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WO2023280026A1 - Composé cyclique hétéroaromatique, son procédé de préparation et son utilisation - Google Patents

Composé cyclique hétéroaromatique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023280026A1
WO2023280026A1 PCT/CN2022/102137 CN2022102137W WO2023280026A1 WO 2023280026 A1 WO2023280026 A1 WO 2023280026A1 CN 2022102137 W CN2022102137 W CN 2022102137W WO 2023280026 A1 WO2023280026 A1 WO 2023280026A1
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Prior art keywords
compound
alkylene
alkyl
halogen
pharmaceutically acceptable
Prior art date
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PCT/CN2022/102137
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English (en)
Chinese (zh)
Inventor
唐建川
任云
刘金明
张新龙
何诰
邰正福
周俊鹏
田强
宋宏梅
葛均友
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN202280033205.2A priority Critical patent/CN117460737A/zh
Publication of WO2023280026A1 publication Critical patent/WO2023280026A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a class of heteroaromatic compounds, a preparation method and application thereof.
  • RAS is a guanine nucleotide binding protein with GTPase activity and has the function of anchoring inside the cell membrane.
  • RAS protein can switch between the GDP-bound inactive state and the GTP-bound active state, affecting multiple signaling pathways such as downstream Raf, PI3K, and RalGDS, and regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis, and migration, etc. .
  • RAS mutations will lead to the continuous activation of downstream signaling pathways and promote the occurrence and development of tumors.
  • RAS mutations mainly occur in KRAS (85%), and the 12-position glycine on KRAS is mutated to aspartic acid (G12D ) has the highest frequency (34.2%).
  • GTPase activity of KRAS decreases and remains active.
  • KRAS mutations are closely related to the occurrence of lung cancer, pancreatic cancer and colorectal cancer.
  • WO2020173935 discloses a class of RAS inhibitors, which use the principle of molecular glue to induce KRAS G12D to form dimers and block the interaction between KRAS and downstream proteins.
  • WO2021041671 discloses a new class of KRAS G12D inhibitors, but does not disclose its specific mechanism of action.
  • PROTACs Proteolysis-Targeting Chimeras
  • PROTACs are bifunctional molecules whose structure includes three parts: (1) the part that binds to the target protein substrate; (2) the part that binds to the E3 ubiquitin ligase and (3) the chain connecting the first two parts.
  • PROTAC can recognize the target protein and E3 ubiquitin ligase respectively, shorten the distance between the target protein and E3 ubiquitin ligase, induce the recruitment of E3 ubiquitin ligase to the surface of the target protein, trigger the ubiquitination process and induce the degradation of the target protein .
  • PROTAC molecules have a wide range of pharmacological activities, high target selectivity, can be used to degrade difficult-to-drug target proteins, have strong degradation efficiency, and can maintain catalytic degradation at low concentrations.
  • the present invention provides compounds useful as degraders and/or inhibitors targeting KRAS G12D protein.
  • the compound of the present invention belongs to PROTAC, one end of which can bind to target protein, and the high-affinity VHL ligand at the other end can recruit target protein to E3 ubiquitin ligase, resulting in ubiquitination and subsequent degradation of KRAS G12D protein.
  • the compounds of the present invention can be used to treat and/or prevent cancers or disorders caused by aggregation and/or overactivation of target proteins.
  • the invention provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or precursor thereof Drug, said compound has the structure of formula (I):
  • X 1 is selected from C(R 1 ) 2 and C(O); and X 2 is selected from N and CR 1 ;
  • X 1 is selected from CR 1 and N; and X 2 is C;
  • X 3 and X 4 are each independently selected from C(R 1 ) 2 , NR 8 and C(O);
  • X 3 and X 4 are each independently selected from CR 1 and N;
  • Each R 1 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, - OC 1-6 haloalkyl and -OC 3-6 cycloalkyl; or two R 1 on the same carbon atom form carbonyl, C 3-6 cycloalkyl or 3-6 membered heterocycle with the carbon atom they are connected to base;
  • R 8 is independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl and C 1-3 haloalkyl;
  • R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl, each of said aryl and heteroaryl is optionally substituted by one or more R 3 ;
  • each R 3 is independently selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C 1 -6 alkyl-OH, -OC 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, Cycloalkyl, heterocyclyl and heteroaryl are each optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -;
  • L 1 is selected from -O-, -S-, -NR 1a -, C 1-6 alkylene, C 3-6 cycloalkylene and 3-10 membered heterocyclylene, said alkylene, alkylene Cycloalkyl and heterocyclylene are each optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • L 2 is a covalent bond, or selected from -O-, -NR 2a -, C 1-6 alkylene, -OC 1-6 alkylene, C 1-6 alkylene-O-, C 3- 6 cycloalkylene groups and 3-10 membered heterocyclylene groups, each of the alkylene, cycloalkylene and heterocyclylene groups is optionally selected from one or more halogen, hydroxyl, cyano, C 1 Substituents of -6 alkyl and C 1-6 haloalkyl;
  • L 3 is a covalent bond, or selected from -O-, -NR 3a -, C 1-6 alkylene, -OC 1-6 alkylene, C 1-6 alkylene-O-, C 3- 6 cycloalkylene groups and 3-10 membered heterocyclylene groups, each of the alkylene, cycloalkylene and heterocyclylene groups is optionally selected from one or more halogen, hydroxyl, cyano, C 1 Substituents of -6 alkyl and C 1-6 haloalkyl;
  • L 4 is a covalent bond, or is selected from -O-, -NR 4a -, C 1-6 alkylene, -OC 1-6 alkylene, C 1-6 alkylene-O-, C 3- 6 cycloalkylene groups and 3-10 membered heterocyclylene groups, each of the alkylene, cycloalkylene and heterocyclylene groups is optionally selected from one or more halogen, hydroxyl, cyano, C 1 Substituents of -6 alkyl and C 1-6 haloalkyl;
  • L 5 is a covalent bond, or selected from -O-, -NR 5a -, C 1-6 alkylene, -OC 1-6 alkylene-, C 1-6 alkylene-O-, C 3 -6 cycloalkylene and 3-10 membered heterocyclylene, said alkylene, cycloalkylene and heterocyclylene are each optionally replaced by one or more selected from halogen, hydroxyl, cyano, C Substituents of 1-6 alkyl and C 1-6 haloalkyl;
  • L 6 is selected from -O-, -S-, -NR 6a -, C 1-6 alkylene, -OC 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R 6a )- and 3-10 membered heterocyclylene, each of the alkylene, cycloalkylene and heterocyclylene optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 1a , R 2a , R 3a , R 4a , R 5a and R 6a are each independently selected from hydrogen and C 1-6 alkyl;
  • M is a small molecule ligand of E3 ubiquitin ligase VHL, preferably its structure is shown in the following formula:
  • E is selected from C 1-6 alkylene, C 3-6 cycloalkylene and 3-10 membered heterocyclylene, each of which is optionally replaced by one Or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7a is selected from hydrogen and C 1-6 alkyl
