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WO2021259331A1 - Composé hétérocyclique à huit chaînons contenant de l'azote - Google Patents

Composé hétérocyclique à huit chaînons contenant de l'azote Download PDF

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Publication number
WO2021259331A1
WO2021259331A1 PCT/CN2021/101868 CN2021101868W WO2021259331A1 WO 2021259331 A1 WO2021259331 A1 WO 2021259331A1 CN 2021101868 W CN2021101868 W CN 2021101868W WO 2021259331 A1 WO2021259331 A1 WO 2021259331A1
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Prior art keywords
compound
added
pharmaceutically acceptable
synthesis
stirred
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PCT/CN2021/101868
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English (en)
Chinese (zh)
Inventor
王廷
洪训
周根源
高娜
沈春莉
吴成德
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2021259331A1 publication Critical patent/WO2021259331A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the present invention relates to a new type of eight-membered N-containing heterocyclic compounds, in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof.
  • the first RAS oncogene was found in rat sarcoma (rat sarcoma), hence the name.
  • the RAS protein is a product expressed by the 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 the combination with 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” at this time. state.
  • 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 will also affect 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 Blastoma rat sarcoma virus oncogene homolog (NRAS).
  • KRAS Kirsten rat sarcoma virus oncogene homolog
  • HRAS Harvey rat sarcoma virus carcinogenic homolog
  • NRAS nerve 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 (P) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl,
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are each independently optionally substituted by 1, 2 or 3 R b replace
  • 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
  • R 3 and R 7 and the connected atoms form a five-membered heteroaryl group
  • R a is independently selected from F, Cl, Br and I;
  • R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from F, Cl, Br, I and CN;
  • R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the R 3 and R 7 and the connected atoms form a five-membered heteroaryl group, so that the structural fragment form Other variables are as defined in the present invention.
  • the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
  • the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
  • the R b is independently selected from F, Cl, Br, I, Other variables are as defined in the present invention.
  • the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl and The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, Cyclobutyl and Each independently is optionally substituted by 1, 2, or 3 R b , and other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl are each independently optionally substituted with 1, 2 or 3 R b ;
  • 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
  • R 3 and R 7 form a five-membered heteroaryl group with the connected atoms, making the structure fragment form
  • R a is independently selected from F, Cl, Br and I;
  • R b is independently selected from F, Cl, Br, I, C 1-4 alkylamino, C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and Hexahydro-1H-pyrrolizinyl, the C 1-4 alkylamino, -C 1-3 alkyl-C 1-4 alkylamino, oxetanyl, pyrrolidinyl, piperazinyl and hexahydro -1H-pyrrolizinyl is independently optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from F, Cl, Br, I and CN;
  • R is each independently selected from F, Cl, Br, I, CH 3 , -CH 2 N(CH 3 ) 2 .
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl and azetidinyl,
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-5 cycloalkyl group and azetidinyl group are optionally substituted with 1, 2 or 3 R b ;
  • 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 is independently selected from H, F, Cl, Br and I;
  • R b is each independently selected from H, F, Cl, Br, I, N(CH 3 ) 2 and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from H, F, Cl, Br, I and CN;
  • R is each independently selected from H, F, Cl, Br, I, and CH 3 .
  • R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I and NH 2 ;
  • R 4 is selected from H, F, Cl, Br, and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 5 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and Cyclopropyl is optionally substituted with 1, 2 or 3 R b ;
  • 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 is independently selected from H, F, Cl, Br and I;
  • R b is each independently selected from H, F, Cl, Br, I and pyrrolidinyl group, said pyrrolidinyl group is optionally substituted with 1, 2 or 3 R;
  • R c are each independently selected from H, F, Cl, Br, I and CN;
  • R is each independently selected from H, F, Cl, Br, I, and CH 3 .
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the R 4 is selected from H, Cl and CH 3, CH 3 optionally substituted by the two or three R a, the other variables are as defined in the present invention.
  • the R 4 is selected from H and Cl, and other variables are as defined in the present invention.
  • the R b is independently selected from H, F, Cl, Br, I and Other variables are as defined in the present invention.
  • the R 5 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 and cyclopropyl are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the R 5 is selected from H, cyclopropyl, Other variables are as defined in the present invention.
  • the R 5 is selected from H, And cyclopropyl, other variables are as defined in the present invention.
  • the R 6 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 6 is selected from H and CH 2 CN, and other variables are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, selected from
  • the compound or a pharmaceutically acceptable salt thereof is 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 or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a KRAS G12C mutein inhibitor.
  • the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned composition in the preparation of a medicine for treating KRAS G12C mutation non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
  • 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 a 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, for example, 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
