WO2021043116A1 - Composés de biphényle, leur procédé de préparation et leur utilisation médicale - Google Patents

Composés de biphényle, leur procédé de préparation et leur utilisation médicale Download PDF

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WO2021043116A1
WO2021043116A1 PCT/CN2020/112755 CN2020112755W WO2021043116A1 WO 2021043116 A1 WO2021043116 A1 WO 2021043116A1 CN 2020112755 W CN2020112755 W CN 2020112755W WO 2021043116 A1 WO2021043116 A1 WO 2021043116A1
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compound
alkyl
substituted
solvent
synthesis
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PCT/CN2020/112755
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Chinese (zh)
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孙宏斌
刘鎏
王仕军
姚智颖
解涛
邬国庆
李幸
柳军
袁浩亮
温小安
许庆龙
陈彩萍
潘燕红
张璞
吴耀军
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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
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • 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
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a biphenyl compound with PD-L1 inhibitory activity.
  • the present invention also relates to a preparation method of the compound and its medical use as a PD-L1 inhibitor and for immunomodulatory treatment Pharmaceutical composition.
  • PD-1 Programmed death receptor 1
  • PD-L1 programmed death ligand 1
  • the ITIM Tyr223) and ITSM ( Tyr248) tyrosine motifs are phosphorylated respectively, and then the protein tyrosine phosphatases SHP-2 and SHP-1 are recruited, and signal transduction intermediates (such as CD3 ⁇ and PLC ⁇ 1, etc.) are dephosphorylated, leading to T cell receptors (The down-regulation of the TCR signal allows tumor cells to escape the immune surveillance of the body (Immunity. 2016, 44(5): 955-972).
  • the combination of PD-1 and PD-L1 can also reduce the expression of cytokines (such as IFN- ⁇ , IL-2 and TNF ⁇ ) and transcription factors (such as GATA-3, T-bet and Eomes) related to effector cell functions.
  • cytokines such as IFN- ⁇ , IL-2 and TNF ⁇
  • transcription factors such as GATA-3, T-bet and Eomes
  • the PD-1/PD-L1 inhibitors currently on the market are all monoclonal antibody drugs, and there are as many as dozens of PD-1/PD-L1 antibodies under development. Compared with biomacromolecule drugs, small molecule drugs have obvious advantages. Because of their smaller molecular weight and strong membrane permeability, they can produce better curative effects on some solid tumors. In addition, small molecule drugs are suitable for oral administration, patient compliance is good, and production costs are low. Currently, PD-1/PD-L1 small molecule inhibitors are still in the pre-development stage. The CA-170 jointly developed by Curis and Aurigene has now completed its phase I clinical study (WO2016142833).
  • BMS company disclosed a class of benzyl phenyl ether small molecule PD-L1 inhibitors (WO2015160641; WO2015034820).
  • Chinese patent application 2019102477713 discloses a benzoxadiazole PD-L1 inhibitor.
  • the chemical stability of this type of compound is very poor, which seriously affects its druggability.
  • the present invention provides a novel biphenyl compound.
  • the inventor found that although a benzoxadiazole PD-L1 inhibitor disclosed in Chinese patent application 2019102477713 has good PD-L1 inhibitory activity, the chemical stability and metabolic stability of this type of compound are not ideal. Thus affecting its medicinal properties.
  • the novel biphenyl compound of the present invention is a potent PD-L1 inhibitor, and has very good chemical and metabolic stability, so it can be used to prevent or treat tumors, autoimmune diseases, organ transplant rejection, Infectious diseases and inflammatory diseases.
  • the invention also provides a preparation method of the biphenyl compound and its intermediate, a pharmaceutical composition and its medical use.
  • R 1 is selected from: H, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , C 1 -C 3 alkyl, C 1- C 4 alkylsulfonyl, C(O)OH, C(O)NH 2 , alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio , Halogenated cycloalkyl or heterocycloalkyl;
  • n 0, 1, 2, 3 or 4;
  • R 9 is selected from: H, C 1 -C 4 alkyl or benzyl
  • R 9' is selected from any of the following:
  • p 0, 1, 2, 3 or 4;
  • R 10 is selected from: H or C 1 -C 3 alkyl
  • R 11 is selected from: H, methyl or benzyl
  • R 11' is selected from: H, or hydroxyl
  • R 12 is selected from: H or C 1 -C 3 alkyl
  • R 12' is selected from: H or C 1 -C 3 alkyl
  • R 13 is selected from: H, C 1 -C 3 alkyl or benzyl
  • R 14 is selected from: H, C 1 -C 3 alkyl or benzyl
  • R 15 is selected from: H, C 1 -C 6 alkyl or C 1 -C 6 alkoxycarbonyl;
  • R 16 is selected from: H or C 1 -C 4 alkyl
  • R 9 and R 9' form a ring together with the N atom to which they are attached, and are selected from any of the following:
  • s 0, 1 or 2;
  • t 1, 2 or 3;
  • Q is selected from: S, O, NH, NCH 3 , N(CH 2 ) 2 OH or CHR 18a ; wherein, R 18a is selected from: H, OH, hydroxy substituted C 1 -C 3 alkyl or C(O) OH;
  • R 17 is selected from: H, C(O)OH, C 1 -C 4 alkyl substituted by hydroxy or C(O)NHSO 2 R 20 ;
  • R 18 is selected from: H, C(O)OH, C 1 -C 4 alkyl substituted by hydroxy, OH, C(O) or C(O)NHSO 2 R 20 ;
  • R 19 is selected from: C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C(O)OH, F, Cl, Br, I, OH, hydroxy substituted C 1 -C 4 alkyl, NR a R b or a phenoxycarbonyl group; wherein the phenyl group of the phenoxycarbonyl group is optionally F, Cl, Br, I, OH, CN, NO 2 , NH 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3, SO 2 NH 2, C (O) OH, C (O) NH 2 or NHC (O) NH 2 substituent; R a and R b are each independently selected from: H, C 1 -C 4 alkoxy Oxycarbonyl or C 1 -C 4 alkylcarbonyl;
