WO2021031788A1 - Composé hétérocyclique à 5 chaînons substitué par un phényle, son procédé de préparation, son utilisation et composition pharmaceutique le comprenant - Google Patents

Composé hétérocyclique à 5 chaînons substitué par un phényle, son procédé de préparation, son utilisation et composition pharmaceutique le comprenant Download PDF

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WO2021031788A1
WO2021031788A1 PCT/CN2020/103850 CN2020103850W WO2021031788A1 WO 2021031788 A1 WO2021031788 A1 WO 2021031788A1 CN 2020103850 W CN2020103850 W CN 2020103850W WO 2021031788 A1 WO2021031788 A1 WO 2021031788A1
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substituted
compound
group
phenyl
membered heterocyclic
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PCT/CN2020/103850
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English (en)
Chinese (zh)
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蒋晟
郝海平
王天雨
王敏敏
张婉衡
倪勇
邱亚涛
吴筱星
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound and a preparation method, application and pharmaceutical composition thereof, in particular to a five-membered heterocyclic compound substituted by a phenyl group, and a preparation method, application and pharmaceutical composition thereof.
  • Tumor immunotherapy refers to a treatment method that stimulates the body's immune system to improve the anti-tumor immune effect, thereby inhibiting and killing tumor cells.
  • the research on immunotherapy has a history of nearly a hundred years. With the comprehensive development and cross-penetration of oncology, immunology and molecular biology, immunotherapy has achieved many results, bringing new hope for tumor treatment.
  • Immune checkpoint inhibitors are currently relatively hot immunotherapy drugs. By up-regulating the expression of immune checkpoint receptors, tumor cells inhibit the activity of immune cell T cells and complete the immune escape of tumor cells. Immune checkpoint inhibitors relieve the suppression of immune cell T cells by inhibiting the immune checkpoint pathway, activate the body's immune killing on tumor cells, and achieve tumor treatment.
  • the immune checkpoints that have been discovered include CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), PD-1 (Programmed cell death 1) and TIM3 (T cell membrane 3), etc. (see Drew M. Pardoll, Nature Review Cancer,2012,12,252).
  • PD-1 Programmed death receptor 1
  • PD-1 is a type of immunoglobulin and belongs to the CD28 superfamily. PD-1 consists of 288 amino acids and has an immunoglobulin variable region and cytoplasmic region. Different from CTLA-4 and other family proteins, PD-1 has a single-molecule structure, and human and mouse PD-1 proteins have approximately 60% identical amino acid sequences, while CTLA-4 is only 16%.
  • PD-1 is expressed in thymocytes, and activated T cells, B cells, natural killer cells and dendritic cells can up-regulate the expression of PD-1. A number of studies on PD-1 deficient mice have shown that these PD-1 deficient mice are susceptible to autoimmune diseases.
  • PD-1 has two types of natural ligands, PD-L1 and PD-L2.
  • T cells When activated T cells up-regulate the expression of PD-1, the body will bind to PD-1 by producing PD-1 ligands to inhibit T cell activity.
  • tumor cells can also inhibit the body's anti-tumor immune activity by expressing PD-L1 (see Yasumasa Ishida, Yasutoshi Agata, et al. The EMBO Journal, 1992, 11, 3887). Therefore, inhibiting the PD-1/PD-L1 signaling pathway can restore the body's anti-tumor immune activity.
  • the study of inhibitors targeting the PD-1/PD-L1 signaling pathway has also become a research hotspot.
  • the first objective of the present invention is to provide a series of phenyl-substituted five-membered heterocyclic compounds that can treat a variety of related tumor diseases with tumor immunotherapy by regulating the PD-1/PD-L1 signaling pathway;
  • the second objective of the present invention is to provide a preparation method of the phenyl substituted five-membered heterocyclic compound
  • the third object of the present invention is to provide the pharmaceutical composition containing the phenyl substituted five-membered heterocyclic compound.
  • Ring A and Ring B are independently an aromatic ring or an aromatic heterocyclic ring
  • X 1 , X 2 and X 3 are independently nitrogen or carbon;
  • Y is oxygen or sulfur or carbon
  • Z 1 and Z 2 are independently nitrogen or carbon or oxygen
  • Each R 1 is independently hydrogen, deuterium, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy, amino acid;
  • the substituent of the substituted alkyl group or substituted alkoxy group is one or more of the following groups: halogen, C 1-4 alkyl, hydroxyl, C 1-4 alkoxy Group, cyano group, trifluoromethyl group, C 1-4 carboxyl group, C 1-4 ester group or C 1-4 amide group; the substituents in the substituted hydroxyl group or substituted amino group are among the following groups One or more: C 1-8 alkyl group, C 1-8 amide group, C 1-8 ester group, C 1-8 carboxyl group, C 1-8 hydroxyl group; wherein the C 1-8 alkyl group, C 1 -8 amido group, C 1-8 ester group, C 1-8 carboxyl group, and C 1-8 hydroxyl group may optionally be substituted by one or more of the following substituents: hydroxyl, carboxy, cyano, amino, cycloalkyl, Aryl, heterocyclyl, alkenyl, alkynyl; when there are
