WO2020259573A1 - 作为kras g12c突变蛋白抑制剂的七元杂环类衍生物 - Google Patents

作为kras g12c突变蛋白抑制剂的七元杂环类衍生物 Download PDF

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WO2020259573A1
WO2020259573A1 PCT/CN2020/098070 CN2020098070W WO2020259573A1 WO 2020259573 A1 WO2020259573 A1 WO 2020259573A1 CN 2020098070 W CN2020098070 W CN 2020098070W WO 2020259573 A1 WO2020259573 A1 WO 2020259573A1
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pharmaceutically acceptable
isomer
acceptable salt
compound
present
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PCT/CN2020/098070
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French (fr)
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丁照中
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 CN202080043619.4A priority Critical patent/CN113993860B/zh
Priority to US17/621,621 priority patent/US20220372036A1/en
Publication of WO2020259573A1 publication Critical patent/WO2020259573A1/zh

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    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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 new class of KRAS G12C mutein inhibitors, and specifically relates to compounds represented by formula (I) and their isomers and pharmaceutically acceptable salts.
  • RAS protein is a product expressed by RAS gene, which refers to a closely related monomer globulin consisting of 189 amino acids, with a molecular weight of 21KDa. It can be combined with guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP).
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the active state of RAS protein has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc. Its activity is regulated by binding to GTP or GDP.
  • the RAS protein When the RAS protein binds to GDP, it is in a dormant state, that is, an "inactive" state; when stimulated by a specific upstream cell growth factor, the RAS protein is induced to exchange GDP and bind to GTP, which is called “activated” status.
  • the RAS protein bound to GTP can activate downstream proteins for signal transmission.
  • RAS protein itself has weak GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transformation from the activated state to the inactivated state can be realized.
  • GAP GTPase activating proteins
  • GAP GTPase activating proteins
  • RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always in an activated state.
  • the activated RAS protein continuously gives growth signals to downstream proteins, which eventually leads to the continuous growth and differentiation of cells, and eventually tumors.
  • RAS gene family There are many members of the RAS gene family, among which the subfamilies closely related to various cancers are mainly Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus carcinogenic homolog (HRAS) and nerve The blastoma rat sarcoma virus oncogene homolog (NRAS).
  • KRAS Kirsten rat sarcoma virus oncogene homolog
  • HRAS Harvey rat sarcoma virus carcinogenic homolog
  • NRAS blastoma rat sarcoma virus oncogene homolog
  • the G12C mutation is one of the more common mutations in the KRAS gene. It refers to the mutation of glycine 12 to cysteine. KRAS G12C mutations are the most common in lung cancer. According to data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutations account for about 10% of all lung cancer patients.
  • the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt or isomer thereof,
  • R 1 is H, F, Cl, Br, I, NH 2 and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, and the C 1-3 alkyl groups are optionally grouped by 1, 2 or 3 R b replaces;
  • T is selected from C(R 6 ) and N;
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 7 is selected from H and -CH 2 -CN;
  • R 8 is selected from H and F
  • L 1 is selected from a single bond
  • R 9 is selected from H, Cl, pyrrolidinyl and C 1-6 alkylamino, said pyrrolidinyl and C 1-6 alkylamino being optionally substituted by 1, 2 or 3 R d ;
  • E is selected from -O-, -NL 2 -L 3 -R 10 ;
  • L 3 is selected from a single bond, -CH 2 -and
  • R 10 is selected from H and C 1-6 alkylamino
  • R a , R b , R c and R d are each independently selected from H, F, Cl, Br, I and CH 3 ;
  • n is selected from 2.
  • the above-mentioned compound, its pharmaceutically acceptable salt or isomer thereof, wherein R 6 is selected from H, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F, other variables are as defined in the present invention.
  • the above-mentioned compound, its pharmaceutically acceptable salt or its isomer, wherein R 9 is selected from H, Cl, And C 1-4 alkylamino, other variables are as defined in the present invention.
  • the above-mentioned compound its pharmaceutically acceptable salt or isomer thereof, wherein the structural unit Selected from H, Cl, Other variables are as defined in the present invention.
  • the above-mentioned compound, its pharmaceutically acceptable salt or isomer thereof, wherein the structural unit -L 2 -L 3 -R 10 is selected from H Other variables are as defined in the present invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined in the present invention.
  • the present invention also provides a compound of the following formula, a pharmaceutically acceptable salt or isomer thereof, selected from
  • the above-mentioned compound, its pharmaceutically acceptable salt or its isomer is selected from
  • the above-mentioned compound, its pharmaceutically acceptable salt or its isomer is selected from
  • the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or isomer thereof,
  • R 1 is H, F, Cl, Br, I, NH 2 and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, and the C 1-3 alkyl groups are optionally grouped by 1, 2 or 3 R b replaces;
  • R 6 is selected from H, F, Cl, Br, I and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R a , R b , and R c are each independently selected from H, F, Cl, Br and I;
  • n is selected from 2.
