WO2022012593A1 - 5,6-dihydropyrazino[2,3-c]isoquinoline compound - Google Patents

5,6-dihydropyrazino[2,3-c]isoquinoline compound Download PDF

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WO2022012593A1
WO2022012593A1 PCT/CN2021/106269 CN2021106269W WO2022012593A1 WO 2022012593 A1 WO2022012593 A1 WO 2022012593A1 CN 2021106269 W CN2021106269 W CN 2021106269W WO 2022012593 A1 WO2022012593 A1 WO 2022012593A1
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compound
pharmaceutically acceptable
heterocycloalkyl
general formula
membered
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PCT/CN2021/106269
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French (fr)
Chinese (zh)
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谢雨礼
吴应鸣
钱立晖
樊后兴
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微境生物医药科技(上海)有限公司
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Priority to CN202180060953.5A priority Critical patent/CN116323617A/en
Publication of WO2022012593A1 publication Critical patent/WO2022012593A1/en

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    • 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
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    • 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
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    • 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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • 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
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    • C07D471/12—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 three hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Definitions

  • the present invention belongs to the field of medicinal chemistry, more particularly, to a class of 5,6-dihydropyrazino[2,3-c]isoquinoline compounds, a preparation method thereof, and the use of such compounds as EGFR inhibitors in Use in the preparation of antitumor drugs.
  • Lung cancer is one of the common malignant tumors.
  • the number of new lung cancer cases in the world is about 1.6 million every year, and the deaths caused by lung cancer are about 1.4 million every year.
  • NSCLC non-small cell lung cancer
  • NSCLC accounts for about 80%-85% of the total number of lung cancers (Nature, 2018, 553, 446-454).
  • the EGFR protein family is a class of protein kinases that are responsible for transducing mitogenic signals and play an important role in growth and development. Analysis and research of a large number of in vitro tumor cells, 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 triggers for the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means to treat related tumors.
  • EGFR gene mutations can be found in about 12 to 47 percent of non-small cell lung cancers.
  • the two most common EGFR gene mutations are deletion in exon 19 (del19) and L858 missense mutation in exon 21. These two types of mutations lead to sustained ligand-independent activation of the EGFR protein.
  • NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFRTKIs) such as erlotinib, gefitinib, afatinib or osimertinib, they can achieve higher clinical outcomes (around 60-85%) ) objective response rate (ORR), but this response is usually not long-lasting, and most patients on first- or second-generation EGFR TKIs experience disease progression at about 11 months.
  • Drug resistance analysis showed that in approximately 50-70% of drug-resistant patients, the molecular mechanism of drug resistance was the acquisition of a second mutation in the EGFR gene, called the T790M mutation (T790M+) (CancerDiscov. 2012, 2, 872-5). This secondary mutation renders first- and second-generation EGFR TKIs inactive against mutant tumor cells.
  • Osimertinib a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without the T790M mutation.
  • osimertinib has a high response rate for resistance caused by the T790M mutation, however, about 70% of patients eventually develop resistance, and the disease progresses again after about 10 months (Lung Cancer. 2017, 108, 228- 231).
  • Molecular mechanisms of resistance to third-generation EGFR TKIs have shown that in approximately 20-40% of patients who undergo osimertinib treatment and relapse, a major resistance mechanism is the acquisition of a third mutation in the EGFR gene, 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 inhibit the EGFR del19/L858R T790M C797S mutant. For example, Boehringer Ingelheim reported a class of macrocyclic compounds BI-4020 with anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity (J Med Chem. 2019, 62, 10272-10293).
  • the present invention aims to provide a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Ring A is (3-11 membered) heterocycloalkylene, (C6-C14) arylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, arylene and heteroarylene
  • the aryl groups may each independently be optionally substituted with one or more of the following groups: -H, halogen, -NO 2 , -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 and -S(O) 2 NR 4 R 5 ;
  • Y is -O-, -N(R 4 )- or chemical bond
  • L 1 is -O- or -NH-
  • X is (C6-C14)arylene or (5-11 membered)heteroarylene, wherein said arylene and heteroarylene may each independently be optionally substituted with one or more of the following groups:- 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 alkoxy and heterocycloalkyl can be Each independently optionally substituted with 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 ;
  • R 2 is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11-membered) heterocycloalkyl; wherein the alkyl, cycloalkane group, aryl, and heterocycloalkyl can each be independently optionally substituted with one or more of the following groups: halogen, -R 4 , -OH, -(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 , -S(O) 2 NR 4 R 5 ;
  • R 3 is (3-11 membered) heterocycloalkyl, wherein the heterocycloalkyl groups may each independently be optionally substituted with 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, (C1-C6) haloalkyl or (C3-C14) cycloalkyl;
  • R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or the N atoms to which R 6 and R 7 are attached can together form a (3-11 member) Heterocycloalkyl, each of which may be independently optionally substituted with one or more of the following groups: -H, -CD 3 , halogen, -R 4 and -OR 4 ;
  • R 8 and R 9 are independently -H, -D, -OR 4 , (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 and the C atom to which they are attached can form together a (C3-C6)cycloalkyl; and
  • 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.
  • ring A is a (5-7 membered) heterocycloalkylene group, a phenylene group or a (5-10 membered) heteroarylene group, wherein the heterocycloalkylene, phenylene and heteroarylene group each independently may be optionally substituted with one or more of the following groups: -H, -NO 2, -F, -Cl, -Br, -CN, - OH, -OCH 3, -NH 2, -N (CH 3) 2, -NHCOCH 3, -NHSO 2 CH 3, -SO 2 CH 3, -CH 3, -CF 3, -CHF 2, -CONH 2 , and -CH 2 OH.
  • a ring is:
  • Y is -CH 2 -, -O-, -NH-, -N(CH 3 )- or a chemical bond.
  • X is a phenylene group or a 6-membered heteroarylene group, wherein the phenylene group and the heteroarylene group can be independently optionally mixed with one or more more of the following groups substituted with: -H, -F, -CH 3, -CH 2 CH 3, -CH (CH 3) 2, -OCH 3 , -OCF 2 H, -OCH 2 CF 3 and -OCF 3 .
  • R 1 is: -H, -N(CH 3 ) 2 , -CH 2 -(6-11 membered) heterocycloalkyl or (6- 11-membered) heterocycloalkyl, wherein the heterocycloalkyl is: and the heterocycloalkyl groups may each independently be optionally substituted with one or more of the following groups: -H, -CH 3 , -N(CH 3 ) 2 , and -CD 3 .
  • R 1 is:
  • 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 the general formula (1) of the present invention, or each of its isomers, Each crystal form, pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  • Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Application in the preparation of medicines for treating diseases related to EGFR mutation.
  • Still another object of the present invention is to provide a method for treating, regulating and/or preventing EGFR mutation-related diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above pharmaceutical compositions.
  • the inventors found that among the compounds of general formula (1), the compounds have unexpectedly strong inhibition of EGFR del19/T790M/C797S and EGFR L858R/T790M/C797S activity and high selectivity for wild-type EGFR WT.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the 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 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 and the like 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, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can adopt the following general reaction scheme 1, general reaction scheme 2, general reaction scheme 3 or General Reaction Scheme 4 Preparation:
  • Embodiment of the compounds of formula (1) may be prepared according to the general reaction Scheme 1, wherein R 1, R 2, R 4 , X, A ring and L 1 are as hereinbefore defined, H represents hydrogen, B represents boronic acid, boronate ester or trifluoroborate.
  • H represents hydrogen
  • B represents boronic acid, boronate ester or trifluoroborate.
  • compound 1-1 reacts with formamide to form compound 1-2
  • compound 1-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 1-3
  • compound 1-3 react with R 2 -NH 2 under basic conditions to form the target compound 1-4
  • compound 1-4 and The coupling reaction is carried out to generate compound 1-5, and compound 1-5 is reduced to obtain the target product 1-6.
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , X, ring A and L 1 are as defined above, H represents hydrogen, and B represents boronic acid, boronic ester or trifluoro Borate, CN stands for nitrile.
  • compound 2-1 reacts with formamide to form compound 2-2
  • compound 2-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 2-3
  • compound 2-3 react with R 2 -NH 2 under basic conditions to form the target compound 2-4
  • compound 2-4 and The coupling reaction is carried out to generate the target product compound 2-5.
  • Embodiment of the compounds of formula (1) may be prepared according to General Reaction Scheme 3, wherein R 1, R 2, X, A ring, Y and L 1 are as hereinbefore defined, H represents hydrogen, B represents boronic acid, boronate ester or Trifluoroborate.
  • R 1, R 2, X, A ring, Y and L 1 are as hereinbefore defined
  • H represents hydrogen
  • B represents boronic acid, boronate ester or Trifluoroborate.
  • compound 3-1 reacts with formamide to form compound 3-2
  • compound 3-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 3-3
  • compound 3-3 react with R 2 -NH 2 under basic conditions to form the target compound 3-4
  • compound 3-4 and The coupling reaction is carried out to generate the target product compound 3-5.
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 4, wherein R 1 , R 2 , R 8 , R 9 , X, A ring and L 1 are as defined above, H represents hydrogen, B represents boronic acid, borate or trifluoroborate.
  • compound 4-1 reacts with formamide to form compound 4-2
  • compound 4-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 4-3
  • compound 4-3 react with R 2 -NH 2 under basic conditions to form the target compound 4-4
  • compound 4-4 and The coupling reaction was carried out and the target product compound 4-5 was generated under acidic conditions.
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc.
  • 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.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. 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.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in both unsolvated and solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form and can also be a polymorph.
  • 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, crystal form, 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 dominate.
  • compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial 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 present 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 compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
  • alkyl includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH 3, CH 3 CH 2, CF 3, CHF 2, CF 3 CH 2, CF 3 (CH 3) CH, i Pr, n Pr, i Bu, n Bu or t Bu.
  • 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. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
  • 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, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
  • cycloalkyl refers to a 3- to 14-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, and the like are examples of the rings.
  • alkoxy refers to 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-butoxy.
  • 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 that 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 phenanthryl.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which 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, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
  • heteroarylene 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 part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members.
  • Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • a heterocycloalkyl group 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 heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg 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 carbon atom or a ring heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azacyclotriene, etc. benzo or thienyl derivatives.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring.
  • heterocycloalkyl examples include azetidine, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9- Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, Quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidine, butyrolactamy
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • 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.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting 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 a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • 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 are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends 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 present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • 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 present invention provides methods of treating diseases including, but not limited to, conditions involving EGFR mutations (eg, cancer) using the compounds of formula (1) or pharmaceutical compositions of the present invention.
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1).
  • 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, gastric cancer, mesothelioma, or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compounds of the present invention may 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (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) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings 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 in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may 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, 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.
  • inert diluents conventionally employed 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,
  • 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 such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as 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 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 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 suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining.
  • Step 2 Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
  • Step 3 Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
  • Step 4 6-Methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H Synthesis of -pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 1):
  • Step 5 6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 2):
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining.
  • Step 2 Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
  • Step 3 Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
  • Step 4 6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 3):
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining.
  • Step 2 Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
  • Step 3 Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
  • Step 4 3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 4):
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining.
  • Step 2 Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
  • Step 3 Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
  • Step 4 Compound 6-(2-(2-Hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidine-1- Synthesis of yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-5):
  • Step 5 Compound 6, 6-Dimethyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrakis Synthesis of Hydro-2H-pyran-4-yl)amino)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 5):
  • the target compound 6-288 in Table 1A can be obtained.
  • Example 2 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
  • WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and the reaction was performed at room temperature for 40 minutes. After the reaction was terminated, 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 luminescence at 615 nm and 665 nm and calculating the 665/615 ratio. Compared to the control group and percent inhibition calculated Compound IC 50. The results are shown in Table 2 below.
  • +++ means inhibition rate greater than 50%.
  • the compounds of the present invention have good inhibitory activity on the enzymatic activities of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S), and have good selectivity for EGFR (WT).

Abstract

A compound represented by general formula (1), a preparation method therefor, and a use of the compound represented by general formula (1), an isomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an EGFR inhibitor in the preparation of a drug that is anti-tumor and other EGFR-related diseases.

Description

5，6-二氢吡嗪并[2，3-c]异喹啉化合物5,6-Dihydropyrazino[2,3-c]isoquinoline compounds
本申请要求申请日为2020年7月17日的中国申请CN202010690210.3的优先权。本申请引用上述中国申请的全文。This application claims the priority of Chinese application CN202010690210.3 with a filing date of July 17, 2020. This application cites the full text of the above Chinese application.
技术领域technical field
本发明属涉及药物化学领域，更具体而言，涉及一类5，6-二氢吡嗪并[2，3-c]异喹啉化合物，及其制备方法和该类化合物作为EGFR抑制剂在制备抗肿瘤药物中的用途。The present invention belongs to the field of medicinal chemistry, more particularly, to a class of 5,6-dihydropyrazino[2,3-c]isoquinoline compounds, a preparation method thereof, and the use of such compounds as EGFR inhibitors in Use in the preparation of antitumor drugs.