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 3-12 membered heterocyclyl;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, each of which is optionally replaced by one or more Substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R is selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl , C 2-6 alkenyl and C 2-6 alkynyl;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, Solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, Isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions comprising the invention.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a pharmaceutically acceptable salt thereof, Metabolites or prodrugs, or pharmaceutical compositions of the present invention, which target the KRAS G12D protein and are used to degrade the KRAS G12D protein.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a pharmaceutically acceptable salt thereof, Metabolites or prodrugs, or pharmaceutical compositions of the present invention, which are used to prevent and/or treat KRAS G12D-mediated related diseases.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a pharmaceutically acceptable salt thereof, Use of metabolites or prodrugs or the pharmaceutical composition of the present invention in the preparation of medicines for preventing and/or treating KRAS G12D-mediated related diseases.
  • the present invention provides a method for preventing and/or treating related diseases mediated by KRAS G12D, which comprises administering a preventive and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable amount thereof to an individual in need thereof.
  • a preventive and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable amount thereof to an individual in need thereof.
  • the invention provides methods for preparing the compounds of the invention.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon group.
  • C 1-6 alkyl refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • alkylene refers to a divalent saturated aliphatic hydrocarbon group obtained by removing one more hydrogen atom from the corresponding "alkyl".
  • C 1-6 alkylene refers to an alkylene group having 1 to 6 carbon atoms, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH( CH3 )CH2- ) , optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds.
  • C alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexene group, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl or 4-methyl-3-pentenyl, etc.), which is optionally replaced by one or more (such as 1, 2 or 3) suitable substituents such as halogen substitution.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds.
  • C2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds (such as ethynyl , 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl or 5-hexynyl, etc.), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl, or bicyclic rings, including spiro, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1] octyl or bicyclo[5.2.0] nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclo
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated non - aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl) optionally substituted by one or more (such as 1, 2 or 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cycloalkylene refers to a divalent group obtained by removing one more hydrogen atom from the corresponding "cycloalkyl”.
  • halo or halogen group is defined to include fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1, 2 or 3) same or different halogen atoms.
  • C 1-6 haloalkyl refers to a haloalkyl group having 1 to 6 carbon atoms, such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , - CH2Cl or -CH2CH2CF3 .
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group, for example having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring atom and one or more (for example 1, 2, 3 or 4) heteroatoms independently selected from N, O or S(O) t (wherein t is 0, 1 or 2), for example 3- 12-membered heterocyclic group, 3-7-membered heterocyclic group, 3-6-membered heterocyclic group, 5-6-membered heterocyclic group, etc.
  • heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyrrolidinyl, hexa Hydrogen-1H-pyrroline, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl or piperazinyl.
  • heterocyclylene refers to a divalent group obtained by removing one more hydrogen atom from the corresponding "heterocyclyl”.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-10 aryl or “C 6-10 aryl ring” refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring).
  • Aryl is optionally substituted with 1 or more (such as 1, 2 or 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 or C 1-6 alkyl, etc.).
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6 , 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially containing 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms, and additionally in each case may be Benzo-fused.
  • a heteroaryl or heteroaryl ring may be selected from thienyl (ring), furyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyryl Azolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), and their benzos Derivatives; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and their benzo derivatives.
  • heteroarylene refers to a divalent group obtained by removing one more hydrogen atom from the corresponding "heteroaryl”.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated atom is in the current instance normal valences and the substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituents can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Substituents of choice are either substituted or unsubstituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected substituents Substituted or not.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (e.g.
  • radioisotopes tritium (ie3H ) and carbon- 14 (ie14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone-d6 or DMSO - d6.
  • stereoisomer means isomers formed as a result of at least one asymmetric center. In compounds with one or more (e.g. 1, 2, 3 or 4) asymmetric centers, which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual non- Enantiomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs, which can directly or indirectly Compounds of the invention or metabolites or residues thereof are provided. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperbenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound.
  • the present invention includes metabolites of compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention which themselves may have little or no pharmacological activity, when administered to the body or
  • prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which themselves may have little or no pharmacological activity, when administered to the body or
  • the above can be converted into compounds of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups During any of the preparations of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, as described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 For those protecting groups, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, and metabolites thereof or prodrugs:
  • X 1 , X 2 , X 3 , X 4 , R 2 , L and M are as defined above.
  • the compound of formula (I) above has a structure as shown in formula (IA) or (IB):
  • R 1 , R 2 , L and M are as defined above, and n is 0, 1, 2, 3 or 4 for R 1 other than hydrogen.