  • Each R 2 is independently hydrogen, deuterium or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or two adjacent R 2 and The two atoms of ring B form a 4-7 membered substituted or unsubstituted carbocyclic or heterocyclic ring;
  • the substituent of the substituted alkyl group or substituted alkoxy group is one or more of the following groups: halogen, C 1-4 alkyl, hydroxyl, C 1-4 alkoxy Group, cyano group, trifluoromethyl group, C 1-4 carboxyl group, C 1-4 ester group or C 1-4 amide group; the substituents in the substituted hydroxyl group or substituted amino group are among the following groups Any one or more: C 1-8 alkyl group, C 1-8 amide group, C 1-8 ester group, C 1-8 carboxyl group, C 1-8 hydroxyl group; wherein the C 1-8 alkyl group, C The 1-8 amide group, C 1-8 ester group, C 1-8 carboxyl group, and C 1-8 hydroxy group are substituted by any one or more of the following substituents: hydroxy, carboxy, cyano, amino, cycloalkyl, aryl , Heterocyclyl, alkenyl, alkynyl; when two
  • R 3 is hydrogen, deuterium, cyano, halogen, vinyl, trifluoromethyl, methoxy or C 1-4 alkyl;
  • n 1, 2 or 3;
  • n 1 or 2.
  • the compound includes a pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof.
  • the compound includes any one of the following structures:
  • the solvent used in the coupling reaction in step (1) includes but is not limited to: benzene, toluene, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, n-hexane, Methyl chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent optionally composed of these solvents;
  • the base used includes but is not limited to: sodium carbonate, potassium carbonate, potassium bicarbonate, carbonic acid Sodium hydrogen, the reaction temperature is 60°C to 120°C;
  • the catalyst used includes palladium catalysts such as tetrakistriphenylphosphine palladium;
  • the solvent used in the carbon disulfide reaction in step (2) includes but is not limited to: benzene, toluene, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, n-hexane, disulfide Methyl chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent optionally composed of these solvents; the reagent used is triphosgene or methyl chloroformate; the catalyst used is triethylene diamine ; The reaction temperature is 0°C to 40°C;
  • the solvent used in the hydrazine hydrate reaction in step (3) includes but is not limited to: benzene, toluene, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, n-hexane, dichloromethane, Chloroform, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent optionally composed of these solvents; the reaction temperature is 60°C to 100°C;
  • the solvent used in the condensation reaction in step (4) includes but is not limited to: benzene, toluene, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, n-hexane , Dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent optionally composed of these solvents;
  • the condensing agent used includes but is not limited to: (1-ethyl-3(3 -Dimethylpropylamine) carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride, p-toluenesulfonic acid; the reaction temperature is 60°C to 100°C;
  • the application of the phenyl-substituted five-membered heterocyclic compound of the present invention is the phenyl-substituted five-membered heterocyclic compound and its pharmaceutically acceptable salts, racemates, and optical isomers Application of body or solvent compound in preparation of immune checkpoint inhibitor.
  • the application of the phenyl-substituted five-membered heterocyclic compound of the present invention is the phenyl-substituted five-membered heterocyclic compound and its pharmaceutically acceptable salts, racemates, and optical isomers Application of body or solvent compound in the preparation of inhibitors with PD-1/PD-L1 inhibitory activity.
  • the application of the phenyl-substituted five-membered heterocyclic compound of the present invention is the phenyl-substituted five-membered heterocyclic compound and its pharmaceutically acceptable salts, racemates, and optical isomers Application of body or solvent compound in the preparation of anti-tumor drugs.
  • composition of the present invention containing a phenyl-substituted five-membered heterocyclic compound is composed of the five-membered heterocyclic compound or a pharmaceutically acceptable salt, racemate, optically active Isomers or solvent compounds serve as active ingredients and pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention containing a five-membered heterocyclic compound substituted with a phenyl group is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalation , Ointment, suppository or patch.
  • the present invention has the following advantages:
  • the present invention provides a class of small molecule inhibitors of immune checkpoints, which has a novel structure and can be administered orally, which solves the defects of treatment and resistance of monoclonal antibody immune checkpoint inhibitors, and is simple to prepare as small molecule inhibitors and is convenient for industry produce.