背景技术Background technique
肺癌是常见的恶性肿瘤之一，每年全球新发肺癌病例数约在160万，因肺癌导致的死亡患者每年约在140万。而其中，非小细胞肺癌(non-small cell lung cancer，NSCLC)约占肺癌总数的80％-85％左右(Nature，2018，553，446-454)。Lung cancer is one of the common malignant tumors. The number of new lung cancer cases in the world is about 1.6 million every year, and the deaths caused by lung cancer are about 1.4 million every 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).
EGFR蛋白家族是一类蛋白激酶，负责传导促有丝***信号，在生长发育中发挥了重要的作用。大量的体外肿瘤细胞，动物模型以及人类肿瘤样本的分析和研究表明EGFR家族蛋白的突变导致人类肿瘤发展，是多种癌症发生和发展的重要诱因之一。因此靶向和抑制EGFR突变蛋白的活性是治疗相关肿瘤的重要手段。The EGFR protein family is a class of protein kinases that are responsible for transducing mitogenic signals and play an important role in growth and development. Analysis and research of a large number of in vitro tumor cells, 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 triggers for the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means to treat related tumors.
研究显示EGFR基因突变在大约12到47％的非小细胞肺癌中能够被发现。在非小细胞肺癌中，两类最常见的EGFR基因突变为外显子19缺失(del19)和在外显子21中的L858R错译(L858 missense mutation)突变。这两类突变会导致EGFR蛋白不依赖配体而持续激活。虽然具有EGFR蛋白Del19或L858R突变的NSCLC患者对于EGFR蛋白激酶抑制剂(EGFRTKI)例如erlotinib、gefitinib、afatinib或osimertinib的靶向治疗更为敏感，能够在临床上获得较高的(60-85％左右)的客观缓解率(objective response rate，ORR)，但是这一响应通常不会持续太久，大多数使用第一代或第二代EGFR TKIs的患者会在约11个月时发生疾病进展。耐药分析显示在大约50-70％耐药患者中，耐药分子机制是EGFR基因获得第二种突变，称为T790M突变(T790M+)(CancerDiscov.2012，2，872-5)。这一二次突变使第一代和第二代EGFR TKIs对于突变肿瘤细胞失去抑制活性。Studies have shown that EGFR gene mutations can be found in about 12 to 47 percent of non-small cell lung cancers. In non-small cell lung cancer, the two most common EGFR gene mutations are deletion in exon 19 (del19) and L858 missense mutation in exon 21. These two types of mutations lead to sustained ligand-independent activation of the EGFR protein. Although NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFRTKIs) such as erlotinib, gefitinib, afatinib or osimertinib, they can achieve higher clinical outcomes (around 60-85%) ) objective response rate (ORR), but this response is usually not long-lasting, and most patients on first- or second-generation EGFR TKIs experience disease progression at about 11 months. Drug resistance analysis showed that in approximately 50-70% of drug-resistant patients, the molecular mechanism of drug resistance was the acquisition of a second mutation in the EGFR gene, called the T790M mutation (T790M+) (CancerDiscov. 2012, 2, 872-5). This secondary mutation renders first- and second-generation EGFR TKIs inactive against mutant tumor cells.
Osimertinib作为第三代共价EGFR TKI，被开发用来治疗具有EGFR del19和L858R突变并伴随或不伴随T790M突变的肿瘤。虽然osimertinib针对T790M突变导致的耐药具有较高的响应率，然而，大约70％的患者最终也会发生耐药，疾病会在大约10个月后再次进展(Lung Cancer.2017，108，228-231)。对第三代EGFR TKI耐药的分子机制研究显示，在大约20-40％经历osimertinib治疗并复发的病人中，一个主要的耐药机制是EGFR 基因获得第三重突变，即C797S突变。而且，在经过第三代EGFR TKI治疗后，具有EGFR del19/L858R T790M C797S突变体的患者已不能再对第一代、第二代或第三代EGFR TKIs响应。2015年Thress等人首次报道了基于15例患者对于osimertinib的耐药分析，发现其中约有40％的耐药由C797S突变而来(Nature Medicine，2015，21，560-562)。2017年ASCO，Piotrowska和周彩存各报道了23例和99例患者耐药分析，两者的分析结果都显示大约有22％左右的耐药由C797S突变引起。所以靶向抑制EGFR del19/L858R T790M C797S突变能够克服osimertinib耐药，但目前还未有上市的EGFR TKI能够抑制EGFR del19/L858R T790M C797S突变体，所以研究和发现***EGFR TKI来满足这一尚未被满足的临床需求非常迫切。Osimertinib, a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without the T790M mutation. Although osimertinib has a high response rate for resistance caused by the T790M mutation, however, about 70% of patients eventually develop resistance, and the disease progresses again after about 10 months (Lung Cancer. 2017, 108, 228- 231). Molecular mechanisms of resistance to third-generation EGFR TKIs have shown that in approximately 20-40% of patients who undergo osimertinib treatment and relapse, a major resistance mechanism is the acquisition of a third mutation in the EGFR gene, the C797S mutation. Furthermore, after treatment with third-generation EGFR TKIs, patients with the EGFR del19/L858R T790M C797S mutant were no longer responsive to first-, second-, or third-generation EGFR TKIs. In 2015, Thress et al. reported the resistance analysis of osimertinib based on 15 patients for the first time, and found that about 40% of the resistance was derived from the C797S mutation (Nature Medicine, 2015, 21, 560-562). In 2017, ASCO, Piotrowska and Zhou Caicun reported drug resistance analysis of 23 and 99 patients respectively, and the results of both analyses showed that about 22% of drug resistance was caused by the C797S mutation. Therefore, targeted inhibition of EGFR del19/L858R T790M C797S mutation can overcome osimertinib resistance, but there is no marketed EGFR TKI that can inhibit EGFR del19/L858R T790M C797S mutant, so the fourth-generation EGFR TKI is studied and discovered to meet this requirement. The unmet clinical needs are very urgent.
EGFR del19/L858R T790M C797S突变体作为经第三代EGFR TKI治疗后新浮现的EGFR突变体，目前的研究还不是很多。目前只有少数***EGFRTKI被报道能够抑制EGFR del19/L858R T790M C797S突变体。比如Boehringer Ingelheim报道了一类大环化合物BI-4020具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性(J Med Chem.2019，62，10272-10293)。而专利WO2019/015655中，报道了一类芳基磷氧化合物具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性。其通式A及代表化合物B(专利中实施例41)结构如下(式中各符号的定义请参照该专利)：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 inhibit the EGFR del19/L858R T790M C797S mutant. For example, Boehringer Ingelheim reported a class of macrocyclic compounds BI-4020 with anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity (J Med Chem. 2019, 62, 10272-10293). In the patent WO2019/015655, it was reported that a class of aryl phosphorus oxides has anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity. Its general formula A and representative compound B (Example 41 in the patent) have the following structures (for the definitions of the symbols in the formula, please refer to the patent):
Figure PCTCN2021106269-appb-000001
Figure PCTCN2021106269-appb-000001
目前，研究和发现具有针对EGFR del19/L858R T790M C797S突变活性好、安全的化合物存在迫切的需求。At present, there is an urgent need to research and discover compounds with good activity and safety against the EGFR del19/L858R T790M C797S mutation.
发明内容SUMMARY OF THE INVENTION
本发明旨在提供一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：The present invention aims to provide a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
Figure PCTCN2021106269-appb-000002
Figure PCTCN2021106269-appb-000002
通式(1)中：In general formula (1):
A环为(3-11元)亚杂环烷基、(C6-C14)亚芳基或(5-10元)亚杂芳基，其中所述亚杂环烷基、亚芳基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、卤素、-NO 2、-R 4、-OR 4、-(CH 2) nOR 4、-(CH 2) nNR 4R 5、-NR 4R 5、-CN、-C(O)NR 4R 5、-NR 5C(O)R 4、-NR 5S(O) 2R 4、-S(O) pR 4和-S(O) 2NR 4R 5； Ring A is (3-11 membered) heterocycloalkylene, (C6-C14) arylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, arylene and heteroarylene The aryl groups may each independently be optionally substituted with one or more of the following groups: -H, halogen, -NO 2 , -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 and -S(O) 2 NR 4 R 5 ;
Y为
Figure PCTCN2021106269-appb-000003
-O-、-N(R 4)-或化学键； Y is
Figure PCTCN2021106269-appb-000003
-O-, -N(R 4 )- or chemical bond;
Z为-C(＝O)-、-C＝N(R 4)-、-C(＝CH 2)-或
Figure PCTCN2021106269-appb-000004
Z is -C(=O)-, -C=N(R 4 )-, -C(=CH 2 )- or
Figure PCTCN2021106269-appb-000004
L 1为-O-或-NH-； L 1 is -O- or -NH-;
X为(C6-C14)亚芳基或(5-11元)亚杂芳基，其中所述亚芳基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、卤素、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烷氧基和(C1-C6)卤代烷氧基；X is (C6-C14)arylene or (5-11 membered)heteroarylene, wherein said arylene and heteroarylene may each independently be optionally substituted with one or more of the following groups:- H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;
R 1为-H、卤素、-(CH 2) nNR 6R 7、-NR 6R 7、-O(CH 2) mNR 6R 7、-N(R 5)(CH 2) mNR 6R 7、(C1-C6)烷氧基、-CH 2-(3-15元)杂环烷基或(3-15元)杂环烷基，其中所述烷氧基和杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-R 4、-(CH 2) nNR 6R 7、-NR 6R 7、-O(CH 2) mNR 6R 7、-N(R 5)(CH 2) mNR 6R 7和-R 3； 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 alkoxy and heterocycloalkyl can be Each independently optionally substituted with 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 ;
R 2为-H、(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基；其中所述烷基、环烷基、芳基、杂环烷基可各自独立任选被1个或多个下列基团取代：卤素、-R 4、-OH、-(CH 2) nOR 4-、-(CH 2) nNR 4R 5-、-OR 4、-NR 4R 5、-CN、-C(O)NR 4R 5、-NR 5C(O)R 4、-NR 5S(O) 2R 4、-S(O) pR 4、-S(O) 2NR 4R 5； R 2 is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11-membered) heterocycloalkyl; wherein the alkyl, cycloalkane group, aryl, and heterocycloalkyl can each be independently optionally substituted with one or more of the following groups: halogen, -R 4 , -OH, -(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 , -S(O) 2 NR 4 R 5 ;
R 3为(3-11元)杂环烷基，其中所述杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CD 3、-R 4、-OR 4和-NR 4R 5； R 3 is (3-11 membered) heterocycloalkyl, wherein the heterocycloalkyl groups may each independently be optionally substituted with one or more of the following groups: -H, -CD 3 , -R 4 , -OR 4 and -NR 4 R 5 ;
R 4和R 5各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基或(C3-C14)环烷基； R 4 and R 5 are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) cycloalkyl;
R 6和R 7各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或R 6和R 7与其连接的N原子能够共同组成一个(3-11元)杂环烷基，此杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CD 3、卤素、-R 4和-OR 4； R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or the N atoms to which R 6 and R 7 are attached can together form a (3-11 member) Heterocycloalkyl, each of which may be independently optionally substituted with one or more of the following groups: -H, -CD 3 , halogen, -R 4 and -OR 4 ;
R 8和R 9为各自独立的-H、-D、-OR 4、(C1-C6)烷基或(C3-C14)环烷基，或R 8和R 9与 其连接的C原子能够共同组成一个(C3-C6)环烷基；和 R 8 and R 9 are independently -H, -D, -OR 4 , (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 and the C atom to which they are attached can form together a (C3-C6)cycloalkyl; and
p为0、1或2的整数，n为0、1、2或3的整数，m为1、2或3的整数。p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
在另一优选例中，其中所述通式(1)中，A环为(5-7元)亚杂环烷基、亚苯基或(5-10元)亚杂芳基，其中所述亚杂环烷基、亚苯基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、-NO 2、-F、-Cl、-Br、-CN、-OH、-OCH 3、-NH 2、-N(CH 3) 2、-NHCOCH 3、-NHSO 2CH 3、-SO 2CH 3、-CH 3、-CF 3、-CHF 2、-CONH 2和-CH 2OH。 In another preferred example, in the general formula (1), ring A is a (5-7 membered) heterocycloalkylene group, a phenylene group or a (5-10 membered) heteroarylene group, wherein the heterocycloalkylene, phenylene and heteroarylene group each independently may be optionally substituted with one or more of the following groups: -H, -NO 2, -F, -Cl, -Br, -CN, - OH, -OCH 3, -NH 2, -N (CH 3) 2, -NHCOCH 3, -NHSO 2 CH 3, -SO 2 CH 3, -CH 3, -CF 3, -CHF 2, -CONH 2 , and -CH 2 OH.