  • the above-mentioned compound of formula (I) has a structure as shown in formula (IC):
  • R 1 , R 2 , L and M are as defined above, and n is 0, 1, 2, 3 or 4 for R 1 other than hydrogen.
  • each R 1 is independently selected from hydrogen and halogen.
  • R 1 is hydrogen, fluorine or chlorine.
  • each R 1 is independently selected from hydrogen and halogen.
  • R1 is hydrogen, fluorine or chlorine ; more preferably, R1 is hydrogen or fluorine.
  • each R 1 is independently selected from hydrogen and halogen.
  • R1 is hydrogen, fluorine or chlorine ; more preferably, R1 is hydrogen or fluorine.
  • R is naphthyl optionally substituted with 1-3 R , and each R is independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, ethynyl and hydroxyl, preferably, each R3 is independently selected from F, Cl, ethynyl and hydroxyl.
  • R is selected from 8 -Cl-naphthalen-1-yl, 3-OH-naphthalen-1-yl, 8-ethynyl-7-F-3-OH-naphthalen-1-yl and 8-ethynyl -7-F-Naphthalen-1-yl.
  • R is naphthyl optionally substituted with 1-3 R , and each R is independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, ethynyl and hydroxyl, preferably, each R3 is independently selected from F, Cl, ethynyl and hydroxyl.
  • R is selected from 8 -Cl-naphthalen-1-yl, 3-OH-naphthalen-1-yl, 8-ethynyl-7-F-3-OH-naphthalen-1-yl and 8-ethynyl -7-F-naphthalen-1-yl; more preferably, R is 8 -Cl-naphthalen-1-yl or 3-OH-naphthalen-1-yl.
  • R 2 is naphthyl optionally substituted with 1-3 R 3 , and each R 3 is independently selected from F, Cl, Br, I, methyl, Ethyl, isopropyl, ethynyl and hydroxyl, preferably, each R3 is independently selected from F, Cl, ethynyl and hydroxyl.
  • R is 8 -Cl-naphthalen-1-yl, 3-OH-naphthalen-1-yl, 8-ethynyl-7-F-3-OH-naphthalen-1-yl or 8-ethynyl- 7-F-naphthalen-1-yl; more preferably R2 is 8 -ethynyl-7-F-3-OH-naphthalen-1-yl.
  • L 1 is -O-.
  • L 1 is -O-.
  • L 1 is -O-.
  • L 2 is C 1-6 alkylene, preferably -CH 2 - or -CH 2 -CH 2 -.
  • L 2 is C 1-6 alkylene, preferably -CH 2 - or -CH 2 -CH 2 -, more preferably is -CH 2 -.
  • L 2 is C 1-6 alkylene, preferably -CH 2 - or -CH 2 -CH 2 -, more preferably -CH 2 -CH 2 -.
  • L 3 is a 3-6 membered heterocyclylene containing one N atom, preferably containing one N atom 5-6 membered heterocyclylene, preferably
  • L 3 is a 3-6 membered heterocyclylene containing one N atom, preferably a 5-6 membered heterocyclylene containing one N atom Heterocyclylene, preferably more preferably
  • L 3 is a 3-6 membered heterocyclylene containing one N atom, preferably a 5-6 membered heterocyclylene containing one N atom, preferably more preferably
  • L and L are each independently selected from a covalent bond, C 1-6 alkylene, -OC 1-6 alkylene- and C 1-6 alkylene-O-.
  • -L 4 -L 5 - is -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH2 -CH2-, -CH2 - CH2 - CH2 - CH2 - CH2-, -CH2 - O - CH2-, or -CH2- .
  • L and L are each independently selected from a covalent bond, C 1-6 alkylene, -OC 1-6 alkylene Alkyl- and C 1-6 alkylene-O-.
  • -L 4 -L 5 - is -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH2 -CH2-, -CH2 - CH2 - CH2 - CH2 - CH2 - CH2-, -CH2 - O - CH2-, or -CH2- .
  • -L 4 -L 5 - is -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -.
  • L and L are each independently selected from a covalent bond, C 1-6 alkylene, -OC 1-6 alkylene-, and C 1-6 alkylene Alkyl-O-.
  • -L 4 -L 5 - is -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH2 -CH2-, -CH2 - CH2 - CH2 - CH2 - CH2 - CH2-, -CH2 - O - CH2-, or -CH2- .
  • -L 4 -L 5 - is -CH 2 -O-CH 2 - or -CH 2 -.
  • L6 is -C(O) - or -O-.
  • L 6 is -C(O)- or -O-, preferably -C(O)-.
  • L 6 is -C(O)- or -O-.
  • L is selected from
  • A is -NH-;
  • R is C 1-6 alkyl, preferably tert-butyl; and
  • R 5 and R6 are both hydrogen.
  • A is -NH-;
  • R 4 is C 1-6 alkyl, preferably tert-butyl; and
  • R 5 and R 6 Both are hydrogen.
  • A is -NH-;
  • R 4 is C 1-6 alkyl, preferably tert-butyl; and
  • R 5 and R 6 are both hydrogen.
  • A is -NH-;
  • R 4 is C 1-6 alkyl, preferably tert-butyl;
  • R 5 is C 1-6 alkyl, preferably methyl; and
  • R 6 is hydrogen.
  • A is 5-10 membered heteroarylene, preferably 5-6 membered heteroarylene, preferably R 4 is C 1-6 alkyl, preferably isopropyl; R 5 is C 1-6 alkyl, preferably methyl; and R 6 is hydrogen.
  • M is selected from the following:
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the compound of formula (I) is selected from:
  • the compound of formula (IA) of the present invention can be prepared by the method shown in scheme I as follows:
  • R 1 , R 2 , n, L and M are as defined above;
  • LG 1a , LG 2a , LG 3a and X each independently represent a leaving group such as halogen, triflate, thiomethyl, methylsulfoxide, methylsulfone, methoxy or ethoxy ;
  • PG 1a and PG 2a each independently represent a protecting group, such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methyl or benzyl;
  • the method comprises the steps of:
  • the reaction of the above step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N , N-dimethylacetamide.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of 0-80°C for 2-24 hours.
