WO2024027695A1 - Composés utiles comme inhibiteurs de her2 - Google Patents

Composés utiles comme inhibiteurs de her2 Download PDF

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Publication number
WO2024027695A1
WO2024027695A1 PCT/CN2023/110515 CN2023110515W WO2024027695A1 WO 2024027695 A1 WO2024027695 A1 WO 2024027695A1 CN 2023110515 W CN2023110515 W CN 2023110515W WO 2024027695 A1 WO2024027695 A1 WO 2024027695A1
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compound
general formula
pharmaceutically acceptable
solvates
hydrates
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PCT/CN2023/110515
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English (en)
Chinese (zh)
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谢雨礼
吴应鸣
钱立晖
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微境生物医药科技(上海)有限公司
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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and more specifically, to a class of compounds with HER2 protein inhibitory effects, preparation methods thereof, and applications of such compounds in preparing drugs for treating or preventing related diseases mediated by HER2.
  • the ErbB family of epidermal growth factors consists of EGFR (ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4).
  • the HER2 protein consists of an extracellular ligand-binding region and a single-chain transmembrane The extracellular domain of HER2 can bind to different ligands or form homo-dimers or heterodimers with ErbB family members. (hetero-dimer), and HER2 protein is often a common partner of heterodimers.
  • HER2 When HER2 binds to its ligand, it activates tyrosine kinase by causing receptor dimerization and autophosphorylation of the intracytoplasmic tyrosine kinase region. amino acid kinase activity.
  • the signal transduction pathway mediated by HER2 protein is mainly transduced through the MAP kinase (mitogen-activated protein kinase) and phosphatidylinositol 3-kinase (PI3K) pathways.
  • MAP kinase mitogen-activated protein kinase
  • PI3K phosphatidylinositol 3-kinase
  • HER2 gene amplification HER2 amplification
  • HER2 protein overexpression HER2overexpression
  • continuously activating HER2 mutants activating HER2 mutants
  • HER2 gene amplification Approximately 1.4% of lung adenocarcinoma patients have HER2 gene amplification, while persistently activating HER2 mutants have been detected in 2.3% of lung adenocarcinomas.
  • the mutations are mainly concentrated in the HER2 tyrosine kinase domain (kinase domain). Especially in the exon 20 region.
  • Exon 20 insertion mutations result in the addition of amino acids between the ⁇ C-helix region (protein sequence 753-768), resulting in persistently activating HER2 mutations.
  • Y772dupYVMA YVMA is the most common mutated form and is detected in 34% of HER2-mutated lung cancer patients.
  • HER2 covalent inhibitors Poziotinib and Afatinib are more active than HER2 non-covalent inhibitors Lapatinib and Tucatinib.
  • HER2 covalent inhibitors Poziotinib and Afatinib simultaneously inhibit wild-type EGFR (WT EGFR ) activity, causing greater toxicity, thus limiting its clinical application.
  • the invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is -H, -CH 3 , -CCH, -OCH 3 or halogen
  • R 2 is -H or halogen
  • R 4 is R 4a or R 4b ;
  • R 4a is wherein Q is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH 3 ;
  • R 4b is wherein Z is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH 3 ;
  • R 5 is -H or -F
  • R 6a and R 6b are each independently -H or (C1-C3) alkyl, wherein said (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R 8 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 5 , R 6a and R 6b is not -H;
  • R 6c is -H or -CH 3 ;
  • R 7 is -H or -CH 3 ;
  • R 8 is each independently -H or (C1-C3)alkyl.
  • R 1 is -H, -CH 3 , -CCH, -OCH 3 , -F or -Cl.
  • R 2 is -H, -F or -Cl.
  • R 7 is -CH 3 .
  • R 8 is each independently -H, -CH 3 or -CH 2 CH 3 .
  • R 6a and R 6b are each independently -H or -CH 3 , and the -CH 3 may be optionally substituted by one of the following groups: - N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ),
  • R 4a is:
  • R 4a is:
  • R 4b is:
  • R 4b is:
  • the compound of general formula (1) has one of the following structures:
  • the present invention also provides a compound represented by the general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 9 is -H, -CH 3 , -CCH, -OCH 3 or halogen
  • R 10 is -H or halogen
  • R 11 is -H or halogen; and at least one of R 9 , R 10 and R 11 is not -H;
  • R 12 is -H or -CH 3 ;
  • R 13 is -H or -F
  • R 14a and R 14b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R 15 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 13 , R 14a and R 14b is not -H;
  • R 14c is -H or -CH 3 ;
  • R 15 is each independently -H or (C1-C3)alkyl.