  • R 1 is selected from NH 2 , and other variables are as defined in the present invention.
  • R 2 is selected from Cl, and other variables are as defined in the present invention.
  • R 3 is selected from H, and other variables are as defined in the present invention.
  • R 4 is selected from Cl, and other variables are as defined in the present invention.
  • R 5 is selected from F, and other variables are as defined in the present invention.
  • R 6 is selected from H, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 , CH 2 F, and other variables are as defined in the present invention.
  • R 6 is selected from CF 3 , and other variables are as defined in the present invention.
  • the present invention also provides a compound of the following formula, a pharmaceutically acceptable salt or isomer thereof, selected from
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned compound, its pharmaceutically acceptable salt or its isomer or the above-mentioned composition in the preparation of KRAS G12C mutein inhibitor.
  • the present invention provides the application of the above-mentioned compound, its pharmaceutically acceptable salt or its isomer or the above-mentioned composition in the preparation of a cancer medicine.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; 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 basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • 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 Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerism 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 enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or 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 enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting 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 heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted 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 is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group 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 group 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 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-4 alkylamino group includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino group and the like.
  • C 1-4 alkylamino groups 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 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, 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, from n to n +m means the number of atoms in the ring is 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-membered ring, 9-membered
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • 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, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as 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 so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • 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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the compound is based on the conventional naming principles in the field or The software is named, and the commercially available compounds use the supplier catalog name.
  • the compound of the present invention is a superior KRAS G12C mutant protein inhibitor.
  • the compounds 1-11A and 1-11D of the present invention show high cell anti-proliferation activity against KRAS G12C mutant cells NCI-H358, and at the same time have weak anti-proliferation activity against wild-type A375 cells, showing high selectivity.
  • the compound 1-11A of the present invention showed high exposure and oral availability.
  • the compound 1-11A of the present invention shows good in vivo efficacy in the human non-small cell lung cancer NCI-H358 subcutaneous allograft tumor model.
  • 1-11A has a strong inhibitory effect on tumor growth, while increasing the dose to 10mg/kg, 1-11A has a stronger tumor inhibitory effect than that at 3mg/kg, and the tumor growth inhibition rate reaches 83.9%.
  • Example 1 Preparation of compounds 1-11A, 1-11B, 1-11C, 1-11D
  • This experiment aims to verify the proliferation inhibitory effect of the compound of the present invention on KRAS G12C mutant NCI-H358 human non-small cell lung cancer cells and wild-type A375 human malignant melanoma cells.
  • Cell line NCI-H358 purchasedd from the Cell Bank of the Chinese Academy of Sciences
  • cell line A375 purchased from the Cell Bank of the Chinese Academy of Sciences
  • DMEM medium penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo cell viability chemiluminescence detection reagent
  • Plant NCI-H358 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 4000 NCI-H358 cells.
  • the cell plate was cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up.
  • the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 1.52 nM.
  • the cell plate was placed in a carbon dioxide incubator for 5 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis. Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use multi-marker analyzer to read. Add 25 ⁇ L of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Use multi-marker analyzer to read.
  • Plant A375 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 2000 A375 cells.
  • the cell plate was cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 2mM to 304nM, 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 gradient dilution compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate.
  • the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 1.52 nM.
  • the cell plate was placed in a carbon dioxide incubator for 5 days.
  • the compounds 1-11A and 1-11D of the present invention show high cell anti-proliferation activity against KRAS G12C mutant cells NCI-H358, and at the same time, they have weak anti-proliferation activity against wild-type A375 cells, reflecting high selection. Sex.
  • Test compound NCI-H358 IC 50 ( ⁇ M) A375 IC 50 ( ⁇ M) 1-11A 0.10 6.12 1-11B 5.03 >10 1-11C 3.58 4.78 1-11D 0.33 >10
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after intravenous and intragastric administration of the test compound. Study the pharmacokinetic behavior of the test compound in mice and evaluate its pharmacokinetic characteristics.
  • Experimental program Experimental animals: 8 healthy adult male SD rats were divided into 4 groups according to the principle of similar body weight, the IV group (two groups) each had 2 rats, and the PO group (two groups) each had 2 rats. The animals were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.
  • Group IV Weigh an appropriate amount of samples, add appropriate amounts of DMSO, PEG400, and water in sequence at a volume ratio of 10:60:30, and stir and ultrasound to reach a clear state of 1.5 mg/mL.
  • PO group Weigh an appropriate amount of samples, add appropriate amounts of DMSO, PEG400, and water according to the volume ratio of 10:60:30, and stir and ultrasound to reach a clear state of 1.0 mg/mL.
  • the IV group was given intravenous administration with a volume of 2 mL/kg and a dose of 3 mg/kg; after a night of fasting, the PO group was given intravenous administration with a volume of 10 mL/kg and a dose of 10 mg/kg.