  • the reaction of the above step (2) is preferably carried out in a suitable organic solvent and in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst may be a palladium metal catalyst, for example selected from tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenyl Palladium phosphine and palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the ligand may be a phosphorus ligand, for example selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',6'-diisopropyl Oxy-1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl and 2-dicyclohexylphosphine-2', 6'-dimethoxy-1,1'-biphenyl, preferably 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.
  • the base may be an organic base or an inorganic base, for example selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate, preferably cesium carbonate.
  • the organic solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably For 1,4-dioxane.
  • the reaction is preferably carried out at a temperature of 50-120°C for 2-16 hours.
  • the deprotection reaction of the above step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable acid.
  • the organic solvent may be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a temperature of 0-40°C for 2-12 hours.
  • the coupling reaction of the above step (4) is preferably carried out in a suitable organic solvent and in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst may be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium and palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • the ligand may be a phosphorus ligand, for example selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',6'-diisopropyl Oxy-1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl, 2-dicyclohexylphosphine-2', 6'-dimethoxy-1,1'-biphenyl, preferably 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl.
  • the base may be an organic base or an inorganic base, for example selected from sodium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate, preferably cesium carbonate.
  • the organic solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably For 1,4-dioxane.
  • the reaction is preferably carried out at a temperature of 50-120°C for 2-16 hours.
  • the reaction of the above step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base and a condensing agent.
  • the organic solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the organic base can be selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazacyclo[5,4,0]undec-7-ene, preferably triethylamine .
  • the condensing agent can be selected from 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide and any combination thereof, preferably 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-12 hours.
  • the deprotection reaction of the above step (6) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotection reagent.
  • the organic solvent may be selected from ethyl acetate, methanol, acetonitrile, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reagent may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, aluminum trichloride and iodotrimethylsilane, preferably trimethyliodosilane.
  • the reaction is preferably carried out at a temperature of 0-80°C for 1-12 hours.
  • R 1 , R 2 , L and M are as defined above;
  • LG b , LG 1b , LG 2b , LG 3b and LG 4b each independently represent a leaving group such as halogen, triflate, thiomethyl, methylsulfoxide, methylsulfone, boronic acid, boron ester, tributyltin, methoxy or ethoxy;
  • PG 1b represents a protecting group, such as benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (Boc);
  • the method comprises the steps of:
  • the reaction of the above step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N , N-dimethylacetamide.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of -50°C to 80°C for 2-24 hours.
  • the reaction of the above step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably to acetonitrile.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of 20°C-100°C for 2-48 hours.
  • the coupling reaction of the above step (3) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base.
  • the metal catalyst may be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, methanesulfonic acid [n- Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), tetrakistriphenylphosphinepalladium and palladium acetate, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride or [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2 -yl) palladium(
  • the base may be an organic base or an inorganic base, for example selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably cesium carbonate or potassium phosphate.
  • the solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably Combination of 1,4-dioxane and water.
  • the reaction is preferably carried out at a temperature of 50-120°C for 2-16 hours.
  • the reaction of the above step (4) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base and a condensing agent.
  • the organic solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the organic base can be selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazacyclo[5,4,0]undec-7-ene, preferably N,N - diisopropylethylamine.
  • the condensing agent can be selected from 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide and any combination thereof, preferably 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-12 hours.
  • the deprotection reaction of the above step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotection reagent.
  • the organic solvent may be selected from ethyl acetate, methanol, acetonitrile, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reagent may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, aluminum trichloride and iodotrimethylsilane, preferably trimethyliodosilane.
  • the reaction is preferably carried out at a temperature of 0-80°C for 1-12 hours.
  • R 1 , R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and M are as defined above;
  • LG b , LG 1b , LG 2b and LG 4b each independently represent a leaving group such as halogen, triflate, thiomethyl, methylsulfoxide, methylsulfone, boronic acid, borate ester, Tributyltin, methoxy or ethoxy;
  • PG 1b represents a protecting group, such as benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (Boc);
  • the method comprises the steps of:
  • the reaction of the above step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N , N-dimethylacetamide.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of -50°C to 80°C for 2-24 hours.
  • the reaction of the above step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably to acetonitrile.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of 20°C-100°C for 2-48 hours.
  • the coupling reaction of the above step (3) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base.
  • the metal catalyst may be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, methanesulfonic acid [n- Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), tetrakistriphenylphosphinepalladium and palladium acetate, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride or [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2 -yl) palladium(
  • the base may be an organic base or an inorganic base, for example selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably cesium carbonate or potassium phosphate.
  • the solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably Combination of 1,4-dioxane and water.
  • the reaction is preferably carried out at a temperature of 50-120°C for 2-16 hours.
  • the reaction of the above step (4) is preferably carried out in a suitable organic solvent and in the presence of a suitable oxidizing agent.
  • the organic solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the oxidizing agent may be selected from Dess-Martin oxidizing agent, 2-iodylbenzoic acid, pyridinium dichromate and pyridinium chlorochromate, preferably Dess-Martin oxidizing agent.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-16 hours.
  • the reaction of the above step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable base and reducing agent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, acetonitrile, methanol, isopropanol and any combination thereof, preferably dichloromethane and isopropanol.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, sodium bicarbonate and sodium acetate trihydrate, preferably sodium acetate trihydrate.
  • the reducing agent may be selected from sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride and 2-picoline borane, preferably 2-picoline borane.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-12 hours.
  • the deprotection reaction of the above step (6) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotection reagent.