  • R 9 is -H, -CH 3 , -CCH, -OCH 3 , -F, -Cl or -Br.
  • R 10 is -H, -F, -Cl or -Br.
  • R 11 is -H, -F or -Cl.
  • R 12 is -CH 3 .
  • R 15 is each independently -H, -CH 3 or -CH 2 CH 3 .
  • R 14a and R 14b are each independently -H or -CH 3 , wherein -CH 3 may be optionally substituted by one of the following groups: -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ),
  • the structural unit W is:
  • the structural unit W is:
  • the compound of general formula (2) has one of the following structures:
  • the invention also provides a compound represented by the general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 16 is -H, -CH 3 , -CCH, -OCH 3 or halogen
  • R 17 is -H or halogen
  • R 18 is -H or halogen; and at least one of R 16 , R 17 and R 18 is not -H;
  • R 19 is -H or -F
  • R 20a and R 20b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R 22 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 19 , R 20a and R 20b is not -H;
  • R 20c is -H or -CH 3 ;
  • R 21 is -H or -CH 3 ;
  • R 22 is each independently -H or (C1-C3)alkyl.
  • R 16 is -H, -CH 3 , -CCH, -OCH 3 , -F, -Cl or -Br.
  • R 17 is -H, -F, -Cl or -Br.
  • R 18 is -H, -F or -Cl; R 18 is -H; R 18 is -F.
  • R 22 is each independently -H, -CH 3 or -CH 2 CH 3 .
  • R 20a and R 20b are each independently -H or -CH 3 , wherein -CH 3 may be optionally substituted by one of the following groups: -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ),
  • the structural unit E is:
  • the structural unit E is:
  • the compound of general formula (3) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains pharmaceutically acceptable carriers, diluents and/or excipients, as well as the general formula (1), general formula (2) and general formula of the present invention.
  • the compound, or each isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, serves as the active ingredient.
  • Another object of the present invention is to provide the compounds represented by the general formula (1), the general formula (2), and the general formula (3) of the present invention, or their respective isomers, crystal forms, and pharmaceutically acceptable salts. , hydrates or solvates or the above pharmaceutical compositions are used in the preparation of drugs for treating, regulating or preventing diseases related to HER2 protein.
  • Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to HER2 protein, which includes administering to a subject a therapeutically effective amount of general formula (1), general formula (2), general formula ( 3)
  • the compounds described above can be synthesized using standard synthetic techniques or well-known techniques combined with the methods described herein.
  • solvents, temperatures and other reaction conditions mentioned herein may be varied.
  • Starting materials for the synthesis of compounds may be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.).
  • the compounds described herein and other related compounds having various substituents may be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound, wherein the compound of general formula (1) can be prepared by using the following general reaction scheme 1 and general reaction scheme 2, and the compound of general formula (2) can be prepared by using the following general reaction Preparation in Scheme 3:
  • Compounds of general formula (3) can be prepared by the following general reaction scheme 4:
  • Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 1, wherein R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or -CH 3 , N represents nitrogen, O represents oxygen, and ring A is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom.
  • R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or -CH 3 , N represents nitrogen, O represents oxygen, and ring A is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom.
  • R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or -CH 3 , N represents nitrogen, O represents oxygen, and ring A is a (4-6 membered
  • Compound 1-4 and compound 1-5 undergoes a substitution reaction under alkaline conditions to generate compound 1-6, compound 1-6 is deprotected to generate compound 1-7, and compound 1-7 reacts with acid chloride 1-8 to generate the target product 1-9 or compound 1-7 and Acid chloride 1-10 reacts to produce target product 1-11.
  • Embodiments of compounds of general formula (1) may also be prepared according to General Reaction Scheme 2, wherein R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or - CH 3 , N represents nitrogen, O represents oxygen, and ring B is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom.
  • R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or - CH 3 , N represents nitrogen, O represents oxygen, and ring B is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom.