  • R 20 is selected from: CF 3 , cyclopropyl, C 1 -C 4 alkyl, dimethylamino or methyl substituted imidazolyl;
  • R 3 and R 4 are each independently selected from: H, F, Cl, Br or I;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from H, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , OR c , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , SO 2 CH 3 , C(O)NHCH 3 , C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, CH 2 C(O)N(R d ) 2 or CH 2 CH 2 C(O)R e ;
  • R c is selected from: substituted or unsubstituted C 1 -C 4 alkyl, said substituted or unsubstituted C 1 -C 4 alkyl is unsubstituted or is one or two or three independently selected from Substituted by the following substituents: OH, (O), C(O)OH, NHR f , N(R d ) 2 , C(O)N(R d ) 2 , pyrrolidin-1-yl, piperidine- 1-yl, 4-hydroxypiperidin-1-yl, 4-hydroxy-4-carboxypiperidin-1-yl, 4-hydroxy-4-carboxylate piperidin-1-yl, 4-hydroxy-4- Nitropiperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholine-1,1-dioxo-4- Group, amino acid or amino acid ester;
  • R d is selected from: C 1 -C 3 alkyl or C 2 -C 3 alkyl substituted by hydroxy;
  • R e is selected from: 4-hydroxy-4-carboxypiperidin-1-yl or 4-hydroxy-4-cyanopiperidin-1-yl;
  • R f is selected from: C 1 -C 3 alkyl, hydroxy-substituted C 2 -C 3 alkyl, or 5-fluoro-2-oxo-2,3-dihydropyrimidin-4-yl;
  • every two of R 5 , R 6 , R 7 and R 8 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted ring Alkane ring, substituted or unsubstituted heterocyclic alkane ring or substituted or unsubstituted heterocyclic alkene ring;
  • W is selected from: H, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , C 1 -C 4 alkyl, alkenyl , Alkynyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl or heterocycloalkyl;
  • Z is selected from: O or S.
  • the biphenyl compound includes not only the compound itself but also its pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, and metabolites. , Metabolic precursors, prodrugs or solvates.
  • R 1 in the biphenyl compound is selected from: H, F, Cl, Br, I, CN, NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , C 1 -C 3 alkyl, C 1 -C 4 alkylsulfonyl, C(O)OH or C(O)NH 2 ;
  • R 2 is -(CH 2 ) m NR 9 R 9' , where m is 1;
  • R 9 is selected from: H or C 1 -C 4 alkyl
  • R 9' is selected from any of the following:
  • p 1 or 2;
  • R 10 is selected from: H;
  • R 11 is H
  • R 12 is selected from: H or C 1 -C 3 alkyl
  • R 13 is selected from: H or C 1 -C 3 alkyl
  • R 14 is selected from: H or C 1 -C 3 alkyl
  • R 15 is selected from: H, C 1 -C 6 alkyl or C 1 -C 6 alkoxycarbonyl;
  • R 9 and R 9' form a ring together with the N atom to which they are attached, and are selected from any of the following:
  • s is 0 or 1;
  • t 2 or 3;
  • Q is selected from: S, O, NH, NCH 3 , N(CH 2 ) 2 OH or CHR 18a ; wherein, R 18a is selected from: H, OH, hydroxy substituted C 1 -C 3 alkyl or C(O) OH;
  • R 17 is selected from: H, C(O)OH, C 1 -C 4 alkyl substituted by hydroxy or C(O)NHSO 2 R 20 ;
  • R 18 is selected from: H, C(O)OH, C 1 -C 4 alkyl substituted by hydroxy, OH, C(O) or C(O)NHSO 2 R 20 ;
  • R 19 is selected from: C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C(O)OH, F, Cl, Br, I, OH, hydroxy substituted C 1 -C 4 alkyl,- NR a R b or a phenoxycarbonyl group; wherein the phenyl group of the phenoxycarbonyl group is optionally selected by F, Cl, Br, I, OH, CN, NO 2 , NH 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3, SO 2 NH 2, C (O) OH, C (O) NH 2 or NHC (O) NH 2 substituent; R a and R b are each independently selected from: H, C 1 -C 4 Alkoxycarbonyl or C 1 -C 4 alkylcarbonyl;
  • R 20 is selected from: CF 3 , cyclopropyl, C 1 -C 4 alkyl, dimethylamino or methyl substituted imidazolyl;
  • R 3 and R 4 are each independently selected from: H, F, Cl, Br or I;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from H, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , OR c , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , SO 2 CH 3 , C(O)NHCH 3 , C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, CH 2 C(O)N(R d ) 2 or CH 2 CH 2 C(O)R e ;
  • R c is selected from: substituted or unsubstituted C 1 -C 4 alkyl, said substituted or unsubstituted C 1 -C 4 alkyl is unsubstituted or is one or two or three independently selected from Substituted by the following substituents: OH, (O), C(O)OH, NHR f , N(R d ) 2 , C(O)N(R d ) 2 , pyrrolidin-1-yl, piperidine- 1-yl, 4-hydroxypiperidin-1-yl, 4-hydroxy-4-carboxypiperidin-1-yl, 4-hydroxy-4-carboxylate piperidin-1-yl, 4-hydroxy-4- Nitropiperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholine-1,1-dioxo-4- Group, amino acid or amino acid ester;
  • R d is selected from: C 1 -C 3 alkyl or C 2 -C 3 alkyl substituted by hydroxy;
  • R e is selected from: 4-hydroxy-4-carboxypiperidin-1-yl or 4-hydroxy-4-cyanopiperidin-1-yl;
  • R f is selected from: C 1 -C 3 alkyl, hydroxy-substituted C 2 -C 3 alkyl, or 5-fluoro-2-oxo-2,3-dihydropyrimidin-4-yl;
  • every two of R 5 , R 6 , R 7 and R 8 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted ring Alkane ring, substituted or unsubstituted heterocyclic alkane ring or substituted or unsubstituted heterocyclic alkene ring;
  • W is selected from: H, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , C 1 -C 4 alkyl, alkenyl , Alkynyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl or heterocycloalkyl;
  • Z is selected from: O or S.