  • the organic solvent may be selected from ethyl acetate, methanol, acetonitrile, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotecting reagent may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, aluminum trichloride and iodotrimethylsilane, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a temperature of 0-80°C for 1-12 hours.
  • R 1 , R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , n and M are as defined above;
  • LG c , LG 1c , LG 2c and LG 3c each independently represent a leaving group such as halogen, triflate, thiomethyl, methylsulfoxide, methylsulfone, boronic acid, borate ester, Tributyltin, methoxy or ethoxy;
  • PG 1c represents a protecting group, such as benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (Boc);
  • the method comprises the steps of:
  • the reaction of the above step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N , N-dimethylacetamide.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of -50°C to 80°C for 2-24 hours.
  • the reaction of the above step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base.
  • the organic solvent can be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably to acetonitrile.
  • the organic base may be selected from N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a temperature of 20°C-100°C for 2-48 hours.
  • the coupling reaction of the above step (3) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base.
  • the metal catalyst may be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, methanesulfonic acid [n- Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), tetrakistriphenylphosphinepalladium and palladium acetate, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride or [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2 -yl) palladium(
  • the base may be an organic base or an inorganic base, for example selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably cesium carbonate or potassium phosphate.
  • the solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably Combination of 1,4-dioxane and water.
  • the reaction is preferably carried out at a temperature of 50-120°C for 2-16 hours.
  • the reaction of the above step (4) is preferably carried out in a suitable organic solvent and in the presence of a suitable oxidizing agent.
  • the organic solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the oxidizing agent may be selected from Dess-Martin oxidizing agent, 2-iodylbenzoic acid, pyridinium dichromate and pyridinium chlorochromate, preferably Dess-Martin oxidizing agent.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-16 hours.
  • the reaction of the above step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable base and reducing agent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, acetonitrile, methanol, isopropanol and any combination thereof, preferably dichloromethane and isopropanol.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, sodium bicarbonate and sodium acetate trihydrate, preferably sodium acetate trihydrate.
  • the reducing agent may be selected from sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride and 2-picoline borane, preferably 2-picoline borane.
  • the reaction is preferably carried out at a temperature of 0-60°C for 1-12 hours.
  • the deprotection reaction of the above step (6) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotection reagent.
  • the organic solvent may be selected from ethyl acetate, methanol, acetonitrile, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotecting reagent may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, aluminum trichloride and iodotrimethylsilane, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a temperature of 0-80°C for 1-12 hours.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph Forms, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a kit comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotope-labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the invention.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions or formulations of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, Soybean oil, mineral oil, sesame oil, etc.
  • the pharmaceutical composition may, for example, be in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation or the like.
  • the solid preparations are, for example, tablets, capsules, powders, granules or suppositories, and the liquid preparations are, for example, solutions, suspensions or injections.
  • the composition can also be in the form of liposomes, microspheres and the like.
  • compositions of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
  • the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.001 mg to about 1000 mg, suitably 0.01-800 mg, preferably 0.05-500 mg, more preferably 0.1-350 mg, especially preferably 0.5-100 mg.
  • the present invention provides a method for preparing the pharmaceutical composition of the present invention, which method comprises the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorphic Forms, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs are combined with one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs, or the pharmaceutical composition of the present invention, which is used for the prevention and/or treatment of related diseases mediated by KRAS G12D.
  • Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs or the pharmaceutical composition of the present invention in the preparation of medicines for the prevention and/or treatment of KRAS G12D-mediated related diseases.
  • Another object of the present invention is to provide a method for preventing and/or treating related diseases mediated by KRAS G12D, which includes administering a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable dose thereof to an individual in need thereof.
  • the related disease mediated by KRAS G12D is tumor or cancer.
  • an effective amount refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, eg, an amount that achieves alleviation of one or more symptoms associated with the disease being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human, this would amount to about 0.007 mg/day to about 3500 mg/day, such as about 0.7 mg/day to about 700 mg/day.
  • Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
  • the dose is divided into several smaller doses to be administered throughout the day.
  • prevention includes the suppression and delay of the onset of the disease, and includes not only the prevention before the development of the disease, but also the prevention of the recurrence of the disease after treatment.
  • treating means reversing, alleviating or eliminating the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) and/or mass spectroscopy (MS).
  • the measuring instrument of 1 H NMR is JEOL Eclipse 400 nuclear magnetic instrument, and the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuteriodimethyl sulfoxide (DMSO-d 6 ), internal standard For tetramethylsilane (TMS), chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the measuring instrument of MS is Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • the thin-layer chromatography silica gel plate uses an aluminum plate (20 ⁇ 20cm) produced by Merck, and the specification used for the separation and purification of the thin-layer chromatography is GF 254 (1mm) produced in Yantai.
  • the monitoring of reaction adopts thin-layer chromatography (TLC) or LC-MS;
  • the developer system that uses comprises: dichloromethane and methanol system, normal hexane and ethyl acetate system, and sherwood oil and ethyl acetate system, the volume of solvent The ratio is adjusted according to the polarity of the compound or by adding triethylamine or the like.
  • Column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • the eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of triethylamine.
  • reaction temperature is room temperature (20°C-35°C).
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tepper Chemical.
  • Step 1 Preparation of 8-benzyl-3-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate
  • the first step the preparation of 3-(3-chloropropoxy) ethyl propionate
  • the second step the preparation of ethyl (S)-3-(3-(2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)propionate
  • the second step 4-(8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((S)-1-( 3-(3-ethoxy-3-oxopropoxy)propyl)pyrrolidin-2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7
  • the third step 3-(2-(((S)-1-(3-(3-ethoxy-3-oxopropoxy)propyl)pyrrolidin-2-yl)methoxy)- Preparation of Benzyl 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step the preparation of 3-benzyloxy-1-bromonaphthalene
  • the second step the preparation of 2-(3-(benzyloxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane
  • the first step the preparation of 3-(3-chloropropoxy) tert-butyl propionate
  • the third step the preparation of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol
  • 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (513 mg, 1.78 mmol) was added into dichloromethane (15 mL), and the temperature was lowered to -40°C. At this temperature, 3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester (481.06mg, 1.95mmol) was added, and N,N-diisopropylethylamine was slowly added dropwise (688.44mg, 5.33mmol), after dropping, keep stirring at this temperature for 10 minutes.
