WO2022199587A1 - 嘧啶并杂环类化合物及其应用 - Google Patents

嘧啶并杂环类化合物及其应用 Download PDF

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WO2022199587A1
WO2022199587A1 PCT/CN2022/082328 CN2022082328W WO2022199587A1 WO 2022199587 A1 WO2022199587 A1 WO 2022199587A1 CN 2022082328 W CN2022082328 W CN 2022082328W WO 2022199587 A1 WO2022199587 A1 WO 2022199587A1
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compound
pharmaceutically acceptable
acceptable salt
independently
independently selected
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PCT/CN2022/082328
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English (en)
French (fr)
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陈新海
张浩宇
陈曙辉
胡国平
黎健
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南京明德新药研发有限公司
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Priority to CN202280016737.5A priority Critical patent/CN117083281A/zh
Publication of WO2022199587A1 publication Critical patent/WO2022199587A1/zh

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a series of pyrimido-heterocyclic compounds and their applications, in particular to the compounds represented by formula (II) and their pharmaceutically acceptable salts.
  • the KRAS gene is one of the most frequently mutated oncogenes in human cancers. In addition to directly promoting the proliferation and survival of tumor cells, KRAS gene mutations can also have an impact on the tumor microenvironment. In human cancers, the mutation occurs in nearly 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. Additionally, 80% of oncogenic mutations occurred at codon 12, with the most common mutations including: p.G12D (41%), p.G12V (28%) and p.G12C (14%).
  • KRAS G12C inhibitors such as Amgen's AMG510 and Mirati Therapeutics' MRTX849, herald the arrival of a new era of precision oncology.
  • KRAS G12D small molecule has entered the clinical research stage, and KRAS G12D- mutated tumor patients have not benefited from precision medicine. Therefore, research in the field of KRAS G12D small molecules is urgently needed.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • T 1 is selected from CH 2 , NH and O;
  • T 2 is selected from CH and N;
  • T 3 and T 4 are independently selected from CH 2 and NH;
  • n, p and x are each independently selected from 0, 1 or 2;
  • r, v and w are each independently selected from 1 or 2;
  • q and u are independently selected from 1, 2 or 3;
  • each R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CF 3 ;
  • E 1 and E 3 are each independently selected from a bond, O, S, Se, NH and CH 2 , each independently optionally substituted with 1 or 2 Ra ;
  • E 2 is selected from -C(O)-, -C(O)-(CH 2 ) g - and -(CH 2 ) h -, when g and h are not selected from 0, the -C(O)- (CH 2 ) g - and -(CH 2 ) h - are each independently optionally substituted with 1, 2 or 3 R b ;
  • X 1 and X 2 are each independently selected from N and CR 4 ;
  • L 1 is selected from a bond and CH 2 optionally substituted with 1 or 2 R c ;
  • R 2 is selected from 5-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R d ;
  • R 3 is selected from C 6-10 aryl and 5-10 membered heteroaryl, said C 6-10 aryl and 5-10 membered heteroaryl respectively independently optionally replaced by 1, 2, 3, 4 or 5 R e substitutions;
  • e is selected from 0, 1, 2 and 3;
  • f, g and h are independently selected from 0, 1 and 2;
  • each R a is independently selected from H and CH 3 ;
  • each of R b and R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and CN;
  • Each R d is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
  • each Rf is independently selected from H, F, Cl, Br, I, OH, NH2 , CN and CH3 ;
  • Each R is independently selected from H, F, Cl, Br, I and CH3 .
  • the ring A is selected from Other variables are as defined in the present invention.
  • the ring A is selected from Other variables are as defined in the present invention.
  • the structural fragment selected from R 1 , e and other variables are as defined herein.
  • the structural fragment selected from Other variables are as defined in the present invention.
  • the E 2 is selected from C(O), C(O)CH 2 , CH 2 and CH 2 CH 2 , and other variables are as defined herein.
  • said R4 is selected from H, F, CH3 and CF3 , and other variables are as defined herein.
  • the X 1 is selected from N, CH and C(CF 3 ), and other variables are as defined herein.
  • the X 2 is selected from N, CH and CF, and other variables are as defined herein.
  • the R d is selected from F, and other variables are as defined herein.
  • the R 2 is selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, and said tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are optionally separated by 1, 2 or 3 R d substitutions, R d and other variables are as defined herein.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the Re is selected from H, F, Cl, Br, I, OH, NH2 , CN, CH3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCH 2CH3 , OCH( CH3 ) 2 , NCH3 , NCH2CH3 , N( CH3 ) 2 , SCH3 , SCH2CH3 , SCH (CH3)2 , -C ⁇ CH , cyclopropyl and Cyclobutyl, the CH3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCH2CH3 , OCH( CH3 ) 2 , NCH3 , NCH2CH3 , N ( CH3 ) 2 , SCH3 , SCH2CH3, SCH( CH3 ) 2 , -C ⁇ CH, cyclopropyl and cyclobutyl are optionally substituted with 1, 2 or 3 R, R and other variables as defined
  • the Re is selected from H, F, Cl, OH, CF 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCF 3 , SCH 3 , -C ⁇ CH, Other variables are as defined in the present invention.
  • the Re is selected from H, F, Cl , OH, NH2 , CH3 , CF3 , CH2CH3 , CH( CH3 ) 2 , OCH3 , OCF3, SCH 3 , SCF 3 , -C ⁇ CH,
  • Other variables are as defined in the present invention.
  • the R is selected from phenyl, naphthyl, and indazolyl, optionally surrounded by 1, 2, 3, 4, or 5 R e Substitution, Re and other variables are as defined herein.
  • the R 3 is selected from Other variables are as defined in the present invention.
  • the R 3 is selected from Other variables are as defined in the present invention.
  • the R 3 is selected from Other variables are as defined in the present invention.
  • the R 3 is selected from Other variables are as defined in the present invention.
  • the structural unit selected from R4 and other variables are as defined in the present invention .
  • the structural unit selected from R4 is selected from H, F, CH3 and CF3 , other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 and R 3 are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 3 and R d are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R d is selected from F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
  • R 3 is as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R d is selected from F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
  • R is as defined in the present invention.
  • the carbon atoms with "*" and “#” are chiral carbon atoms and exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • T 1 is selected from CH 2 , NH and O;
  • T 2 is selected from CH and N;
  • T 3 and T 4 are independently selected from CH 2 and NH;
  • n, p and x are each independently selected from 0, 1 or 2;
  • r, v and w are each independently selected from 1 or 2;
  • q, s and u are each independently selected from 1, 2 or 3;
  • each R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CF 3 ;
  • E 1 and E 3 are each independently selected from a bond, O, S, Se, NR a and CH 2 , said CH 2 being optionally substituted with 1 or 2 Ra ;
  • E 2 is selected from -C(O)-, -C(O)-(CH 2 ) g - and -(CH 2 ) h -, when g and h are not selected from 0, the -C(O)- (CH 2 ) g - and -(CH 2 ) h - are optionally substituted with 1, 2 or 3 R b ;
  • X 1 and X 2 are each independently selected from N and CR 4 ;
  • L 1 is selected from a bond and CH 2 optionally substituted with 1 or 2 R c ;
  • R 2 is selected from 5-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R d ;
  • R 3 is selected from C 6-10 aryl and 5-10 membered heteroaryl, the C 6-10 aryl and 5-10 membered heteroaryl are optionally replaced by 1, 2, 3, 4 or 5 R e replace;
  • e is selected from 0, 1, 2 and 3;
  • f, g and h are independently selected from 0, 1 and 2;
  • each R a is independently selected from H and CH 3 ;
  • each of R b and R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and CN;
  • Each R d is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and -OCO-C 1-3 alkylamino;
  • each Rf is independently selected from H, F, Cl, Br, I, OH, NH2 , CN and CH3 ;
  • Each R is independently selected from H, F, Cl, Br, I and CH3 .
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, which compound is selected from,
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • the present invention also provides following synthetic method:
  • R 3p is selected from
  • R 3 is selected from
  • R 3p is selected from
  • R 3 is selected from
  • the present invention also provides the following test methods:
  • control compound stock solution 1 mM
  • concentration of the test compound stock solution 10 mM.