  • mice Female, 6-8 weeks old, weighing 18-21 grams, need a total of 96 mice, provided by Shanghai Lingchang Laboratory Animal Co., Ltd. Resuspend the NCI-H358 tumor cells in PBS to prepare a cell suspension of 0.1mL (5 ⁇ 10 6 cells) and inoculate subcutaneously on the right back of each mouse (5 ⁇ 10 6 /mouse) to wait for the tumor to grow . Randomized intragastric administration was started when the average tumor volume reached about 150-200mm 3. The frequency of administration was once a day. The dosage is shown in Table 3. The tumor diameter was measured with vernier calipers twice a week.
  • TGI 0.5a ⁇ b 2
  • a and b represent the long diameter and short diameter of the tumor, respectively.
  • the anti-tumor efficacy of the compound was evaluated by TGI (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • Calculation of TGI(%): TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group)/(Average tumor volume at the end of the solvent control group -The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the compound 1-11A of the present invention shows good in vivo efficacy in the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model.
  • 1-11A has a strong inhibitory effect on tumor growth, while increasing the dose to 10 mg/kg, 1-11A has a stronger tumor-inhibiting effect than at 3 mg/kg, and the tumor growth inhibition rate reaches 83.9%.

Abstract

一类KRAS G12C突变蛋白抑制剂，具体公开了式(II)所示化合物及其异构体、药学上可接受的盐。

Description

作为KRAS G12C突变蛋白抑制剂的七元杂环类衍生物
本申请主张如下优先权：
CN201910556652.6，申请日2019年06月25日；
CN201910990276.1，申请日2019年10月17日；
CN201911410783.X，申请日2019年12月31日。
技术领域
本发明涉及新的一类KRAS G12C突变蛋白抑制剂，具体涉及式(I)所示化合物及其异构体、药学上可接受的盐。
背景技术
第一个RAS癌基因发现自大鼠肉瘤(rat sarcoma)，因此得名。RAS蛋白是由RAS基因表达的产物，指一类紧密相关的，由189个氨基酸组成的单体球蛋白，其分子量为21KDa。它可以与鸟嘌呤三核苷酸磷酸(GTP)或鸟嘌呤二核苷酸磷酸(GDP)结合。RAS蛋白的活性状态对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响，其活性是通过与GTP或GDP的结合进行调节。当RAS蛋白与GDP结合时，它处于休眠状态，也就是“失活”状态；当有上游特定的细胞生长因子刺激时，RAS蛋白被诱导交换GDP，与GTP结合，此时称为“活化”状态。与GTP结合的RAS蛋白能够活化下游的蛋白，进行信号传递。RAS蛋白自身具有弱的水解GTP水解活性，能够水解GTP到GDP。这样就可以实现从活化状态到失活状态的转化。在这个水解过程中，还需要GAP(GTPase activating proteins,GTP水解酶活化蛋白)参与。它能与RAS蛋白作用，大大促进其水解GTP到GDP的能力。RAS蛋白的突变将影响其与GAP的作用，也就影响了其水解GTP到GDP的能力，使其一直处于活化状态。活化的RAS蛋白持续的给予下游蛋白生长信号，最终导致细胞不停的生长和分化，最终产生肿瘤。RAS基因家族成员众多，其中与各种癌症密切相关的亚家族主要有克尔斯滕大鼠肉瘤病毒致癌基因同源物(KRAS)、哈维大鼠肉瘤病毒致癌同源物(HRAS)和神经母细胞瘤大鼠肉瘤病毒致癌基因同源物(NRAS)。人们发现大约30％的人类肿瘤中都携带某些突变的RAS基因，其中以KRAS突变最为显著，占到所有RAS突变中的86％。对于KRAS突变，最为常见的突变出现在12号甘氨酸(G12)，13号甘氨酸(G13)和61号谷氨酰胺(Q61)残基上，其中G12突变占到83％。
G12C突变是KRAS基因突变中比较常见的一个，它是指12号甘氨酸突变为半胱氨酸。KRAS G12C突变在肺癌中最为常见，根据文献(Nat Rev Drug Discov 2014；13:828-851)报道的数据推算，KRAS G12C突变占到所有肺癌患者的10％左右。
发明内容
本发明提供式(II)所示化合物、其药学上可接受的盐或其异构体，
Figure PCTCN2020098070-appb-000001
其中，
R 1为H、F、Cl、Br、I、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2、R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
T选自C(R 6)和N；
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
R 7选自H和-CH 2-CN；
R 8选自H和F；
L 1选自单键、