在另一优选例中，其中所述通式(1)中，A环为：In another preferred embodiment, wherein in the general formula (1), A ring is:
Figure PCTCN2021106269-appb-000005
Figure PCTCN2021106269-appb-000005
Figure PCTCN2021106269-appb-000006
Figure PCTCN2021106269-appb-000006
Figure PCTCN2021106269-appb-000007
Figure PCTCN2021106269-appb-000007
在另一优选例中，其中所述通式(1)中，Y为-CH 2-、-O-、-NH-、-N(CH 3)-或化学键。 In another preferred example, in the general formula (1), Y is -CH 2 -, -O-, -NH-, -N(CH 3 )- or a chemical bond.
在另一优选例中，其中所述通式(1)中，Z为-C(＝O)-、-C(＝NH)-、-C(＝CH 2)-、-CH 2-、-CH(CH 3)-、-CH(OH)-、-C(CH 3) 2-、-CD(CH 3)-、-CD 2-、
Figure PCTCN2021106269-appb-000008
-CH(CF 3)-或-CH(CHF 2)-。 In another preferred example, in the general formula (1), Z is -C(=O)-, -C(=NH)-, -C(=CH 2 )-, -CH 2 -, - CH(CH 3 )-, -CH(OH)-, -C(CH 3 ) 2 -, -CD(CH 3 )-, -CD 2 -,
Figure PCTCN2021106269-appb-000008
-CH (CF 3) - or -CH (CHF 2) -.
在另一优选例中，其中所述通式(1)中，X为亚苯基或6元亚杂芳基，其中所述亚苯基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、-F、-CH 3、-CH 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021106269-appb-000009
-OCH 3、-OCF 2H、-OCH 2CF 3和-OCF 3。 In another preferred embodiment, in the general formula (1), X is a phenylene group or a 6-membered heteroarylene group, wherein the phenylene group and the heteroarylene group can be independently optionally mixed with one or more more of the following groups substituted with: -H, -F, -CH 3, -CH 2 CH 3, -CH (CH 3) 2,
Figure PCTCN2021106269-appb-000009
-OCH 3 , -OCF 2 H, -OCH 2 CF 3 and -OCF 3 .
在另一优选例中，其中所述通式(1)中，X为：In another preferred example, wherein in the general formula (1), X is:
Figure PCTCN2021106269-appb-000010
Figure PCTCN2021106269-appb-000010
Figure PCTCN2021106269-appb-000011
Figure PCTCN2021106269-appb-000011
在另一优选例中，其中所述通式(1)中，R 1为：-H、-N(CH 3) 2、-CH 2-(6-11元)杂环烷基或(6-11元)杂环烷基，其中所述杂环烷基为：
Figure PCTCN2021106269-appb-000012
Figure PCTCN2021106269-appb-000013
和所述杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CH 3、
Figure PCTCN2021106269-appb-000014
-N(CH 3) 2、
Figure PCTCN2021106269-appb-000015
Figure PCTCN2021106269-appb-000016
和-CD 3。 In another preferred example, in the general formula (1), R 1 is: -H, -N(CH 3 ) 2 , -CH 2 -(6-11 membered) heterocycloalkyl or (6- 11-membered) heterocycloalkyl, wherein the heterocycloalkyl is:
Figure PCTCN2021106269-appb-000012
Figure PCTCN2021106269-appb-000013
and the heterocycloalkyl groups may each independently be optionally substituted with one or more of the following groups: -H, -CH 3 ,
Figure PCTCN2021106269-appb-000014
-N(CH 3 ) 2 ,
Figure PCTCN2021106269-appb-000015
Figure PCTCN2021106269-appb-000016
and -CD 3 .
在另一优选例中，其中所述通式(1)中，R 1为： In another preferred embodiment, wherein in the general formula (1), R 1 is:
-H、-N(CH 3) 2、
Figure PCTCN2021106269-appb-000017
Figure PCTCN2021106269-appb-000018
-H, -N(CH 3 ) 2 ,
Figure PCTCN2021106269-appb-000017
Figure PCTCN2021106269-appb-000018
在另一优选例中，其中所述通式(1)中，R 2为： In another preferred example, wherein in the general formula (1), R 2 is:
Figure PCTCN2021106269-appb-000019
Figure PCTCN2021106269-appb-000019
在各种不同实施方式中，通式(1)化合物具有以下结构之一：In various embodiments, the compound of general formula (1) has one of the following structures:
Figure PCTCN2021106269-appb-000020
Figure PCTCN2021106269-appb-000020
Figure PCTCN2021106269-appb-000021
Figure PCTCN2021106269-appb-000021
Figure PCTCN2021106269-appb-000022
Figure PCTCN2021106269-appb-000022
Figure PCTCN2021106269-appb-000023
Figure PCTCN2021106269-appb-000023
Figure PCTCN2021106269-appb-000024
Figure PCTCN2021106269-appb-000024
Figure PCTCN2021106269-appb-000025
Figure PCTCN2021106269-appb-000025
Figure PCTCN2021106269-appb-000026
Figure PCTCN2021106269-appb-000026
Figure PCTCN2021106269-appb-000027
Figure PCTCN2021106269-appb-000027
Figure PCTCN2021106269-appb-000028
Figure PCTCN2021106269-appb-000028
Figure PCTCN2021106269-appb-000029
Figure PCTCN2021106269-appb-000029
Figure PCTCN2021106269-appb-000030
Figure PCTCN2021106269-appb-000030
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。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 the general formula (1) of the present invention, or each of its isomers, Each crystal form, pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗与EGFR突变相关疾病药物中的应用。Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Application in the preparation of medicines for treating diseases related to EGFR mutation.
本发明的再一个目的还提供治疗、调节和/或预防与EGFR突变相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。Still another object of the present invention is to provide a method for treating, regulating and/or preventing EGFR mutation-related diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above pharmaceutical compositions.
通过合成和仔细研究了多类涉及具有EGFR抑制作用的新化合物，发明人发现在通式(1)化合物中，化合物意外地具有很强的EGFR del19/T790M/C797S和EGFR L858R/T790M/C797S抑制活性，并且对于野生型EGFR WT有较高的选择性。 By synthesizing and carefully studying a variety of new compounds involving EGFR inhibition, the inventors found that among the compounds of general formula (1), the compounds have unexpectedly strong inhibition of EGFR del19/T790M/C797S and EGFR L858R/T790M/C797S activity and high selectivity for wild-type EGFR WT.
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
化合物的合成compound synthesis
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of the general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein. In addition, the 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 with 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), Green and Wuts, PROTECTIVE GROUPS iN ORGANIC SYNTHESIS 3 rd Ed., method (Wiley 1999) in. The general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、 溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1、一般反应流程2、一般反应流程3或一般反应流程4制备：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like 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, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can adopt the following general reaction scheme 1, general reaction scheme 2, general reaction scheme 3 or General Reaction Scheme 4 Preparation:
一般反应流程1General Reaction Scheme 1
Figure PCTCN2021106269-appb-000031
Figure PCTCN2021106269-appb-000031
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 4、X、A环和L 1如上文中所定义，H表示氢，B表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程1所示，化合物1-1和甲酰胺反应生成化合物1-2，化合物1-2和R 1-X-L 1-H在碱性条件下反应生成化合物1-3，化合物1-3和R 2-NH 2在碱性条件下反应生成目标化合物1-4，化合物1-4和
Figure PCTCN2021106269-appb-000032
进行偶联反应生成化合物1-5，还原化合物1-5得到目标产物1-6。 Embodiment of the compounds of formula (1) may be prepared according to the general reaction Scheme 1, wherein R 1, R 2, R 4 , X, A ring and L 1 are as hereinbefore defined, H represents hydrogen, B represents boronic acid, boronate ester or trifluoroborate. As shown in general reaction scheme 1, compound 1-1 reacts with formamide to form compound 1-2, compound 1-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 1-3, compound 1-3 react with R 2 -NH 2 under basic conditions to form the target compound 1-4, compound 1-4 and
Figure PCTCN2021106269-appb-000032
The coupling reaction is carried out to generate compound 1-5, and compound 1-5 is reduced to obtain the target product 1-6.
一般反应流程2General Reaction Scheme 2
Figure PCTCN2021106269-appb-000033
Figure PCTCN2021106269-appb-000033
通式(1)化合物的实施方式可根据一般反应流程2制备，其中R 1、R 2、X、A环和L 1如上文中所定义，H表示氢，B表示硼酸、硼酸酯或三氟硼酸盐，CN代表腈基。如一般反应流程2所示，化合物2-1和甲酰胺反应生成化合物2-2，化合物2-2和R 1-X-L 1-H在碱性条件下反应生成化合物2-3，化合物2-3和R 2-NH 2在碱性条件下反应生成目标化合物2-4，化合物2-4和
Figure PCTCN2021106269-appb-000034
进行偶联反应生成目标产物化合物2-5。 Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , X, ring A and L 1 are as defined above, H represents hydrogen, and B represents boronic acid, boronic ester or trifluoro Borate, CN stands for nitrile. As shown in general reaction scheme 2, compound 2-1 reacts with formamide to form compound 2-2, compound 2-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 2-3, and compound 2-3 react with R 2 -NH 2 under basic conditions to form the target compound 2-4, compound 2-4 and
Figure PCTCN2021106269-appb-000034
The coupling reaction is carried out to generate the target product compound 2-5.
一般反应流程3General Reaction Scheme 3
Figure PCTCN2021106269-appb-000035
Figure PCTCN2021106269-appb-000035
通式(1)化合物的实施方式可根据一般反应流程3制备，其中R 1、R 2、X、A环、Y和L 1如上文中所定义，H表示氢，B表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程3所示，化合物3-1和甲酰胺反应生成化合物3-2，化合物3-2和R 1-X-L 1-H在碱性条件下反应生成化合物3-3，化合物3-3和R 2-NH 2在碱性条件下反应生成目标化合物3-4，化合物3-4和
Figure PCTCN2021106269-appb-000036
进行偶联反应生成目标产物化合物3-5。 Embodiment of the compounds of formula (1) may be prepared according to General Reaction Scheme 3, wherein R 1, R 2, X, A ring, Y and L 1 are as hereinbefore defined, H represents hydrogen, B represents boronic acid, boronate ester or Trifluoroborate. As shown in general reaction scheme 3, compound 3-1 reacts with formamide to form compound 3-2, compound 3-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 3-3, compound 3-3 react with R 2 -NH 2 under basic conditions to form the target compound 3-4, compound 3-4 and
Figure PCTCN2021106269-appb-000036
The coupling reaction is carried out to generate the target product compound 3-5.
一般反应流程4General Reaction Scheme 4
Figure PCTCN2021106269-appb-000037
Figure PCTCN2021106269-appb-000037
通式(1)化合物的实施方式可根据一般反应流程4制备，其中R 1、R 2、R 8、R 9、X、A环和L 1如上文中所定义，H表示氢，B表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程4所示，化合物4-1和甲酰胺反应生成化合物4-2，化合物4-2和R 1-X-L 1-H在碱性条件下反应生成化合物4-3，化合物4-3和R 2-NH 2在碱性条件下反应生成目标化合物4-4，化合物4-4和
Figure PCTCN2021106269-appb-000038
进行偶联反应并在酸性条件下生成目标产物化合物4-5。 Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 4, wherein R 1 , R 2 , R 8 , R 9 , X, A ring and L 1 are as defined above, H represents hydrogen, B represents boronic acid, borate or trifluoroborate. As shown in general reaction scheme 4, compound 4-1 reacts with formamide to form compound 4-2, compound 4-2 reacts with R 1 -XL 1 -H under basic conditions to form compound 4-3, compound 4-3 react with R 2 -NH 2 under basic conditions to form the target compound 4-4, compound 4-4 and
Figure PCTCN2021106269-appb-000038
The coupling reaction was carried out and the target product compound 4-5 was generated under acidic conditions.
化合物的进一步形式further forms of compounds
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。The term "pharmaceutically acceptable salt" refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc. , 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.
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以 非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。It should be understood that references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. 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. For example, the hydrate of the compound of general formula (1) 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. Furthermore, the compounds mentioned herein can exist in both unsolvated and solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other specific embodiments, compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms. In addition, the compound of the general formula (1) includes a crystalline form and can also be a polymorph. 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, crystal form, 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 dominate.
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur. Each chiral center or axial 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 present invention. The present invention is meant to include all such isomeric forms of these compounds.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). For another example, a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。 Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, 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 CH 3, CH 3 CH 2, CF 3, CHF 2, CF 3 CH 2, CF 3 (CH 3) CH, i Pr, n Pr, i Bu, n Bu or t Bu.
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。Unless otherwise specified, "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. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。Unless otherwise specified, "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, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
除非另有规定，“环烷基”指3至14元全碳单环脂肪烃基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。例如，环丙基、环丁基、环戊基、环己烷、环己二烯等。Unless otherwise specified, "cycloalkyl" refers to a 3- to 14-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, and the like.
