WO2023143344A1 - Nouvel inhibiteur d'egfr - Google Patents

Nouvel inhibiteur d'egfr Download PDF

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WO2023143344A1
WO2023143344A1 PCT/CN2023/073042 CN2023073042W WO2023143344A1 WO 2023143344 A1 WO2023143344 A1 WO 2023143344A1 CN 2023073042 W CN2023073042 W CN 2023073042W WO 2023143344 A1 WO2023143344 A1 WO 2023143344A1
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heterocycloalkyl
membered
pharmaceutically acceptable
compound
general formula
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PCT/CN2023/073042
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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to novel EGFR inhibitors, more specifically, to a class of pyrazine compounds, a preparation method thereof and the use of the compounds as EGFR inhibitors in the preparation of antitumor drugs.
  • Lung cancer is one of the most common malignant tumors. There are approximately 1.6 million new lung cancer cases worldwide each year, and approximately 1.4 million deaths due to lung cancer each year. Among them, non-small cell lung cancer (NSCLC) accounts for about 80%-85% of the total number of lung cancers (Nature, 2018, 553, 446–454).
  • NSCLC non-small cell lung cancer
  • the EGFR protein family is a class of protein kinases that are responsible for transmitting mitogenic signals and play an important role in growth and development. Analysis and research on a large number of tumor cells in vitro, animal models and human tumor samples have shown that mutations in EGFR family proteins lead to the development of human tumors and are one of the important causes of the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means of treating related tumors.
  • EGFR gene mutations can be found in approximately 12 to 47% of non-small cell lung cancers.
  • NSCLC the two most common types of EGFR gene mutations are exon 19 deletion (del19) and L858 missense mutation in exon 21. These two types of mutations lead to the continuous activation of EGFR protein independent of ligand.
  • NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib, or osimertinib, they can achieve a higher (60-85% However, this response usually does not last long, and most patients treated with first- or second-generation EGFR TKIs develop disease progression at about 11 months.
  • Drug resistance analysis shows that in about 50-70% of drug-resistant patients, the molecular mechanism of drug resistance is the acquisition of a second mutation in the EGFR gene, called T790M mutation (T790M+) (Cancer Discov. 2012, 2, 872-5). This secondary mutation makes the first-generation and second-generation EGFR TKIs lose their inhibitory activity against mutant tumor cells.
  • Osimertinib as a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without T790M mutations. Although osimertinib has a high response rate for drug resistance caused by the T790M mutation, about 70% of patients will eventually develop drug resistance, and the disease will re-progress after about 10 months (Lung Cancer.2017,108,228-231) .
  • Thress et al first reported the drug resistance analysis of osimertinib based on 15 patients, and found that about 40% of the drug resistance came from the C797S mutation (Nature Medicine, 2015, 21, 560-562).
  • ASCO Piotrowska and Zhou Caicun reported drug resistance analysis of 23 and 99 patients respectively, and the analysis results of both showed that about 22% of the drug resistance was caused by the C797S mutation.
  • the EGFR del19/L858R T790M C797S mutant is a newly emerged EGFR mutant after the third-generation EGFR TKI treatment, and there are not many studies at present. Only a few fourth-generation EGFR TKIs have been reported to be able to inhibit the EGFR del19/L858R T790M C797S mutant. For example, Boehringer Ingelheim reported that a class of macrocyclic compounds BI-4020 has anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity (J Med Chem.2019, 62, 10272-10293).
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Y is (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl, wherein The (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl can optionally be Substituted by one or more of the following groups: -H, halogen, -R 4 , -OR 4 , -(CH 2 ) n OR 4 , -(CH 2 ) n NR 4 R 5 , -NR 4 R 5 , -CN, -C(O)NR 4 R 5 , -NR 5 C(O)R 4 , -NR 5 S(O) 2 R 4 , -S(O) p R 4 , -S(O) 2 NR 4 R5 and -O-
  • X1 is N or CH
  • X2 is N or CH
  • X3 is N or CH
  • X is (C6-C14) arylene group or (5-11 yuan) heteroarylene group, wherein said (C6-C14) arylene group or (5-11 yuan) heteroarylene group can be optionally replaced by 1 Or more of the following groups are substituted: -H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;
  • R 1 is -H, halogen, -(CH 2 ) n NR 6 R 7 , -NR 6 R 7 , -O(CH 2 ) m NR 6 R 7 , -N(R 5 )(CH 2 ) m NR 6 R 7 , (C1-C6) alkoxy, -CH 2 -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein the (C1-C6) alkoxy, -CH 2 -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl may be optionally substituted by one or more of the following groups: -H, -R 4 , -(CH 2 ) n NR 6 R 7 , -NR 6 R 7 , -O(CH 2 ) m NR 6 R 7 , -N(R 5 )(CH 2 ) m NR 6 R 7 and -R 3
  • L 1 is -O-, -NH- or a chemical bond
  • R 2 is (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 yuan) heterocycloalkyl, wherein said (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, halogen, -R 4 , -(CH 2 ) n OR 4 -, -(CH 2 ) n NR 4 R 5 -, -OR 4 , -NR 4 R 5 , -CN, -C(O)NR 4 R 5 , -NR 5 C( O)R 4 , -NR 5 S(O) 2 R 4 , -S(O) p R 4 and -S(O) 2 NR 4 R 5 ;
  • R 3 is a (3-11 membered) heterocycloalkyl group, wherein the (3-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CD 3 , -R 4 , -OR 4 and -NR 4 R 5 ;
  • R 4 and R 5 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl;
  • R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 6 and R 7 can jointly form a (3-11 member) Heterocycloalkyl, wherein the (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, -CD 3 , halogen, -R 4 and -OR 4 ;
  • p is an integer of 0, 1 or 2
  • n is an integer of 0, 1, 2 or 3
  • m is an integer of 1, 2 or 3.
  • Y is (C1-C3) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) heteroaryl, wherein said (C1-C3) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) Heteroaryl can be optionally substituted with one or more of the following groups: -H, -F, -Cl, -Br, -CN, -OH, -OCH 3 , -NH 2 , -N(CH 3 ) 2 , -NHCOCH3 , -NHSO2CH3 , -SO2CH3 , -CH3, -CONH2, -CH2OH , and -O - CH2- O-.
  • Y is: -CH 3 , -CH 2 CH 3 ,
  • X is phenylene or 6-membered heteroarylene, wherein the phenylene or 6-membered heteroarylene can be optionally replaced by 1 or Substitution of multiples of the following groups: -H, -F, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCF 2 H and -OCF 3 .
  • X is:
  • R 1 is: -H, -N(CH 3 ) 2 , -CH 2 -(6-11 membered) heterocycloalkyl or (6- 11 yuan) heterocycloalkyl, wherein the (6-11 yuan) heterocycloalkyl is:
  • the (6-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CH 3 , -N(CH 3 ) 2 , and - CD 3 .
  • R 1 is: -H, -N(CH 3 ) 2 ,
  • R 2 is:
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to EGFR mutations.
  • said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