  • Test Method 2 Anticellular Proliferative Effects of Compounds in Tumor Cell Lines AsPC-1 and GP2D
  • RPMI 1640 fetal bovine serum
  • FBS fetal bovine serum
  • Antibiotic-antimycotic antibiotic-antifungal
  • L-glutamine L-glutamine
  • DMSO dimethyl sulfoxide
  • the tumor cell lines were cultured in a 37°C, 5% CO2 incubator according to the culture conditions indicated in the culture method. Periodically passaged, cells in logarithmic growth phase were taken for plating.
  • the ULA plates were centrifuged at 1000 rpm for 10 minutes at room temperature. NOTE: After centrifugation, be careful not to cause unnecessary shaking. The plates were incubated overnight in an incubator at 37°C, 5% CO2 , and 100% relative humidity.
  • Preparation of 10X compound working solution and compound treatment of cells (the first day): After preparing 10X compound working solution (DMSO 10X working solution), add 15 ⁇ L of 10X compound working solution to ULA culture plate respectively, and add 15 ⁇ L of 10X compound working solution to the vehicle control and blank control. Add 15 ⁇ L of DMSO-cell culture medium mixture to it. Return the 96-well cell plate to the incubator for 120 hours. Cell spheroidization was observed every day until the end of the experiment.
  • CellTiter-Glo Luminescence Cell Viability Assay Day 5: The following steps were performed according to the instructions of Promega CellTiter-Glo 3D Luminescence Cell Viability Assay Kit (Promega#G9683). Add 150 ⁇ L (equivalent to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate in aluminum foil to protect from light. Shake the plate on an orbital shaker for 5 minutes. Mix the air mixture carefully by pipetting up and down 10 times. Make sure the spheroids are sufficiently detached before proceeding to the next step. The solution in the ULA plate was then transferred to a black bottom plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescent signal. Luminescent signals were detected on a 2104EnVision plate reader.
  • IR(%) (1 ⁇ (RLU compound ⁇ RLU blank control)/(RLU vehicle control ⁇ RLU blank control)*100%.
  • the inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters, including the minimum inhibition rate, the maximum inhibition rate and IC 50 .
  • the compound of the present invention has a good binding effect with KRAS G12D protein, can effectively inhibit p-ERK of GP2D cells, and has significant cell proliferation inhibitory activity on KRAS G12D mutant cells.
  • the compounds of the present invention have good in vivo pharmacokinetic properties and significant antitumor effects.
  • 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 the neutral forms of 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 the neutral form of 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 provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • 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 and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. 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
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, 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. "Optional" or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • 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.
  • aromatic ring is a cyclic group having a conjugated pi-electron system, the atoms of which are covered by a cloud of delocalized pi-electrons.
  • the structural formula when it conforms to the valence state and covalent bonding rules, it can be written in the form of alternating single and double bonds, or it can be written as represents the delocalized ⁇ electron cloud.
  • the structural formula The structures represented are all the same, the structural formula The structures represented are all the same. It can be a monocyclic or fused polycyclic ring system, wherein each ring is aromatic. Unless otherwise specified, the ring optionally contains 0, 1 or more heteroatoms independently selected from O, S and N.
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • 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 1-3 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.
  • C1-3alkoxy 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 1-3 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.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups and the like. Examples of C1-3 alkylthio groups include, but are not limited to, -SCH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , and the like.
  • C 2-4 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group may be monovalent, divalent or multivalent.
  • Examples of C 2-4 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like.
  • C 2-4 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond can be located anywhere in the group.
  • the C 2-4 alkynyl groups include C 2-3 , C 4 , C 3 and C 2 alkynyl groups and the like. It can be monovalent, bivalent or multivalent. Examples of C2-4alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 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, bicyclic and tricyclic rings, wherein bicyclic and tricyclic rings include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 5-10-membered heterocycloalkyl includes 5-6-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, and the like.
  • Examples of 5-10 membered heterocycloalkyl include, but are not limited to, 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-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, he
  • C 6-10 aryl ring and “C 6-10 aryl group” can be used interchangeably in the present invention
  • C 6-10 aryl ring” or C 6-10 aryl group means by A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which may be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It may be monovalent, divalent or polyvalent, and C6-10 aryl groups include C6-9 , C9 , C10 and C6 aryl groups and the like. Examples of C6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).
  • 5-10-membered heteroaryl ring and “5-10-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10-membered heteroaryl” refers to a ring consisting of 5 to 10 rings.
  • a cyclic group composed of atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10-membered heteroaryl groups include 5-8-membered, 5-7-membered, 5-6-membered, 5- and 6-membered, 7-membered, 8-membered, 9-membered, 10-membered and other heteroaryl groups.
  • Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • 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.
  • TBDPS tert-butyltriphenylsilyl
  • MOM methoxymethyl
  • TIPS tri-tert-butylsilyl
  • hr hours
  • min minutes.
  • 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 solvent used in the present invention is commercially available.
  • Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
  • 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.
  • the molecular docking process was performed by using Maestro ( Glide SP [1] and default options in version 2020-2).
  • Maestro Glide SP [1] and default options in version 2020-2).
  • For the preparation of the protein model select the crystal structure PDB: 5V6S of KRAS_G12C in the PDB database, mutate Cys12 to Asp12, use the protein preparation wizard module of Maestro [2] to add hydrogen atoms, and use the OPLS3 force field after energy optimization, as Docking template.
  • the three-dimensional structure of the molecule was generated using LigPrep and energy minimization was performed [3] , and the small molecule conformation was sampled using the confgen module.
  • the side length of the docking template was generated as The cube docking grid of , and the related molecules were docked using this grid file. Then, according to the calculated docking scrore and binding mode, a reasonable docking conformation was selected and saved, and Pymol was used to generate a binding mode map. Binding patterns of compounds A to J to KRAS G12D protein are shown in Figures 1 to 10 .
  • the compound of the present invention has good binding with KRAS G12D .
  • Lithium aluminum hydride (12.5 g, 329.38 mmol, 6.16 eq) was added to the reaction solution of compound A-4 (9.85 g, 53.48 mmol, 1 eq) in anhydrous tetrahydrofuran (200 mL) at 0 °C, and gradually warmed to room temperature (20 °C) stirring for 16hr. After the reaction, water (12.5 mL) was added dropwise with stirring at low temperature, 15% sodium hydroxide solution (12.5 mL) was added dropwise, and then water (25 mL) was added dropwise.
  • reaction solution was washed with saturated ammonium chloride (100 mL*3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried.
  • Triethylamine (16.54g, 163.43mmol, 22.75mL, 5eq) and di-tert-butyl carbonate (6.42g, 29.42mmol, 6.76mL, 0.9eq) were added to compound A-6 (12.44g, 32.69mmol) at 0°C , 1 eq) in anhydrous DCM (150 mL), stirred at 0 °C for 2 hr. After the reaction was completed, saturated ammonium chloride solution (80mL*3) was added to the reaction solution to quench the reaction, the layers were separated, the organic phase was taken, washed with saturated brine (80mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was Spin dry.
  • the concentrate was prepared by high performance liquid chromatography (HPLC) (column: Phenomenex C18150*40mm*5 ⁇ m; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: acetonitrile %: 1%-30%, 8min) Purified, and then subjected to supercritical fluid chromatography (SFC) (chiral column: DAICEL Chiralcel OD-3 100*4.6mm I.D., 3 ⁇ m); mobile phase: [A: carbon dioxide, B: ethanol (0.05% diethylamine)]; Elution gradient: B: 40%; flow rate: 2.8 mL/min) separation to give compound 1a and compound 1b.
  • HPLC high performance liquid chromatography
  • SFC supercritical fluid chromatography
  • the purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12D mutant GP2D human colon cancer cells.
  • cell line GP2D cell line GP2D, DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • 3D Cell Viability Assay (3D Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
  • GP2D cells were seeded in a 96-well U-bottom cell culture plate, 80 ⁇ L of cell suspension per well, which contained 2000 GP2D cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration, that is, from 200 ⁇ M to 2.56 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to the cell plate ranged from 1 ⁇ M to 0.0128 nM. The cell plates were placed in a carbon dioxide incubator for 5 days.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compound of the present invention has a significant inhibitory effect on the proliferation of GP2D cells.
  • GP2D cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37°C overnight;
  • the compounds of the present invention have a significant inhibitory effect on p-ERK in GP2D cells.
  • the purpose of this experiment is to verify the inhibitory effect of the compounds of the present invention on the proliferation of AsPC-1 cells with KRAS G12D mutation.