  • the biphenyl compound of the present invention or a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer, metabolite, metabolic is selected from the compounds shown in Table 1 below:
  • the biphenyl compounds of the present invention can also be used as pharmaceutical salts.
  • the salt may be the acid salt of at least one of the following acids: galactonic acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, niacin, nitric acid, orotic acid
  • the salt may also be a salt formed by the compound of the present invention and metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.) or ammonium ions. .
  • the present invention also provides the biphenyl compound or a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer, metabolite, metabolic precursor, and prodrug thereof Or the application of solvates in the preparation of PD-L1 inhibitors.
  • the biphenyl compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer, Metabolites, metabolic precursors, prodrugs or solvates are PD-L1 inhibitors, which can significantly inhibit PD-1 and PD-L1 protein-protein interactions, increase the proliferation of T cells, and promote the production of immune factors. And activate the anti-tumor immune activity of T cells, so it can be used for tumor immunotherapy.
  • the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer thereof , Metabolites, metabolic precursors, prodrugs or solvates also have the effect of suppressing immune inflammatory response.
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or Solvates can be used to prepare immunomodulatory drugs.
  • the immunomodulator drugs can be used to prevent or treat tumors, autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases.
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates Can be used to prevent or treat tumors.
  • the tumors include, but are not limited to: bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelodysplastic disease, multiple myeloma, myelodysplastic syndrome, Huo Chikin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningiosarcoma, glioma, neuroblastoma, astrocytoma, medulloblastoma, ependymoma Tumor, germ cell tumor (pineal tumor), glioblastoma multiforme
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates It can be used to prevent or treat autoimmune diseases.
  • the autoimmune diseases include, but are not limited to: ulcerative colitis, Crohn's disease, systemic lupus erythematosus, familial frostbite lupus, Chagas disease, rheumatoid arthritis, psoriasis, multiple sclerosis, Scleroderma, Behcet's disease, autoimmune hepatitis and Aicardi-Goutines syndrome, etc.
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates It can be used to prevent or treat organ transplant rejection.
  • organ transplantation includes, but is not limited to: bone marrow transplantation, liver transplantation, lung transplantation, heart transplantation, kidney transplantation, and the like.
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates Can be used to prevent or treat infectious diseases.
  • infectious diseases include but are not limited to: hepatitis B virus infection, hepatitis C virus infection, HIV virus infection, new coronavirus infection, herpes virus infection, bacterial infection, and the like.
  • the biphenyl compounds of the present invention include their pharmaceutically acceptable salts, tautomers, mesosomes, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates It can be used to prevent or treat inflammatory diseases.
  • the inflammatory diseases include, but are not limited to: non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, asthma, bronchitis, bronchitis, pneumonia, respiratory distress syndrome, lung gas Swelling, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, rhinitis, myocarditis, nephritis and neurodermatitis.
  • the compound of formula (I) or formula (II) of the present invention may be used alone. In some embodiments, the compound of formula (I) or formula (II) of the present invention can be used in combination with one or more other drugs.
  • Anti-tumor drugs that can be used in combination with the biphenyl compound of the present invention include but are not limited to: chemotherapy drugs, such as docetaxel, paclitaxel, abraxane, doxorubicin, oxaliplatin, carboplatin, cisplatin, Irinotecan, gemcitabine, cyclophosphamide, AST-1001 and AST-3424, etc.; immune checkpoint inhibitors, such as CTLA-4 inhibitors (such as Yervoy), PD-1 inhibitors (such as Keytruda and Opdivo), PD- L1 inhibitors (such as Tecentriq), LAG-3 inhibitors (such as BMS986016, REGN3767 and LAG525), TIM-3 inhibitors (such as TSR-022 and MBG-453), TIGIT inhibitors (such as MTIG7192A), B7H4 inhibitors and VISTA inhibitors (such as JNJ-61610588), etc.; antibody drug conjugates (ADC
  • Anti-autoimmune disease drugs that can be used in combination with the biphenyl compound of the present invention include but are not limited to: anti-psoriatic drugs (such as calcipotriol, tacalciferol, glucocorticoids, tazarotene, Tretinoin, tacrolimus and pimecrolimus, etc.), anti-ulcerative colitis drugs (such as sulfasalazine, mesalazine, prednisone and dexamethasone, etc.), anti-Crohn's disease drugs ( Such as sulfasalazine, 5-aminosalicylic acid, hydrocortisone, methylprednisolone, infliximab, adalimumab, and certuzumab, etc.), anti-systemic lupus erythematosus drugs (such as chloroquine, hydroxychloroquine, cyclosporine A, methotrexate and azathioprin
  • Anti-infectious disease drugs that can be used in combination with the biphenyl compound of the present invention include but are not limited to: anti-hepatitis B virus drugs (such as entecavir and adefovir, etc.), anti-hepatitis C virus drugs (such as sofosbuvir and vitamin Patavir, etc.), anti-HIV virus drugs (such as tenofovir and emtricitabine, etc.) and antibiotics (such as cephalosporins, etc.).