  • Another object of the present invention is also to provide a method for treating, regulating or preventing diseases related to EGFR mutant protein, comprising administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its various Constructs, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
  • the inventors found that in the compound of general formula (1), when Y is aryl or heteroaryl, the compound unexpectedly has a strong EGFR del19/ T790M/C797S and EGFR L858R/T790M/C797S inhibit activity, and have higher selectivity for wild-type EGFRWT.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). General methods for the preparation of compounds can be obtained by using appropriate reagents and The conditions under which different groups are introduced in the formulas provided herein vary.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination 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 represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , X, Y, X 1 and L 1 are as defined above, H represents hydrogen, when L 1 is -O- or When -NH-, B 1 represents hydrogen, when L 1 is a chemical bond, B 1 represents boric acid, boric acid ester or trifluoroborate, and B 2 represents boric acid, boric acid ester or trifluoroborate.
  • compound 1-1 reacts with compound 1-2 to generate compound 1-3
  • compound 1-3 undergoes chlorination reaction to generate compound 1-4
  • compound 1-4 and R 2 -L 1 -B 1 reaction to generate compound 1-5
  • compound 1-5 undergoes coupling reaction with R 1 -XB 2 to generate compound 1-6
  • compound 1-6 and compound 1-7 flourish substitution reaction to generate compound 1-8
  • compound 1-8 The protecting group is removed to obtain the target compound 1-9.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection , and Use 1st Ed., Acids and Bases in (Wiley, 2002).
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selected during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. selectively formed. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • 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, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to 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 meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • 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).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 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 with 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 carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.
  • alkenylene means 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.
  • alkynylene means a divalent alkynyl group as defined above.
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or thioxo. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, 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, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarcinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above.
  • alkoxy means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with 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, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with 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 rest of the molecule through an ether oxygen atom.
  • Examples of aryloxy 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 phenanthrenylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is 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, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as rings A portion of a structure having at least one heteroatom ring member independently selected from 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. may be referred to as a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, 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.
  • Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or thioxo or other oxidized linkages (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties also known as partially unsaturated heterocycles
  • having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, Benzo derivatives of morpholine, azepine or thienyl, etc.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, 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.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up 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 portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to 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 meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
  • the present invention provides methods for treating diseases, including but not limited to conditions involving EGFR mutations (such as cancer), using compounds of general formula (1) or pharmaceutical compositions of the present invention.
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
  • the cancer is mediated by EGFR mutations.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • examples of usable embedding components are polymeric substances and waxy substances.
  • the active compound It 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 used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, 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, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can 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 in addition to the active compounds, may contain 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 comprise 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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound 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 which may be required, if necessary.
  • 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, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • CDCl 3 represents deuterated chloroform
  • CD 3 OD represents deuterated methanol
  • DMSO-d6 represents deuterated dimethyl sulfoxide
  • EtOAc represents ethyl acetate
  • Hexane represents n-hexane
  • MeCN represents acetonitrile
  • DCM stands for dichloromethane
  • DIPEA stands for diisopropylethylamine
  • NMP stands for 1-methylpyrrolidin-2-one
  • Dioxane stands for 1,4-dioxane
  • DMF stands for N,N-dimethylformazan amide
  • DMSO stands for dimethyl sulfoxide
  • h stands for hour
  • K 3 PO 4 stands for potassium phosphate
  • min stands for minute
  • MS stands for mass spectrum
  • NaH stands for sodium hydride
  • NMR stands for nuclear magnetic resonance
  • Pd(dppf)Cl 2 represents 1,1'-
  • Example 659 Detection of the inhibitory activity of the compounds of the present invention on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzymes
  • EGFR del19/T790M/C797S
  • EGFR L858R/T790M/C797S
  • WT EGFR
  • WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, then biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and reacted at room temperature for 40 minutes. After terminating the reaction, Eu3+-Cryptate labeled antibody against TK and streptavidin-XL665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting the luminescence at 615 nm and 665 nm and calculating the ratio 665/615. The percent inhibition of the compound was calculated compared to the control group. The results are shown in Table 3 below.
  • the inhibitory activity of the compounds of the present invention to EGFR indicates that the inhibition rate is less than or equal to 20% ++ means 20% to 50% inhibition +++ indicates an inhibition rate greater than 50%.
  • ND means activity not determined