  • R 1 , R 2 , R 3 , R 5 , R 6a , R 6b and R 6c are as defined above and Y represents -H or - CH 3 , N represents nitrogen, O represents oxygen, and ring B is a (4-6 membere
  • Compound 2-4 and compound 2-5 undergoes a substitution reaction under alkaline conditions to generate compound 2-6, compound 2-6 is deprotected to generate compound 2-7, and compound 2-7 reacts with acid chloride 2-8 to generate the target product 2-9 or compound 2-7 React with acid chloride 2-10 to produce the target product 2-11.
  • Embodiments of compounds of general formula (2) may be prepared according to General Reaction Scheme 3, wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14a , R 14b and R 14c are as defined above and N represents nitrogen, O represents oxygen.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14a , R 14b and R 14c are as defined above and N represents nitrogen, O represents oxygen.
  • compound 3-1 and compound 3-2 undergo a substitution reaction under alkaline conditions to generate compound 3-3.
  • Compound 3-3 undergoes an oxidation reaction to generate compound 3-4.
  • Embodiments of compounds of general formula (3) may be prepared according to General Reaction Scheme 4, wherein R 16 , R 17 , R 18 , R 19 , R 21 , R 20a , R 20b and R 20c are as defined above and N represents nitrogen, O represents oxygen.
  • R 16 , R 17 , R 18 , R 19 , R 21 , R 20a , R 20b and R 20c are as defined above and N represents nitrogen, O represents oxygen.
  • compound 4-1 and compound 4-2 undergo a substitution reaction under alkaline conditions to generate compound 4-3.
  • Compound 4-3 undergoes an oxidation reaction to generate compound 4-4.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not obliterate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance will not cause undesirable biological effects or Interact in a harmful way with any of its components.
  • pharmaceutically acceptable salt refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not obliterate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting compounds of the general formula with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid, propionic acid , oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid,
  • references to pharmaceutically acceptable salts include solvent-added or crystalline forms, especially solvates or polymorphs.
  • Solvent The compound contains stoichiometric or non-stoichiometric solvents and is selectively formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the general formula is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula are prepared in different forms, including, but not limited to, amorphous, comminuted, and nano-particulate forms.
  • the compound of the general formula includes a crystalline form and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystalline form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
  • compounds of the general formula may present chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and cis-trans isomers.
  • Each chiral center or axis of chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is intended to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • hydrogen atoms can be replaced with heavy hydrogen to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs usually have the advantages of reducing side effects and increasing the number of drugs. Stability, enhanced efficacy, extended half-life of drugs in vivo and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted by one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 )CH , iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.
  • alkenylene refers to a divalent alkenyl group as defined above.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl or 1-butynyl.
  • alkynylene refers to a divalent alkynyl group as defined above.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic). If the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” "Alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as "cycloalkynyl”. Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl is monocyclic.
  • cycloalkyl is monocyclic or bicyclic.
  • the ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form oxo or sulfide radicals.
  • Cycloalkyl also includes cycloalkylene.
  • cycloalkyl groups contain 0, 1, or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, etc.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted by one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, which may be monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom.
  • aryloxy groups include, but are not limited to, phenoxy and naphthyloxy.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which may be monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrole[3,2-b]pyridyl, 1H-pyrrole[2,3-c]pyridyl, 1H-pyrrole[3,2-c]pyridyl, 1H- Pyrrole[2,3-b]pyridyl,
  • heteroaryl refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl refers to a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as ring A portion of a structure having at least one heteroatom ring member independently selected from the group consisting of boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond.
  • heterocycloalkynyl Can be called "heterocycloalkynyl".
  • Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be oxidized to form oxo or sulfide radicals or other oxidative linkages (e.g., C(O), S(O), C(S), or S(O) 2. N-oxide, etc.), or the nitrogen atom can be quaternized.
  • Heterocycloalkyl groups may be attached via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, or Benzo derivatives such as thienyl. Heterocycloalkyl groups containing fused aromatic rings may be linked via any ring-forming atom, including ring-forming atoms of fused aromatic rings.
  • heterocycloalkyl examples include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuryl, dihydropyranyl, N-morpholinyl, 3-oxa -9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxypiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, scopolanoyl, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolid
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • halogen means fluorine, chlorine, bromine or iodine.
  • halogenated or halogen substituted
  • appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted in any combination with F, Cl, Br or I, preferably Replaced by F or Cl.