  • anti-hepatitis B virus drugs such as entecavir and adefovir, etc.
  • anti-hepatitis C virus drugs such as sofosbuvir and vitamin Patavir, etc.
  • anti-HIV virus drugs such as tenofovir and emtricitabine, etc.
  • antibiotics such as cephalosporins, etc.
  • Anti-inflammatory drugs that can be used in combination with the biphenyl compound of the present invention include but are not limited to: steroidal anti-inflammatory drugs (such as budesonide and dexamethasone, etc.) and non-steroidal anti-inflammatory drugs (such as water Salicylic acid and celecoxib etc.) and so on.
  • steroidal anti-inflammatory drugs such as budesonide and dexamethasone, etc.
  • non-steroidal anti-inflammatory drugs such as water Salicylic acid and celecoxib etc.
  • the present invention also provides a pharmaceutical composition for immunomodulatory therapy, which contains a therapeutically effective amount of the biphenyl compound represented by formula (I) or formula (II) as described in the present invention or a pharmaceutically acceptable Salts, tautomers, mesoisomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs, or solvates of the compounds are used as active ingredients and pharmaceutically acceptable carriers.
  • the arbitrarily mixed carrier can be changed according to the dosage form, administration form, and the like. Examples of carriers include excipients, binders, disintegrants, lubricants, correctives, flavors, colorants, sweeteners, and the like.
  • the pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, patches and other conventional pharmaceutics.
  • the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, glyceryl monostearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil
  • adsorption promoters such as quaternaryl, sodium glyceryl tristearate, coconut
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
  • disintegrants such as agar and kelp powder.
  • any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension can be sterilized to prepare an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • usual dissolving agents, buffers and analgesics can also be added.
  • the diluent may be a conventional diluent in the art.
  • the pharmaceutical composition can be in the form of oral or sterile injection solution, and the oral or injection composition can be prepared according to any method known in the art for preparing pharmaceutical compositions.
  • T and Y are bromine, chlorine, iodine, p-toluenesulfonate, mesylate or trifluoromethanesulfonate; R 1 , R 3 , R 4 , R 5 , R 6 , R 7.
  • R 8 , R 9 , R 9'and W are consistent with the definitions in the compound of formula (I) or formula (II); the synthesis of the compound specifically includes the following steps:
  • Compound N-3 is obtained by reacting compound N-1 with compound N-2 under the action of a base;
  • compound N-5a or N-8a can be obtained from compound N-4a or N-7a through reduction reaction;
  • the preparation of the biphenyl compound of the present invention can be carried out according to the method in the examples.
  • R 2 in the compound of formula (I) or formula (II) is -(CH 2 ) m NR 9 R 10 , and m is 1
  • the preparation of the biphenyl compound of the present invention can refer to the following Synthetic route or improved method.
  • T and Y are bromine, chlorine, iodine, p-toluenesulfonate, mesylate or trifluoromethanesulfonate;
  • the definitions of 7 , R 8 , R 9 , R 9' , W and Z are consistent with the definitions in the compound of formula (I) or formula (II).
  • the synthesis of the compound specifically includes the following steps:
  • LA-2 is obtained by nitration reaction of LA-1, the solvent used includes but not limited to: sulfuric acid, acetic acid, trifluoroacetic acid, acetic anhydride, trifluoroacetic anhydride or a mixed solvent optionally composed of these solvents;
  • the used nitrating reagents include but are not limited to: nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, nitric tetrafluoroborate or nitroxyl chloride; the reaction temperature is 0°C to 100°C, preferably 20°C to 60°C;
  • Compound LA-3 is obtained by reacting compound LA-2 with azide.
  • the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-di Chloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or A mixed solvent optionally composed of these solvents is preferably acetone, N,N-dimethylformamide, tetrahydrofuran or acetonitrile;
  • the azide used includes but is not limited to: sodium azide or potassium azide; reaction temperature It is 0°C to 150°C, preferably the temperature is 50°C to 100°C;
  • Compound LA-4 is obtained by cyclization reaction of compound LA-3.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloro Ethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or use these solvents
  • Optional mixed solvent preferably acetone, N,N-dimethylformamide, tetrahydrofuran, toluene or acetonitrile; the reaction temperature is room temperature to 200°C, preferably 50°C to 150°C;
  • Compound LA-5 is obtained by reaction of compound LA-4 under the action of a deoxidizer.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1, 2 -Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or A mixed solvent optionally composed of these solvents is preferably N,N-dimethylformamide, tetrahydrofuran or acetonitrile; the deoxidizer used includes but is not limited to: triphenylphosphine, triethylphosphine, tributylphosphine or Tricyclohexylphosphin
  • Compound LA-6 is obtained by reduction reaction of compound LA-5, the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane Alkane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide or any of these solvents
  • the mixed solvent of the selected composition is preferably methanol, ethanol or tetrahydrofuran;
  • the reducing agent used includes but is not limited to: sodium borohydride or potassium borohydride;
  • the reaction temperature is -20°C to 100°C, preferably the temperature is room temperature to 70°C;
  • Compound LA-7 is obtained from compound LA-6 through halogenation or sulfonic acid esterification.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1, 2-Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or use these solvents
  • Optional mixed solvent the used halogenating agent includes but not limited to: PPh 3 /CBr 4 , PBr 3 , POBr 3 , HBr, PCl 3 , POCl 3 , HCl or HI; the used sulfonic acid esterification reagent ( Under the action of a base) including but not
  • Compound LB-2 is obtained by cyclizing compound LB-1 with thionyl chloride under the action of a base.