  • the sixth step 3-(2-(((S)-1-(3-(3-(tert-butoxy)-3-oxopropoxy)propyl)pyrrolidin-2-yl)methoxy
  • benzyl -7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step the preparation of tert-butyl 4-(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate
  • N-tert-butoxycarbonyl-4-piperidinemethanol (3.0g, 13.95mmol)
  • rhodium diacetate (0.31g, 0.7mmol
  • dichloromethane (30mL) were added successively.
  • the reaction mixture was cooled to 0°C, and ethyl diazoacetate (2.39 g, 20.93 mmol) was slowly added dropwise thereto in batches.
  • the reaction mixture was warmed up to 25°C and reacted for 12 hours with stirring.
  • the second step the preparation of 2-(4-piperidinylmethoxy) ethyl acetate hydrochloride
  • the third step the preparation of ethyl 2-(1-(2-hydroxyethyl)piperidin-4-yl)methoxy)acetate
  • the fourth step 3-(7-chloro-2-(2-(4-((2-ethoxy-2-oxoethoxy)methyl)piperidin-1-yl)ethoxy)- Preparation of tert-butyl 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step the preparation of 2-(3-bromoisoxazol-5-yl)ethanol
  • the second step the preparation of 2-(3-bromoisoxazol-5-yl)acetic acid
  • the third step the preparation of 2-(3-bromoisoxazol-5-yl) methyl acetate
  • the fourth step the preparation of 2-(3-bromoisoxazol-5-yl)-3-methylbutanoic acid
  • Step 7 Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutyric acid methyl ester
  • Step 9 Preparation of 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoic acid
  • the first step the preparation of 7-bromo-8-fluoro-1H-quinazoline-2,4-dione
  • the second step the preparation of 7-bromo-2,4-dichloro-8-fluoroquinazoline
  • reaction solution was poured into water (40 mL), extracted twice with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the fifth step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) Preparation of tert-butyl 2-(2-hydroxyethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the sixth step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) Preparation of tert-butyl 2-(2-oxoethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step the preparation of tert-butyl 4-((2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate
  • the second step the preparation of 2-(piperidin-4-ylmethoxy) ethyl acetate
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-(3-(3-ethoxy-3-oxopropoxy)propyl )pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1]
  • the third step 3-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-(3-(3-(((S)-1-((2S,4R) -4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane Alk-2-yl)amino)-3-oxopropoxy)propyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d Preparation of ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester
  • the first step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(((S)-1-(3-(3-(tert-butoxy)-3-oxo Propoxy)propyl)pyrrolidin-2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo [3.2 .1]
  • the third step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-8-fluoro-2-(((S)-1-(3-(3-(((S)- 1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-di Methyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidine- Preparation of 4-yl)-3,8- diazabicyclo [3.2.1]octane-8-carboxylate benzyl ester
  • the temperature of the reaction system was controlled at about 0°C in an ice bath, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53.86 mg, 141.64 ⁇ mol) and N,N-diisopropylethylamine (71.82mg, 555.67 ⁇ mol).
  • the reaction system was stirred at this temperature for 1 hour, and added dropwise into ice water (10 mL). The precipitated solid was filtered with suction, and the filter cake was dried to obtain the title compound (108 mg, yield: 78.20%).
  • the first step 4-((8-(benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl))-2-(S)-1-( 5-ethoxy-5-oxopentyl)pyrrolidin-2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tert Preparation of butyl ester
  • the third step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(((S)-1-(5-ethoxy-5-oxopentyl)pyrrolidine -2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane
  • the fourth step 5-((S)-2-(((4-(8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(3-(Benzyloxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrole
  • the fifth step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(S)-1-(5-(S)-1-(2S,4R)-4- Hydroxy-2-(4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2- Base)amino)-5-oxopentyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)- Preparation of benzyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 6 (2S,4R)-1-((S)-2-(5-((S)-2-(((4-(3,8-diazabicyclo[3.2.1]octane -3-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methylpyrrole
  • Alkyl-1-yl)pentanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2- Preparation of formamide.
  • the first step 3-(2-(2-(4-((2-ethoxy-2-oxoethoxy)methylpiperidin-1-yl)ethoxy)-8-fluoro-7 -(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-4- Preparation of tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 2-((1-(2-((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8- Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d] Preparation of pyrimidin-2-yl)oxy)ethyl)piperidin-4-yl)methoxy)acetic acid
  • the third step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(2-(4-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methyl Thiazol-5-yl)phenyl)ethyl)))carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- Oxoethoxy)methyl)piperidin-1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]- Preparation of tert-butyl octane-8-carboxylate
  • the reaction mixture was poured into water, extracted three times with ethyl acetate (10 mL), the organic phase was washed twice with saturated brine (10 mL), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the title compound (166 mg, yield: 85.7%).