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an 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, and diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-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 groups. All these isomers and their mixtures are included in 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” 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 non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional 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 dashed 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 tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformations.
  • keto-enol tautomerization is the tautomerization 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 one wants 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 compound 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).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong 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.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
  • the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
  • Oxygen substitution does 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 can 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 groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms that are 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 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 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest 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 groups and the like.
  • Examples of C 1-3 alkoxy 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 rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 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 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • 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.; similarly, from n to n +m member means that 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, and 9-membered ring, and 9
  • 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 their combination 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 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.
  • SXRD single crystal X-ray diffraction
  • the cultivated single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the compound is based on 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 has a certain inhibitory effect on KRAS G12C mutant protein, and has high selectivity for KRAS G12C.
  • the compound of the present invention has low clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties.
  • the compound of the present invention has a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously in nude mice.
  • the compound of the present invention has significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.
  • anhydrous sodium sulfate 500g, 3.52mol, 357.14mL was added to the raw material chloral hydrate (47.88g, 289.45mmol) in deionized water (750mL), and the raw material 1-1 (50g, 263.14mmol) ), sulfuric acid (1M, 200mL) and hydroxylamine hydrochloride (54.86g, 789.42mmol), the resulting mixture was heated to 130°C under reflux and stirred for 0.5 hours, then the reaction solution was cooled to 50°C, a large amount of light brown solid precipitated, filtered, water ( 1000 mL) was washed, the filter cake was collected, and dried under reduced pressure to obtain compound 1-2.
  • Formamidine acetate (135.72 g, 1.30 mol) was added to a solution of raw material 1-5 (35 g, 130.37 mmol) in ethanol (300 mL), and the resulting mixture was heated to reflux at 80° C. and stirred for 40 hours.
  • the reaction solution was concentrated under reduced pressure to remove ethanol, water (200 mL) was added to the residue, stirred for 10 minutes, filtered, washed with water (200 mL), and the filter cake was dried to obtain compound 1-6.
  • N-chlorosuccinimide 8mg, 59.91 ⁇ mol was added to a solution of raw material 4-3 (15mg, 29.88 ⁇ mol) in N,N-dimethylformamide (0.5mL) to obtain The mixture was heated to 65°C and stirred for 1 hour. Water (50mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL*3). The organic phase was collected and concentrated under reduced pressure. The crude product obtained was purified by thin-layer chromatography to obtain compound 4. -4. LCMS (ESI) m/z: 470.3/472.3 [M-Boc+1] + .
  • Trifluoroacetic acid (0.8 mL, 10.80 mmol) was added to the dichloromethane (1 mL) solution of raw material 5-5 (50 mg, 93.56 ⁇ mol), and stirring was continued for 1 hour at room temperature and 20°C. The reaction solution was concentrated under reduced pressure to obtain the crude product 5-6.
  • Potassium phosphate (3.95g, 18.61mmol) was added to a solution of raw material 6-3 (2.6g, 4.65mmol) and compound 1-10 (2.08g, 9.30mmol) in toluene (30mL) and water (3mL) and replaced with nitrogen three times , Add catalyst chlorination (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) )] Palladium (0.67g, 0.93mmol), and the resulting mixture was heated to 70°C and stirred for 6 hours.
  • Tetrahydrofuran 50 mL
  • compound 8-4 50 mg, 73.97 ⁇ mol
  • sodium hydrogen 14.79 mg, 369.83 ⁇ mol, 60% purity
  • Saturated aqueous ammonium chloride solution 100 mL
  • ethyl acetate 50 mL
  • Trifluoroacetic acid (0.43 mL) was added to a solution of raw material 10-10 (0.2 g, 0.29 mmol) in dichloromethane (3 mL), the resulting mixture was stirred at room temperature and 25°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 10-11 The trifluoroacetate.
  • Trifluoroacetic acid (0.22mL) was added to a solution of raw material 12-10 (0.1g, 0.15mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 12-11 The trifluoroacetate.
  • Trifluoroacetic acid (0.15mL) was added to a solution of the starting material 13-5 (75mg, 0.10mmol) in dichloromethane (2mL), the resulting mixture was stirred at room temperature and 25°C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 13-6. Trifluoroacetate. LCMS (ESI) m/z: 625.1/627.2 [M+1] + .
  • Tetrahydrofuran (62 mL), compound 17-5 (62 mg, 86.06 ⁇ mol) and sodium hydrogen (17.21 mg, 430.30 ⁇ mol, 60% purity) were added to a three-necked flask, and heated to 65° C. for 1 hour under nitrogen protection.
  • the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (1 mL) was added, and the mixture was concentrated under reduced pressure.
  • Dichloromethane (20 mL) was added to the residue, filtered, and the filtrate was concentrated to obtain compound 17-6.
  • Tetrahydrofuran (710 mL), compound 18-2 (710 mg, 912.06 ⁇ mol) and sodium hydrogen (182.41 mg, 4.56 mmol, 60% purity) were added to the three-necked flask, and the mixture was heated to 65°C for 1 hour under the protection of nitrogen.