  • the solvents used include but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane Methane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide
  • a mixed solvent optionally composed of these solvents preferably dichloromethane, toluene or chloroform
  • the base used includes but is not limited to: triethylamine, diisopropylethylamine, 1,8-diaza heterocycle [5 ,4,0] Undecene-7, potassium carbonate, sodium carbonate
  • Compound LB-3 is obtained by halogenation reaction of compound LB-2, the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane Alkane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of these solvents Solvent; the halogenating agent used includes but is not limited to: Cl 2 , Br 2 or NBS; the reaction temperature is 0°C to 120°C, preferably the temperature is 20°C to 80°C;
  • Compound LC-2 is obtained by reacting compound LC-1 with an oxidizing agent in the presence of a base.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1, 2-Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide Or a mixed solvent optionally composed of these solvents, preferably methanol, ethanol or tetrahydrofuran;
  • the alkali used includes but is not limited to: sodium hydroxide or potassium hydroxide;
  • the oxidant used includes, but is not limited to: sodium hypochlorite, potassium hypochlorite, hydrogen peroxid
  • Compound LC-3 is obtained by reaction of compound LC-2 under the action of deoxidizer.
  • the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1, 2 -Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or A mixed solvent optionally composed of these solvents is preferably N,N-dimethylformamide, tetrahydrofuran or acetonitrile;
  • the deoxidizer used includes but is not limited to: triphenylphosphine, triethylphosphine, tributylphosphine or Tricyclohexylphosphin
  • Compound LC-4 is obtained by halogenation reaction of compound LC-3.
  • the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane Alkane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of these solvents Solvent; the halogenating agent used includes but is not limited to: Cl 2 , Br 2 or NBS; the reaction temperature is 0°C to 120°C, preferably the temperature is 20°C to 80°C;
  • Compound LD-2 is obtained by cyclizing compound LD-1 with thionyl chloride under the action of a base.
  • the solvents used include but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane Methane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide
  • a mixed solvent optionally composed of these solvents preferably dichloromethane, toluene or chloroform
  • the base used includes but is not limited to: triethylamine, diisopropylethylamine, 1,8-diaza heterocycle [5 ,4,0] Undecene-7, potassium carbonate, sodium carbonate
  • Compound LD-3 is obtained from compound LD-2 through halogenation reaction.
  • the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane Alkane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of these solvents Solvent; the halogenating agent used includes but is not limited to: Cl 2 , Br 2 or NBS; the reaction temperature is 0°C to 120°C, preferably the temperature is 20°C to 80°C;
  • Compound N-3 is obtained by reacting compound N-1 with compound N-2 under the action of a base.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane , 1,2-Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide , Dimethyl sulfoxide or a mixed solvent optionally composed of these solvents, preferably acetone, N,N-dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane; the base used includes but is not limited to: triethylamine, Diisopropylethylamine, 1,8-diaza hetero
  • Compound N-4 is obtained by reacting compound N-3 with LA-7 or LB-3 under the action of a base.
  • the solvent used includes but not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, Dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl Sulfoxide or a mixed solvent optionally composed of these solvents, preferably acetone, N,N-dimethylformamide, tetrahydrofuran or acetonitrile;
  • the bases used include but are not limited to: triethylamine, diisopropylethylamine, 1,8-Diazacyclo[5,4,0]undecene-7, potassium carbonate,
  • Compound Ia is obtained by reductive amination reaction of compound N-4 and NHR 9 R 9' .
  • the solvents used include but are not limited to: acetic acid, benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane , 1,2-Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfide Sulfone or a mixed solvent optionally composed of these solvents;
  • the reducing agent used includes but is not limited to: sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride;
  • the reaction temperature is -20°C to 80°C, The preferred temperature is 0°C to 50°C;
  • compound N-5 is obtained by reduction reaction of compound N-4, and the reducing agent used includes but not limited to: sodium borohydride or potassium borohydride; N-5 is then halogenated or sulfonic acid esterified to obtain compound N-6, the halogenating agent used includes but not limited to: PPh 3 /CBr 4 , PBr 3 , POBr 3 , HBr, PCl 3 , POCl 3 , HCl or HI, the sulfonic acid esterification reagent used (in the base under the action) include but are not limited to: p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride; N-6 was alkylated with NHR 9 R 9 'under the action of a base Chemical reaction to obtain compound (Ia), the
  • Compound N-7 is obtained by reacting compound N-3 with LC-4 or LD-3 under the action of a base.
  • the solvents used include but are not limited to: benzene, toluene, chloroform, n-hexane, cyclohexane, Dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl Sulfoxide or a mixed solvent optionally composed of these solvents, preferably acetone, N,N-dimethylformamide, tetrahydrofuran or acetonitrile;
  • the bases used include but are not limited to: triethylamine, diisopropylethylamine, 1,8-Diazacyclo[5,4,0]undecene-7, potassium
  • Compound IIa is obtained by reductive amination reaction of compound N-7 and NHR 9 R 9' .