  • the substituent "-O-CH 2 -O-" means that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of the heterocycloalkyl group, aryl group or heteroaryl group, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • ring includes any cyclic structure.
  • element is intended to indicate the number of backbone atoms constituting the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific part or functional group of a molecule. Chemical fragments are generally thought of as chemical entities contained in or attached to molecules.
  • use wedge-shaped solid line keys and wedge-shaped dotted keys To express the absolute configuration of a three-dimensional center, use the straight shape line key and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • acceptable means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or symptoms; making a disease or symptoms subside; alleviating complications caused by a disease or symptoms, or preventing or treating signs caused by a disease or symptoms.
  • a compound or pharmaceutical composition when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributable to or related to administration, whether fixed or temporary, continuous or intermittent.
  • Active ingredient refers to the compounds of the present invention, as well as pharmaceutically acceptable inorganic or organic salts of the compounds of the present invention.
  • the compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is intended to include all such isomeric forms of these compounds.
  • composition refers to a substance when administered to an individual (human or animal), a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound. wait.
  • the compounds or pharmaceutical compositions of general formula (1), general formula (2), general formula (3) of the present invention can generally be used to inhibit HER2 protein, and therefore can be used to treat one or more conditions related to HER2 protein activity. Accordingly, in certain embodiments, the present invention provides methods for treating HER2 protein-mediated disorders, the methods comprising administering to a patient in need thereof the compounds of the present invention, Formula (1), Formula (2), Compounds of general formula (3), or pharmaceutically acceptable compositions thereof.
  • cancers include, but are not limited to, hematological malignancies (leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes) and solid tumors (cancers such as prostate , breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumor), etc.
  • hematological malignancies leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes
  • solid tumors cancers such as prostate , breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumor
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within a safe and effective amount and pharmaceutically acceptable excipients or carriers.
  • the "safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective dosage of the compound is determined based on the age, condition, course of treatment and other specific conditions of the treatment subject.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” here refers to the ability of the components of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • talc
  • administering When administering the compounds of the present invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • the daily dose is usually 1 to 2000 mg, preferably 50 to 100 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • 1 H-NMR was recorded with a Vian Mercury 400 nuclear magnetic resonance instrument, and the chemical shift was expressed in ⁇ (ppm); the silica gel used for separation was all 200-300 mesh (not specified), and the eluent ratios were all volume ratios.
  • the target compound 2-145 in Table 1 can be obtained.
  • the target compounds 147-229 in Table 2 can be obtained.
  • the target compounds 231-285 in Table 3 can be obtained.
  • Example 286 Anti-proliferative activity of compounds of the present invention on Ba/F3 (HER2 YVMA mutant) cells, Ba/F3 (HER2 WT) cells and Ba/F3 (EGFR WT) cells
  • 3000 Ba/F3 cells carrying EGFR (WT), or 3000 Ba/F3 cells carrying HER2 (WT), or 3000 Ba/F3 cells carrying HER2 (YVMA mutant), were planted in a 384-well plate and grown One day later, serial dilutions of compound were added. Three days after adding the compound, Cell Titer Glow was added to evaluate cell growth, and the percentage of cell growth inhibited by the compound and the IC 50 value were calculated. The results are shown in Table 4 below.
  • IC 50 is less than or equal to 10nM
  • +++ indicates IC 50 of 10nM to 50nM

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Abstract

Une classe de composés en tant qu'inhibiteurs de HER2. Spécifiquement, la présente invention concerne des composés tels que représentés dans la formule générale (1), la formule générale (2) et la formule générale (3), leur procédé de préparation, et l'utilisation des composés de formule générale (1), de formule générale (2) et de formule générale (3), et des isomères, des formes cristallines, des sels pharmaceutiquement acceptables, des hydrates ou des solvates de ceux-ci comme inhibiteurs de HER2. Ces composés et leurs isomères, formes cristallines, sels pharmaceutiquement acceptables, hydrates ou solvates peuvent être utilisés dans la préparation de médicaments pour le traitement ou la prévention de maladies associées à une protéine HER2.
PCT/CN2023/110515 2022-08-04 2023-08-01 Composés utiles comme inhibiteurs de her2 WO2024027695A1 (fr)

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