  • RPMI-1640 medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo Cell Viability Chemiluminescence Detection Reagent
  • the AsPC-1 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • AsPC-1 cells were seeded in white 96-well plates, 80 ⁇ L of cell suspension per well, which contained 3000 AsPC-1 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
  • the compounds to be tested were diluted 5-fold to the 8th concentration with a spray gun, that is, from 2 mM to 25.6 nM, and a double-well experiment was set up.
  • Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM.
  • the cell plates were placed in a carbon dioxide incubator for 6 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compounds of the present invention have a significant inhibitory effect on the proliferation of AsPC-1 cells.
  • the purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present invention on KRAS G12D mutant PANC0403 cells
  • Cell line PANC0403 was purchased from Nanjing Kebai, RPMI1640 medium was purchased from BI, penicillin/streptomycin antibiotics were purchased from Yuanbi, and fetal bovine serum was purchased from Gibco.
  • 3D Cell Viability Assay (3D Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. experimental method:
  • the PANC0403 cells were seeded in a 96-well U-bottom cell culture plate, 80 ⁇ L of cell suspension per well, which contained 4000 PANC0403 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the 8th concentration, that is, from 2000 ⁇ M to 25.6 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.128 nM.
  • the cell plates were placed in a carbon dioxide incubator for 5 days. After the incubation of the cell plate with the compound added, 100 ⁇ L of cell viability chemiluminescence detection reagent was added to the cell plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compound of the present invention has a significant inhibitory effect on the proliferation of PANC0403 cells.
  • IP intraperitoneal injection
  • C max the highest blood drug concentration after administration
  • T max the time required to reach the peak drug concentration after administration
  • T 1/2 the time required for the blood drug concentration to drop by half
  • AUC 0-last the area under the drug-time curve, which refers to the area enclosed by the blood drug concentration curve versus the time axis.
  • the compounds of the present invention exhibit higher drug exposure, longer half-life, and have good in vivo pharmacokinetic properties.
  • mice Female Balb/c nude mice were inoculated subcutaneously with the PANC0403 human pancreatic cancer cell line and randomly divided into vehicle control and compound groups (6 animals per group) according to tumor volume and body weight on day 23 after inoculation, and administered as described below.
  • Drug treatment 6 animals per group
  • Group 1 vehicle control group: administration started in the afternoon on the day of grouping (the day of administration was the 0th day of administration), and the vehicle was administered by intraperitoneal injection at a dose of 0.1 mL/10 g body weight twice a day.
  • Group 2 compound group: administration started in the afternoon on the day of grouping (the day of administration was the 0th day of administration), and the compound was administered by intraperitoneal injection at a dose of 5 mg/kg body weight twice a day.
  • the vehicle was 10% Sulfobutylcyclodextrin in 50 mM pH 5.0 citric acid buffer, Sulfobutylcyclodextrin Supplier: CyDex Pharmaceuticals, KS.
  • T tumor volume
  • TGI tumor inhibition rate
  • T/C tumor proliferation rate
  • the compounds of the present invention have significant antitumor effect on human pancreatic cancer PANC0403 xenograft tumor model.

Abstract

一系列嘧啶并杂环类化合物及其应用，具体涉及式（II）所示化合物或其药学上可接受的盐，

Description

嘧啶并杂环类化合物及其应用
本发明主张如下优先权：
CN202110312693.8，申请日：2021年03月24日；
CN202111127361.9，申请日：2021年09月18日；
CN202210108554.8，申请日：2022年01月28日；
CN202210179950.X，申请日：2022年02月25日。
技术领域
本发明涉及一系列嘧啶并杂环类化合物及其应用，具体涉及式(II)所示化合物及其药学上可接受的盐。
背景技术
KRAS基因是人类癌症中最常出现突变的致癌基因之一。KRAS基因突变除了直接促进肿瘤细胞的增殖和生存以外，还能够对肿瘤微环境产生影响。在人类癌症中，该突变出现在接近90％的胰腺癌中，30％-40％的结肠癌中，15％-20％的肺癌中。另外，80％的致癌突变发生在密码子12上，最常见的突变包括：p.G12D(41％)、p.G12V(28％)和p.G12C(14％)。
KRAS的激活可以通过多种效应蛋白来控制各种各样的细胞功能，如细胞增殖、凋亡、代谢等等。直接抑制KRAS癌蛋白细胞一直是精准肿瘤学的一个长期追求。目前，直接靶向KRAS突变的小分子主要集中在KRAS G12C领域。一些小分子KRAS G12C抑制剂，如Amgen公司的AMG510和和Mirati Therapeutics的MRTX849，它们的发现及临床开发，预示着精准肿瘤学新时代的到来。但至今还没有KRAS G12D小分子进入临床研究阶段，KRAS G12D突变的肿瘤患者也还没有从精准医疗中获益，因此亟需KRAS G12D小分子领域的研究。
发明内容
本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2022082328-appb-000001
其中，
环A选自
Figure PCTCN2022082328-appb-000002
T 1选自CH 2、NH和O；
T 2选自CH和N；
T 3和T 4分别独立地选自CH 2和NH；
m、n、p和x分别独立地选自0、1或2；
r、v和w分别独立地选自1或2；
q和u分别独立地选自1、2或3；
各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CF 3；
E 1和E 3分别独立地选自键、O、S、Se、NH和CH 2，所述NH和CH 2分别独立地任选被1或2个R a取代；
E 2选自-C(O)-、-C(O)-(CH 2) g-和-(CH 2) h-，当g和h不选自0时，所述-C(O)-(CH 2) g-和-(CH 2) h-分别独立地任选被1、2或3个R b取代；
X 1和X 2分别独立地选自N和CR 4；
L 1选自键和CH 2，所述CH 2任选被1或2个R c取代；
R 2选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R d取代；
R 3选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基和5-10元杂芳基分别独立地任选被1、2、3、4或5个R e取代；
R 4选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基，所述C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基分别独立地任选被1、2或3个R f取代；
e选自0、1、2和3；
f、g和h分别独立地选自0、1和2；
各R a分别独立地选自H和CH 3；
各R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和CN；
各R d分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
各R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1- 3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基，所述C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基分别独立地任选被1、2或3个R取代；
各R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
各R分别独立地选自H、F、Cl、Br、I和CH 3。
在本发明的一些方案中，所述环A选自
Figure PCTCN2022082328-appb-000003
