WO2022152316A1 - Dérivé de biphényle et son utilisation - Google Patents

Dérivé de biphényle et son utilisation Download PDF

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WO2022152316A1
WO2022152316A1 PCT/CN2022/072583 CN2022072583W WO2022152316A1 WO 2022152316 A1 WO2022152316 A1 WO 2022152316A1 CN 2022072583 W CN2022072583 W CN 2022072583W WO 2022152316 A1 WO2022152316 A1 WO 2022152316A1
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compound
μmol
mmol
reaction
added
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PCT/CN2022/072583
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Chinese (zh)
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吴凌云
王才林
徐雄彬
童海骏
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280010036.0A priority Critical patent/CN116710460A/zh
Publication of WO2022152316A1 publication Critical patent/WO2022152316A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a biphenyl derivative, its preparation method and its application in preparation and treatment of related diseases, in particular to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
  • PD-1 Programmed cell death 1
  • CD279 is an important immunosuppressive molecule in the CD28/CTLA-4 receptor family. It is a membrane protein containing 268 amino acid residues and is widely expressed in T.
  • PD-L1 is a protein encoded by the CD274 gene and mainly expressed on the surface of tumor cells, dendritic cells and macrophages.
  • the PD-1/PD-L1 signaling pathway is activated, which in turn inhibits the activation of T cells, causing T cell inactivation and contributing to the immune escape of tumor cells.
  • Another ligand of PD-1, PD-L2 is mainly expressed on the surface of dendritic cells, macrophages and B cells and is associated with inflammation and autoimmune diseases.
  • PD-1 negatively regulates immune responses by binding to its ligand PD-L1 and dephosphorylating multiple key molecules in the TCR signaling pathway.
  • the activation of PD-1/PD-L1 signaling pathway can avoid the surrounding tissue damage caused by excessive immune response, thereby reducing the occurrence of autoimmune diseases.
  • the expressions of PD-1 and PD-L1 are abnormally increased, and tumor cells can successfully escape the recognition and detection of the immune system by the binding of these PD-L1 molecules to PD-1 on T cells. attack.
  • PD-(L)1 mAb can block this "tumor immune escape mechanism" and restore the patient's own immune system's anti-cancer function.
  • mAbs monoclonal antibodies
  • FDA Food and Drug Administration
  • Incyte's PD-L1 small molecule inhibitor INCB86550 (WO2018119263, WO2019191707) and Gilead's PD-L1 small molecule inhibitor GS-4224 (US20180305315, WO2019160882) ) has entered the clinical phase 2, and the small molecule PD-1/PD-L1 inhibitor of BMS benzyl phenyl ether (WO2015034820, WO2015160641) is in the preclinical research stage.
  • small-molecule drugs can cross the cell membrane and act on intracellular targets, they have the advantages of convenient storage and transportation, low production cost, no immunogenicity, and usually oral administration. Therefore, research and development of small molecule blockers of PD-1/PD-L1 has broad application prospects.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, CN and C 1-3 alkyl optionally substituted with 1 , 2 or 3 halogens;
  • R 3 is selected from H, CN, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1- 3 alkylamino groups are each independently optionally substituted with 1, 2 or 3 halogens;
  • R 4 and R 5 are each independently selected from H, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl and -C 1-3 alkyl-(3-6 membered heterocycloalkane base), the C 1-6 alkyl, C 1-6 alkylamino , C 3-6 cycloalkyl and -C 1-3 alkyl-(3-6 membered heterocycloalkyl) are independently optional is substituted with 1, 2 or 3 R a ; alternatively, R 4 and R 5 are joined to form a 3-8 membered heterocycloalkyl optionally substituted by 1, 2 or 3 R b replace;
  • R 6 is selected from C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ;
  • L is selected from -C 1-6 alkyl- optionally substituted with 1, 2 or 3 R d ;
  • X is selected from CH and N;
  • Y is selected from CH and N;
  • Z 1 is selected from a single bond and CH 2 ;
  • Z 2 is selected from CH and N;
  • the 3-6 membered heterocycloalkyl group and the 3-8 membered heterocycloalkyl group each independently contain 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, O, S and NH.
