); 7.83 (d, 2H, J =8.5 Hz); 7.73 (m, 2H); 7.64 (dd, 1H, J = 6.8Hz, 9.3 Hz); 7.48 (d, 2H, J = 8.5 Hz); 7.04 (s, 1H); 2.02 (s, 3H).

[0199] - N-(3-(4-chlorophenyl)-1-(2,5-dichlorophenyl)-1 H Synthesis of 5-pyrazole-5-yl)acetamide (ALIPD396)

[0200] The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6:4) as the eluent. It was a white powder. Yield: 68%. mp: 186 ± 1℃. LC-MS (ES) + ): 382, ​​t r = 2.34 minutes. 1 H NMR (DMSO) δ (ppm):10.06 (s, 1H); 7.86 (d, 2H, J =8.5 Hz); 7.76 (d, 1H, J = 1.9 Hz); 7.75 (d, 1H, J = 8.0 Hz); 7.69 (dd, 1H, J = 8.0 Hz, J' = 1.9 Hz); 7.48 (d, 2H, J = 8.5 Hz); 6.99 (1H, s); 1.99 (s, 3H).

[0201] result: To identify novel small molecules as inhibitors of the PD-1 / PD-L1 interaction, the inventors screened an internal chemical library. Two related and complementary methods were used for screening: (i) in vitro microthermophoresis (MST) and (ii) cell-based Forster resonance energy transfer (FRET) assays. MST is a powerful method for quantifying protein-ligand interactions with low sample consumption based on the movement of molecules along local temperature gradients, and can be used to assess the affinity (KD) of compounds for PD-L1, as previously described (Smith et al.). FRET assays assessed the ability of compounds to effectively disrupt the PD-L1:PD-1 interaction and inhibit the recruitment of a Src homology domain-containing phosphatase (SHP2, a downstream effector protein) to PD-1.

[0202] Specifically, after screening, the inventors identified and synthesized several compounds based on the general formula (I) of this invention, as disclosed in Table 1 below. The inventors then confirmed that these compounds could block PD-1 / PD-L1 interaction by performing physicochemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Promega blockade assay, T cell assay).

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210] in conclusion In summary, the compounds of general formula (I) of the present invention, particularly compounds ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395, and ALIPD396, have genuine therapeutic significance in the treatment of cancer. They possess an affinity (Kd) in the pM range, which is higher than that of the clinically used antibody atezolizumab. In fact, compared to atezolizumab with a Kd of 6.7 nM, the corresponding Kds of compounds ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395, and ALIPD396 are 423 pM, 729 pM, 710 pM, 412 pM, 123 pM, and 526 pM, respectively. This affinity is associated with the in vitro activity of compounds ALIPD304, ALIPD307, ALIPD381, ALIPD395, and ALIPD396, resulting in IC50 values ​​(77 nM, 25 nM, 2.5 nM, 429 pM, and 556 pM) comparable to or better than the IC50 (15.3 nM) of atezolizumab observed in Promega assays. Therefore, the compounds of the present invention, particularly ALIPD304, ALIPD307, ALIPD381, ALIPD395, and ALIPD396, possess the aforementioned capabilities due to their affinity for PD-L1 and their ability to block PD1 / PD-L1 interactions to restore antitumor immune responses. Thus, the compounds of the present invention represent promising therapeutic agents for the treatment of cancer.

[0211] References 1. Schildberg FA, Klein SR, Freeman GJ, Sharpe AH. Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 2016;44:955-72.

[0212] 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.

[0213] 3. Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nature Reviews Clin Oncol 2017;14:655-68.

[0214] 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. *American Journal of Translation Studies*. 2019; 11:529-541.

Claims

1. A compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: （I） -(a)where Y 3 Let C represent the sum of C and R. 3 Represents H; and -R 1 This indicates a phenyl group that has been substituted by one Cl group; -R 2 Indicates C1-C6 alkyl; - Can be the same or different R 4 R 5 R 6 and R 7 This indicates H, halogen, CN, C1-C6 alkoxy group, or (CH2). m -NH2、(CH2) m -NH-(CH2) n -C(O)OH、(CH2) m -NH-(CH2) n -C(O)O-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; or -(b)where Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and -R 1 It represents a C(O)OC1-C6 alkyl group or a phenyl group substituted with one Cl group; -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C(O)NH2, C(O)OH, and (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-C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; Or the following compound ALIPD347 ;or -(c)where Y 3 Let N be an integer, and R be a variable. 3 It does not exist; and -R 1 The phenyl group is optionally substituted with one or two substituents selected from the group consisting of: halogens, C1-C6 alkoxy groups, and C1-C6 alkyl groups. -R 2 Indicates C1-C6 alkyl; -R 4 R 5 R 6 and R 7 They are the same, and represent H.

2. The compound according to claim 1, characterized in that, (a)Y 3 Let C represent the sum of C and R. 3 H represents H; and where: -R 1 express ; -R 2 It represents CH3; and - Can be the same or different R 4 R 5 R 6 and R 7 It represents H, Cl, CN, OCH3, CH2NH2, CH2NH(CH2)2C(O)OH or CH2NH(CH2)2C(O)OCH2CH3.