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。 Unless otherwise specified, "alkoxy" refers to 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-butoxy. As used herein, "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.
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
除非另有规定，“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于，亚苯基、亚萘基和亚菲基。Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrene.
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3，2-b]吡啶基、1H-吡咯[2，3-c]吡啶基、1H-吡咯[3，2-c]吡啶基、1H-吡咯[2，3-b]吡啶基、
Figure PCTCN2021106269-appb-000039
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
Figure PCTCN2021106269-appb-000039
除非另有规定，“亚杂芳基”指二价的如上所定义的杂芳基。Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.
除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫离子基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。 在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分，例如哌啶、吗啉、氮杂环庚三烯等的苯并或噻吩基衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1，2，3，4-四氢喹啉基、莨菪烷基、4，5，6，7-四氢噻唑并[5，4-c]吡啶基、4，5，6，7-四氢-1H-咪唑并[4，5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2，4(1H，3H)-二酮基、1，4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S，S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
Figure PCTCN2021106269-appb-000040
Figure PCTCN2021106269-appb-000041
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members. Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, a heterocycloalkyl group 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 heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg 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 carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azacyclotriene, etc. benzo or thienyl derivatives. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring. Examples of heterocycloalkyl include azetidine, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9- Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, Quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidine, butyrolactamyl, Valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4- Dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl, pyridone base, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrothienyl, 2-azaspiro[3.3]heptyl, indolinyl,
Figure PCTCN2021106269-appb-000040
Figure PCTCN2021106269-appb-000041
除非另有规定，“亚杂环烷基”指二价的如上所定义的杂环烷基。Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen-substituted") appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2021106269-appb-000042
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:
Figure PCTCN2021106269-appb-000042
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.
除非另有说明，用楔形实线键
Figure PCTCN2021106269-appb-000043
和楔形虚线键
Figure PCTCN2021106269-appb-000044
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021106269-appb-000045
和直形虚线键
Figure PCTCN2021106269-appb-000046
表示立体中心的相对构型，用波浪线
Figure PCTCN2021106269-appb-000047
表示楔形实线键
Figure PCTCN2021106269-appb-000048
或楔形虚线键
Figure PCTCN2021106269-appb-000049
或用波浪线
Figure PCTCN2021106269-appb-000050
表示直形实线键
Figure PCTCN2021106269-appb-000051
或直形虚线键
Figure PCTCN2021106269-appb-000052
Use solid wedge keys unless otherwise specified
Figure PCTCN2021106269-appb-000043
and wedge-dotted keys
Figure PCTCN2021106269-appb-000044
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2021106269-appb-000045
and straight dashed keys
Figure PCTCN2021106269-appb-000046
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2021106269-appb-000047
Represents a solid wedge key
Figure PCTCN2021106269-appb-000048
or wedge-dotted key
Figure PCTCN2021106269-appb-000049
or with wavy lines
Figure PCTCN2021106269-appb-000050
Represents a straight solid key
Figure PCTCN2021106269-appb-000051
or straight dashed key
Figure PCTCN2021106269-appb-000052
特定药学及医学术语Certain Pharmacy and Medical Terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting 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 a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"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 are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers. The number of asymmetric centers that can exist depends 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 present invention. The present invention is meant to include all such isomeric forms of these compounds.
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein, and all refer to when administered to an individual (human or animal), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering or, administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broader scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from individual testing methods. As used herein, "about" generally means within plus or minus 10%, 5%, 1%, or 0.5% of the actual value of a particular value or range. Alternatively, the word "about" means that the actual value lies within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless expressly stated otherwise, all ranges, amounts, values and percentages used herein (eg, to describe material amounts, time periods, temperatures, operating conditions, amount ratios and other similar ) are modified by "about". Accordingly, unless stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximations that can be modified as required. At a minimum, these numerical parameters should be construed to mean the number of significant digits indicated and the numerical values obtained using ordinary rounding.
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理 解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless contradicting the context, the singular noun used in this specification covers the plural form of the noun; and the plural noun used also covers the singular form of the noun.
治疗用途therapeutic use
本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法，包括但不限于涉及EGFR突变的病况(例如癌症)。The present invention provides methods of treating diseases including, but not limited to, conditions involving EGFR mutations (eg, cancer) using the compounds of formula (1) or pharmaceutical compositions of the present invention.
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症由EGFR突变介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、***癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。In some embodiments, methods for cancer treatment are provided, the methods comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1). In some embodiments, the cancer is mediated by EGFR mutations. In other embodiments, 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, gastric cancer, mesothelioma, or all cancer metastases.
给药途径Route of administration
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount. . The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021106269-appb-000053
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity . "Compatibility" as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)
Figure PCTCN2021106269-appb-000053
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、 片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (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) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings 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 in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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 excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。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 if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.
具体实施方式detailed description
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, properties and advantages of the above-described compounds, methods, and pharmaceutical compositions will be set forth in detail so that the content of the present invention will become apparent. It should be understood herein that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the present application.
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all the examples, 1 H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh not specified, and the proportions of eluents were all volume ratios.
本发明采用下述缩略词：CDCl 3代表氘代氯仿；EtOAc代表乙酸乙酯；Hexane代表正己烷；MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1，4-二氧六环；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；h代表小时；min代表分钟；K 2CO 3代表碳酸钾；KF代表氟化钾；K 3PO 4代表磷酸钾；K 2S 2O 8代表过硫酸钾；min代表分钟；MeOH代表甲醇；MS代表质谱；(NH 4) 2S 2O 8代表过硫酸铵；NMR代表核磁共振；Pd/C代表钯碳；Pd(dppf)Cl 2代表1，1′-双(二苯基膦基)二茂铁]二氯化钯；TLC代表薄层色谱。 The following abbreviations are used in the present invention: CDCl 3 for deuterated chloroform; EtOAc for ethyl acetate; Hexane for n-hexane; MeCN for acetonitrile; DCM for dichloromethane; DIPEA for diisopropylethylamine; Dioxane for 1 , 4-dioxane; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; h for hours; min for minutes; K 2 CO 3 for potassium carbonate; KF for potassium fluoride; K 3 PO 4 for potassium phosphate; K 2 S 2 O 8 for potassium persulfate; min for minutes; MeOH for methanol; MS for mass spectrometry; (NH 4 ) 2 S 2 O 8 for ammonium persulfate; NMR for nuclear magnetic resonance; Pd / C Representative palladium on carbon; Pd (dppf) Cl 2 representative of 1,1'-bis (diphenylphosphino) ferrocene palladium] dichloride; TLC thin layer chromatography Representative.
合成方法A：Synthetic Method A:
使用合成方法A进行具体实施例1(6-亚甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺)及具体实施例2(6-甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺)的合成Specific Example 1 (6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) was carried out using Synthetic Method A -5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide) and specific example 2 (6- Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4 -yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide) synthesis
Figure PCTCN2021106269-appb-000054
Figure PCTCN2021106269-appb-000054
步骤1：化合物3，5-二氯-6-碘吡嗪-2-羧酰胺(化合物int_2)的合成：Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
500mL单口瓶中加入3，5-二氯-2-碘吡嗪(15g，54.57mmol)，甲酰胺(300mL)，混合液搅拌升温至90℃，后分批加入(NH 4) 2S 2O 8(25g，109.1mmol)固体，混合液保温在90℃搅拌2h，后再次分批补加K 2S 2O 8(30g，109.1mmol)固体，混合液保温在90℃搅拌20h。LC-MS监测反应有产物，剩余部分原料。混合液中加入EtOAc(150mL)，水(300mL)，搅拌、分液，水相再用EtOAc(150mL)萃取，合并有机相用饱和氯化钠溶液(150mL)洗涤、浓缩，残留物柱层析纯化(EtOAc∶Hexane＝0∶1 to 1∶5 to 1∶2)得产物(1.82g，收率：10.5％)，回收原料(10.3g，收率：68.7％)。 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining. EtOAc (150 mL) and water (300 mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150 mL), the combined organic phases were washed with saturated sodium chloride solution (150 mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).
1H NMR(400MHz，CDCl 3)δ7.28(s，1H)，5.78(s，1H)；MS(ESI)：317[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .
步骤2：化合物5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(化合物int_3)的合成：Step 2: Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
50mL单口瓶中加入3，5-二氯-6-碘吡嗪-2-羧酰胺(280mg，0.883mmol)，4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(267mg，0.971mmol)，Dioxane(20mL)和DIPEA(228mg，1.766mmol)，混合液氩气置换后搅拌升温至回流反应2h。LC-MS监测反应完成后，混合液浓缩，残留物柱层析纯化得产物(368mg，收率：75％)。3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazine-1-yl)piperidine-1 was added to the 50mL single-necked bottle -yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol), the mixed solution was replaced with argon and heated to reflux for 2 h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).
1H NMR(400MHz，CDCl 3)δ10.69(s，1H)，7.53(d，J＝3.8Hz，1H)，7.51-7.44(m，2H)，6.99-6.88(m，2H)，5.67(d，J＝3.9Hz，1H)，3.80-3.63(m，2H)，2.84-2.42(m，10H)，2.39(ddt，J＝11.4，7.3，3.7Hz，1H)，1.96(dt，J＝12.2，3.0Hz，2H)，1.70(qd，J＝12.1，4.0Hz，2H)；MS(ESI)：556[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.69 (s, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99-6.88 (m, 2H), 5.67 ( d, J=3.9Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96 (dt, J= 12.2, 3.0 Hz, 2H), 1.70 (qd, J=12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .
步骤3：化合物6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(化合物int_4)的合成：Step 3: Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
50mL单口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(150mg，0.27mmol)，无水碳酸钾(186mg，1.35mmol)，无水氟化钾(31mg，0.54mmol)，DMSO(5mL)，
Figure PCTCN2021106269-appb-000055
分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 to the 50mL single-necked bottle -carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL),
Figure PCTCN2021106269-appb-000055
Molecular sieve (200mg, powder), the mixed solution was argon replaced and stirred at room temperature for 15min, then 3-tetrahydro-2H-pyran-4-amine (32mg, 0.32mmol) was added, and the mixed solution was stirred and heated to 120 °C after argon replacement. ℃ reaction 2h. LC-MS monitored the completion of the reaction, and the mixture was cooled down and purified by column chromatography to obtain the product (110 mg, yield: 65.7%).
1H NMR(400MHz，CDCl 3)δ10.64(s，1H)，7.62-7.39(m，2H)，7.21(s，1H)，6.96-6.76(m，2H)，5.41-5.12(m，2H)，4.03(dq，J＝11.4，3.7Hz，3H)，3.67(d，J＝12.0Hz，2H)，3.51(td，J＝11.6，2.2Hz，2H)，2.84-2.50(m，10H)，2.44(d，J＝11.4Hz，1H)，2.37(s，3H)，2.11-1.89(m，4H)，1.78-1.51(m，4H)；MS(ESI)：621[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.64 (s, 1H), 7.62-7.39 (m, 2H), 7.21 (s, 1H), 6.96-6.76 (m, 2H), 5.41-5.12 (m, 2H) ), 4.03 (dq, J=11.4, 3.7Hz, 3H), 3.67 (d, J=12.0Hz, 2H), 3.51 (td, J=11.6, 2.2Hz, 2H), 2.84-2.50 (m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] + .
步骤4：6-亚甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物1)的合成：Step 4: 6-Methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H Synthesis of -pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 1):
将6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(700mg，1.22mmol)，2-乙酰基苯硼酸(400mg，2.44mmol)，Pd(dppf)Cl 2(89mg，0.12mmol)，K 3PO 4(648mg，3.05mmol)加至Dioxane/H 2O(10mL/2mL)中，氩气保护，100℃反应约0.5h。LC/MS检测反应完全。旋干，残留物加水(20mL)，滴加TFA至完全溶清，柱层析纯化[H 2O(1‰TFA)/MeCN，5％-5％，100mL，5％-50％，700mL，50％-95％，50mL，95％-95％，300mL]收集产物流分，后加饱和NaHCO 3(10mL)，以DCM(30mL*3)萃取三次，有机相干燥旋干得黄色固体产物(606mg，收率：83％)。 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran 4- yl) amino) pyrazine-2-carboxamide (700mg, 1.22mmol), 2- acetyl-boronic acid (400mg, 2.44mmol), Pd ( dppf) Cl 2 (89mg, 0.12mmol), K 3 PO 4 (648 mg, 3.05 mmol) was added to Dioxane/H 2 O (10 mL/2 mL), under argon protection, and reacted at 100° C. for about 0.5 h. The reaction was complete by LC/MS. Spin dry, add water (20 mL) to the residue, add TFA dropwise until it is completely dissolved, and purify by column chromatography [H 2 O(1‰TFA)/MeCN, 5%-5%, 100 mL, 5%-50%, 700 mL, 50%-95%, 50mL, 95%-95%, 300mL] product fractions were collected, then saturated NaHCO 3 (10 mL) was added, extracted three times with DCM (30 mL*3), and the organic phase was dried and spin-dried to obtain a yellow solid product ( 606 mg, yield: 83%).