  • the above Z 2 is selected from CH, and other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, CN, CF 3 and CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H, CN, CH 3 , -OCH 3 and The CH 3 , -OCH 3 and Each independently is optionally substituted with 1, 2 or 3 halogens, other variables are as defined herein.
  • R 3 is selected from H, CN, CH 3 , -OCH 3 , Other variables are as defined in the present invention.
  • R 4 and R 5 are each independently selected from H, C 1-4 alkyl, C 1-3 alkylamino, cyclopropyl and The C 1-4 alkyl, C 1-3 alkylamino, cyclopropyl and Each independently is optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • R 4 and R 5 are independently selected from H, Other variables are as defined in the present invention.
  • R 4 is selected from H, Other variables are as defined in the present invention.
  • R 5 is selected from H, Other variables are as defined in the present invention.
  • R4 and R5 described above are linked to form pyrrolidinyl, 8 - azabicyclo[3.2.1]octyl, azetidinyl and 2-azaspiro[3.3]heptyl alkyl, the pyrrolidinyl, 8-azabicyclo[3.2.1]octyl, azetidinyl, and 2-azaspiro[3.3]heptyl, respectively, independently optionally replaced by 1, 2 or 3 R b substitutions, other variables are as defined in the present invention.
  • R 4 and R 5 are linked to form Other variables are as defined in the present invention.
  • R 6 is selected from CH 3 and other variables are as defined in the present invention.
  • the above L is selected from Other variables are as defined in the present invention.
  • the above-mentioned compounds are selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 are as defined in the present invention
  • the above-mentioned compounds are selected from
  • R 1 , R 2 , R 3 , R 6 , Z 1 , Z 2 , X and Y are as defined in the present invention
  • Ring A is selected from 3-8 membered heterocycloalkyl
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
  • the above-mentioned compounds are selected from
  • the present invention also provides the use of the above compounds or their pharmaceutically acceptable salts in the preparation of PD-1/PD-L1 inhibitors.
  • the above PD-1/PD-L1 inhibitor is an anti-tumor drug.
  • the compound of the present invention has a good inhibitory effect on the excessive activation of the PD-1/PD-L1 signaling pathway, thereby obtaining excellent tumor growth inhibitory activity.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-6alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n - propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-6 alkylamino includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino Wait.
  • C 1-6 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH2CH3 ) , -NHCH2CH2CH3 , -NHCH2 ( CH3 ) 2 , -NHCH2CH2CH2CH3 , etc.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "3- to 8-membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 8 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule.
  • the 3-8 membered heterocycloalkyl includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 3-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • the proportions of reagents used in silica gel column chromatography, silica gel column chromatography and silica gel thin-layer chromatography plates in the present invention are all volume ratios.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DMSO stands for di- Methyl sulfoxide
  • CD3OD for deuterated methanol
  • CDCl3 for deuterated chloroform
  • TBSO for tert-butyldimethylsilyloxy.
  • the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
  • MS-ESI calculated [M+H] + 760, found 760.
  • reaction solution was quenched with water (10 mL), diluted with dichloromethane (5 mL), extracted with dichloromethane (10 mL ⁇ 3), and the organic phase was washed with saturated brine (20 mL ⁇ 2), and the solution was washed with sodium sulfate. Dry, filter and concentrate.
  • MS-ESI calculated [M+H] + 401, found 403.
  • reaction solution was quenched with water (10 mL), diluted with dichloromethane (5 mL), extracted with dichloromethane (10 mL ⁇ 3), and the organic phase was washed with saturated brine (20 mL ⁇ 2), and the solution was washed with sodium sulfate. Dry, filter and concentrate.