  • the second step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl)- tert-butyl 2-(2-hydroxyethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate preparation
  • the third step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl)- tert-Butyl 2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate preparation of
  • the fourth step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(2-(4-(((5-(1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-methylthiazol-5-yl)benzene Base) ethyl) carbamoyl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazol-3-yl) oxy) methyl) piperidine- Preparation of 1-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • the fifth step 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(4-(((5- (1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine -1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)methyl)piperidin-1-yl)ethoxy)pyrido[4,3 Preparation of -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • the first step 3-(2-(4-(2-ethoxy-2-oxoethoxy)methyl)piperidin-1-yl)ethoxy)-8-fluoro-7-(7 -Fluoro-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Preparation of tert-butyl octane-8-carboxylate
  • the second step 2-(1-(2-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-( 7-fluoro-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)ethyl)piperidin-4- base) the preparation of methoxy) acetic acid
  • the third step 3-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(4-(2-(S) -1-(2S,4R)-4-Hydroxy-2-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1- base)-3,3-dimethyl-1-oxobutane-2-amino)-2-oxyl)methyl)piperidin-1-yl)ethoxy)pyrido[4,3-d Preparation of tert-butyl ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step 3-(2-(2-(4-((2-ethoxy-2-oxoethoxy)methyl)piperidin-1-yl)ethoxy)-8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazolin-4-yl)-3, Preparation of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 2-((1-(2-((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8 -Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazolin-2-yl) Preparation of oxy)ethyl)piperidin-4-yl)methoxy)acetic acid
  • the third step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(2-(4-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methyl Thiazol-5-yl)phenyl)ethyl)))carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- Oxoethoxy)methyl)piperidin-1-yl)ethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert Preparation of butyl ester
  • the first step 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(2-(4-(((5-(1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5- Base) phenyl) ethyl)) carbamoyl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazol-3-yl) oxy) methyl
  • Protein immobilization buffer 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP;
  • Running buffer A 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP;
  • Running buffer B 10mM HEPES, 150mM NaCl, 0.05% Tween-20, 10 ⁇ M GDP and 1% DMSO;
  • Binding and dissociation time 120s on/200s off;
  • Chip S series NTA sensor chip.
  • Chip surface activation select flow cell 2, automatically inject 10 mM NiCl 2 , the flow rate is 4 ⁇ L/min, and the injection time is 500 s.
  • the temperature was set at 25°C and the flow rate was set at 50 ⁇ L/min.
  • the program first performs 8 injections of running buffer B, and then sets the automatic injection according to the order of compound concentration from small to large, so that the compound flows over the immobilized protein surface on the chip and binds to the chip.
  • Set flow cell 1 as the reference channel, and set 0 concentration as the built-in blank control.
  • the needle was rinsed with 50% DMSO after each cycle. A 1% DMSO standard curve was used to correct for the signal value effect of DMSO.
  • the binding and dissociation signals of the compound and the protein were recorded in real time, and the signal values of the reference channel and the built-in blank control were subtracted (double subtraction) during data processing (Biacore T200 evaluation software).
  • the sensorgram of the double-subtracted signal values of the reference channel and the built-in blank control was fitted by Kinetics or steady-state Affinity (1:1) mode.
  • the K D value (K d /K a ) is used to characterize the affinity of the compound to the protein, where K d is the dissociation rate constant and K a is the association rate constant.
  • the compound of the present invention shows a strong affinity.
  • Test Example 2 KRAS-G12D (guanine-5'-triphosphate (GTP) hydrolase G12D mutant)/SOS1 protein binding in vitro Inhibitory Activity Test
  • Proteins Tag1-SOS1 and Tag2-KRAS G12D;
  • Buffer dilution buffer and detection buffer
  • KRAS-G12D/SOS1 binding assay kit components Tag1-SOS1, Tag2-KRAS G12D, Anti tag1 tb 3+ and Anti tag2 XL665 are all 1x;
  • Reaction time of protein and label 4 °C sealed incubation for 3 hours or extended to overnight;
  • Microplate reader BMG PHERAstar Fluorescence, homogeneous time-resolved fluorescence (HTRF) method, excitation wavelength 337nm, emission wavelength 665nm and 620nm.
  • HTRF homogeneous time-resolved fluorescence
  • test compounds were incubated with a mixture of Tag1-SOS1, Tag2-KRAS G12D, and GTP in dilution buffer for 15 minutes at room temperature. Add labels diluted in Assay Buffer to the reaction plate and incubate at 4°C for 3 hr or extend to overnight. Put the reaction plate into the microplate reader, and use the HTRF method to read the signal value of each well in the plate.
  • the curve was fitted according to the four-parameter model, and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated.
  • the KRAS-G12D/SOS1 in vitro protein binding inhibitory activity of the compounds was determined according to the above method, and the results are shown in Table 2.
  • the compound of the present invention exhibits strong inhibitory binding activity.
  • Test Example 3 Compound and KRAS-G12D (guanine-5'-triphosphate (GTP) hydrolase G12D mutant)/VHL in vitro Enzymatic Ternary Complex Binding Activity Assay
  • Anti-6xHis AlphaLISA receptor beads 20 ⁇ g/mL
  • ⁇ -Glutathione donor microspheres (PerkinElmer): 20 ⁇ g/mL
  • Microplate reader BMG PHERAstar Fluorescence, AlphaLISA method, excitation wavelength 680nm, emission wavelength 615nm
  • the compound to be tested was pre-incubated with KRAS/K-Ras (G12D&Q61H) protein and human VHL recombinant protein at 23° C. for 60 minutes to bind. Add acceptor beads and donor beads and incubate at 23 °C for 60 min in the dark. Put the reaction plate into the microplate reader, and use the AlphaLISA method to read the signal value of each well in the plate.
  • the wells where the samples were added (containing samples of different dilution concentrations, KRAS/K-Ras (G12D&Q61H) protein, human VHL recombinant protein, anti-6xHis AlphaLISA acceptor microspheres and ⁇ -glutathione donor microspheres) were used as the test group , with the vehicle group (containing KRAS/K-Ras (G12D&Q61H) protein, human VHL recombinant protein, anti-6xHis AlphaLISA acceptor microspheres and ⁇ -glutathione donor microspheres, 1% DMSO) as negative control, calculate the For the relative activation activity of the compounds, the standard curve was fitted using the four-parameter equation of SigmaPlot 12.5 software, and the EC 50 was calculated.