Figure PCTCN2020098070-appb-000002
R 9选自H、Cl、吡咯烷基和C 1-6烷氨基，所述吡咯烷基和C 1-6烷氨基任选被1、2或3个R d取代；
E选自-O-、-N-L 2-L 3-R 10；
L 2选自单键、-CH 2-和-C(＝O)-；
L 3选自单键、-CH 2-和
Figure PCTCN2020098070-appb-000003
R 10选自H和C 1-6烷氨基；
R a、R b、R c和R d分别独立地选自H、F、Cl、Br、I和CH 3；
n选自2。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 1选自NH 2，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 2选自Cl和Br，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 3选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 4选自Cl和Br，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 5选自F，其他 变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，结构单元
Figure PCTCN2020098070-appb-000004
选自
Figure PCTCN2020098070-appb-000005
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 6选自H、F、Cl、Br、I、CH 3、CF 3、CHF 2和CH 2F，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 6选自CF 3和CH 3，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 9选自H、Cl、
Figure PCTCN2020098070-appb-000006
和C 1-4烷氨基，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 9选自H、Cl、
Figure PCTCN2020098070-appb-000007
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，结构单元
Figure PCTCN2020098070-appb-000008
选自H、Cl、
Figure PCTCN2020098070-appb-000009
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，R 10选自H和
Figure PCTCN2020098070-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中结构单元-L 2-L 3-R 10选自H、
Figure PCTCN2020098070-appb-000011
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其中，化合物选自
Figure PCTCN2020098070-appb-000012
其中，R 1、R 2、R 3、R 4、R 5、R 6和n如本发明所定义。
本发明还提供下式化合物、其药学上可接受的盐或其异构体，选自
Figure PCTCN2020098070-appb-000013
Figure PCTCN2020098070-appb-000014
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，选自
Figure PCTCN2020098070-appb-000015
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，选自
Figure PCTCN2020098070-appb-000016
本发明提供了式(I)所示化合物、其药学上可接受的盐或其异构体，
Figure PCTCN2020098070-appb-000017
其中，
R 1为H、F、Cl、Br、I、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2、R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
R a、R b、R c分别独立地选自H、F、Cl、Br和I；
n选自2。
在本发明的一些方案中，上述式(I)中，R 1选自NH 2，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，R 2选自Cl，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，R 3选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，R 4选自Cl，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，R 5选自F，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，结构单元
Figure PCTCN2020098070-appb-000018
选自
Figure PCTCN2020098070-appb-000019
在本发明的一些方案中，上述式(I)中，R 6选自H、F、Cl、Br、I、CH 3、CF 3、CHF 2、CH 2F，其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)中，R 6选自CF 3，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。
本发明还提供了下式化合物、其药学上可接受的盐或其异构体，选自
Figure PCTCN2020098070-appb-000020
本发明还有一些方案是由上述各变量任意组合而来。
本发明提供了一种药物组合物，包括作为活性成分的治疗有效量的本发明所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明提供了上述的化合物、其药学上可接受的盐或其异构体或上述组合物在制备KRAS G12C突变蛋白抑制剂的应用。
本发明提供了上述的化合物、其药学上可接受的盐或其异构体或上述组合物制备治疗癌症药物中的应用。