1H NMR(400MHz，CDCl 3)δ10.87(s，1H)，8.16-8.10(m，1H)，7.67-7.62(m，2H)，7.54(d，J＝8.9Hz，2H)，7.44-7.39(m，1H)，7.36-7.31(m，1H)，6.95(d，J＝8.9Hz，2H)，5.34(s，1H)，5.10(d，J＝2.4Hz，1H)，4.96-4.87(m，1H)，4.83(d，J＝2.4Hz，1H)，4.12(dd，J＝11.4，4.7Hz，2H)，3.70(d，J＝12.1Hz，2H)，3.53(t，J＝11.9Hz，2H)，2.94-2.81(m，2H)，2.69(dd，J＝22.0，10.3Hz，6H)，2.38(t，J＝11.4Hz，2H)，2.30(s，3H)，1.96(d，J＝12.6Hz，2H)，1.77-1.68(m，4H)；MS(ESI)：595[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.87 (s, 1H), 8.16-8.10 (m, 1H), 7.67-7.62 (m, 2H), 7.54 (d, J=8.9Hz, 2H), 7.44- 7.39(m, 1H), 7.36-7.31(m, 1H), 6.95(d, J=8.9Hz, 2H), 5.34(s, 1H), 5.10(d, J=2.4Hz, 1H), 4.96-4.87 (m, 1H), 4.83 (d, J=2.4Hz, 1H), 4.12 (dd, J=11.4, 4.7Hz, 2H), 3.70 (d, J=12.1Hz, 2H), 3.53 (t, J= 11.9Hz, 2H), 2.94-2.81(m, 2H), 2.69(dd, J=22.0, 10.3Hz, 6H), 2.38(t, J=11.4Hz, 2H), 2.30(s, 3H), 1.96( d, J=12.6 Hz, 2H), 1.77-1.68 (m, 4H); MS (ESI): 595 [M+H] + .
步骤5：6-甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物2)的合成：Step 5: 6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 2):
将6-亚甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(606mg，1.02mmol)溶于MeOH/DCM(50mL/20mL)中，加10％Pd/C(1.2g)，通入H 2，换气2次后室温常压反应过夜。LC/MS检测反应完全，砂芯漏斗铺硅藻土过滤，滤饼以MeOH(20mL*3)洗三次，滤液旋干得黄色固体产物(550mg，收率：90％)。 6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyridine) Furan-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (606 mg, 1.02 mmol) was dissolved in MeOH/DCM (50 mL/20 mL) and added 10% Pd/C (1.2g) was introduced into H 2 , and the reaction was carried out at room temperature and normal pressure overnight after 2 times of ventilation. LC/MS detected that the reaction was complete, the sand core funnel was covered with diatomaceous earth for filtration, the filter cake was washed three times with MeOH (20 mL*3), and the filtrate was spin-dried to obtain a yellow solid product (550 mg, yield: 90%).
1H NMR(400MHz，CDCl 3)δ10.88(s，1H)，8.00(dd，J＝7.7，1.4Hz，1H)，7.61(s，1H)，7.57-7.53(m，2H)，7.33(td，J＝7.5，1.3Hz，1H)，7.27(td，J＝7.4，1.4Hz，1H)，7.09(dd，J＝7.7，1.3Hz，1H)，6.92-6.86(m，2H)，5.31(d，J＝13.2Hz，1H)，4.82(q，J＝6.4Hz，1H)，4.66(ddd，J＝12.1，8.4，3.7Hz，1H)，4.11(d，J＝11.5Hz，2H)，3.66(d，J＝12.1Hz，2H)，3.59-3.47(m，2H)，3.01(s，7H)，2.69(t，J＝11.5Hz，2H)，2.60(s，3H)，2.20-2.10(m，2H)，1.98(dq，J＝19.8，7.7，6.0Hz，4H)，1.69(t，J＝14.7Hz，5H)，1.33(d，J＝6.5Hz，3H)；MS(ESI)：597[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.88 (s, 1H), 8.00 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57-7.53 (m, 2H), 7.33 ( td, J=7.5, 1.3Hz, 1H), 7.27 (td, J=7.4, 1.4Hz, 1H), 7.09 (dd, J=7.7, 1.3Hz, 1H), 6.92-6.86 (m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82 (q, J=6.4Hz, 1H), 4.66 (ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11 (d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10 (m, 2H), 1.98 (dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69 (t, J=14.7Hz, 5H), 1.33 (d, J=6.5Hz, 3H); MS (ESI ): 597[M+H] + .
采用手性分离技术，可以得到2个光学纯手性异构体：Using chiral separation technology, two optically homochiral isomers can be obtained:
Figure PCTCN2021106269-appb-000056
Figure PCTCN2021106269-appb-000056
(R)-6-甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物2-A)：(R)-6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H -pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 2-A):
1H NMR(400MHz，CDCl 3)δ10.88(s，1H)，8.00(dd，J＝7.7，1.4Hz，1H)，7.61(s，1H)，7.57-7.53(m，2H)，7.33(td，J＝7.5，1.3Hz，1H)，7.27(td，J＝7.4，1.4Hz，1H)，7.09(dd，J＝7.7，1.3Hz，1H)，6.92-6.86(m，2H)，5.31(d，J＝13.2Hz，1H)，4.82(q，J＝6.4Hz，1H)，4.66(ddd，J＝12.1，8.4，3.7Hz，1H)，4.11(d，J＝11.5Hz，2H)，3.66(d，J＝12.1Hz，2H)，3.59-3.47(m，2H)，3.01(s，7H)，2.69(t，J＝11.5Hz，2H)，2.60(s，3H)，2.20-2.10(m，2H)，1.98(dq，J＝19.8，7.7，6.0Hz，4H)，1.69(t，J＝14.7Hz，5H)，1.33(d，J＝6.5Hz，3H)；MS(ESI)：597[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.88 (s, 1H), 8.00 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57-7.53 (m, 2H), 7.33 ( td, J=7.5, 1.3Hz, 1H), 7.27 (td, J=7.4, 1.4Hz, 1H), 7.09 (dd, J=7.7, 1.3Hz, 1H), 6.92-6.86 (m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82 (q, J=6.4Hz, 1H), 4.66 (ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11 (d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10 (m, 2H), 1.98 (dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69 (t, J=14.7Hz, 5H), 1.33 (d, J=6.5Hz, 3H); MS (ESI ): 597[M+H] + .
(S)-6-甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物2-B)：(S)-6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H -pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 2-B):
1H NMR(400MHz，CDCl 3)δ10.88(s，1H)，8.00(dd，J＝7.7，1.4Hz，1H)，7.61(s，1H)，7.57-7.53(m，2H)，7.33(td，J＝7.5，1.3Hz，1H)，7.27(td，J＝7.4，1.4Hz，1H)，7.09(dd，J＝7.7，1.3Hz，1H)，6.92-6.86(m，2H)，5.31(d，J＝13.2Hz，1H)，4.82(q，J＝6.4Hz，1H)，4.66(ddd，J＝12.1，8.4，3.7Hz，1H)，4.11(d，J＝11.5Hz，2H)，3.66(d，J＝12.1Hz，2H)，3.59-3.47(m，2H)，3.01(s，7H)，2.69(t，J＝11.5Hz，2H)，2.60(s，3H)，2.20-2.10(m，2H)，1.98(dq，J＝19.8，7.7，6.0Hz，4H)，1.69(t，J＝14.7Hz，5H)，1.33(d，J＝6.5Hz，3H)；MS(ESI)：597[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.88 (s, 1H), 8.00 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57-7.53 (m, 2H), 7.33 ( td, J=7.5, 1.3Hz, 1H), 7.27 (td, J=7.4, 1.4Hz, 1H), 7.09 (dd, J=7.7, 1.3Hz, 1H), 6.92-6.86 (m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82 (q, J=6.4Hz, 1H), 4.66 (ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11 (d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10 (m, 2H), 1.98 (dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69 (t, J=14.7Hz, 5H), 1.33 (d, J=6.5Hz, 3H); MS (ESI ): 597[M+H] + .
合成方法B：Synthetic method B:
使用合成方法B进行具体实施例3(6-亚氨基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺)的合成：Using Synthetic Method B for Specific Example 3 (6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 Synthesis of -(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):
Figure PCTCN2021106269-appb-000057
Figure PCTCN2021106269-appb-000057
步骤1：化合物3，5-二氯-6-碘吡嗪-2-羧酰胺(化合物int_2)的合成：Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
500mL单口瓶中加入3，5-二氯-2-碘吡嗪(15g，54.57mmol)，甲酰胺(300mL)，混合液搅拌升温至90℃，后分批加入(NH 4) 2S 2O 8(25g，109.1mmol)固体，混合液保温在90℃搅拌2h，后再次分批补加K 2S 2O 8(30g，109.1mmol)固体，混合液保温在90℃搅拌20h。LC-MS监测反应有产物，剩余部分原料。混合液中加入EtOAc(150mL)，水(300mL)，搅拌、分液，水相再用EtOAc(150mL)萃取，合并有机相用饱和氯化钠溶液(150mL)洗涤、浓缩，残留物柱层析纯化(EtOAc∶Hexane＝0∶1 to 1∶5 to 1∶2)得产物(1.82g，收率：10.5％)，回收原料(10.3g，收率：68.7％)。 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining. EtOAc (150 mL) and water (300 mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150 mL), the combined organic phases were washed with saturated sodium chloride solution (150 mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).
1H NMR(400MHz，CDCl 3)δ7.28(s，1H)，5.78(s，1H)；MS(ESI)：317[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .
步骤2：化合物5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(化合物int_3)的合成：Step 2: Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
50mL单口瓶中加入3，5-二氯-6-碘吡嗪-2-羧酰胺(280mg，0.883mmol)，4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(267mg，0.971mmol)，Dioxane(20mL)和DIPEA(228mg，1.766mmol)，混合液氩气置换后搅拌升温至回流反应2h。LC-MS监测反应完成后，混合液浓缩，残留物柱层析纯化得产物(368mg，收率：75％)。3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazine-1-yl)piperidine-1 was added to the 50mL single-necked bottle -yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol), the mixed solution was replaced with argon and heated to reflux for 2 h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).
1H NMR(400MHz，CDCl 3)δ10.69(s，1H)，7.53(d，J＝3.8Hz，1H)，7.51-7.44(m，2H)，6.99-6.88(m，2H)，5.67(d，J＝3.9Hz，1H)，3.80-3.63(m，2H)，2.84-2.42(m，10H)，2.39(ddt，J＝ 11.4，7.3，3.7Hz，1H)，1.96(dt，J＝12.2，3.0Hz，2H)，1.70(qd，J＝12.1，4.0Hz，2H)；MS(ESI)：556[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.69 (s, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99-6.88 (m, 2H), 5.67 ( d, J=3.9Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96 (dt, J= 12.2, 3.0 Hz, 2H), 1.70 (qd, J=12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .
步骤3：化合物6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(化合物int_4)的合成：Step 3: Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
50mL单口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(150mg，0.27mmol)，无水碳酸钾(186mg，1.35mmol)，无水氟化钾(31mg，0.54mmol)，DMSO(5mL)，
Figure PCTCN2021106269-appb-000058
分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 to the 50mL single-necked bottle -carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL),
Figure PCTCN2021106269-appb-000058
Molecular sieve (200mg, powder), the mixed solution was argon replaced and stirred at room temperature for 15min, then 3-tetrahydro-2H-pyran-4-amine (32mg, 0.32mmol) was added, and the mixed solution was stirred and heated to 120 °C after argon replacement. ℃ reaction 2h. LC-MS monitored the completion of the reaction, and the mixture was cooled down and purified by column chromatography to obtain the product (110 mg, yield: 65.7%).
1H NMR(400MHz，CDCl 3)δ10.64(s，1H)，7.62-7.39(m，2H)，7.21(s，1H)，6.96-6.76(m，2H)，5.41-5.12(m，2H)，4.03(dq，J＝11.4，3.7Hz，3H)，3.67(d，J＝12.0Hz，2H)，3.51(td，J＝11.6，2.2Hz，2H)，2.84-2.50(m，10H)，2.44(d，J＝11.4Hz，1H)，2.37(s，3H)，2.11-1.89(m，4H)，1.78-1.51(m，4H)；MS(ESI)：621[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.64 (s, 1H), 7.62-7.39 (m, 2H), 7.21 (s, 1H), 6.96-6.76 (m, 2H), 5.41-5.12 (m, 2H) ), 4.03 (dq, J=11.4, 3.7Hz, 3H), 3.67 (d, J=12.0Hz, 2H), 3.51 (td, J=11.6, 2.2Hz, 2H), 2.84-2.50 (m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] + .