  • reaction solution was quenched with water (10 mL), diluted with dichloromethane (5 mL), extracted with dichloromethane (10 mL ⁇ 3), and the organic phase was washed with saturated brine (20 mL ⁇ 2), and the solution was washed with sodium sulfate. Dry, filter and concentrate.
  • Small molecule compounds can competitively inhibit the binding of PD-1 and PD-L1 by binding to PD-L1; when the PD-1 molecule as the donor is very close to the PD-L1 molecule as the acceptor, the donor molecule will The energy is transferred to the receptor molecule, which in turn causes the receptor molecule to emit fluorescence; by detecting the intensity of fluorescence, the ability of small molecules to prevent the binding of PD-L1 to PD-1 can be tested.
  • a homogeneous time-resolved fluorescence (HTRF) binding assay was used to detect the ability of the compounds of the present invention to inhibit the mutual binding of PD-1/PD-L1.
  • PD-1/PD-L1TR-FRET detection kit was purchased from BPS Biosciences. Nivo Multilabel Analyzer (PerkinElmer).
  • Dilute PD1-Eu, Dye-labeled acceptor, PD-L1-biotin and test compound with the buffer in the kit.
  • the compound to be tested was diluted 5-fold to the 8th concentration with a row gun, that is, from 40 ⁇ M to 0.5 nM, and the DMSO concentration was 4%, and a double-well experiment was set up.
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 1 provides the inhibitory activity of the compounds of the examples of the present invention on PD1/PD-L1 binding.
  • test compound IC50 (nM) Compound 2 1.49 Formate salt of compound 8 4.61 Compound 12 3.13 Compound 15 4.20
  • the compound of the present invention has a significant inhibitory effect on the binding of PD-1/PD-L1.
  • MDA-MB-231 triple-negative breast cancer cell line
  • PD-L1 molecules on the cell surface can be degraded by lysosomal and proteasome pathways, and small molecule inhibitors are added to induce PD-L1 endocytosis.
  • flow cytometry Fluorescence-activated Cell Sorting, FACS
  • FACS Fluorescence-activated Cell Sorting
  • Phosphate buffered saline 1640 medium, penicillin-streptomycin, fetal bovine serum, non-essential amino acids, ⁇ -mercaptoethanol (2-ME), human interferon ⁇ , LIVE/DEAD staining solution, staining solution (staining buffer), fixation buffer, 0.25% trypsin, EDTA, anti-human PD-L1 (Anti-human PD-L1), isotype control anti-human PD-L1 (Anti-human PD-L1 Isotype ).
  • 1640 complete medium configuration 439.5 ml of 1640 medium was added with 50 ml of fetal bovine serum, 5 ml of non-essential amino acids, 5 ml of penicillin-streptomycin and 0.5 ml of ⁇ liter mercaptoethanol, and mixed.
  • 10mM EDTA configuration add 1ml of 0.5M EDTA to 49ml of DPBS and mix.
  • MDA-MB-231 cell counting and plating remove the culture flask, remove the medium and rinse once with DPBS. After washing, add 3 ml of 0.25% trypsin to the culture flask and place it in a 37°C incubator for 1.5 min. Remove the culture flask and add 9 ml of 1640 complete medium to stop the reaction, transfer the cells to a 50 ml centrifuge tube, and centrifuge at 1000 rpm at 37°C for 5 min. Add an appropriate volume of culture medium to resuspend the cells according to the number of cells, and count with a cell counter. The cell concentration was adjusted to 5 x 10 5 cells/ml with the medium.
  • Plating A volume of 200 ⁇ L of cell suspension was added to each well of a 96-well plate, so that the number of cells in each well was 1 ⁇ 10 5 . Incubate overnight in an incubator.
  • Staining Dilute anti-human PD-L1 (2 ⁇ L per well) and LIVE/DEAD staining solution (1:1000) in staining solution, add 50 ⁇ L to each well, and stain at 4°C for 30 min. Wash twice with 200 ⁇ L of staining solution. Fixation: Add 100 ⁇ L of fixative to each well, and fix at 4°C for 15 min. Wash twice with 200 ⁇ L of staining solution. Resuspend cells in 150 ⁇ L. FACS detection. Table 2 provides the effects of the compounds of the examples of the present invention on the expression level of PD-L1 in MDA-MR-231 cells.