  • TLC monitors the completion of the reaction of the raw materials, filters out insoluble materials, and concentrates the filtrate by column chromatography (volume ratio of petroleum ether: ethyl acetate is 3:1) for purification to obtain 1.02 g of white solid compound 1-B.
  • the compound 3 can be obtained by replacing N-acetylethylenediamine with ethanolamine.
  • N-acetylethylenediamine is replaced with L-serine, and compound 5 can be prepared.
  • compound 3-A can be prepared.
  • the compound 4-B was dissolved in ethanol, hydroxylamine hydrochloride and DBU were added, TLC monitored until the reaction of the raw materials was completed, and the spin-dried solvent was purified by column chromatography to obtain compound 4-C.
  • the acetaminobenzyl alcohol was dissolved in pyridine, and trifluoromethanesulfonic anhydride was added dropwise under ice bath conditions. After the addition, the reaction was moved to 80 degrees Celsius. After four hours, the reaction was monitored by TLC and the pyridine was removed by the oil pump. .
  • compound 6-A With reference to the synthesis of compound 1-C, replacing p-aminobenzyl alcohol with 2-methanol-4-aminophenol, compound 6-A can be prepared.
  • the compound 45 can be prepared.
  • the compound 46 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • 3.79 s, 2H
  • 3.25(t,J 3.1Hz,2H)
  • Example 48 replacing the benzyl bromide with m-cyanobenzyl chloride, the compound 49 can be prepared.
  • compound 52 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • 2.93 s, 2H
  • 2.81 (d, J 21.9Hz, 4H)
  • compound 64 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • 7.09(d,J 4.9Hz,1H)
  • 3.92(d,J 12.3Hz,1H)
  • compound 65 can be prepared.
  • compound 66 can be prepared.
  • compound 68 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • compound 69 can be prepared.
  • compound 70 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • ⁇ 8.54(d,J 1.2Hz,1H),7.84-7.05(m,13H)
  • 4.40(t,J 5.0Hz, 1H)
  • 4.32 s, 2H
  • 3.08 (t, J 4.0 Hz, 2H)
  • 2.87 (t, J 1.0 Hz, 2H), 2.43 (s, 3H).
  • compound 71 can be prepared.
  • 1H NMR 300MHz, Chloroform-d
  • compound 73 can be prepared.
  • compound 74 can be prepared.
  • Example 1 Mix compound 1 (50g), hydroxypropylmethylcellulose E (150g), starch (200g), povidone K30 and magnesium stearate (1g) prepared in Example 1, granulate and press .
  • the compounds prepared in Examples 1-66 can be given to different pharmaceutical excipients to form capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, according to the conventional preparation method of the pharmacopoeia 2015 edition. Agent, suppository or patch, etc.
  • Pharmacological tests prove that the PD-1/PD-L1 inhibitory activity of the present invention can be used to prepare antitumor drugs.
  • the following are the pharmacological test results of some compounds of the present invention:
  • test compound test concentration is 30000nM starting, 3 times dilution, 10 concentration points, single-well detection. Dilute it into a 100-fold final concentration solution in a 384-well plate, and then use Echo550 to transfer 200nL to a 384 reaction plate for use. Add 200 nL of 100% DMSO to the negative control well and the positive control well respectively.
  • Ratio_sample is the ratio of the sample wells
  • Ratio_min the average ratio of the negative control wells, representing the readings of the wells without PD-1/PD-L1 interaction
  • Ratio_max the average ratio of the positive control wells, representing the readings of the wells without compound inhibition.
  • the following table shows the activity range or IC 50 of the compound's inhibitory activity against PD-1/PD-L1 interaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de point de contrôle immunitaire capable de bloquer une voie de signalisation PD-1/PD-L1, un composé hétérocyclique à cinq chaînons substitué par un phényle ou un sel pharmaceutiquement acceptable, un racémate, un isomère optique ou un composé de solvant de celui-ci, un procédé de préparation correspondant, une utilisation associée et une composition pharmaceutique le comprenant. Ce composé est représenté par la formule I ci-dessous.
PCT/CN2020/103850 2019-08-19 2020-07-23 Composé hétérocyclique à 5 chaînons substitué par un phényle, son procédé de préparation, son utilisation et composition pharmaceutique le comprenant WO2021031788A1 (fr)

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CN201910763655.7A CN111718310B (zh) 2019-08-19 2019-08-19 苯基取代的五元杂环类化合物及其制备方法、用途和药物组合物

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CN112479988B (zh) * 2020-12-09 2024-05-03 药康众拓(江苏)医药科技有限公司 取代联苯类化合物及其制备方法、用途和药物组合物
CN113121464B (zh) * 2021-04-21 2023-02-24 药康众拓(江苏)医药科技有限公司 五元杂环取代的联苯类化合物及其制备方法和用途
CN113248449B (zh) * 2021-05-06 2022-09-23 中国药科大学 一种含甲脒的芳基螺环类化合物及其制备方法与应用
WO2023217275A1 (fr) * 2022-05-13 2023-11-16 青岛清原化合物有限公司 Composé aromatique substitué par un hétérocycle, son procédé de préparation, composition herbicide et son utilisation

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