  • the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (2 mL) was added, and the mixture was concentrated under reduced pressure.
  • Dichloromethane 50 mL was added to the residue, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain compound 18-3.
  • 1 H NMR 400MHz, CD 3 OD
  • 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 placed in a carbon dioxide incubator for overnight culture.
  • 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 dosing to participate in data analysis. Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature 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 at room temperature for 10 minutes 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 placed in a carbon dioxide incubator for overnight culture.
  • 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 culture 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.
  • IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
  • NA 0.015 NA 8 0.017 NA 9 0.196 NA 10 0.189 NA 11 0.059 NA 14 0.005 NA 16 0.029 NA 17 0.105 NA 18 0.135 NA twenty one 0.003 NA twenty two 0.143 NA twenty four 0.019 NA 26 0.112 NA 27 0.020 NA
  • the compound of the present invention shows excellent cell anti-proliferation activity against KRAS G12C mutant cell NCI-H358.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • CD-1 male mice aged 7 to 10 weeks were selected, and the doses for intravenous and oral administration were 3 mg/kg and 10 mg/kg, respectively.
  • the test animals eat and drink freely throughout the test period.
  • the animals in the intravenous group were given a single injection of the compound through the tail vein with a volume of 3 mL/kg; the oral group was given the compound through a single gavage with a volume of 10 mL/kg.
  • the sample collection time is: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, 24h.
  • Approximately 30 ⁇ L of whole blood was collected through the saphenous vein at each time point to prepare plasma for high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for concentration determination. All animals were euthanized by CO 2 anesthesia after collecting PK samples at the last time point.
  • mice The evaluation results of PK properties in mice are shown in Table 2.
  • C max represents the maximum plasma concentration
  • T max represents the peak time
  • T 1/2 represents the half-life
  • Vdss represents the apparent volume of distribution
  • Cl represents the clearance rate
  • AUC 0-last represents the area of the curve (0-t)
  • AUC 0-inf represents the area of the curve (0-inf); NA represents not tested.
  • the compound of the present invention has a good clearance rate in mice, oral AUC, good bioavailability, and good pharmacokinetic properties.
  • Cell culture Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) are cultured in a monolayer in vitro, and the culture conditions are DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubation Box culture. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, resuspended in an appropriate amount of PBS, and matrigel is added 1:1 to obtain a cell suspension with a cell density of 25 x 10 6 cells/mL .
  • Mia PaCa-2 cells were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 118mm At 3 o'clock, randomly grouped according to tumor volume, each group has 6 animals, the dose of the blank group is 0, the dose of the test group is 10 mg/kg, the dose volume is 10 ⁇ L/g, oral administration, 22 days of administration, Once a day.
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • 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 treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • test compound of the present invention exhibits a good in vivo efficacy in a Balb/c Nude mouse model of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously into a tumor Balb/c Nude mouse model.
  • Cell culture Human non-small cell lung cancer NCI-H358 is cultured in a monolayer in vitro.
  • the culture conditions are DMEM/F12 medium with 20% fetal bovine serum, 1% double antibody, 37°C and 5% carbon dioxide incubator.
  • the cells are collected, counted, and resuspended in an appropriate amount of PBS.
  • Matrigel is added 1:1 to obtain a cell suspension with a cell density of 25 ⁇ 10 6 cells/mL .
  • NCI-H358 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 102mm 3 At the time, random grouping was carried out according to the tumor volume, each group of 6 animals, the dose of the blank group was 0, the dose of the test group was 20mg/kg, the dose volume was 10 ⁇ L/g, orally administered for 30 days, every day once.
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • 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 treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • test compound of the present invention exhibits significant in vivo efficacy in a Balb/c Nude mouse model of human non-small cell lung cancer NCI-H358 cells transplanted subcutaneously in nude mice.

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Abstract

L'invention concerne un composé hétérocyclique à huit chaînons contenant de l'azote, tel que représenté par la formule (P), et son utilisation dans la préparation d'un inhibiteur de protéine mutante de KRAS G12C.
PCT/CN2021/101868 2020-06-24 2021-06-23 Composé hétérocyclique à huit chaînons contenant de l'azote WO2021259331A1 (fr)

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US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022214102A1 (fr) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Composé hétérocyclique agissant comme inhibiteur de kras g12d
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras

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CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
CN110869357A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 化合物及其用于治疗癌症的使用方法
CN110869358A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 Kras的共价抑制剂

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WO2016044772A1 (fr) * 2014-09-18 2016-03-24 Araxes Pharma Llc Thérapies combinatoires pour le traitement du cancer
CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
CN110869357A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 化合物及其用于治疗癌症的使用方法
CN110869358A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 Kras的共价抑制剂

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022214102A1 (fr) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Composé hétérocyclique agissant comme inhibiteur de kras g12d
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras

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