步骤4：6-亚氨基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物3)的合成：Step 4: 6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 3):
将6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(300mg，0.52mmol)，2-氰基苯硼酸(115mg，0.78mmol)，Pd(dppf) 2Cl 2(38mg，0.05mmol)溶于NMP(9mL)中，加入碳酸钠水溶液(2.0M，0.9mL)，氩气保护下，升温120℃反应1小时，LC-MS监测，反应完毕，冷却，反应液直接Flash反相柱层析，得到浅黄色固体210mg，收率67％。 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran 4- yl) amino) pyrazine-2-carboxamide (300mg, 0.52mmol), 2- cyano-phenyl boronic acid (115mg, 0.78mmol), Pd ( dppf) 2 Cl 2 (38mg, 0.05mmol) was dissolved in NMP (9mL), add sodium carbonate aqueous solution (2.0M, 0.9mL), under the protection of argon, heat up at 120 DEG C and react for 1 hour, monitor by LC-MS, the reaction is completed, cooled, and the reaction solution is directly Flash reversed-phase column chromatography to obtain Light yellow solid 210 mg, yield 67%.
1H NMR(400MHz，CDCl 3)δ10.94(s，1H)，8.48(s，1H)，8.35(dd，J＝7.9，1.2Hz，1H)，7.80(d，J＝13.3Hz，1H)，7.72(d，J＝4.4Hz，1H)，7.64-7.54(m，3H)，7.48(ddd，J＝8.4，7.2，1.3Hz，1H)，7.02-6.94(m，2H)，5.76(brs，1H)，5.55-5.48(m，1H)，4.15-4.06(m，2H)，3.76-3.66(m，2H)，3.54(td，J＝11.9，2.1Hz，2H)，3.30(brs，2H)，2.75-2.56(m，6H)，2.47(brs，2H)，2.37(tt，J＝11.4，3.7Hz，1H)，2.28(s，3H)，1.99-1.90(m，2H)，1.76-1.63(m，4H)，1.58(d，J＝12.7Hz，2H)；MS(ESI)：596[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.94 (s, 1H), 8.48 (s, 1H), 8.35 (dd, J=7.9, 1.2 Hz, 1H), 7.80 (d, J=13.3 Hz, 1H) , 7.72(d, J=4.4Hz, 1H), 7.64-7.54(m, 3H), 7.48(ddd, J=8.4, 7.2, 1.3Hz, 1H), 7.02-6.94(m, 2H), 5.76(brs , 1H), 5.55-5.48 (m, 1H), 4.15-4.06 (m, 2H), 3.76-3.66 (m, 2H), 3.54 (td, J=11.9, 2.1Hz, 2H), 3.30 (brs, 2H) ), 2.75-2.56(m, 6H), 2.47(brs, 2H), 2.37(tt, J=11.4, 3.7Hz, 1H), 2.28(s, 3H), 1.99-1.90(m, 2H), 1.76- 1.63 (m, 4H), 1.58 (d, J=12.7Hz, 2H); MS (ESI): 596 [M+H] + .
合成方法C：Synthetic method C:
使用合成方法C进行具体实施例4(3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-6-氧杂-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺)的合成：Using Synthetic Method C for Specific Example 4 (3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5 Synthesis of -(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):
Figure PCTCN2021106269-appb-000059
Figure PCTCN2021106269-appb-000059
步骤1：化合物3，5-二氯-6-碘吡嗪-2-羧酰胺(化合物int_2)的合成：Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
500mL单口瓶中加入3，5-二氯-2-碘吡嗪(15g，54.57mmol)，甲酰胺(300mL)，混合液搅拌升温至90℃，后分批加入(NH 4) 2S 2O 8(25g，109.1mmol)固体，混合液保温在90℃搅拌2h，后再次分批补加K 2S 2O 8(30g，109.1mmol)固体，混合液保温在90℃搅拌20h。LC-MS监测反应有产物，剩余部分原料。混合液中加入EtOAc(150mL)，水(300mL)，搅拌、分液，水相再用EtOAc(150mL)萃取，合并有机相用饱和氯化钠溶液(150mL)洗涤、浓缩，残留物柱层析纯化(EtOAc∶Hexane＝0∶1 to 1∶5 to 1∶2)得产物(1.82g，收率：10.5％)，回收原料(10.3g，收率：68.7％)。 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining. EtOAc (150 mL) and water (300 mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150 mL), the combined organic phases were washed with saturated sodium chloride solution (150 mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).
1H NMR(400MHz，CDCl 3)δ7.28(s，1H)，5.78(s，1H)；MS(ESI)：317[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .
步骤2：化合物5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(化合物int_3)的合成：Step 2: Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
50mL单口瓶中加入3，5-二氯-6-碘吡嗪-2-羧酰胺(280mg，0.883mmol)，4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(267mg，0.971mmol)，Dioxane(20mL)和DIPEA(228mg，1.766mmol)，混合液氩气置换后搅拌升温至回流反应2h。LC-MS监测反应完成后，混合液浓缩，残留物柱层析纯化得产物(368mg，收率：75％)。3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazine-1-yl)piperidine-1 was added to the 50mL single-necked bottle -yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol), the mixed solution was replaced with argon and heated to reflux for 2 h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).
1H NMR(400MHz，CDCl 3)δ10.69(s，1H)，7.53(d，J＝3.8Hz，1H)，7.51-7.44(m，2H)，6.99- 6.88(m，2H)，5.67(d，J＝3.9Hz，1H)，3.80-3.63(m，2H)，2.84-2.42(m，10H)，2.39(ddt，J＝11.4，7.3，3.7Hz，1H)，1.96(dt，J＝12.2，3.0Hz，2H)，1.70(qd，J＝12.1，4.0Hz，2H)；MS(ESI)：556[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.69 (s, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99- 6.88 (m, 2H), 5.67 ( d, J=3.9Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96 (dt, J= 12.2, 3.0 Hz, 2H), 1.70 (qd, J=12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .
步骤3：化合物6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(化合物int_4)的合成：Step 3: Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
50mL单口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(150mg，0.27mmol)，无水碳酸钾(186mg，1.35mmol)，无水氟化钾(31mg，0.54mmol)，DMSO(5mL)，
Figure PCTCN2021106269-appb-000060
分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 to the 50mL single-necked bottle -carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL),
Figure PCTCN2021106269-appb-000060
Molecular sieve (200mg, powder), the mixed solution was argon replaced and stirred at room temperature for 15min, then 3-tetrahydro-2H-pyran-4-amine (32mg, 0.32mmol) was added, and the mixed solution was stirred and heated to 120 °C after argon replacement. ℃ reaction 2h. LC-MS monitored the completion of the reaction, and the mixture was cooled down and purified by column chromatography to obtain the product (110 mg, yield: 65.7%).
1H NMR(400MHz，CDCl 3)δ10.64(s，1H)，7.62-7.39(m，2H)，7.21(s，1H)，6.96-6.76(m，2H)，5.41-5.12(m，2H)，4.03(dq，J＝11.4，3.7Hz，3H)，3.67(d，J＝12.0Hz，2H)，3.51(td，J＝11.6，2.2Hz，2H)，2.84-2.50(m，10H)，2.44(d，J＝11.4Hz，1H)，2.37(s，3H)，2.11-1.89(m，4H)，1.78-1.51(m，4H)；MS(ESI)：621[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.64 (s, 1H), 7.62-7.39 (m, 2H), 7.21 (s, 1H), 6.96-6.76 (m, 2H), 5.41-5.12 (m, 2H) ), 4.03 (dq, J=11.4, 3.7Hz, 3H), 3.67 (d, J=12.0Hz, 2H), 3.51 (td, J=11.6, 2.2Hz, 2H), 2.84-2.50 (m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] + .
步骤4：3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-6-氧杂-5-(四氢-2H-吡喃-4-基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物4)的合成：Step 4: 3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5-(tetrahydro-2H- Synthesis of pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (compound 4):
将6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(200mg，0.35mmol)，2-甲氧羰基苯硼酸(94mg，0.52mmol)，Pd(dppf) 2Cl 2(26mg，0.04mmol)，K 3PO 4(185mg，0.87mmol)，溶于二氧六环、水的混合溶液(40mL)中，氩气保护下，升温100℃反应0.5小时，LC-MS监测，反应完毕，浓缩，残留物用二氯甲烷(50mL)溶解，水洗(30mL*2)，二氯甲烷相浓缩，制备液相纯化，得到浅黄色固体(60mg，收率29％)。 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran 4- yl) amino) pyrazine-2-carboxamide (200mg, 0.35mmol), 2- methoxycarbonylphenylboronic acid (94mg, 0.52mmol), Pd ( dppf) 2 Cl 2 (26mg, 0.04mmol), K 3 PO 4 (185 mg, 0.87 mmol), dissolved in a mixed solution of dioxane and water (40 mL), under argon protection, heated at 100 °C and reacted for 0.5 hours, monitored by LC-MS, the reaction was completed, concentrated, and the residue It was dissolved in dichloromethane (50 mL), washed with water (30 mL*2), the dichloromethane phase was concentrated, and the preparative liquid phase was purified to obtain a pale yellow solid (60 mg, yield 29%).
1H NMR(400MHz，CDCl 3)δ10.97(s，1H)，8.45-8.40(m，1H)，8.38(dd，J＝8.2，1.3Hz，1H)，7.81(d，J＝4.3Hz，1H)，7.78-7.71(m，1H)，7.59-7.53(m，3H)，7.00-6.95(m，2H)，5.68(ddt，J＝12.0，7.9，4.0Hz，1H)，5.59(d，J＝4.3Hz，1H)，4.13(dd，J＝11.2，4.4Hz，2H)，3.72(d，J＝12.1Hz，4H)，3.52(td，J＝11.9，2.0Hz，2H)，3.10(qd，J＝12.4，4.6Hz，2H)，2.79-2.57(m，6H)，2.52-2.40(m，4H)，2.37(ddt，J＝11.4，7.3，3.7Hz，1H)，2.28(s，3H)，1.95(d，J＝13.2Hz，2H)，1.69(dd，J＝11.8，3.8Hz，2H)；MS(ESI)：597[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.97 (s, 1H), 8.45-8.40 (m, 1H), 8.38 (dd, J=8.2, 1.3 Hz, 1H), 7.81 (d, J=4.3 Hz, 1H), 7.78-7.71 (m, 1H), 7.59-7.53 (m, 3H), 7.00-6.95 (m, 2H), 5.68 (ddt, J=12.0, 7.9, 4.0Hz, 1H), 5.59 (d, J=4.3Hz, 1H), 4.13 (dd, J=11.2, 4.4Hz, 2H), 3.72 (d, J=12.1Hz, 4H), 3.52 (td, J=11.9, 2.0Hz, 2H), 3.10 ( qd, J=12.4, 4.6Hz, 2H), 2.79-2.57 (m, 6H), 2.52-2.40 (m, 4H), 2.37 (ddt, J=11.4, 7.3, 3.7Hz, 1H), 2.28 (s, 3H), 1.95 (d, J=13.2Hz, 2H), 1.69 (dd, J=11.8, 3.8Hz, 2H); MS (ESI): 597 [M+H] + .
合成方法D：Synthetic method D:
使用合成方法D进行具体实施例5(6，6-二甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)氨基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺)的合成：Using Synthetic Method D for Specific Example 5 (6,6-Dimethyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )-5-(tetrahydro-2H-pyran-4-yl)amino)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide) synthesis:
Figure PCTCN2021106269-appb-000061
Figure PCTCN2021106269-appb-000061
步骤1：化合物3，5-二氯-6-碘吡嗪-2-羧酰胺(化合物int_2)的合成：Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
500mL单口瓶中加入3，5-二氯-2-碘吡嗪(15g，54.57mmol)，甲酰胺(300mL)，混合液搅拌升温至90℃，后分批加入(NH 4) 2S 2O 8(25g，109.1mmol)固体，混合液保温在90℃搅拌2h，后再次分批补加K 2S 2O 8(30g，109.1mmol)固体，混合液保温在90℃搅拌20h。LC-MS监测反应有产物，剩余部分原料。混合液中加入EtOAc(150mL)，水(300mL)，搅拌、分液，水相再用EtOAc(150mL)萃取，合并有机相用饱和氯化钠溶液(150mL)洗涤、浓缩，残留物柱层析纯化(EtOAc∶Hexane＝0∶1 to 1∶5 to 1+2)得产物(1.82g，收率：10.5％)，回收原料(10.3g，收率：68.7％)。 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol) and formamide (300mL) were added to a 500mL single-neck flask, the mixture was stirred and heated to 90°C, and (NH 4 ) 2 S 2 O was added in batches 8 (25 g, 109.1 mmol) solid, the mixture was kept at 90 °C and stirred for 2 h, then K 2 S 2 O 8 (30 g, 109.1 mmol) solid was added in batches, and the mixed solution was kept at 90 ° C and stirred for 20 h. The reaction was monitored by LC-MS for product, with some starting material remaining. EtOAc (150 mL) and water (300 mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150 mL), the combined organic phases were washed with saturated sodium chloride solution (150 mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1+2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).