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 PCTCN2020098070-appb-000021
和楔形虚线键
Figure PCTCN2020098070-appb-000022
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020098070-appb-000023
和直形虚线键
Figure PCTCN2020098070-appb-000024
表示立体中心的相对构型，用波浪线
Figure PCTCN2020098070-appb-000025
表示楔形实线键
Figure PCTCN2020098070-appb-000026
或楔形虚线键
Figure PCTCN2020098070-appb-000027
或用波浪线
Figure PCTCN2020098070-appb-000028
表示直形实线键
Figure PCTCN2020098070-appb-000029
和直形虚线键
Figure PCTCN2020098070-appb-000030
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，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 PCTCN2020098070-appb-000031
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 PCTCN2020098070-appb-000032
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 PCTCN2020098070-appb-000033
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“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 1-6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6个碳原子的烷基基团。所述C 1-6烷氨基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4、C 3和C 2烷氨基等。C 1-6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、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。
除非另有规定，术语“C 1-4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4个碳原子的烷基基团。所述C 1-4烷氨基包括C 1-3、C 1-2、C 2-4、C 4、C 3和C 2烷氨基等。C 1-4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、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。
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。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
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
Figure PCTCN2020098070-appb-000034
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物是优效的KRAS G12C突变蛋白抑制剂。本发明化合物1-11A和1-11D对于KRAS G12C突变型细胞NCI-H358显示了较高的细胞抗增殖活性，同时对于野生型的A375细胞抗增殖活性较弱，体现了高的选择性。在小鼠药代动力学评价实验中，本发明化合物1-11A显示出高的暴露量和口服利用度。本发明化合物1-11A在人非小细胞肺癌NCI-H358皮下异体移植肿瘤模型中展示出良好的体内药效。3mg/kg同等剂量下，1-11A对肿瘤的生长抑制效果强，而增大剂量到10mg/kg，1-11A的抑瘤效果比3mg/kg下更强，肿瘤生长抑制率达到83.9％。
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。
实施例1:化合物1-11A，1-11B，1-11C，1-11D的制备
Figure PCTCN2020098070-appb-000035
第一步：
将化合物1-1(5.0克，13.54毫摩尔，1.0当量)的丙酸(50毫升)溶液加热到125摄氏度，随后缓慢加入发烟硝酸(2.56克，40.63毫摩尔，1.83毫升，3.0当量)，反应液在125摄氏度下反应2小时。反应液缓慢的倒入质量分数为10％的冰盐水(100毫升)中，过滤后将滤饼干燥得到化合物1-2。 1H NMR(400MHz,DMSO-d 6)δ8.86(s,1H),8.35(d,J＝8.31Hz,1H),8.11-8.19(m,1H),8.02-8.10(m,1H),7.61(s, 1H).LCMS(ESI)m/z:415.0(m+1) +。
第二步：
将化合物1-2(2.5克，6.04毫摩尔，1.0当量)的三氯氧磷(41.25克，269.02毫摩尔，25毫升，44.57当量)溶液加热到100摄氏度，随后加入N,N-二甲基苯胺(731.37毫克，6.04毫摩尔，765.03微升，1.0当量)，该反应混合液在100摄氏度下搅拌反应30分钟，然后将反应液减压蒸馏除去溶剂，得到的残余物用乙酸乙酯(20毫升)稀释后缓慢的加入到冰水(50毫升)中，混合液用乙酸乙酯(50毫升)萃取两次。合并有机相用饱和食盐水(50毫升)洗涤两次，无水硫酸钠干燥，过滤减压浓缩得到化合物1-3。LCMS(ESI)m/z:433.0(m+1) +。
第三步：
向化合物1-3(500毫克，1.16毫摩尔，1.0当量)的二甲基亚砜(5毫升)溶液中加入二异丙基乙基胺(448.05毫克，3.47毫摩尔，603.85微升，3.0当量)和化合物1-4(532.28毫克，2.31毫摩尔，2.0当量)，反应液用氮气置换三次后，25摄氏度反应16小时。向反应液中加入常温水(50毫升)后用乙酸乙酯(50毫升)萃取三次。合并有机相用饱和食盐水(50毫升)洗涤两次，无水硫酸钠干燥，过滤减压浓缩，得到的残余物通过层析硅胶柱(石油醚：乙酸乙酯＝2:1到二氯甲烷：甲醇＝20:1)纯化，得到化合物1-5。LCMS(ESI)m/z:627.2(m+1) +。