  • the compound of the present invention has a significant inhibitory effect on the expression level of PD-L1 in MDA-MR-231 cells.
  • the engineered T cells express PD-1 molecule and T cell receptor (TCR) on the surface, which can activate the NFAT signaling pathway of T cells after co-culture with engineered antigen presenting cells (APC).
  • TCR T cell receptor
  • APC engineered antigen presenting cells
  • the expression of PD-L1 molecules on APCs can effectively attenuate the NFAT signaling pathway in T cells; the use of PD-L1 inhibitors can effectively block the PD-1/PD-L1 regulatory mechanism, thereby reversing the weakened NFAT signaling pathway.
  • APC engineered antigen presenting cells
  • PD-1/PD-L1 NFAT detection kit was purchased from BPS Biosciences. Birght-Glo reagent was purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).
  • the TCR Activitor/PD-L1 CHO cells with a growth confluence of 80% were plated into the plate at 35,000 cells per well and placed in a 37°C cell culture incubator overnight; the compounds to be tested were diluted 5-fold to the 8th Each concentration was diluted from 20 ⁇ M to 0.25 nM, and the DMSO concentration was 2%, and a double-well experiment was set up. Discard the TCR Activitor/PD-L1 CHO cell supernatant, add 50 ⁇ l of compound working solution to each well, and incubate at 37°C for 30 minutes; after the incubation, add 50 ⁇ L of PD-1/NFAT Reporter-Jurkat at a density of 4X10 5 /ml to each well. The cell suspension was incubated at 37°C for 5 hours. After the incubation, 100 ⁇ L Bright-Glo was added to each well, and after mixing, the chemiluminescence signal was read using a Nivo multi-label analyzer.
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 3 provides the inhibitory activity of the compounds of the examples of the present invention on PD-1/PD-L1 binding.
  • the compound of the present invention can inhibit the interaction of PD-1/PD-L1 at the cellular level, thereby significantly activating the NFAT signaling pathway of T cells.
  • mice Male, 8 weeks old, body weight 25g-30g
  • mice The pharmacokinetic-related parameters of the compounds of the examples of the present invention in mice are shown in the following table.
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • Experimental Example 5 Pharmacodynamic evaluation of the compound in the C57BL/6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model
  • Experimental purpose To evaluate the compound in the mouse colorectal cancer MC38-hPDL1 transplanted humanized mice Antitumor effects in C57BL/6-hPDL1.
  • mice mouse colon cancer cells MC38-hPDL1 were recovered, and the recovery time was Pn+6.
  • the MC38-hPDL1 cells in logarithmic growth phase were collected, and the culture medium was removed and washed twice with PBS before inoculation (before tumor-bearing, tumor-bearing
  • the survival rates of MC38-hPDL1 cells were: 97.4% and 95.0%, respectively), inoculation volume: 1 ⁇ 10 6 /100 ⁇ L/cell, inoculation location: right forelimb of mice.
  • mice On the 7th day after inoculation, when the average tumor volume reached 85.23 mm 3 , the mice were randomly divided into 5 groups according to the tumor volume, with 8 mice in each group. The day of grouping was defined as D0 day, and the administration started on D0 day. The remaining mice were used for subsequent supplementary experiments.
  • Tumor size was observed on days 0, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, and 25 after the start of administration.