3. The compound according to claim 2, characterized in that: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 Represents Cl, CN, OCH3, CH2NH2, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3; preferably R 5 Represents Cl or CH2NH(CH2)2C(O)OH; more preferably R 5 Represents Cl; or (ii)-R 5 R 6 and R 7 They are the same, and represent H; and -R 4 It represents Cl.

4. The compound according to claim 1, characterized in that, (b)Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; and wherein: -R 1 It represents C(O)OCH2CH3 or More preferably R 1 express ; -R 2 Represents H, CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; preferably R 2 Represents CH3, CH2C(O)OCH2CH3 or CH2C(O)OH; more preferably R 2 It represents CH3 or CH2C(O)OCH2CH3; or even more preferably R 2 It represents CH3; and - Can be the same or different R 4 R 5 R 6 and R 7 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 or .

5. The compound according to claim 4, characterized in that: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 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, Preferably R 5 This represents Cl, C(O)OH, CH2-NH-C(O)-CH2-C(O)OH, CH2NH(CH2)2C(O)OH, CH2NH(CH2)2C(O)OCH2CH3, ;or (ii)-R 4 R 5 and R 6 They are the same, and represent H; and -R 7 Represents Cl; or (iii)-R 4 R 5 and R 7 They are the same, and represent H; and -R 6 It represents Cl.

6. The compound according to claim 5, characterized in that: (i)-R 4 R 6 and R 7 They are the same, and represent H; and -R 5 express Or Cl; preferably R 5 It represents Cl.

7. The compound according to claim 1, characterized in that, (c)Y 3 Let N be an integer, and R be a variable. 3 It does not exist; And among them: -R 1 This indicates a phenyl group optionally substituted with one or two substituents selected from the group consisting of: Cl, OCH3, and CH3; preferably R 1 express , , , , , or More preferably R 1 express ; -R 2 It represents CH3; and -R 4 R 5 R 6 and R 7 H represents H.

8. The compound according to any one of claims 1 to 7, wherein the compound is selected from the group consisting of: 。 9. The compound according to claim 8, wherein the compound is selected from the group consisting of: ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381, ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, and 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 general formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising at least one compound of general formula (I) and at least one pharmaceutically acceptable excipient; wherein the compound or the pharmaceutical composition is used in a method of preventing and / or treating a disease in a subject, particularly a human: （I） -where (a)Y 3 Let C represent the sum of C and R. 3 H represents H; and where: -R 1 aryl group substituted by one or two substituents selected from the group consisting of: halogens, C1-C6 alkoxy groups and C1-C6 alkyl groups; -R 2 Indicates C1-C6 alkyl; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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- C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3; or -where (b)Y 3 Let C represent the sum of C and R. 3 The halogen is represented, preferably Cl; or (c)Y. 3 Let N be an integer, and R be a variable. 3 It does not exist; and among them: -R 1 The aryl group represents a C1-C6 alkyl group, a C(O)OC1-C6 alkyl group, or an aryl group optionally substituted with one or two substituents selected from the group consisting of: halogen, C1-C6 alkoxy, and C1-C6 alkyl. -R 2 Indicates H, C1-C6 alkyl, (CH2) m -C(O)OC1-C6 alkyl or (CH2) m -C(O)OH, where m represents an integer between 1 and 3; - Can be the same or different R 4 R 5 R 6 and R 7 These represent H, halogens, CN, C1-C6 alkoxy groups, C(O)NH2, C(O)OH, and (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- C1-C6 alkyl, C(O)NH(CH2) m -C5-C 10 Heterocyclic groups or C(O)-C5-C 10 Heterocyclic -C(O)-C1-C6 alkyl, where m represents an integer between 1 and 3, and n represents an integer between 1 and 3.

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

13. The compound or composition for use according to claim 11 or 12, characterized in that, The diseases mentioned are those related to the interaction of PD-1 and PD-L1 in the subjects, particularly in humans, such as cancer, chronic inflammatory diseases, neurological diseases, and chronic infections.

14. The compound or composition for use according to claim 13, characterized in that: - The cancers mentioned are selected from the group consisting of: lung cancer (non-small cell and small cell), head and neck cancer, bladder cancer, kidney cancer, triple-negative breast cancer, pancreatic cancer, melanoma, gastric cancer, colon cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioblastoma, multiple myeloma, acute myeloid leukemia, cholangiocarcinoma (gallbladder cancer), Merkel carcinoma, squamous cell carcinoma, and endometrial cancer; -The neurological disease mentioned is Alzheimer's disease. - The chronic inflammatory disease mentioned is psoriasis; and / or - The chronic infection is selected from the group consisting of: human immunodeficiency virus (HIV), malaria, tuberculosis and hepatitis B.

15. The compound or composition for use according to any one of claims 11 to 14, characterized in that: -R 1 R 2 R 3 R 4 R 5 R 6 and R 7 As defined in any one of claims 2 to 7; or - The compound is selected from the group consisting of: 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, A LIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396; preferably selected from the group consisting of: ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381, ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, more preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, and even more preferably ALIPD304, ALIPD395 and ALIPD396.

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