第四步：
向化合物1-5(360毫克，574.61微摩尔，1.0当量)的N,N-二甲基甲酰胺(36毫升)溶液中加入碳酸钾(158.83毫克，1.15毫摩尔，2.0当量)，反应液在120摄氏度油浴中反应14小时。反应液加入常温水(50毫升)后用乙酸乙酯(50毫升)萃取两次。合并有机相用饱和食盐水(50毫升)洗涤两次，减压浓缩，得到的残余物通过层析硅胶柱(石油醚：乙酸乙酯＝1:1)纯化，得到化合物1-6。 1H NMR(400MHz,CDCl 3-d)δ8.52(d,J＝1.00Hz,1H),8.13-8.23(m,1H),7.73(dt,J 1＝8.41Hz,J 2＝5.27Hz,1H),7.57-7.67(m,1H),7.20(d,J＝5.52Hz,1H),4.57(br d,J＝.90Hz,1H),4.10-4.19(m,2H),3.80(br s,1H),3.22-3.49(m,4H),2.78-2.93(m,1H),2.18-2.46(m,2H),1.51(s,9H).LCMS(ESI)m/z:580.3(m+1) +。
第五步：
向化合物1-6(200毫克，342.30微摩尔，1.0当量)的乙醇(5毫升)和水(2.5毫升)的混合溶液中加入铁粉(95.58毫克，1.71毫摩尔，5.0当量)和氯化铵(91.55毫克，1.71毫摩尔，5.0当量)，反应液在80摄氏度油浴中反应2小时。将反应液过滤，滤饼用乙醇(20毫升)洗涤。滤液减压浓缩，得到的残余物用乙酸乙酯(20毫升)稀释后分别用常温水(20毫升)和饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤减压浓缩得到化合物1-7。 1H NMR(400MHz,CDCl 3-d)δ8.48-8.55(m,1H),7.15-7.26(m,2H),6.55-6.68(m,2H),4.50-4.63(m,1H),4.27-4.37(m,1H),3.71-3.88(m,3H),3.22-3.49(m,4H),2.33-2.45(m,1H),2.14-2.26(m,1H),1.51(s,9H).LCMS(ESI)m/z:550.3(m+3).LCMS(ESI)m/z:550.3(m+1) +。
第六步：
0摄氏度下，向化合物1-7(300毫克，545.93微摩尔，1.0当量)的乙腈(6毫升)溶液中加入氯代丁二酰亚胺(138.51毫克，1.04毫摩尔，1.9当量)，反应液放入60摄氏度油浴中反应2小时。将反 应液缓慢地加入到饱和的亚硫酸钠(20毫升)溶液中，所得混合液用乙酸乙酯(20毫升)萃取两次。合并有机相，用饱和食盐水(20毫升)洗涤两次，无水硫酸钠干燥，过滤减压浓缩，得到的残余物通过层析硅胶柱(石油醚：乙酸乙酯＝2:1)纯化，得到化合物1-8A和1-8B。LCMS(ESI)m/z:618.2(m+1) +。第七步：
向化合物1-8A(Rf＝0.5)(70毫克，113.19微摩尔，1.0当量)的乙酸乙酯(0.5毫升)溶液中加入盐酸乙酸乙酯(4摩尔/升，0.5毫升，17.67当量)，反应液在25摄氏度下反应1小时。将反应液减压浓缩得到化合物1-9A的盐酸盐。LCMS(ESI)m/z:518.1(m+1) +。
第八步：
在0摄氏度下，向化合物1-9A(62毫克，111.76微摩尔，1.0当量，盐酸盐)的二氯甲烷(2毫升)溶液中加入二异丙基乙基胺(72.22毫克，558.81微摩尔，97.33微升，5.0当量)和化合物1-10(11.13毫克，122.94微摩尔，10.02微升，1.1当量)，反应液在0摄氏度下反应0.5小时。向反应液在加入饱和氯化铵(10毫升)，乙酸乙酯(10毫升)萃取两次。合并有机相，减压浓缩，得到的残余物通过制备HPLC(流动相：水(10毫摩尔碳酸氢铵)-乙腈，梯度：乙腈31％-61％，10分钟)纯化，得到的产品用制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，10um)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4.8分钟，35分钟)分离纯化得到1-11A(保留时间＝0.953min)和1-11B(保留时间＝1.264min)。
1-11A： 1H NMR(400MHz,MeOH-d 4)δ8.41(s,1H),7.53(d,J＝7.38Hz,1H),7.33(s,1H),6.74-6.96(m,1H),6.28(br d,J＝17.26Hz,1H),5.82(dd,J 1＝10.63Hz,J 2＝1.75Hz,1H),4.55(br d,J＝3.13Hz,1H),4.24(br s,2H),3.82-4.07(m,2H),3.72(br s,1H),3.45-3.51(m,1H),3.38(br d,J＝10.76Hz,2H),2.17-2.37(m,2H)；LCMS(ESI)m/z:572.0(m+1) +。
1-11B： 1H NMR(400MHz,MeOH-d 4)δ8.41(s,1H),7.53(d,J＝7.38Hz,1H),7.33(s,1H),6.75-6.97(m,1H),6.28(br d,J＝17.13Hz,1H),5.82(dd,J 1＝10.63Hz,J 2＝1.75Hz,1H),4.54(br d,J＝6.13Hz,1H),4.17-4.39(m,2H),3.83-4.08(m,2H),3.72(br s,1H),3.45-3.51(m,1H),3.38(br d,J＝11.63Hz,2H),2.16-2.35(m,2H)；LCMS(ESI)m/z:572.0(m+1) +。
第九步：
向化合物1-8B(Rf＝0.4)(80毫克，129.36微摩尔，1.0当量)的乙酸乙酯(0.5毫升)溶液中加入盐酸乙酸乙酯(4摩尔/升，0.5毫升，15.46当量)，反应液在25摄氏度下反应1小时。将反应液减压浓缩得到化合物1-9B的盐酸盐。LCMS(ESI)m/z:518.1(m+1) +。
第十步：
0摄氏度下，向化合物1-9B(71毫克，127.99微摩尔，1.0当量，盐酸盐)的二氯甲烷(2毫升)溶液中加入二异丙基乙基胺(82.71毫克，639.93微摩尔，111.46微升，5.0当量)和化合物1-10(12.74毫克，140.78微摩尔，11.48微升，1.1当量)，反应液在0摄氏度下反应0.5小时。向反应液在加入饱和氯化铵(10毫升)，乙酸乙酯(10毫升)萃取两次。合并有机相减压浓缩，得到的残余物通过制备HPLC(流动相：水(10毫摩尔碳酸氢铵)-乙腈，梯度：乙腈30％-63％，11分钟)纯化，得到的产品用制备SFC(DAICEL CHIRALPAK AD(250mm*30mm，10um)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，3.2分钟，40分钟)分离纯化得到1-11C(保留时间＝0.632min)和1-11D (保留时间＝1.519min)。