Figure PCTCN2022082328-appb-000004
其他变量如本发明所定义。
在本发明的一些方案中，所述环A选自
Figure PCTCN2022082328-appb-000005
Figure PCTCN2022082328-appb-000006
其他变量如本发明所定义。
在本发明的一些方案中，所述结构片段
Figure PCTCN2022082328-appb-000007
选自
Figure PCTCN2022082328-appb-000008
R 1、e及其他变量如本发明所定义。
在本发明的一些方案中，所述结构片段
Figure PCTCN2022082328-appb-000009
选自
Figure PCTCN2022082328-appb-000010
其他变量如本发明所定义。在本发明的一些方案中，所述E 2选自C(O)、C(O)CH 2、CH 2和CH 2CH 2，其他变量如本发明所定义。
在本发明的一些方案中，所述结构片段
Figure PCTCN2022082328-appb-000011
选自
Figure PCTCN2022082328-appb-000012
Figure PCTCN2022082328-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，所述结构片段
Figure PCTCN2022082328-appb-000014
选自
Figure PCTCN2022082328-appb-000015
其他变量如本发明所定义。
在本发明的一些方案中，所述R 4选自H、F、CH 3和CF 3，其他变量如本发明所定义。
在本发明的一些方案中，所述X 1选自N、CH和C(CF 3)，其他变量如本发明所定义。
在本发明的一些方案中，所述X 2选自N、CH和CF，其他变量如本发明所定义。
在本发明的一些方案中，所述R d选自H、F和-O-C(＝O)-N(CH 3) 2，其他变量如本发明所定义。
在本发明的一些方案中，所述R d选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自四氢吡咯基和六氢-1H-吡咯里嗪基，所述四氢吡咯基和六氢-1H-吡咯里嗪基任选被1、2或3个R d取代，R d及其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自
Figure PCTCN2022082328-appb-000016
其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自
Figure PCTCN2022082328-appb-000017
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000018
选自
Figure PCTCN2022082328-appb-000019
Figure PCTCN2022082328-appb-000020
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000021
选自
Figure PCTCN2022082328-appb-000022
其他变量如本发明所定义。
在本发明的一些方案中，所述R e选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH(CH 3) 2、NCH 3、NCH 2CH 3、N(CH 3) 2、SCH 3、SCH 2CH 3、SCH(CH 3) 2、-C≡CH、环丙基和环丁基，所述CH 3、CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、OCH(CH 3) 2、NCH 3、NCH 2CH 3、N(CH 3) 2、SCH 3、SCH 2CH 3、SCH(CH 3) 2、-C≡CH、环丙基和环丁基任选被1、2或3个R取代，R及其他变量如本发明所定义。
在本发明的一些方案中，所述R e选自H、F、Cl、OH、CF 3、CH 2CH 3、CH(CH 3) 2、OCF 3、SCH 3、-C≡CH、
Figure PCTCN2022082328-appb-000023
其他变量如本发明所定义。
在本发明的一些方案中，所述R e选自H、F、Cl、OH、NH 2、CH 3、CF 3、CH 2CH 3、CH(CH 3) 2、OCH 3、OCF 3、SCH 3、SCF 3、-C≡CH、
Figure PCTCN2022082328-appb-000024
其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自苯基、萘基和吲唑基，所述苯基、萘基和吲唑基任选被1、2、3、4或5个R e取代，R e及其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自
Figure PCTCN2022082328-appb-000025
Figure PCTCN2022082328-appb-000026
Figure PCTCN2022082328-appb-000027
其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自
Figure PCTCN2022082328-appb-000028
Figure PCTCN2022082328-appb-000029
Figure PCTCN2022082328-appb-000030
其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自
Figure PCTCN2022082328-appb-000031
其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自
Figure PCTCN2022082328-appb-000032
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000033
选自
Figure PCTCN2022082328-appb-000034
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000035
选自
Figure PCTCN2022082328-appb-000036
Figure PCTCN2022082328-appb-000037
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000038
选自
Figure PCTCN2022082328-appb-000039
R 4及其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022082328-appb-000040
选自
Figure PCTCN2022082328-appb-000041
R 4选自H、F、CH 3和CF 3，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000042
其中，R 2和R 3如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000043
其中，R 3和R d如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000044
其中，
R d选自F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
R 3如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000045
其中，
R d选自F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
R 3如本发明所定义；
带“*”和“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022082328-appb-000046
其中，
环A选自
Figure PCTCN2022082328-appb-000047
T 1选自CH 2、NH和O；
T 2选自CH和N；
T 3和T 4分别独立地选自CH 2和NH；
m、n、p和x分别独立地选自0、1或2；
r、v和w分别独立地选自1或2；
q、s和u分别独立地选自1、2或3；
各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CF 3；
E 1和E 3分别独立地选自键、O、S、Se、NR a和CH 2，所述CH 2任选被1或2个R a取代；
E 2选自-C(O)-、-C(O)-(CH 2) g-和-(CH 2) h-，当g和h不选自0时，所述-C(O)-(CH 2) g-和-(CH 2) h-任选被1、2或3个R b取代；
X 1和X 2分别独立地选自N和CR 4；
L 1选自键和CH 2，所述CH 2任选被1或2个R c取代；
R 2选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R d取代；
R 3选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R e取代；
R 4选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基，所述C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基任选被1、2或3个R f取代；
e选自0、1、2和3；
f、g和h分别独立地选自0、1和2；
各R a分别独立地选自H和CH 3；
各R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和CN；
各R d分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
各R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1- 3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基，所述C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基任选被1、2或3个R取代；
各R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
各R分别独立地选自H、F、Cl、Br、I和CH 3。
在本发明的一些方案中，所述结构片段
Figure PCTCN2022082328-appb-000048
选自
Figure PCTCN2022082328-appb-000049
其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明提供了下式化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000050
Figure PCTCN2022082328-appb-000051
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000052
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022082328-appb-000053
Figure PCTCN2022082328-appb-000054
本发明还提供了下列合成方法：
方法1：
Figure PCTCN2022082328-appb-000055
方法2：
Figure PCTCN2022082328-appb-000056
Figure PCTCN2022082328-appb-000057
其中，R 3p选自
Figure PCTCN2022082328-appb-000058
Figure PCTCN2022082328-appb-000059
R 3选自
Figure PCTCN2022082328-appb-000060
方法3：
Figure PCTCN2022082328-appb-000061
其中，R 3p选自
Figure PCTCN2022082328-appb-000062
Figure PCTCN2022082328-appb-000063
R 3选自
Figure PCTCN2022082328-appb-000064
本发明还提供了下列测试方法：
测试方法1.KRAS G12D抑制活性测试
1、目的：通过TR-FRET的方法，筛选出能有效抑制KRAS与GTP结合的化合物。
2、耗材和仪器信息见表1。
表1 耗材和仪器信息
Figure PCTCN2022082328-appb-000065
3、试剂准备
a.储存试剂：
1)KRAS核苷酸交换缓冲液
取20mL 1000mM HEPES，20mL 500mM EDTA，10mL 5M氯化钠，100％0.1mL吐温20，949.9mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。
2)KRAS实验缓冲液