  • the solvent used includes but not limited to: acetic acid, benzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane , 1,2-Dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfide Sulfone or a mixed solvent optionally composed of these solvents;
  • the reducing agent used includes but is not limited to: sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride;
  • the reaction temperature is -20°C to 80°C, The preferred temperature is 0°C to 50°C;
  • compound N-8 can be obtained from compound N-7 through a reduction reaction.
  • the reducing agent used includes but is not limited to: sodium borohydride or potassium borohydride; N-8 is then halogenated or sulfonic acid esterified to obtain compound N-8 N-9, the halogenating agent used includes but is not limited to: PPh 3 /CBr 4 , PBr 3 , POBr 3 , HBr, PCl 3 , POCl 3 , HCl or HI, the sulfonic acid esterification reagent used (in the base under the action) include but are not limited to: p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride; N-9 alkylation with NHR 9 R 9 'under the action of a base Chemical reaction to obtain compound II
  • the dosage of the prodrug or solvate can be appropriately changed according to the patient's age, weight, symptoms, and route of administration.
  • the lower limit of the dose at one time is 0.1 mg (preferably 1 mg), and the upper limit is 1000 mg (preferably 500 mg).
  • the lower limit of the single dose is 0.01 mg (preferably 0.1 mg), and the upper limit is 500 mg (preferably 250 mg). It can also deviate from this dosage range according to the degree of disease and the different dosage forms.
  • the present invention has the following advantages:
  • the biphenyl compound of the present invention is a new type of PD-L1 inhibitor, which can significantly inhibit the protein-protein interaction between PD-1 and PD-L1, and has significantly better activity than the known PD-L1 inhibitor BMS-1016 .
  • the biphenyl compound of the present invention can significantly block the inhibitory effect of PD-L1 on T cells, and can block tumor cells from inhibiting T cell proliferation and secreting IFN- ⁇ , thus having the effect of enhancing T cell anti-tumor immunity . It is especially important that the biphenyl compounds of the present invention show significant anti-tumor efficacy in tumor-bearing animals. Therefore, the biphenyl compound of the present invention as a PD-L1 inhibitor can be used to prepare drugs for tumor immunotherapy.
  • the biphenyl compounds of the present invention can inhibit the release of inflammatory factors in animal models of psoriasis, and have a significant curative effect on psoriasis, which suggests that the biphenyl compounds of the present invention can be used for Prevent and treat autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases. Therefore, the compounds of the present invention can be used to prepare immunomodulatory drugs for the prevention or treatment of tumors, autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases.
  • the synthetic route of the biphenyl compound of the present invention is ingeniously designed, simple and convenient, the raw materials are cheap and easy to obtain, the synthesis process is safe, environmentally friendly, and easy to scale production. It is particularly important that the novel biphenyl compound of the present invention not only has high inhibitory activity against PD-L1, but also has very good chemical stability and metabolic stability, and thus has good drug-making properties. Compared with a benzoxadiazole PD-L1 inhibitor disclosed in Chinese patent application 2019102477713, the chemical stability and metabolic stability of the biphenyl compound of the present invention have been greatly improved, and it has very good properties. safety. Therefore, the biphenyl compound of the present invention has very good druggability.
  • the biphenyl compound of the present invention has the advantages of low cost, easy preparation, and less side effects of immune reaction compared with the existing PD-1/PD-L1 antibody drugs. It can be used alone or in combination with chemotherapeutics or other anti-tumor drugs, and is expected to become a new tumor immunotherapy drug.
  • the compound of the present invention was docked with the reported eutectic structure of hPD-L1 (PDB number: 6R3K).
  • the results showed that the benzoxadiazole heterocyclic ring in the dominant structure of the compound of the present invention It can interact well with the hPD-L1 protein, in which the oxygen atom of the heterocyclic ring and the guanidine group on the 125th arginine in the hPD-L1 protein produce a key hydrogen bond interaction; the benzoxadiazole heterocyclic ring It produces a key ⁇ - ⁇ interaction with the benzene ring on tyrosine 123, and the strong electron withdrawing effect of the oxadiazole ring in benzoxadiazole will strengthen the strength of the ⁇ - ⁇ interaction and make the side chain The binding strength to the protein is higher, so that a molecule with better binding ability to the hPD-L1 protein can be obtained.
  • the score of the compound 9 in the present invention is -11.627, and if the benzoxadiazole in compound 9 is replaced with a benzene ring, the score of the corresponding compound is -9.87, which is significantly lower than the score of the compound. 9.
  • benzoxadiazole scores higher than those replaced by benzene ring are very important for the improvement of compound activity, that is, by introducing the benzoxadiazole side chain, this type of compound blocks the PD-1 and PD-L1 proteins- The ability of proteins to interact is significantly increased.