1H NMR(400MHz，CDCl 3)δ7.28(s，1H)，5.78(s，1H)；MS(ESI)：317[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .
步骤2：化合物5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(化合物int_3)的合成：Step 2: Compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2- Synthesis of carboxamide (compound int_3):
50mL单口瓶中加入3，5-二氯-6-碘吡嗪-2-羧酰胺(280mg，0.883mmol)，4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(267mg，0.971mmol)，Dioxane(20mL)和DIPEA(228mg，1.766mmol)，混合液氩气置换后搅拌升温至回流反应2h。LC-MS监测反应完成后，混合液浓缩，残留物柱层析纯化得产物(368mg，收率：75％)。3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazine-1-yl)piperidine-1 was added to the 50mL single-necked bottle -yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol), the mixed solution was replaced with argon and heated to reflux for 2 h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).
1H NMR(400MHz，CDCl 3)δ10.69(s，1H)，7.53(d，J＝3.8Hz，1H)，7.51-7.44(m，2H)，6.99-6.88(m，2H)，5.67(d，J＝3.9Hz，1H)，3.80-3.63(m，2H)，2.84-2.42(m，10H)，2.39(ddt，J＝ 11.4，7.3，3.7Hz，1H)，1.96(dt，J＝12.2，3.0Hz，2H)，1.70(qd，J＝12.1，4.0Hz，2H)；MS(ESI)：556[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.69 (s, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99-6.88 (m, 2H), 5.67 ( d, J=3.9Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96 (dt, J= 12.2, 3.0 Hz, 2H), 1.70 (qd, J=12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .
步骤3：化合物6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(化合物int_4)的合成：Step 3: Compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-4):
50mL单口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)吡嗪-2-羧酰胺(150mg，0.27mmol)，无水碳酸钾(186mg，1.35mmol)，无水氟化钾(31mg，0.54mmol)，DMSO(5mL)，
Figure PCTCN2021106269-appb-000062
分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 to the 50mL single-necked bottle -carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL),
Figure PCTCN2021106269-appb-000062
Molecular sieves (200mg, powder), the mixed solution was replaced with argon and stirred at room temperature for 15min, then 3-tetrahydro-2H-pyran-4-amine (32mg, 0.32mmol) was added, and the mixed solution was replaced with argon and heated to 120 °C with stirring. ℃ reaction 2h. LC-MS monitored the completion of the reaction, and the mixture was cooled down and purified by column chromatography to obtain the product (110 mg, yield: 65.7%).
1H NMR(400MHz，CDCl 3)δ10.64(s，1H)，7.62-7.39(m，2H)，7.21(s，1H)，6.96-6.76(m，2H)，5.41-5.12(m，2H)，4.03(dq，J＝11.4，3.7Hz，3H)，3.67(d，J＝12.0Hz，2H)，3.51(td，J＝11.6，2.2Hz，2H)，2.84-2.50(m，10H)，2.44(d，J＝11.4Hz，1H)，2.37(s，3H)，2.11-1.89(m，4H)，1.78-1.51(m，4H)；MS(ESI)：621[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 10.64 (s, 1H), 7.62-7.39 (m, 2H), 7.21 (s, 1H), 6.96-6.76 (m, 2H), 5.41-5.12 (m, 2H) ), 4.03 (dq, J=11.4, 3.7Hz, 3H), 3.67 (d, J=12.0Hz, 2H), 3.51 (td, J=11.6, 2.2Hz, 2H), 2.84-2.50 (m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] + .
步骤4：化合物6-(2-(2-羟基丙基-2-基)苯基)-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(化合物int_5)的合成：Step 4: Compound 6-(2-(2-Hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidine-1- Synthesis of yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (compound int-5):
将6-碘-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(200mg，0.35mmol)，(2-(2-羟基丙基-2-基)苯基)硼酸(93mg，0.52mmol)，Pd(dppf) 2Cl 2(26mg，0.04mmol)，K 3PO 4(185mg，0.87mmol)，溶于二氧六环、水的混合溶液(40mL)中，氩气保护下，升温100℃反应0.5小时，LC-MS监测，反应完毕，浓缩，残留物用二氯甲烷(50mL)溶解，水洗(30mL*2)，二氯甲烷相浓缩，制备液相纯化，得到浅黄色固体(75mg，收率34％)。 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran -4-yl)amino)pyrazine-2-carboxamide (200mg, 0.35mmol), (2-(2-hydroxypropyl-2-yl)phenyl)boronic acid (93mg, 0.52mmol), Pd(dppf) 2 Cl 2 (26 mg, 0.04 mmol), K 3 PO 4 (185 mg, 0.87 mmol), dissolved in a mixed solution of dioxane and water (40 mL), under argon protection, heated to 100 ° C for 0.5 hours, LC -MS monitoring, the reaction was completed, concentrated, the residue was dissolved in dichloromethane (50mL), washed with water (30mL*2), the dichloromethane phase was concentrated, and the preparative liquid phase was purified to obtain a pale yellow solid (75mg, yield 34%) .
MS(ESI)：629[M+H] +. MS(ESI): 629[M+H] + .
步骤5：化合物6，6-二甲基-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(四氢-2H-吡喃-4-基)氨基)-5，6-二氢吡嗪并[2，3-c]异喹啉-2-甲酰胺(化合物5)的合成：Step 5: Compound 6, 6-Dimethyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrakis Synthesis of Hydro-2H-pyran-4-yl)amino)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 5):
将6-(2-(2-羟基丙基-2-基)苯基)-3-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-羧酰胺(100mg，0.16mmol)溶于二氯甲烷(10mL)中，氩气保护下，在0℃，将三氟化硼***(22.7mg，0.16mmol)滴加到上述溶液中，混合溶液慢慢升至室温反应2小时，LC-MS监测，反应完毕，浓缩，制备液相纯化，得到浅黄色固体(15mg，收率15％)。6-(2-(2-Hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene yl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (100 mg, 0.16 mmol) was dissolved in dichloromethane (10 mL) under argon , at 0 ° C, boron trifluoride ether (22.7 mg, 0.16 mmol) was added dropwise to the above solution, the mixed solution was slowly raised to room temperature and reacted for 2 hours, monitored by LC-MS, the reaction was completed, concentrated, and purified by liquid phase preparation , a pale yellow solid (15 mg, 15% yield) was obtained.
MS(ESI)：611[M+H] +. MS(ESI): 611[M+H] + .
实施例化合物6-288的合成Synthesis of Example Compound 6-288
使用合成方法A、合成方法B、合成方法C或合成方法D，采用不同原料，可以得到表 1A中目标化合物6-288。Using synthetic method A, synthetic method B, synthetic method C or synthetic method D, using different raw materials, the target compound 6-288 in Table 1A can be obtained.
表1ATable 1A
Figure PCTCN2021106269-appb-000063
Figure PCTCN2021106269-appb-000063
Figure PCTCN2021106269-appb-000064
Figure PCTCN2021106269-appb-000064
Figure PCTCN2021106269-appb-000065
Figure PCTCN2021106269-appb-000065
Figure PCTCN2021106269-appb-000066
Figure PCTCN2021106269-appb-000066
Figure PCTCN2021106269-appb-000067
Figure PCTCN2021106269-appb-000067
Figure PCTCN2021106269-appb-000068
Figure PCTCN2021106269-appb-000068
Figure PCTCN2021106269-appb-000069
Figure PCTCN2021106269-appb-000069
Figure PCTCN2021106269-appb-000070
Figure PCTCN2021106269-appb-000070
Figure PCTCN2021106269-appb-000071
Figure PCTCN2021106269-appb-000071
Figure PCTCN2021106269-appb-000072
Figure PCTCN2021106269-appb-000072
Figure PCTCN2021106269-appb-000073
Figure PCTCN2021106269-appb-000073
Figure PCTCN2021106269-appb-000074
Figure PCTCN2021106269-appb-000074
Figure PCTCN2021106269-appb-000075
Figure PCTCN2021106269-appb-000075
Figure PCTCN2021106269-appb-000076
Figure PCTCN2021106269-appb-000076
Figure PCTCN2021106269-appb-000077
Figure PCTCN2021106269-appb-000077
Figure PCTCN2021106269-appb-000078
Figure PCTCN2021106269-appb-000078
Figure PCTCN2021106269-appb-000079
Figure PCTCN2021106269-appb-000079
Figure PCTCN2021106269-appb-000080
Figure PCTCN2021106269-appb-000080
Figure PCTCN2021106269-appb-000081
Figure PCTCN2021106269-appb-000081
Figure PCTCN2021106269-appb-000082
Figure PCTCN2021106269-appb-000082
Figure PCTCN2021106269-appb-000083
Figure PCTCN2021106269-appb-000083
Figure PCTCN2021106269-appb-000084
Figure PCTCN2021106269-appb-000084
Figure PCTCN2021106269-appb-000085
Figure PCTCN2021106269-appb-000085
Figure PCTCN2021106269-appb-000086
Figure PCTCN2021106269-appb-000086
Figure PCTCN2021106269-appb-000087
Figure PCTCN2021106269-appb-000087
Figure PCTCN2021106269-appb-000088
Figure PCTCN2021106269-appb-000088
Figure PCTCN2021106269-appb-000089
Figure PCTCN2021106269-appb-000089
Figure PCTCN2021106269-appb-000090
Figure PCTCN2021106269-appb-000090
Figure PCTCN2021106269-appb-000091
Figure PCTCN2021106269-appb-000091
Figure PCTCN2021106269-appb-000092
Figure PCTCN2021106269-appb-000092
Figure PCTCN2021106269-appb-000093
Figure PCTCN2021106269-appb-000093
Figure PCTCN2021106269-appb-000094
Figure PCTCN2021106269-appb-000094
Figure PCTCN2021106269-appb-000095
Figure PCTCN2021106269-appb-000095
Figure PCTCN2021106269-appb-000096
Figure PCTCN2021106269-appb-000096
Figure PCTCN2021106269-appb-000097
Figure PCTCN2021106269-appb-000097
表1B.表1A中的部分化合物的核磁数据Table 1B. NMR data of some compounds in Table 1A
Figure PCTCN2021106269-appb-000098
Figure PCTCN2021106269-appb-000098
Figure PCTCN2021106269-appb-000099
Figure PCTCN2021106269-appb-000099
实施例2 本发明化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶的抑制活性的检测Example 2 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
运用HTRF方法测定化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶活的抑制作用。具体如下：The inhibitory effect of compounds on EGFR(del19/T790M/C797S), EGFR(L858R/T790M/C797S) or EGFR(WT) enzymatic activity was determined by HTRF method. details as follows:
将WT或者突变型EGFR蛋白与梯度稀释的化合物在28℃孵育10分钟后加入biotin-标记的通用酪氨酸激酶底物(TK)和ATP，在室温反应40分钟。终止反应后加入针对TK的Eu3+-Cryptate标记抗体和streptavidin-XL665，在室温孵育60分钟。通过检测615nm和665nm的发光，计算665/615的比值，定量TK底物磷酸化的水平。与对照组相比，计算化合物抑制百分比和IC 50。结果见下列表2。 WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and the reaction was performed at room temperature for 40 minutes. After the reaction was terminated, 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 luminescence at 615 nm and 665 nm and calculating the 665/615 ratio. Compared to the control group and percent inhibition calculated Compound IC 50. The results are shown in Table 2 below.
表2.本发明化合物对EGFR(del19/T790M/C797S)，EGFR(L858R/T790M/C797S)或EGFR(WT)的抑制活性Table 2. Inhibitory activity of compounds of the present invention on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT)
Figure PCTCN2021106269-appb-000100
Figure PCTCN2021106269-appb-000100
Figure PCTCN2021106269-appb-000101
Figure PCTCN2021106269-appb-000101
Figure PCTCN2021106269-appb-000102
Figure PCTCN2021106269-appb-000102
+表示抑制率小于或等于20％+ indicates that the inhibition rate is less than or equal to 20%
++表示抑制率为20％至50％++ means 20% to 50% inhibition
+++表示抑制率大于50％。+++ means inhibition rate greater than 50%.
N.D表示活性未测N.D means activity not tested
从表2数据可知，本发明化合物对EGFR(del19/T790M/C797S)和EGFR(L858R/T790M/C797S)的酶活性有较好的抑制活性，且对EGFR(WT)有较好的选择性。It can be seen from the data in Table 2 that the compounds of the present invention have good inhibitory activity on the enzymatic activities of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S), and have good selectivity for EGFR (WT).