取20mL 1000mM HEPES，10mL 1000mM氯化镁，30mL 5M氯化钠，100％0.05mL吐温20，939.95mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。
3)KRAS/Bodipy GDP/Tb-SA混合液
取9.5μL 95μM KRAS蛋白，440.5μL KRAS核苷酸交换缓冲液混合，室温下孵育1小时后，与8.4μL 17.9μM Tb-SA，1.8μL 5mM Bodipy GDP，9539.8μL KRAS实验缓冲液，配制成1L溶液，混合后室温下静置6小时，储存至-80℃条件下。
b.实验试剂：
1)KRAS酶溶液
取73.3μL KRAS/Bodipy GDP/Tb-SA混合液，2126.7μL KRAS实验缓冲液，配制成2200μL溶液。
2)SOS/GTP混合液
取1.59μL 166μM SOS蛋白，198μL 100mM GTP，2000.41μL KRAS实验缓冲液，配制成2200μL溶液。
4、实验流程
1)对照化合物母液浓度为1mM，待测化合物母液浓度为10mM。转移9μL对照化合物和待测化合物至384-LDV板内；
2)使用Bravo将LDV板上的化合物进行10点3倍稀释；
3)使用ECHO将LDV板上的化合物转移9nL至实验板；
4)使用Dragonfly自动加样仪依次向实验板每孔中加入3μL 3nM Kras/0.5nM TB-SA/30nM BodipyGDP混合液和3μL Ras buffer，以1000rpm/min，将实验板离心1分钟；
5)实验板在室温中孵育1小时；
6)使用Dragonfly自动加样仪在实验板每孔加入3μL 120nM SOS/9mM GTP混合液，以1000rpm/min，将实验板离心1分钟；
7)实验板在室温中孵育1小时；
8)使用Envision读板并记录数据；
9)使用Excel和Xlfit进行数据分析，计算待测化合物IC 50。
测试方法2.化合物在肿瘤细胞系AsPC-1和GP2D中的抗细胞增殖作用
研究目的：本实验通过检测化合物在肿瘤细胞系AsPC-1和GP2D中对体外细胞活性的影响而研究化合物抑制细胞增殖的作用。
实验材料见表2。
表2 实验材料
细胞系 肿瘤类型 生长特点 培养方法
AsPC-1 胰腺癌 贴壁生长 RPMI 1640+10％FBS
GP2D 结肠癌 贴壁生长 DMEM+10％FBS+2mM L-glutamine
Ultra Low Cluster-96孔板(Corning-7007)
Greiner CELLSTAR 96-孔板(#655090)
Promega CellTiter-Glo 3D发光法细胞活性检测试剂盒(Promega-G9683)
2104-10EnVision读板器，PerkinElmer
RPMI 1640，DMEM，PBS(磷酸盐缓冲溶液)，FBS(胎牛血清)，Antibiotic-antimycotic(抗生素-抗真菌药)，L-glutamine(L-谷氨酰胺)，DMSO(二甲基亚砜)
实验方法及步骤
(1)细胞培养
将肿瘤细胞系按培养方法所示的培养条件在37℃，5％CO2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。
(2)细胞铺板
用台盼兰进行细胞染色并计数活细胞。将AsPC-1细胞浓度调整至7000个细胞每孔，将GP2D细胞浓度调整至8000个细胞每孔。
在ULA培养板中每孔加入135μL细胞悬液，在空白对照空中加入同样体积且不含细胞的培养液。
铺板后，立刻在室温条件下将ULA培养板离心10分钟，离心条件1000rpm。注意：在离心后，务必小心处理后续操作，不要造成不必要的震荡。将培养板在37℃,5％CO 2,及100％相对湿度的培养箱中培养过夜。
10X化合物工作液的配制及化合物处理细胞(第一天)：配制好10X化合物工作液(DMSO 10X工作液)后，分别向ULA培养板内加入15μL的10X化合物工作液，在溶媒对照和空白对照中加入15μL DMSO-细胞培养液混合液。将96孔细胞板放回培养箱中培养120小时。每天观察细胞成球情况直至实验终点。
CellTiter-Glo发光法细胞活性检测(第五天)：以下步骤按照Promega CellTiter-Glo 3D发光法细胞活性检测试剂盒(Promega#G9683)的说明书来进行。在每孔中加入150μL(等于每孔中细胞培养液体积)的CellTiter-Glo 3D试剂。用铝箔纸包裹细胞板以避光。将培养板在轨道摇床上振摇5分钟。小心的用移液管上下吹打10次，混匀空内混合物。在继续下一步之前需确保细胞球体充分被分离。然后将ULA培养板内的溶液转移至黑底培养板(#655090)中，在室温放置25分钟以稳定发光信号。在2104EnVision读板器上检测发光信号。
数据分析：
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC 50。
技术效果
本发明化合物与KRAS G12D蛋白有较好的结合作用，可有效抑制GP2D细胞p-ERK，对KRAS G12D突变的细胞具有显著的细胞增殖抑制活性。此外，本发明化合物具有良好的体内药物代谢动力学性质和显著的抗肿瘤作用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022082328-appb-000066
和楔形虚线键
Figure PCTCN2022082328-appb-000067
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022082328-appb-000068
和直形虚线键
Figure PCTCN2022082328-appb-000069
表示立体中心的相对构型，用波浪线
Figure PCTCN2022082328-appb-000070
表示楔形实线键
Figure PCTCN2022082328-appb-000071
或楔形虚线键
Figure PCTCN2022082328-appb-000072
或用波浪线
Figure PCTCN2022082328-appb-000073
表示直形实线键
Figure PCTCN2022082328-appb-000074
和直形虚线键
Figure PCTCN2022082328-appb-000075
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用
Figure PCTCN2022082328-appb-000076
表示，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％， 或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022082328-appb-000077
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022082328-appb-000078
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022082328-appb-000079
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“芳香性环”为具有共轭π电子体系的环状基团，其原子间被离域π电子云覆盖。在结构式中，在符合原子价态和共价键成键规则时，可以书写为单双键交替的形式，也可以用
Figure PCTCN2022082328-appb-000080
表示离域π电子云。例如，结构式
Figure PCTCN2022082328-appb-000081
所表示的结构均相同，结构式
Figure PCTCN2022082328-appb-000082
Figure PCTCN2022082328-appb-000083
所表示的结构均相同。其可以是单环或稠合多环体系，其中各个环均为芳香性的。除非另有规定，该环任选地包含0、1或多个独立选自O、S和N的杂原子。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，术语“C 1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷硫基包括C 1-3、C 1-2和C 3烷硫基等。C 1-3烷硫基的实例包括但不限于-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2等。
除非另有规定，“C 2-4烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至4个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C 2-4烯基包括C 2-3、C 4、C 3和C 2烯基等；所述C 2-4烯基可以是一价、二价或者多价。C 2-4烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、丁间二烯基等。
除非另有规定，“C 2-4炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至4个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C 2-4炔基包括C 2-3、C 4、C 3和C 2炔基等。其可以是一价、二价或者多价。C 2-4炔基的实例包括但不限于乙炔基、丙炔基、丁炔基等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-10元杂环烷基包括5-6元、5元、6元、7元、8元、9元、10元等杂环烷基等。5-10元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基 等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元、7元、8元、9元、10元等杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝 对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022082328-appb-000084
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明采用下述缩略词：TBDPS：叔丁基三苯基硅基；MOM：甲氧基甲基；TIPS：三叔丁基硅基；hr：小时；min：分钟。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用
Figure PCTCN2022082328-appb-000085
软件命名，市售化合物采用供应商目录名称。
附图说明
图1.化合物A与KRAS G12D蛋白的结合模式图。
图2.化合物B与KRAS G12D蛋白的结合模式图。
图3.化合物C与KRAS G12D蛋白的结合模式图。
图4.化合物D与KRAS G12D蛋白的结合模式图。
图5.化合物E与KRAS G12D蛋白的结合模式图。
图6.化合物F与KRAS G12D蛋白的结合模式图。
图7.化合物G与KRAS G12D蛋白的结合模式图。
图8.化合物H与KRAS G12D蛋白的结合模式图。
图9.化合物I与KRAS G12D蛋白的结合模式图。
图10.化合物J与KRAS G12D蛋白的结合模式图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
计算例1
Figure PCTCN2022082328-appb-000086
分子对接过程是通过使用Maestro(
Figure PCTCN2022082328-appb-000087
版本2020-2)中的Glide SP [1]和默认选项进行的。对于蛋白模型的准备，选取PDB数据库中KRAS_G12C的晶体结构PDB:5V6S，将Cys12模拟突变为Asp12，使用Maestro [2]的蛋白质准备向导模块添加氢原子，并使用OPLS3力场经过能量优化后，作为对接模板。对于配体的准备，使用LigPrep生成了分子的三维结构，并进行了能量最小化 [3]，使用confgen模块对小分子构象进行采样。以5V6S的配体作为质心针对对接模板生成了边长为
Figure PCTCN2022082328-appb-000088
的正方体对接网格，使用该网格文件对相关分子进行了对接。然后根据计算得到的docking scrore以及结合模式选择并保存了合理对接构象，使用Pymol生成结合模式图。化合物A～J与KRAS G12D蛋白的结合模式图如附图1～10 所示。
[1]Glide,
Figure PCTCN2022082328-appb-000089
LLC,New York,NY,2020.
[2]Maestro,
Figure PCTCN2022082328-appb-000090
LLC,New York,NY,2020.
[3]LigPrep,
Figure PCTCN2022082328-appb-000091
LLC,New York,NY,2020.
[4]Pymol,
Figure PCTCN2022082328-appb-000092
LLC,New York,NY,2020.