1-11C: 1H NMR(400MHz,MeOH-d 4)δ8.41(s,1H),7.53(d,J＝7.38Hz,1H),7.35(br s,1H),6.75-6.98(m,1H),6.29(br dd,J 1＝17.26Hz,J 2＝6.50Hz,1H),5.82(br d,J＝10.63Hz,1H),4.56(br d,J＝12.51Hz,1H),4.01-4.29(m,2H),3.95(br d,J＝6.88Hz,2H),3.76(br s,1H),3.48(br d,J＝12.51Hz,1H),3.34-3.42(m,2H),2.18-2.38(m,2H)；LCMS(ESI)m/z:572.0(m+1) +。
1-11D: 1H NMR(400MHz,MeOH-d 4)δ8.40(s,1H),7.53(d,J＝7.34Hz,1H),7.34(s,1H),6.72-6.99(m,1H),6.29(br dd,J 1＝16.81Hz,J 2＝5.20Hz,1H),5.82(br d,J＝10.64Hz,1H),4.32-4.71(m,3H),4.21(br s,1H),3.95(br s,1H),3.74(br d,J＝11.49Hz,1H),3.47(br d,J＝12.72Hz,1H),3.35(br s,2H),2.26(br d,J＝7.09Hz,2H)；LCMS(ESI)m/z:572.0(m+1) +。
实验例1：细胞实验
实验目的：
本实验旨在验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞和野生型的A375人恶性黑色素瘤细胞的增殖抑制效果。
实验材料：
细胞株NCI-H358(购自中国科学院细胞库)、细胞株A375(购自中国科学院细胞库)、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。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。
实验方法：
1)NCI-H358细胞抗增殖实验：
将NCI-H358细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含4000个NCI-H358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3倍稀释至第9个浓度，即从2mM稀释至304nM，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1.52nM。细胞板置于二氧化碳培养箱中培养5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。
2)A375细胞抗增殖实验：
将A375细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含2000个A375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3倍稀释至第9个浓度，即从2mM稀释至304nM，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1.52nM。细胞板置于二氧化碳培养箱中培养5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：本发明化合物对NCI-H358(G12C突变)细胞和A375(野生型)细胞的抗增殖活性IC 50的数据在表1中展示。
实验结论：本发明化合物1-11A和1-11D对于KRAS G12C突变型细胞NCI-H358显示了较高的细胞抗增殖活性，同时对于野生型的A375细胞抗增殖活性较弱，体现了高的选择性。
表1
受试化合物 NCI-H358 IC 50(μM) A375 IC 50(μM)
1-11A 0.10 6.12
1-11B 5.03 ＞10
1-11C 3.58 4.78
1-11D 0.33 ＞10
实验例2：小鼠药代动力学评价实验
实验目的：
以雄性CD-1小鼠为受试动物，应用LC/MS/MS法测定小鼠静脉和灌胃给予受试化合物后不同时刻血浆中的药物浓度。研究受试化合物在小鼠体内的药代动力学行为，评价其药动学特征。
实验方案：试验动物：健康成年雄性SD大鼠8只，按照体重相近的原则分成4组，IV组(两组)每组2只，PO组(两组)每组2只。动物购买自北京维通利华实验动物有限公司。
药物配制：
IV组：称取适量样品，按照体积比10:60:30依次加入适量DMSO，PEG400和水，搅拌超声后达到1.5mg/mL的澄清状态。
PO组：称取适量样品，按照体积比10:60:30依次加入适量DMSO，PEG400和水，搅拌超声后达到1.0mg/mL的澄清状态。
给药：
IV组分别进行静脉给药，给药体积为2mL/kg，剂量为3mg/kg；禁食一夜后，PO组分别进行灌胃给药，给药体积为10mL/kg，剂量为10mg/kg。
实验操作：
雄性SD大鼠静脉注射组分别给与受试化合物后，在0.0833，0.25，0.5，1，2，4，8，及24小时采血30μL，置于预先加有EDTA-K 2的商品化抗凝管中。灌胃给药组分别给与受试化合物后，分别在0.25，0.5，1，2，4，8，12及24小时采血200uL，置于预先加有EDTA-K 2的商品化抗凝管中。将试管离心15分钟分离血浆，并于-60℃保存。给药2小时后动物可进食。用LC/MS/MS法测定大鼠静脉和灌胃给药后，血浆中的受试化合物含量。方法的线性范围为2.00～6000nM；血浆样品经乙腈沉淀蛋白处理后进行分析。
实验结果：见表2。
实验结论：在小鼠药代动力学评价实验中，本发明化合物1-11A显示出高的暴露量和口服利用度。
表2
Figure PCTCN2020098070-appb-000036
注：Cl：清除率；V d：分布容积；AUC：暴露量；T 1/2：半衰期；C max：口服给药后化合物浓度最大值；T max：达到C max的时间；F：生物利用度。
实验例3：体内药效试验
实验目的：
评价受试化合物在人非小细胞肺癌NCI-H358皮下异体移植肿瘤模型上的体内药效。
实验操作：
BALB/c裸小鼠，雌性，6-8周龄，体重18-21克，共需96只，由上海灵畅实验动物有限公司提供。将NCI-H358肿瘤细胞重悬于PBS中，制备成0.1mL(5×10 6个)的细胞悬液，皮下接种于每只小鼠的右后背(5×10 6/只)等待肿瘤生长。在肿瘤平均体积达到约150-200mm 3时开始进行随机分组灌胃给药，给药频率为一天一次，剂量如表3所示。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