  • PBMC peripheral blood mononuclear cells
  • Figure 2 is a diagram showing the effect of biphenyl compounds in blocking tumor cells and inhibiting the proliferation of human T cells: the proliferation of T cells in the blank control group, the activated group, the inhibitory group and the compound group with different concentrations after 48 hours;
  • Figure 5 is a sensorgram of the binding of compound 9 to hPD-L1 protein at different concentrations
  • Figure 6 is a graph showing the effect of compound 8 on the body weight change of subacute experimental mice
  • Figure 7 is a graph showing the effect of compound 8 on the weight of internal organs in mice with subacute toxicity
  • Figure 8 is a graph showing the effect of compound 8 on the changes of plasma indexes in subacute experimental mice
  • Figure 9 is a graph showing the effect of compound 8 on the change of tumor volume over time in a mouse melanoma highly metastatic cell (B16F10) subcutaneous tumor model;
  • Figure 10 is a graph showing the effect of compound 8 on the change of tumor volume in MC38-hPD-L1 colon cancer cell transplantation C57BL/6-hPD-L1 tumor-bearing model;
  • Fig. 11 is a graph showing the effect of compound 8 on the weight change of mice in a C57BL/6-hPD-L1 tumor-bearing model transplanted with MC38-hPD-L1 colon cancer cells;
  • Figure 12 is a graph showing the effect of compound 8 on the weight change of psoriasis model mice
  • Figure 13 is a graph showing the effect of compound 8 on the PASI scoring results of a psoriasis model
  • Figure 14 is a graph showing the effect of Compound 8 on the ear thickness of psoriasis model mice
  • Figure 15 is a graph showing the effect of ELISA on the effect of compound 8 on the plasma IL-17A content of psoriasis model mice;
  • Figure 16 is a graph showing the effect of qPCR on the effect of compound 8 on the expression of inflammation-related genes in the back tissue of psoriasis model mice;
  • Figure 17 is a graph showing the effect of qPCR on the effect of compound 8 on the expression of inflammation-related genes in the ear tissue of psoriasis model mice.
  • the compound XA-3 (1.5 g) was dissolved in toluene (20 mL) and heated in an oil bath at 110°C. After about 5 hours, the heating was stopped, and the solvent was evaporated under reduced pressure to obtain a dark yellow solid compound XA-4 (1.2 g).
  • HRMS(ESI) m/z 500.1982[M+H] + .
  • Dissolve compound A-1 (6.15g) in anhydrous tetrahydrofuran (50mL), slowly add borane tetrahydrofuran complex (60mL) dropwise under an ice salt bath, react at room temperature for about 5 hours to stop the reaction, and quench by adding water under ice bath reaction. It was extracted with ethyl acetate (50 mL x 4), washed with saturated brine (30 mL x 2), and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a white solid compound A-2 (5.18 g).
  • HRMS(ESI) m/z 550.1293[M+H] + .
  • Example 5 With reference to the method of Example 5, the D-serine ethyl ester hydrochloride in Example 5 was replaced with L-phenylglycine methyl ester hydrochloride to obtain compound 7: 1 H NMR (300MHz, DMSO-d 6 ) ⁇ 8 .09–7.94(m,2H), 7.68–7.53(m, 2H), 7.54–7.27(m,10H), 7.23–7.11(m,2H), 7.11–6.99(m,2H), 5.30(s, 4H),3.79(s,1H),3.57(s,2H).
  • Dissolve compound B-1 (4.2g, 2.8mL) in water (10mL), slowly add hydrochloric acid (6mL) under an ice-salt bath, stir for 5 minutes, slowly add an aqueous solution of sodium nitrite (1.88g), 20 minutes After the addition, after stirring for 30 minutes under an ice-salt bath, an aqueous solution of potassium iodide (7.5 g) was slowly added dropwise to the reaction solution, and the reaction was stopped after 8 hours at room temperature.
  • Example 9 With reference to the method of Example 9, the D-serine ethyl ester hydrochloride in Example 9 was replaced with L-serine ethyl ester hydrochloride to obtain compound 10: 1 H NMR (300MHz, DMSO-d 6 ) ⁇ 8.
  • HRMS(ESI) m/z 596.0769[M+H] + .
  • Dissolve compound C-2 (9.0g) in water (50mL), slowly add hydrochloric acid (20mL) under an ice-salt bath, stir for 10 minutes, slowly add an aqueous solution of sodium nitrite (3.2g) dropwise, about 30 minutes to complete the addition After stirring for about 45 minutes in an ice-salt bath, an aqueous solution of potassium iodide (8.4 g) was slowly added dropwise to the reaction solution, and the reaction was stopped after 8 hours of reaction at room temperature.
  • Example 5 Referring to the method of Example 5, the D-serine ethyl ester hydrochloride in Example 5 was replaced with (2R, 4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride to obtain compound 25: MS(ESI): m/z 620.5[M+H] + .
  • Example 36 Referring to the method of Example 36, the D-serine ethyl ester hydrochloride in Example 36 was replaced with taurine to obtain compound 39: MS(ESI): m/z 669.5[M+H] + .
  • Example 36 Referring to the method of Example 36, the D-serine ethyl ester hydrochloride in Example 36 was replaced with N-(2-aminoethyl)methanesulfonamide to obtain compound 40: MS(ESI): m/z 682.2 [M+H] + .
  • Example 36 Referring to the method of Example 36, the D-serine ethyl ester hydrochloride in Example 36 was replaced with 2-methyl-L-serine ethyl ester hydrochloride to obtain compound 41: MS(ESI): m/z 663.6[M+H] + .
  • Example 42 Referring to the method of Example 42, the (S)-piperidine-2-carboxylic acid methyl ester hydrochloride in Example 42 was replaced with (2R, 4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride Salt to prepare compound 44: MS (ESI): m/z 689.7[M+H] + .
  • Example 46 Referring to the method of Example 46, the D-serine ethyl ester hydrochloride in Example 46 was replaced with ethanolamine to obtain compound 48: MS(ESI): m/z 561.2[M+H] + .
  • Example 46 Referring to the method of Example 46, the D-serine ethyl ester hydrochloride in Example 46 was replaced with taurine to obtain compound 49: MS(ESI): m/z 623.0[M+H] + .
  • Example 46 Referring to the method of Example 46, the D-serine ethyl ester hydrochloride in Example 46 was replaced with N-(2-aminoethyl)methanesulfonamide to obtain compound 50: MS(ESI): m/z 638.2 [M+H] + .