  • Cells Human colon cancer cell line GP2D or human metastatic pancreatic adenocarcinoma AsPC-1 cells
  • Protein electrophoresis electrophoresis tank (Thermo) 180V constant voltage electrophoresis
  • the cells were plated in a six-well plate with a cell volume of 1.5x10 6 cells per well. Adhesive culture was carried out overnight, and compounds (concentrations of 0.25, 2.5, and 25 ⁇ M) were added for treatment for 24 hours.
  • Degradation rate (%) (1-(experimental group KRAS-G12D intensity ⁇ control group ⁇ -Tubulin intensity)/(experimental group ⁇ -Tubulin intensity ⁇ control group KRAS-G12D intensity)) ⁇ 100%
  • the compound of the present invention exhibits strong degrading activity on target protein in cells.
  • Test Example 5 Cell Proliferation Inhibitory Activity Test of Compounds
  • AsPC-1, GP2D, Panc 04.03 and AGS cells were cultured in RPMI1640+10% fetal bovine serum (FBS), DMEM+10% FBS, RPMI1640+15% FBS+10 ⁇ g/mL insulin, and Ham's F12 medium, respectively. Cultured in a carbon dioxide incubator at 37°C. Cells were plated in a 96-well flat-bottomed cell culture plate, with 2000 cells per well, and cultured overnight. The next day, compound dilutions were added.
  • FBS fetal bovine serum
  • DMEM+10% FBS fetal bovine serum
  • RPMI1640+15% FBS+10 ⁇ g/mL insulin fetal bovine serum
  • Ham's F12 medium Ham's F12 medium
  • the compound was diluted to a maximum concentration of 100 ⁇ M, and 9 concentration points were diluted in a 4-fold concentration gradient, or the compound was diluted to a maximum concentration of 3 ⁇ M, and a 3-fold concentration gradient was diluted to 9 concentration points, and DMSO was used as a control.
  • the final concentration of DMSO in the cell culture medium was 1%.
  • the compound of the present invention exhibits strong proliferation inhibitory activity on KRAS G12D mutant cells.

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Abstract

L'invention concerne un composé cyclique hétéroaromatique, son procédé de préparation et son utilisation. Plus particulièrement, la présente invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un tautomère, un polymorphe, un solvate, un N-oxyde, un composé marqué par un isotope, un métabolite ou un promédicament de celui-ci, une composition pharmaceutique le contenant, son procédé de préparation et son utilisation dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées médiées par KRAS G12D.
PCT/CN2022/102137 2021-07-05 2022-06-29 Composé cyclique hétéroaromatique, son procédé de préparation et son utilisation Ceased WO2023280026A1 (fr)

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WO2023185864A1 (fr) * 2022-03-28 2023-10-05 Jingrui Biopharma Co., Ltd. Composés pour la dégradation ciblée de kras
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024019103A1 (fr) 2022-07-21 2024-01-25 アステラス製薬株式会社 Composé hétérocyclique agissant sur la protéine kras portant la mutation g12d
WO2024034593A1 (fr) 2022-08-09 2024-02-15 アステラス製薬株式会社 Composé hétérocyclique destiné à induire la dégradation de la protéine kras portant une mutation ｇ１２ｖ
WO2024034591A1 (fr) 2022-08-09 2024-02-15 アステラス製薬株式会社 Composé hétérocyclique pour inhiber et/ou induire la dégradation de la protéine kras
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024083258A1 (fr) * 2022-10-21 2024-04-25 上海领泰生物医药科技有限公司 Agent de dégradation de kras g12c, son procédé de préparation et son utilisation
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211663A1 (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
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
WO2024261257A1 (fr) * 2023-06-22 2024-12-26 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
WO2025006753A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de la protéine kras
WO2025006783A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de kras
WO2025024732A1 (fr) * 2023-07-26 2025-01-30 Arvinas Operations, Inc. Composés utiles dans le traitement de troubles médiés par kras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12421254B2 (en) 2023-03-15 2025-09-23 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
CN110869358A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 Kras的共价抑制剂
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
CN112955137A (zh) * 2018-09-10 2021-06-11 米拉蒂治疗股份有限公司 组合疗法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
CN110869358A (zh) * 2017-05-25 2020-03-06 亚瑞克西斯制药公司 Kras的共价抑制剂
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
CN112955137A (zh) * 2018-09-10 2021-06-11 米拉蒂治疗股份有限公司 组合疗法
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023185864A1 (fr) * 2022-03-28 2023-10-05 Jingrui Biopharma Co., Ltd. Composés pour la dégradation ciblée de kras
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024019103A1 (fr) 2022-07-21 2024-01-25 アステラス製薬株式会社 Composé hétérocyclique agissant sur la protéine kras portant la mutation g12d
KR20250036820A (ko) 2022-07-21 2025-03-14 아스텔라스세이야쿠 가부시키가이샤 G12d 변이 kras 단백에 작용하는 복소환 화합물
WO2024034593A1 (fr) 2022-08-09 2024-02-15 アステラス製薬株式会社 Composé hétérocyclique destiné à induire la dégradation de la protéine kras portant une mutation ｇ１２ｖ
WO2024034591A1 (fr) 2022-08-09 2024-02-15 アステラス製薬株式会社 Composé hétérocyclique pour inhiber et/ou induire la dégradation de la protéine kras
WO2024083258A1 (fr) * 2022-10-21 2024-04-25 上海领泰生物医药科技有限公司 Agent de dégradation de kras g12c, son procédé de préparation et son utilisation
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
US12421254B2 (en) 2023-03-15 2025-09-23 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211663A1 (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
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024261257A1 (fr) * 2023-06-22 2024-12-26 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
WO2025006753A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de la protéine kras
WO2025006783A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de kras
WO2025024732A1 (fr) * 2023-07-26 2025-01-30 Arvinas Operations, Inc. Composés utiles dans le traitement de troubles médiés par kras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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