  • TGItv tumor volume change
  • TGITV relative tumor inhibition rate
  • TGItv(%) [1-(meanTVtn-meanTVt0)/(meanTVvn-mean TVv0)] ⁇ 100%
  • meanTVtn the mean tumor volume of a given group when measured on day n
  • meanTVt0 the mean tumor volume of a given group when measured on day 0
  • meanTVvn mean tumor volume of the solvent control group when measured on day n
  • mean TVv0 mean tumor volume of the solvent control group measured on day 0
  • mice in the colorectal cancer MC38-hPDL1 subcutaneous transplantation model of C57BL/6-hPDL1 mice are shown in Table 8 below:
  • the compound of the present invention has excellent tumor-inhibiting effect on the colorectal cancer MC38-hPDL1 subcutaneous transplantation model of C57BL/6-hPDL1 mice, and the animal body weight does not decrease significantly during the administration process, and the tolerance is good.
  • Dosagemg/kg Dosing volume ml/kg Theoretical concentration mg/ml Dosing frequency vehicle control 0 0 0 Once a day low dose 15 5 3 Once a day medium dose 50 5 10 Once a day high dose 150 5 30 Once a day
  • the body weight of the compounds of the present invention did not decrease significantly during the administration process, and the tolerance was good; compared with the vehicle control group, gastrointestinal reactions, cough, salivation and total bilirubin (TBIL) were mainly seen.
  • Target organs were liver, lung, thymus, spleen, mesenteric lymph nodes, submandibular lymph nodes, and ileum. All the above changes can be seen to recover or recover in the recovery period, and the compounds of the present invention have good safety.

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Abstract

L'invention concerne un dérivé de biphényle, son procédé de préparation et son utilisation dans la préparation d'un médicament pour le traitement de maladies associées. En particulier, la présente invention concerne un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/072583 2021-01-18 2022-01-18 Dérivé de biphényle et son utilisation WO2022152316A1 (fr)

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WO2018119236A1 (fr) * 2016-12-22 2018-06-28 Incyte Corporation Dérivés de triazolo[1,5-a]pyridine en tant qu'immunomodulateurs
CN110267953A (zh) * 2016-12-22 2019-09-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
WO2019217821A1 (fr) * 2018-05-11 2019-11-14 Incyte Corporation Dérivés de tétrahydro-imidazo[4,5-c]pyridine en tant qu'immunomodulateurs de pd-l1
CN111039942A (zh) * 2018-10-12 2020-04-21 上海长森药业有限公司 含氮杂环类化合物，及其制备方法、药物组合物和应用
CN111936475A (zh) * 2018-04-03 2020-11-13 贝达药业股份有限公司 免疫调节剂及其组合物和制备方法
WO2021063404A1 (fr) * 2019-09-30 2021-04-08 南京明德新药研发有限公司 Composé utilisé comme inhibiteur de pd-1/pd-l1 à petites molécules et application associée
WO2021254005A1 (fr) * 2020-06-17 2021-12-23 上海和誉生物医药科技有限公司 Immunosuppresseur, son procédé de préparation et son utilisation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018119221A1 (fr) * 2016-12-22 2018-06-28 Incyte Corporation Dérivés pyridine utilisés en tant qu'immunomodulateurs
WO2018119236A1 (fr) * 2016-12-22 2018-06-28 Incyte Corporation Dérivés de triazolo[1,5-a]pyridine en tant qu'immunomodulateurs
CN110267953A (zh) * 2016-12-22 2019-09-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
CN111936475A (zh) * 2018-04-03 2020-11-13 贝达药业股份有限公司 免疫调节剂及其组合物和制备方法
WO2019217821A1 (fr) * 2018-05-11 2019-11-14 Incyte Corporation Dérivés de tétrahydro-imidazo[4,5-c]pyridine en tant qu'immunomodulateurs de pd-l1
CN111039942A (zh) * 2018-10-12 2020-04-21 上海长森药业有限公司 含氮杂环类化合物，及其制备方法、药物组合物和应用
WO2021063404A1 (fr) * 2019-09-30 2021-04-08 南京明德新药研发有限公司 Composé utilisé comme inhibiteur de pd-1/pd-l1 à petites molécules et application associée
WO2021254005A1 (fr) * 2020-06-17 2021-12-23 上海和誉生物医药科技有限公司 Immunosuppresseur, son procédé de préparation et son utilisation

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