结论：本发明化合物与KRAS G12D有较好的结合。
参考例1 中间体A的合成
Figure PCTCN2022082328-appb-000093
第一步
将硫酸二甲酯(31.7g,251.33mmol,23.83mL,1.44eq)加入到化合物A-1中(25g,174.65mmol,1eq)中，油浴60℃搅拌19小时。反应液冷却至室温后，逐滴加入到三乙胺(120mL)中，搅拌1小时，加水(300mL)，用乙酸乙酯(300mL*3)萃取，合并所有有机相，用无水硫酸钠干燥，过滤，滤液旋干，得到化合物A-2，未经纯化直接投下一步。
1H NMR(400MHz,CDCl 3)δ＝2.13-2.24(m,1H),2.28-2.39(m,1H),2.44-2.66(m,2H),3.73(s,3H),3.85(s,3H),4.49-4.55(m,1H)。
第二步
将化合物A-2(44g,279.96mmol,1eq)和2-硝基乙酸甲酯(44.28g,371.85mmol,1.33eq)混合后，油浴60℃搅拌40小时。反应液冷却至室温后，粗产品经过柱层析纯化(石油醚：二氯甲烷＝1:1～0:1，接着石油醚：乙酸乙酯＝3:1)得到化合物A-3。
1H NMR(400MHz,CDCl 3)δ＝2.26-2.37(m,1H),2.44-2.55(m,1H),3.15-3.44(m,2H),3.80-3.87(m,6H),4.62(ddd,J＝17.38,9.10,5.65Hz,1H),9.42-10.02(m,1H)。
第三步
将湿钯碳(含钯10％，含水50％)加入到化合物A-3(18.00g,73.71mmol,1eq)的无水甲醇(250mL)溶液中，用氢气置换三次后，在H 2(45psi)氛围下，油浴60℃搅拌2天。反应液冷却至室温后过滤，滤液旋干，得到化合物A-4。
1H NMR(400MHz,CDCl 3)δ＝1.29-2.30(m,9H),3.71-3.75(m,3H),3.76-3.81(m,6H),4.02-4.13(m,2H),4.41(d,J＝4.13Hz,1H),6.11-6.38(m,1H)。
第四步
将氢化铝锂(12.5g,329.38mmol,6.16eq)在0℃下加入到化合物A-4(9.85g,53.48mmol,1eq)的无水四氢呋喃(200mL)反应液中，逐渐升至室温(20℃)搅拌16hr。反应结束后，低温搅拌下滴加水(12.5mL)，再滴加15％氢氧化钠溶液(12.5mL)，然后再加入水(25mL)。此刻反应体系将成为砂状固体，补加四氢呋喃(200mL)，室温搅拌1hr，直接过滤，取滤液；滤渣再加四氢呋喃(500mL*3)搅拌1hr，过滤，取滤液，合并上述滤液旋干，得到化合物A-5。
1H NMR(400MHz,CDCl 3)δ＝0.94-2.44(m,6H),2.47-3.05(m,2H),3.22-4.03(m,3H)。
第五步
将叔丁基二苯基氯硅烷(39.43g,143.46mmol,36.85mL,1.5eq)，咪唑(13.02g,191.28mmol,2eq)和4-二甲氨基吡啶(2.34g,19.14mmol,0.2eq)加入到化合物A-5(13.6g,95.64mmol,1eq)的无水二氯甲烷(200mL)溶液中，室温(25℃)搅拌20hr。反应结束后，反应液用饱和氯化铵(100mL*3)洗，有机相用饱和食盐水(100mL)洗后，用无水硫酸钠干燥，过滤，滤液旋干。粗品通过柱层析进行纯化(石油醚:乙酸乙酯＝10:1，接着二氯甲烷:甲醇＝10:1)得到化合物A-6。
MS(ESI)m/z:381.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ＝1.00-1.10(m,9H),1.87-2.02(m,3H),2.07-2.22(m,1H),2.59(br d,J＝12.80Hz,1H),2.72-2.89(m,1H),3.15-3.30(m,1H),3.39-3.60(m,3H),3.64-3.84(m,1H),3.86-3.99(m,1H),7.35-7.47(m,6H),7.59-7.73(m,4H)。
第六步
将三乙胺(16.54g,163.43mmol,22.75mL,5eq)和碳酸二叔丁酯(6.42g,29.42mmol,6.76mL,0.9eq)加入到0℃的化合物A-6(12.44g,32.69mmol,1eq)的无水DCM(150mL)溶液中，0℃搅拌2hr。反应结束后，向反应液中加饱和氯化铵溶液(80mL*3)淬灭反应，分液，取有机相，用饱和食盐水(80mL)洗后，用无水硫酸钠干燥，过滤，滤液旋干。粗品经过柱层析纯化(石油醚：四氢呋喃＝10:1～8:1)，得到中间体A。MS(ESI)m/z:481.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ＝1.02-1.11(m,9H),1.25-1.51(m,9H),1.57-2.04(m,4H),2.38-3.17(m,3H),3.37-3.78(m,2H),4.01-4.69(m,2H),7.35-7.47(m,6H),7.59-7.73(m,4H)。
实施例1
Figure PCTCN2022082328-appb-000094
Figure PCTCN2022082328-appb-000095
第一步
向化合物1-1(18.77g，115.15mmol)的N,N-二甲基甲酰胺(100mL)和乙腈(100mL)溶液中加入(1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(48.95g，138.18mmol)，反应在80℃搅拌1小时。反应完全后，向反应液加入500mL水，用乙酸乙酯萃取两次，每次100mL，有机相用水洗涤两次，每次100mL，再用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，经制备色谱柱(柱子:Phenomenex luna C18(250*70毫米，10微米)；流动相：[水(甲酸)-乙腈]；梯度：乙腈％:24％-54％,24分钟)纯化，得到化合物1-2。MS(ESI)m/z:181.1[M+H] +。
第二步
向化合物1-2(8g，44.20mmol)的乙腈(80mL)溶液中，加入N-碘琥珀酰亚胺(14.92g，66.30mmol)，一水合对甲苯磺酸(420.38mg，2.21mmol)，反应液70℃搅拌1小时。反应完全后，加入10mL饱和亚硫酸钠，20mL水，用乙酸乙酯萃取两次，每次20mL，合并的有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，得到化合物1-3。MS(ESI)m/z:306.9[M+H] +。
第三步
向化合物1-3(13.5g，43.99mmol)的N,N-二甲基乙酰胺(100mL)中，加入氰化亚铜(5.91g，65.98mmol)，反应在140℃氮气保护下搅拌2小时。反应完全后，反应液加入400mL水，200mL乙酸乙酯，过滤，滤液用乙酸乙酯萃取两次，每次100mL，合并有机层，水洗两次，每次100mL，再用100mL饱和氯化钠水溶液洗一次，无水硫酸钠干燥，过滤，滤液减压浓缩干，得到化合物1-4。MS(ESI)m/z:205.9[M+H] +。
第四步
向浓硫酸(30mL)中加入化合物1-4(11.5g，55.82mmol)，反应液在70℃搅拌2小时。反应完全后，反应液加入到300mL冰水中，用饱和碳酸钾调节pH到7-8，,用乙酸乙酯萃取两次，每次200mL，合并的乙酸乙酯相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，得到到化合物1-5。MS(ESI)m/z:224.0[M+H] +。
第五步
向化合物1-5(5.09g，22.72mmol)的N,N-二甲基甲酰胺(70mL)溶液中，加入碳酸钾(12.56g，90.88mmol)，羰基二咪唑(14.74g，90.88mmol)，反应在90℃下搅拌14小时。反应完全后，反应液加入200mL水中，用1N盐酸调节pH到6-7，,用乙酸乙酯萃取两次，每次200mL，合并的乙酸乙酯相，用200mL水洗涤，200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，加入5mL乙酸乙酯，25mL石油醚，20℃打浆搅拌30分钟，过滤，滤饼减压浓缩干得到化合物1-6。MS(ESI)m/z:249.8[M+H] +。
第六步
将化合物1-6(4g,16.00mmol,1eq.)溶解到无水甲醇(150mL)中，然后加入甲醇钠(1.90g,35.20mmol,2.2eq.)，升高温度至70℃反应12小时。反应完成后，减压浓缩，加入1N的盐酸水溶液150mL并搅拌10分钟。过滤，收集滤饼并减压浓缩。得到化合物1-7。MS(ESI)m/z:245.9[M+H] +。
第七步
将化合物1-7(1g,4.07mmol,1eq.)溶解到***(20mL)中，然后加入N,N-二异丙基乙胺(1.48g,11.48mmol,2mL,2.82eq.)，升高温度至90℃反应1小时。反应完成后，减压浓缩，浓缩物通过二氯甲烷80mL稀释，然后倒入冰的4M碳酸氢钠水溶液(200mL)中，洗涤分液，收集有机相，水相用二氯甲烷萃取(70mL x 2)，合并有机相，减压浓缩，经硅胶柱(石油醚:乙酸乙酯＝1:0～5:1)纯化得到化合物1-8。
第八步
将化合物1-8(535mg,1eq.)和中间体A(1.00g,2.08mmol,1.1eq.)依次加入到二氯甲烷(10mL)中，然后加入N,N-二异丙基乙胺(734.30mg,5.68mmol,989.63μL,3eq.)，反应在25℃反应12小时。反应完成后，减压浓缩。浓缩物通过硅胶柱(石油醚:乙酸乙酯＝1:0～5:1)纯化得到化合物1-9。MS(ESI)m/z:732.1[M+H] +。
第九步
向化合物1-9(800mg,1.09mmol,1eq.)溶于四氢呋喃(5mL)中，然后加入甲硫醇钠(107.36mg,1.53mmol,97.60μL,1.4eq.)，反应在25℃搅拌反应1小时。反应完成后，加入水10mL，乙酸乙酯20mL(10mL*2)萃取，合并有机相，减压浓缩。浓缩物通过硅胶柱(石油醚:乙酸乙酯＝1:0～2:1)纯化得到化合物1-10。MS(ESI)m/z:742.2[M+H] +。
第十步
将化合物1-10(720mg,969.30μmol,1eq.)溶于四氢呋喃(5mL)中，然后加入四丁基氟化铵(1M四氢呋喃溶液)(1M,1.07mL,1.1eq.)，25℃反应1小时。反应完成后减压浓缩，浓缩物通过硅胶柱(石油醚:乙酸乙酯＝1:0～3:1)纯化得到化合物1-11
MS(ESI)m/z:468.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ＝4.94-5.12(d,J＝13.20Hz,1H),3.96-4.61(m,5H),3.09-3.25(m,1H),2.59(s,3H),1.88-2.12(m,2H),1.68-1.86(m,2H),1.42-1.54(s,9H)。
第十一步
将化合物1-11(250mg,534.25μmol,1eq.),化合物1-12(410.73mg,801.38μmol,1.5eq.)，1,1-二(叔丁基膦基)二茂铁氯化钯(27.48mg,53.43μmol,0.1eq.)和碳酸钠(169.87mg,1.60mmol,3eq.)加入到二氧六环(10mL)和水(2mL)混合溶液中，氮气保护下90℃搅拌反应12小时，反应完成后，减压浓缩。浓缩物通过硅胶柱(石油醚:乙酸乙酯＝1:0～3:1)纯化得到化合物1-13。MS(ESI)m/z:818.4[M+H] +。