实验结果：见表3。
表3
组别 肿瘤体积(mm 3)(第20天) TGI(％)
溶剂对照组 634 --
1-11A 3mg/kg(0-20天) 332 64.1
1-11A 10mg/kg(0-20天) 240 83.9
实验结论：
本发明化合物1-11A在人非小细胞肺癌NCI-H358皮下异体移植肿瘤模型中展示出良好的体内药效。3mg/kg剂量下，1-11A对肿瘤的生长抑制效果强，而增大剂量到10mg/kg，1-11A的抑瘤效果比3mg/kg下更强，肿瘤生长抑制率达到83.9％。

Claims (21)

  1. 式(II)所示化合物、其药学上可接受的盐或其异构体，
    Figure PCTCN2020098070-appb-100001
    其中，
    R 1为H、F、Cl、Br、I、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    R 2、R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
    T选自C(R 6)和N；
    R 6选自H、F、Cl、Br、I和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
    R 7选自H和-CH 2-CN；
    R 8选自H和F；
    L 1选自单键、
    Figure PCTCN2020098070-appb-100002
    R 9选自H、Cl、吡咯烷基和C 1-6烷氨基，所述吡咯烷基和C 1-6烷氨基任选被1、2或3个R d取代；
    E选自-O-、-N-L 2-L 3-R 10；
    L 2选自单键、-CH 2-和-C(＝O)-；
    L 3选自单键、-CH 2-和
    Figure PCTCN2020098070-appb-100003
    R 10选自H和C 1-6烷氨基；
    R a、R b、R c和R d分别独立地选自H、F、Cl、Br、I和CH 3；
    n选自2。
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或其异构体，其中，R 1选自NH 2。
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 2选自Cl和Br。
  4. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 3选自H。
  5. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 4选自Cl和Br。
  6. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 5选自F。
  7. 根据权利要求6所述的化合物、其药学上可接受的盐或其异构体，其中，结构单元
    Figure PCTCN2020098070-appb-100004
    选自
    Figure PCTCN2020098070-appb-100005
  8. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 6选自H、F、Cl、Br、I、CH 3、CF 3、CHF 2和CH 2F。
  9. 根据权利要求8所述的化合物、其药学上可接受的盐或其异构体，其中，R 6选自CF 3和CH 3。
  10. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 9选自H、Cl、
    Figure PCTCN2020098070-appb-100006
    和C 1-4烷氨基。
  11. 根据权利要求10所述的化合物、其药学上可接受的盐或其异构体，其中，R 9选自H、Cl、
    Figure PCTCN2020098070-appb-100007
    Figure PCTCN2020098070-appb-100008
  12. 根据权利要求1、2或11所述的化合物、其药学上可接受的盐或其异构体，其中，结构单元
    Figure PCTCN2020098070-appb-100009
    选自H、Cl、
    Figure PCTCN2020098070-appb-100010
  13. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中，R 10选自H、
    Figure PCTCN2020098070-appb-100011
  14. 根据权利要求1、2或13所述的化合物、其药学上可接受的盐或其异构体，其中结构单元-L 2-L 3-R 10选自H、
    Figure PCTCN2020098070-appb-100012
  15. 根据权利要求1～14任意一项所述的化合物、其药学上可接受的盐或其异构体，其中，化合物选自式(I)
    Figure PCTCN2020098070-appb-100013
    其中，R 1、R 2、R 3、R 4、R 5、R 6和n如权利要求1～14任意一项所定义。
  16. 下式化合物、其药学上可接受的盐或其异构体，选自
    Figure PCTCN2020098070-appb-100014
    Figure PCTCN2020098070-appb-100015
  17. 根据权利要求16所述的化合物、其药学上可接受的盐或其异构体，选自
    Figure PCTCN2020098070-appb-100016
  18. 根据权利要求17所述的化合物、其药学上可接受的盐或其异构体，选自
    Figure PCTCN2020098070-appb-100017
    Figure PCTCN2020098070-appb-100018
  19. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
  20. 根据权利要求1～18任意一项所述的化合物、其药学上可接受的盐或其异构体或根据权利要求19所述的组合物在制备KRAS G12C突变蛋白抑制剂的应用。
  21. 根据权利要求1～18任意一项所述的化合物、其药学上可接受的盐或其异构体或根据权利要求19所述的组合物制备治疗癌症药物中的应用。
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