  • Example 46 Referring to the method of Example 46, the D-serine ethyl ester hydrochloride in Example 46 was replaced with 2-methyl-L-serine ethyl ester hydrochloride, and then hydrolyzed to obtain compound 51: MS(ESI) :m/z 619.6[M+H] + .
  • compound 53 was prepared by hydrolysis according to the method in Example 1: MS(ESI): m/z 629.2[M+H] + .
  • Example 52 Referring to the method of Example 52, the (S)-piperidine-2-carboxylic acid methyl ester hydrochloride in Example 52 was replaced with (2R, 4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride Salt to prepare compound 54: MS (ESI): m/z 645.5 [M+H] + .
  • Dissolve compound R-2 (9.0g) in water (50mL), slowly add hydrochloric acid (20mL) under an ice-salt bath, stir for 10 minutes, slowly add an aqueous solution of sodium nitrite (3.2g) dropwise, about 30 minutes after the addition is complete After stirring for about 45 minutes in an ice-salt bath, an aqueous solution of potassium iodide (8.4 g) was slowly added dropwise to the reaction solution, and the reaction was stopped after 8 hours of reaction at room temperature.
  • Example 1 Referring to the method of Example 1, replacing I-6 in Example 1 with R-10, the compound 56 was prepared: 1 H NMR (300MHz, DMSO-d 6 ) ⁇ 8.15(s, 1H), 8.13-8.04 (m,2H),7.82-7.75(m,2H),7.65-7.48(m, 7H),7.20(s,1H),5.56(s,2H),5.53(s,2H),3.93-3.75(m ,3H),3.53–3.47(m,2H),2.90(s,1H).MS(ESI): m/z 595.5[M+H] + .
  • Example 4 Take compound H-1 (1.35g) in Example 4 and dissolve it in anhydrous acetonitrile (20mL), add anhydrous sodium bicarbonate (1.08g), stir at room temperature for 30 minutes, then slowly add BB-1 (2.43g), 70 °C oil bath heating. After reacting for about 20 hours, the heating was stopped, a white solid was precipitated out and filtered directly with suction, washed with water (60 mL), and the solvent was dried to obtain an off-white solid compound BB-2 (2.47 g).
  • D-serine ethyl ester hydrochloride (156mg) in a mixed solvent of dichloromethane and methanol (2:1, 3mL), add N,N-diisopropylethylamine (DIPEA, 115mg) and stir at room temperature for 20 minutes , Compound BB-6 (150 mg) and sodium triacetoxyborohydride (STAB, 194 mg) were added, and the reaction was stopped after 12 hours at room temperature.
  • DIPEA N,N-diisopropylethylamine
  • STAB sodium triacetoxyborohydride
  • Dissolve compound 84 (80mg) in a mixed solvent of methanol and tetrahydrofuran (2:1, 3mL), add lithium hydroxide monohydrate (10mg), react at room temperature for 12 hours, evaporate the solvent under reduced pressure, and add water (5mL).
  • Dissolve compound 87 (100mg) in a mixed solvent of methanol and tetrahydrofuran (2:1, 3mL), add lithium hydroxide monohydrate (20mg), react at room temperature for 12 hours, distill off the solvent under reduced pressure, and add water (2mL).
  • Dissolve compound 89 (65mg) in a mixed solvent of methanol and tetrahydrofuran (2:1, 3mL), add lithium hydroxide monohydrate (20mg), react at room temperature for 12 hours, evaporate the solvent under reduced pressure, and add water (3mL).
  • D-serine ethyl ester hydrochloride (104mg) in a mixed solvent of dichloromethane and methanol (3:1, 4mL), add N,N-diisopropylethylamine (DIPEA, 79mg) and stir at room temperature for 20 minutes , Compound UA-4 (80 mg) and sodium triacetoxyborohydride (STAB, 129 mg) were added, and the reaction was stopped after 12 hours at room temperature.
  • DIPEA N,N-diisopropylethylamine
  • STAB sodium triacetoxyborohydride
  • Dissolve compound 91 (55mg) in a mixed solvent of methanol and tetrahydrofuran (2:1, 3mL), add lithium hydroxide monohydrate (17mg), react at room temperature for 12 hours, distill off the solvent under reduced pressure, and add water (3mL).

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Abstract

La présente invention concerne des composés de biphényle, leur procédé de préparation et leur utilisation médicale. La structure des composés de biphényle est représentée par la formule (I) ou la formule (II). Les composés de biphényle de la présente invention, ou un tautomère, un mésomère, un racémate, un stéréoisomère, un métabolite, un précurseur métabolique, un promédicament, un solvate ou un sel de qualité pharmaceutique de ceux-ci, sont des inhibiteurs de PD-L1, qui présentent un effet inhibiteur significatif sur les interactions protéine-protéine de PD-1 et PD-L1, et peuvent ainsi être utilisés pour préparer des inhibiteurs de PD-L1, ainsi que pour préparer des médicaments immunomodulateurs pour la prévention ou le traitement de tumeurs, de maladies auto-immunes, d'un rejet de greffe d'organe, de maladies infectieuses et de maladies inflammatoires.
PCT/CN2020/112755 2019-09-02 2020-09-01 Composés de biphényle, leur procédé de préparation et leur utilisation médicale WO2021043116A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910822253.X 2019-09-02
CN201910822253 2019-09-02
CN202010876949.3A CN111909108B (zh) 2019-09-02 2020-08-27 联苯类化合物及其制备方法和医药用途
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