第十二步
将化合物1-13(325mg,397.28μmol,1eq.)溶于二氯甲烷(10mL)中，然后加间氯过氧苯甲酸(182.82mg,794.57μmol,75％含量,2eq.)，25℃反应20分钟。反应完成后，过滤，滤液直接湿法上样通过硅胶柱，(石油醚:乙酸乙酯＝1:0～0:1)纯化得到化合物1-14。MS(ESI)m/z:850.4[M+H] +。
第十三步
将化合物1-14(100mg,117.64μmol,1eq.)和化合物1-15(93.64mg,588.20μmol,5eq.)溶于二氯甲烷(5mL)中，然后加入氢化钠(14.12mg,352.92μmol,60％纯度,3eq.)，25℃反应10分钟。反应完成后，向反应液滴加5mL 1N的盐酸水溶液淬灭，然后通过薄层硅胶色谱法(石油醚:乙酸乙酯＝1:1)纯化得到化合物1-16。MS(ESI)m/z:929.4[M+H] +。
第十四步
将化合物1-16(105mg,113.01μmol,1eq.)溶于四氢呋喃(5mL)中，然后四丁基氟化铵(1M四氢呋喃溶液)(1M,339.02μL,3eq.)，25℃反应10分钟。反应完成后，反应液通过薄层硅胶色谱法(二氯甲烷:乙酸乙酯＝1:1)纯化得到化合物1-17。MS(ESI)m/z:773.2[M+H] +。
第十五步
将化合物1-17(120mg,155.28μmol,1eq.)溶于甲醇(3mL)中，然后加入盐酸甲醇溶液(4M,2mL,51.52eq.)，25℃反应12分钟。反应完成后，减压浓缩，浓缩物加入饱和碳酸氢钠水溶液10mL中，乙酸乙酯30mL(10mL*3)萃取，合并有机相，减压浓缩。浓缩物通过高效液相色谱法(HPLC)(分离柱:Phenomenex C18150*40mm*5μm；流动相:[水(0.1％甲酸)-乙腈]；梯度：乙腈％:1％-30％,8min)制备纯化，再经超临界流体色谱(SFC)(手性柱:DAICEL Chiralcel OD-3 100*4.6mm I.D.,3μm)；流动相:[A:二氧化碳，B:乙醇(0.05％二乙胺)]；洗脱梯度：B：40％；流速:2.8mL/min)分离，得到化合物1a和化合物1b。
化合物1a(SFC分析方法：手性柱:Chiralcel OD-3 100*4.6mm I.D.,3μm；流动相:[A:二氧化碳，B:乙醇(0.05％二乙胺)]洗脱梯度：B：40％；流速:2.8mL/min，保留时间：2.239min，ee＝96％)：MS(ESI)m/z:629.4[M+H] +； 1H NMR(400MHz,CD 3OD)δ:7.80-7.90(m,1H),7.17-7.40(m,3H),5.27-5.50(m,1H),5.04(br d,J＝13.6Hz,1H),4.57-4.69(m,1H),4.28-4.53(m,3H),4.15(br d,J＝6.4Hz,1H),3.65-3.86(m,2H),3.35-3.62(m,4H),3.10-3.30(m,2H),1.75-2.55(m,10H)。
化合物1b(SFC分析方法：手性柱:Chiralcel OD-3 100*4.6mm I.D.,3μm；流动相:[A:二氧化碳，B:乙醇(0.05％二乙胺)]洗脱梯度：B：40％；流速:2.8mL/min，保留时间：3.392min，ee＝99％)：MS(ESI)m/z:629.4[M+H] +； 1H NMR(400MHz,CD 3OD)δ:7.82-7.86(m,1H),7.13-7.38(m,3H),5.25-5.45(m,1H),5.03-5.06(m,1H),4.56-4.64(m,2H),4.25-4.50(m,3H),4.15(br d,J＝7.3Hz,1H),3.64-3.81(m,2H),3.34-3.61(m,3H),3.20-3.30(m,1H),3.04-3.15(m,1H),1.85-2.40(m,10H)。
参考实施例1的合成步骤，制备如下化合物：
Figure PCTCN2022082328-appb-000096
Figure PCTCN2022082328-appb-000097
生物测试数据
实验例1：GP2D CTG试验
实验目的：本实验旨在验证本发明化合物对KRAS G12D突变的GP2D人结肠癌细胞的增殖抑制效果。
实验材料：细胞株GP2D、DMEM培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。
Figure PCTCN2022082328-appb-000098
3D Cell Viability Assay(3D细胞活率化学发光检测试剂)试剂购自Promega。
实验方法：
将GP2D细胞种于96孔U底细胞培养板中，80μL细胞悬液每孔，其中包含2000个GP2D细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进5倍稀释至第8个浓度，即从200μM稀释至2.56nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是1μM至0.0128nM。细胞板置于二氧化碳培养箱中培养5天。加入化合物的细胞板结束孵育后，向细胞板中加入每孔100 μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析：
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。
实验结果：结果见表3。
表3 本发明化合物对GP2D CTG细胞增殖抑制活性测试结果
供试品 GP2D CTG IC 50(nM)
化合物1b 8.92
结论：本发明化合物具有显著的GP2D细胞增殖抑制作用。
实验例2：GP2D p-ERK实验
实验目的：通过HTRF的方法，筛选出能有效抑制GP2D细胞p-ERK的化合物。
实验方法：
1)GP2D细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个细胞，细胞板放入二氧化碳培养箱，37℃过夜孵育；
2)取2μL化合物加入78μL细胞培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时；
3)结束孵育后，弃掉细胞上清加入50μL 1X细胞裂解液每孔，室温摇晃孵育30分钟；
4)使用detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
5)取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育至少4小时
6)孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm,665nm
7)计算待测化合物IC 50。
实验结果：实验结果见表4。
表4 本发明化合物对GP2D p-ERK细胞抑制活性测试结果
供试品 GP2D p-ERK抑制活性IC 50(nM)
化合物1b 2.11
结论：本发明化合物具有显著的GP2D细胞p-ERK抑制作用。
实验例3：AsPC1 CTG实验
实验目的：本实验旨在验证本发明化合物对KRAS G12D突变的AsPC-1细胞的增殖抑制效果。
实验材料：
RPMI-1640培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。AsPC-1细胞系购自南京科佰生物科技有限公司。Nivo多标记分析仪(PerkinElmer)。
实验方法：
将AsPC-1细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个AsPC-1细胞。细胞板置于二氧化碳培养箱中过夜培养。
将待测化合物用排枪进5倍稀释至第8个浓度，即从2mM稀释至25.6nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.128nM。细胞板置于二氧化碳培养箱中培养6天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析：
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。
实验结果：实验结果见表5。
表5 本发明化合物对AsPC-1 CTG细胞抑制活性测试结果
供试品 AsPC-1 CTG IC 50(nM)
化合物1b 45.8
结论：本发明化合物具有显著的AsPC-1细胞增殖抑制作用。
实验例4：PANC0403 CTG实验
实验目的：本实验旨在验证本发明化合物对KRAS G12D突变的PANC0403细胞的增殖抑制效果
实验材料：
细胞株PANC0403购自南京科佰、RPMI1640培养基购自BI，盘尼西林/链霉素抗生素购自源培，胎牛血清购自Gibco。
Figure PCTCN2022082328-appb-000099
3D Cell Viability Assay(3D细胞活率化学发光检测试剂)试剂购自Promega。实验方法：
将PANC0403细胞种于96孔U底细胞培养板中，80μL细胞悬液每孔，其中包含4000个PANC0403 细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进5倍稀释至第8个浓度，即从2000μM稀释至25.6nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.128nM。细胞板置于二氧化碳培养箱中培养5天。加入化合物的细胞板结束孵育后，向细胞板中加入每孔100μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析：
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。
实验结果：实验结果见表6。
表6 本发明化合物对PANC0403 CTG细胞抑制活性测试结果
供试品 PANC0403 CTG抑制活性IC 50(nM)
化合物1b 54
结论：本发明化合物具有显著的PANC0403细胞增殖抑制作用。
实验例5：药代动力学数据
实验目的：测试化合物在CD-1小鼠体内药代动力学数据
实验方法：
称量受试化合物2.08mg于样品瓶中，加入204μL Solutol，搅拌3分钟，加入(1000+837)μL纯水，搅拌3分钟得到澄清溶液。选取7-10周龄雄性CD-1小鼠，腹腔注射(IP)给予待测化合物溶液，剂量为10mg/kg。收集0.25、0.5、1、2、4、8、24小时的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
各参数定义：IP：腹腔注射；C max：给药后出现的血药浓度最高值；T max：给药后达到药峰浓度所需的时间；T 1/2：血药浓度下降一半所需的时间；T last：最后一个检测点的时间；AUC 0-last：药时曲线下面积，指血药浓度曲线对时间轴所包围的面积。
实验结果：实验结果见表7：
表7 本发明化合物血浆中的PK测试结果
Figure PCTCN2022082328-appb-000100
结论：本发明化合物展现了较高的药物暴露量，较长的半衰期，具有良好的体内药物代谢动力学性质。
实验例6：体内药效实验
实验目的：在人胰腺癌PANC0403异种移植瘤模型上考察本发明化合物的抑瘤效果
