WO2022012593A1 - Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine - Google Patents

Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine 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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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/zh
Publication of WO2022012593A1 publication Critical patent/WO2022012593A1/fr

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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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
    • C07D471/14—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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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
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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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
    • C07D498/14—Ortho-condensed systems
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    • C07D513/00—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—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
    • 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
    • C07D513/14—Ortho-condensed systems
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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

L'invention concerne un composé représenté par la formule générale (1), un procédé de préparation associé et une utilisation du composé représenté par la formule générale (1), d'un isomère de celui-ci, d'une forme cristalline de celui-ci, d'un sel pharmaceutiquement acceptable de celui-ci, d'un hydrate de celui-ci ou d'un solvate de celui-ci en tant qu'inhibiteur d'EGFR dans la préparation d'un médicament qui est un antitumoral et dirigé contre d'autres maladies associées à EGFR.
PCT/CN2021/106269 2020-07-17 2021-07-14 Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine WO2022012593A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680298A (en) * 1983-05-31 1987-07-14 Schering Corporation Tricyclic anti-allergy and use as anti-inflammatory agents
WO2000076980A1 (fr) * 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives heterocycliques azotes ou leurs sels
CN1902193A (zh) * 2003-12-04 2007-01-24 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的喹喔啉
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
WO2012053606A1 (fr) * 2010-10-22 2012-04-26 アステラス製薬株式会社 Carboxamide arylaminohétérocyclique
CN104080774A (zh) * 2012-01-17 2014-10-01 安斯泰来制药株式会社 吡嗪甲酰胺化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680298A (en) * 1983-05-31 1987-07-14 Schering Corporation Tricyclic anti-allergy and use as anti-inflammatory agents
WO2000076980A1 (fr) * 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives heterocycliques azotes ou leurs sels
CN1902193A (zh) * 2003-12-04 2007-01-24 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的喹喔啉
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
WO2012053606A1 (fr) * 2010-10-22 2012-04-26 アステラス製薬株式会社 Carboxamide arylaminohétérocyclique
CN104080774A (zh) * 2012-01-17 2014-10-01 安斯泰来制药株式会社 吡嗪甲酰胺化合物

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