实施例3 本发明化合物对Ba/F3(EGFR del19/T790M/C797S)三突变细胞和A431(EGFR WT)细胞的抗增殖活性 Example 3 Antiproliferative activity of compounds of the present invention on Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells and A431 (EGFR WT) cells
3000个携带EGFR(del19/T790M/C797S)的Ba/F3细胞，或者2000个A431细胞种植于384孔板中，生长一天后，加入梯度稀释的化合物(Ba/F3细胞最高500nM，A431细胞最高10uM)。加入化合物三天后，加入Cell Titer Glow评价细胞生长，计算化合物抑制细胞生长的百分率和IC 50值，结果见下列表3。 3000 Ba/F3 cells carrying EGFR (del19/T790M/C797S), or 2000 A431 cells were seeded in a 384-well plate, and after one day of growth, serially diluted compounds (up to 500nM for Ba/F3 cells and 10uM for A431 cells) were added. ). After the compound was added three days, added to Cell Titer Glow assess cell growth, and the compound is calculated IC 50 values of percent inhibition of cell growth, results of the following Table 3.
表3.本发明化合物对Ba/F3(EGFR del19/T790M/C797S)三突变细胞、A431野生型(EGFR WT)细胞的抗增殖活性 Table 3. Antiproliferative activity of compounds of the present invention on Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells, A431 wild type (EGFR WT) cells
Figure PCTCN2021106269-appb-000103
Figure PCTCN2021106269-appb-000103
Figure PCTCN2021106269-appb-000104
Figure PCTCN2021106269-appb-000104
从表3数据可知，本发明绝大多数化合物对Ba/F3(EGFR del19/T790M/C797S)三突变细胞的抗增殖活性都小于100nM，可见本发明化合物都具有很强的Ba/F3(EGFR del19/T790M/C797S)三突变细胞的抗增殖活性。 From the data in Table 3, it can be seen that the anti-proliferative activity of most compounds of the present invention on Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells is less than 100 nM, which shows that the compounds of the present invention have strong Ba/F3 (EGFR del19 /T790M/C797S ) antiproliferative activity in triple mutant cells.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (13)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
    Figure PCTCN2021106269-appb-100001
    Figure PCTCN2021106269-appb-100001
    通式(1)中：In general formula (1):
    A环为(3-11元)亚杂环烷基、(C6-C14)亚芳基或(5-10元)亚杂芳基，其中所述亚杂环烷基、亚芳基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、卤素、-NO 2、-R 4、-OR 4、-(CH 2) nOR 4、-(CH 2) nNR 4R 5、-NR 4R 5、-CN、-C(O)NR 4R 5、-NR 5C(O)R 4、-NR 5S(O) 2R 4、-S(O) pR 4和-S(O) 2NR 4R 5； Ring A is (3-11 membered) heterocycloalkylene, (C6-C14) arylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, arylene and heteroarylene The aryl groups may each independently be optionally substituted with one or more of the following groups: -H, halogen, -NO 2 , -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 and -S(O) 2 NR 4 R 5 ;
    Y为
    Figure PCTCN2021106269-appb-100002
    -O-、-N(R 4)-或化学键；     Y is
    Figure PCTCN2021106269-appb-100002
    -O-, -N(R 4 )- or chemical bond;
    Z为-C(＝O)-、-C＝N(R 4)-、-C(＝CH 2)-或
    Figure PCTCN2021106269-appb-100003
    Z is -C(=O)-, -C=N(R 4 )-, -C(=CH 2 )- or
    Figure PCTCN2021106269-appb-100003
    L 1为-O-或-NH-； L 1 is -O- or -NH-;
    X为(C6-C14)亚芳基或(5-11元)亚杂芳基，其中所述亚芳基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、卤素、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烷氧基和(C1-C6)卤代烷氧基；X is (C6-C14)arylene or (5-11 membered)heteroarylene, wherein said arylene and heteroarylene may each independently be optionally substituted with one or more of the following groups:- H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;
    R 1为-H、卤素、-(CH 2) nNR 6R 7、-NR 6R 7、-O(CH 2) mNR 6R 7、-N(R 5)(CH 2) mNR 6R 7、(C1-C6)烷氧基、-CH 2-(3-15元)杂环烷基或(3-15元)杂环烷基，其中所述烷氧基和杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-R 4、-(CH 2) nNR 6R 7、-NR 6R 7、-O(CH 2) mNR 6R 7、-N(R 5)(CH 2) mNR 6R 7和-R 3； 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 alkoxy and heterocycloalkyl can be Each independently optionally substituted with 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 ;
    R 2为-H、(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基；其中所述烷基、环烷基、芳基、杂环烷基可各自独立任选被1个或多个下列基团取代，卤素、-R 4、-OH、-(CH 2) nOR 4-、-(CH 2) nNR 4R 5-、-OR 4、-NR 4R 5、-CN、-C(O)NR 4R 5、-NR 5C(O)R 4、-NR 5S(O) 2R 4、-S(O) pR 4、-S(O) 2NR 4R 5； R 2 is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11-membered) heterocycloalkyl; wherein the alkyl, cycloalkane The radical, aryl, and heterocycloalkyl can be independently optionally substituted by one or more of the following groups: halogen, -R 4 , -OH, -(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 , -S(O) 2 NR 4 R 5 ;
    R 3为(3-11元)杂环烷基，其中所述杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CD 3、-R 4、-OR 4和-NR 4R 5； R 3 is (3-11 membered) heterocycloalkyl, wherein the heterocycloalkyl groups may each independently be optionally substituted with one or more of the following groups: -H, -CD 3 , -R 4 , -OR 4 and -NR 4 R 5 ;
    R 4和R 5各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基或(C3-C14)环烷基； R 4 and R 5 are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) cycloalkyl;
    R 6和R 7各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或R 6和R 7与其连接的N原子能够共同组成一个(3-11元)杂环烷基，此杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CD 3、卤素、-R 4和-OR 4； R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or the N atoms to which R 6 and R 7 are attached can together form a (3-11 member) Heterocycloalkyl, each of which may be independently optionally substituted with one or more of the following groups: -H, -CD 3 , halogen, -R 4 and -OR 4 ;
    R 8和R 9为各自独立的-H、-D、-OR 4、(C1-C6)烷基或(C3-C14)环烷基，或R 8和R 9与其连接的C原子能够共同组成一个(C3-C6)环烷基；和 R 8 and R 9 are each independently -H, -D, -OR 4 , (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 and the C atom to which they are attached can form together a (C3-C6)cycloalkyl; and
    p为0、1或2的整数，n为0、1、2或3的整数，m为1、2或3的整数。p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，A环为(5-7元)亚杂环烷基、亚苯基或(5-10元)亚杂芳基，其中所述亚杂环烷基、亚苯基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、-NO 2、-F、-Cl、-Br、-CN、-OH、-OCH 3、-NH 2、-N(CH 3) 2、-NHCOCH 3、-NHSO 2CH 3、-SO 2CH 3、-CH 3、-CF 3、-CHF 2、-CONH 2和-CH 2OH。 The compound according to claim 1 or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is (5-7 membered) heterocycloalkylene, phenylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, phenylene and heteroarylene may each independently be optionally combined with one or more groups that are substituted with: -H, -NO 2, -F, -Cl, -Br, -CN, -OH, -OCH 3, -NH 2, -N (CH 3) 2, -NHCOCH 3, -NHSO 2 CH 3, -SO 2 CH 3 , -CH 3, -CF 3, -CHF 2, -CONH 2 and -CH 2 OH.
  3. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，A环为：The compound according to claim 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), ring A is:
    Figure PCTCN2021106269-appb-100004
    Figure PCTCN2021106269-appb-100004
    Figure PCTCN2021106269-appb-100005
    Figure PCTCN2021106269-appb-100005
    Figure PCTCN2021106269-appb-100006
    Figure PCTCN2021106269-appb-100006
  4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Y为-CH 2-、-O-、-NH-、-N(CH 3)-或化学键。 The compound according to any one of claims 1-3, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Y It is -CH 2 -, -O-, -NH-, -N(CH 3 )- or chemical bond.
  5. 如权利要求1-4中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Z为-C(＝O)-、-C(＝NH)-、-C(＝CH 2)-、-CH 2-、 -CH(CH 3)-、-CH(OH)-、-C(CH 3) 2-、-CD(CH 3)-、-CD 2-、
    Figure PCTCN2021106269-appb-100007
    -CH(CF 3)-或-CH(CHF 2)-。     The compound according to any one of claims 1-4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Z is -C (= O) -, - C (= NH) -, - C (= CH 2) -, - CH 2 -, -CH (CH 3) -, - CH (OH) -, - C (CH 3) 2 -, - CD ( CH 3) -, - CD 2 -,
    Figure PCTCN2021106269-appb-100007
    -CH (CF 3) - or -CH (CHF 2) -.
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X为亚苯基或6元亚杂芳基，其中所述亚苯基和亚杂芳基可各自独立任选被1个或多个下列基团取代：-H、-F、-CH 3、-CH 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021106269-appb-100008
    -OCH 3、-OCF 2H、-OCH 2CF 3和-OCF 3。     The compound according to any one of claims 1-5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), X is phenylene or 6-membered heteroarylene, wherein the phenylene and heteroarylene may each independently be optionally substituted with one or more of the following groups: -H, -F, -CH 3 , - CH 2 CH 3 , -CH(CH 3 ) 2 ,
    Figure PCTCN2021106269-appb-100008
    -OCH 3 , -OCF 2 H, -OCH 2 CF 3 and -OCF 3 .
  7. 如权利要求6所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X为：The compound according to claim 6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), X is:
    Figure PCTCN2021106269-appb-100009
    Figure PCTCN2021106269-appb-100009
  8. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为：-H、-N(CH 3) 2、-CH 2-(6-11元)杂环烷基或(6-11元)杂环烷基，其中所述杂环烷基为：
    Figure PCTCN2021106269-appb-100010
    Figure PCTCN2021106269-appb-100011
    和所述杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CH 3、
    Figure PCTCN2021106269-appb-100012
    -N(CH 3) 2、
    Figure PCTCN2021106269-appb-100013
    Figure PCTCN2021106269-appb-100014
    和-CD 3。     The compound according to any one of claims 1-7 or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the general formula (1), R 1 is: -H, -N(CH 3 ) 2 , -CH 2 -(6-11 membered) heterocycloalkyl or (6-11 membered) heterocycloalkyl, wherein the heterocycloalkyl is:
    Figure PCTCN2021106269-appb-100010
    Figure PCTCN2021106269-appb-100011
    and the heterocycloalkyl groups may each independently be optionally substituted with one or more of the following groups: -H, -CH 3 ,
    Figure PCTCN2021106269-appb-100012
    -N(CH 3 ) 2 ,
    Figure PCTCN2021106269-appb-100013
    Figure PCTCN2021106269-appb-100014
    and -CD 3 .
  9. 如权利要求8所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为：-H、-N(CH 3) 2、
    Figure PCTCN2021106269-appb-100015
    Figure PCTCN2021106269-appb-100016
    The compound according to claim 8, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 is: -H, -N(CH 3 ) 2 ,
    Figure PCTCN2021106269-appb-100015
    Figure PCTCN2021106269-appb-100016
  10. 如权利要求1-9中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 2为： The compound according to any one of claims 1-9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 2 is:
    Figure PCTCN2021106269-appb-100017
    Figure PCTCN2021106269-appb-100018
    Figure PCTCN2021106269-appb-100017
    Figure PCTCN2021106269-appb-100018
  11. 如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：The compound of any one of claims 1-10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:
    Figure PCTCN2021106269-appb-100019
    Figure PCTCN2021106269-appb-100019
    Figure PCTCN2021106269-appb-100020
    Figure PCTCN2021106269-appb-100020
    Figure PCTCN2021106269-appb-100021
    Figure PCTCN2021106269-appb-100021
    Figure PCTCN2021106269-appb-100022
    Figure PCTCN2021106269-appb-100022
    Figure PCTCN2021106269-appb-100023
    Figure PCTCN2021106269-appb-100023
    Figure PCTCN2021106269-appb-100024
    Figure PCTCN2021106269-appb-100024
    Figure PCTCN2021106269-appb-100025
    Figure PCTCN2021106269-appb-100025
    Figure PCTCN2021106269-appb-100026
    Figure PCTCN2021106269-appb-100026
    Figure PCTCN2021106269-appb-100027
    Figure PCTCN2021106269-appb-100027
    Figure PCTCN2021106269-appb-100028
    Figure PCTCN2021106269-appb-100028
    Figure PCTCN2021106269-appb-100029
    Figure PCTCN2021106269-appb-100029
  12. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-11中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-11, or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  13. 一种如权利要求1-11中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求12所述的药物组合物用于制备治疗、调节或预防与EGFR突变相关疾病的药物中的应用。A compound as claimed in any one of claims 1-11, or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the drug of claim 12 The use of the composition in the preparation of a medicament for treating, regulating or preventing diseases related to EGFR mutation.
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WO2000076980A1 (en) * 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Novel nitrogen-contaiing heterocyclic derivatives or salts thereof
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