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Abstract

L'invention concerne un nouvel inhibiteur d'EGFR. Spécifiquement, la présente invention concerne un composé représenté par la formule générale (1) et son procédé de préparation, ainsi qu'une utilisation du composé représenté par la formule générale (1) et des isomères, des formes cristallines, un sel pharmaceutiquement acceptable, un hydrate ou un solvate de celui-ci en tant qu'inhibiteur d'EGFR dans la préparation d'un médicament pour lutter contre les tumeurs et d'autres maladies liées à l'EGFR.
PCT/CN2023/073042 2022-01-30 2023-01-19 Nouvel inhibiteur d'egfr WO2023143344A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106817900A (zh) * 2014-07-17 2017-06-09 默克专利有限公司 新颖的萘啶和异喹啉及其作为cdk8/19抑制剂的用途
CN107428692A (zh) * 2015-02-11 2017-12-01 巴斯利尔药物国际股份公司 被取代的单氮杂萘衍生物和多氮杂萘衍生物及其用途
CN113336747A (zh) * 2020-03-03 2021-09-03 轶诺(浙江)药业有限公司 新型hpk1抑制剂及其制备方法和应用
CN113968856A (zh) * 2020-07-23 2022-01-25 上海赛岚生物科技有限公司 一类具有激酶抑制活性的化合物
WO2022214044A1 (fr) * 2021-04-07 2022-10-13 劲方医药科技(上海)有限公司 Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106817900A (zh) * 2014-07-17 2017-06-09 默克专利有限公司 新颖的萘啶和异喹啉及其作为cdk8/19抑制剂的用途
CN107428692A (zh) * 2015-02-11 2017-12-01 巴斯利尔药物国际股份公司 被取代的单氮杂萘衍生物和多氮杂萘衍生物及其用途
CN113336747A (zh) * 2020-03-03 2021-09-03 轶诺(浙江)药业有限公司 新型hpk1抑制剂及其制备方法和应用
CN113968856A (zh) * 2020-07-23 2022-01-25 上海赛岚生物科技有限公司 一类具有激酶抑制活性的化合物
WO2022214044A1 (fr) * 2021-04-07 2022-10-13 劲方医药科技(上海)有限公司 Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation

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