实验材料：磺丁基环糊精(供应商：CyDex Pharmaceuticals,KS)，
实验方法：
在雌性Balb/c nude小鼠皮下接种PANC0403人胰腺癌细胞株，接种后第23天按照肿瘤体积和体重随机分为溶媒对照组与化合物组(每组6只动物)，并且按照下列描述进行给药处理：
第1组(溶媒对照组)：分组当天下午开始给药(给药当天为给药第0天)，每天两次按照0.1mL/10g体重的剂量腹腔注射给药溶媒。第2组(化合物组)：分组当天下午开始给药(给药当天为给药第0天)，每天两次按照5mg/kg体重的剂量腹腔注射给药化合物。溶媒为10％磺丁基环糊精的50mM pH 5.0柠檬酸缓冲溶液，磺丁基环糊精供应商：CyDex Pharmaceuticals,KS。
测定肿瘤的长(a)和宽(b)，计算肿瘤体积(Tumor volume，T)、肿瘤抑制率(TGI)和肿瘤增殖率(T/C)。计算公式为：T＝a×b 2/2；TGI(％)＝[1-(化合物组给药第n天肿瘤体积－化合物组给药第0天肿瘤体积)/(溶媒对照组第n天肿瘤体积－溶媒对照组第0天肿瘤体积)]×100％；T/C(％)＝化合物组肿瘤体积/对照组肿瘤体积×100％。
实验结果：实验结果见表8。
表8 本发明化合物对PANC0403异种移植瘤模型的抑瘤效果
Figure PCTCN2022082328-appb-000101
注*：平均值±SEM，n＝6。
结论：在人胰腺癌PANC0403异种移植瘤模型上，本发明化合物具有显著的抗肿瘤作用。

Claims (25)

  1. 式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022082328-appb-100001
    其中，
    环A选自
    Figure PCTCN2022082328-appb-100002
    T 1选自CH 2、NH和O；
    T 2选自CH和N；
    T 3和T 4分别独立地选自CH 2和NH；
    m、n、p和x分别独立地选自0、1或2；
    r、v和w分别独立地选自1或2；
    q和u分别独立地选自1、2或3；
    各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CF 3；
    E 1和E 3分别独立地选自键、O、S、Se、NH和CH 2，所述NH和CH 2分别独立地任选被1或2个R a取代；
    E 2选自-C(O)-、-C(O)-(CH 2) g-和-(CH 2) h-，当g和h不选自0时，所述-C(O)-(CH 2) g-和-(CH 2) h-分别独立地任选被1、2或3个R b取代；
    X 1和X 2分别独立地选自N和CR 4；
    L 1选自键和CH 2，所述CH 2任选被1或2个R c取代；
    R 2选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R d取代；
    R 3选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基和5-10元杂芳基分别独立地任选被1、2、3、4或5个R e取代；
    R 4选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基，所述C(＝O)NH 2、C 1-3烷基、C 1-3烷氧基、C 2-4烯基和C 2-4炔基分别独立地任选被1、2或3个R f取代；
    e选自0、1、2和3；
    f、g和h分别独立地选自0、1和2；
    各R a分别独立地选自H和CH 3；
    各R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和CN；
    各R d分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
    各R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、COOH、C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1- 3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基，所述C(＝O)NH 2、C 1-6烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基、C 2-4烯基、C 2-4炔基和C 3-5环烷基分别独立地任选被1、2或3个R取代；
    各R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
    各R分别独立地选自H、F、Cl、Br、I和CH 3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R d选自H、F和-O-C(＝O)-N(CH 3) 2。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R e选自H、F、Cl、OH、NH 2、CH 3、CF 3、CH 2CH 3、CH(CH 3) 2、OCH 3、OCF 3、SCH 3、SCF 3、
    Figure PCTCN2022082328-appb-100003
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2022082328-appb-100004
    Figure PCTCN2022082328-appb-100005
  5. 根据权利要求1或4所述化合物或其药学上可接受的盐，其中，结构片段
    Figure PCTCN2022082328-appb-100006
    选自
    Figure PCTCN2022082328-appb-100007
  6. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构片段
    Figure PCTCN2022082328-appb-100008
    选自
    Figure PCTCN2022082328-appb-100009
    Figure PCTCN2022082328-appb-100010
  7. 根据权利要求6所述的化合物或其药学上可接受的盐，其中，结构片段
    Figure PCTCN2022082328-appb-100011
    选自
    Figure PCTCN2022082328-appb-100012
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，X 1选自N、CH和C(CF 3)。
  9. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，X 2选自N、CH和CF。
  10. 根据权利要求1、8和9任意一项所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082328-appb-100013
    选自
    Figure PCTCN2022082328-appb-100014
    R 4选自H、F、CH 3和CF 3。
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 2选自四氢吡咯基和六氢-1H-吡咯里嗪基，所述四氢吡咯基和六氢-1H-吡咯里嗪基任选被1、2或3个R d取代。
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2022082328-appb-100015
    Figure PCTCN2022082328-appb-100016
  13. 根据权利要求1、11和12任意一项所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082328-appb-100017
    选自
    Figure PCTCN2022082328-appb-100018
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082328-appb-100019
    选自
    Figure PCTCN2022082328-appb-100020
  15. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 3选自苯基、萘基和吲唑基，所述苯基、萘基和吲唑基任选被1、2、3、4或5个R e取代。
  16. 根据权利要求15所述的化合物或其药学上可接受的盐，其中，R 3选自
    Figure PCTCN2022082328-appb-100021
    Figure PCTCN2022082328-appb-100022
  17. 根据权利要求16所述的化合物或其药学上可接受的盐，其中，R 3选自
    Figure PCTCN2022082328-appb-100023
    Figure PCTCN2022082328-appb-100024
  18. 根据权利要求16或17所述的化合物或其药学上可接受的盐，其中，R 3选自
    Figure PCTCN2022082328-appb-100025
  19. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100026
    其中，R 2和R 3如权利要求1～18任意一项所定义。
  20. 根据权利要求19所述的化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100027
    其中，R 3和R d如权利要求19所定义。
  21. 根据权利要求20所述的化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100028
    其中，
    R d选自F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
    R 3如权利要求20所定义。
  22. 根据权利要求21所述的化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100029
    其中，
    R d选自F、Cl、Br、I、OH、NH 2、CN和-OCO-C 1-3烷氨基；
    R 3如权利要求21所定义；
    带“*”和“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  23. 下式化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100030
  24. 根据权利要求23所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100031
  25. 根据权利要求23或24所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022082328-appb-100032
    Figure PCTCN2022082328-appb-100033
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