WO2021244505A1 - 新型吡嗪化合物 - Google Patents

新型吡嗪化合物 Download PDF

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WO2021244505A1
WO2021244505A1 PCT/CN2021/097583 CN2021097583W WO2021244505A1 WO 2021244505 A1 WO2021244505 A1 WO 2021244505A1 CN 2021097583 W CN2021097583 W CN 2021097583W WO 2021244505 A1 WO2021244505 A1 WO 2021244505A1
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compound
heterocycloalkyl
pharmaceutically acceptable
membered
general formula
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French (fr)
Chinese (zh)
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谢雨礼
吴应鸣
樊后兴
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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Priority to EP21817710.3A priority Critical patent/EP4159731A4/en
Priority to BR112022022220A priority patent/BR112022022220A2/pt
Priority to JP2022574270A priority patent/JP7777544B2/ja
Priority to MX2022013397A priority patent/MX2022013397A/es
Priority to KR1020227044988A priority patent/KR20230019444A/ko
Priority to CN202180039487.2A priority patent/CN115698000B/zh
Priority to US17/917,435 priority patent/US12600714B2/en
Priority to AU2021284676A priority patent/AU2021284676A1/en
Priority to CA3179395A priority patent/CA3179395A1/en
Publication of WO2021244505A1 publication Critical patent/WO2021244505A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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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
    • C—CHEMISTRY; METALLURGY
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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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, to a class of pyrazine compounds, a preparation method thereof, and the use of this class of compounds as EGFR inhibitors in the preparation of anti-tumor drugs.
  • Lung cancer is one of the common malignant tumors.
  • the number of new lung cancer cases worldwide is about 1.6 million every year, and the number of deaths due to lung cancer is 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 type of protein kinases responsible for transmitting mitogenic signals and playing an important role in growth and development.
  • the analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples show that the mutation of EGFR family proteins leads to the development of human tumors, which is one of the important inducements for the occurrence and development of a variety of 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 approximately 12 to 47% of non-small cell lung cancers.
  • the two most common types of EGFR gene mutations are the deletion of exon 19 (del19) and the L858R missense mutation in exon 21. These two types of mutations will cause the EGFR protein to continue to activate independently of the ligand.
  • NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib or osimertinib, they can obtain a higher clinical level (60-85%).
  • Osimertinib As a third-generation covalent EGFR TKI, Osimertinib was developed to treat tumors with EGFR del19 and L858R mutations with or without T790M mutations. Although osimertinib has a high response rate to the resistance caused by the T790M mutation, about 70% of patients will eventually develop resistance, and the disease will progress again after about 10 months (Lung Cancer. 2017, 108, 228- 231). Studies on the molecular mechanism of third-generation EGFR TKI resistance have shown that in about 20-40% of patients who undergo osimertinib treatment and relapse, a major resistance mechanism is the third mutation in the EGFR gene, which is the C797S mutation.
  • the EGFR del19/L858R T790M C797S mutant is a newly emerged EGFR mutant after the third-generation EGFR TKI treatment.
  • Boehringer Ingelheim reported that a class of macrocyclic compound BI-4020 has anti-EGFR del19/L858R T790M C797S mutant activity and anti-tumor activity in vivo (J Med Chem. 2019, 62, 10272-10293).
  • the present invention aims to provide a compound represented by the general formula (1) or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Y is (3-11 membered) heterocycloalkyl, (C6-C14) aryl or (5-10 membered) heteroaryl, wherein the heterocycloalkyl, aryl and heteroaryl may be optionally selected by 1
  • One or more of the following groups are substituted: -H, halogen, -R 4 , -OR 4 , -(CH 2 ) n OR 4 , -(CH 2 ) n NR 4 R 5 , -NR 4 R 5 , -CN , -C(O)NR 4 R 5 , -NR 5 C(O)R 4 , -NR 5 S(O) 2 R 4 , -S(O) p R 4 , -S(O) 2 NR 4 R 5 and -O-CH 2 -O-;
  • L 1 is -O- or -NH-
  • X is (C6-C14) arylene or (5-11 membered) heteroarylene, wherein the arylene and heteroarylene may be optionally substituted by 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 Optionally substituted by one or more of the following groups: -H, -R 4 , -(CH 2 ) n NR 6 R 7 , -NR 6 R 7 , -O(CH 2 ) m NR 6 R 7 ,- N(R 5 )(CH 2 ) m NR 6 R 7 and -R 3 ;
  • L 2 is -O-, -NH- or a chemical bond
  • R 2 is (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-4 membered) heterocycloalkyl, Or (6-11 membered) heterocycloalkyl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, It can be optionally substituted by one or more of the following groups: -H, halogen, -R 4 , -(CH 2 ) n OR 4 -, -(CH 2 ) n NR 4 R 5 -, -OR 4 ,- NR 4 R 5 , -CN, -C(O)NR 4 R 5 , -NR 5 C(O)R 4 , -NR 5 S(O) 2 R 4 , -S(O) p R 4 and -S (O) 2 NR 4 R 5 ;
  • R 3 is a (3-11 membered) heterocycloalkyl group, wherein the heterocycloalkyl group may be optionally substituted by one or more of the following groups: -H, -CD 3 , -R 4 , -OR 4 and -NR 4 R 5 ;
  • R 4 and R 5 are each independently -H, (C1-C6)alkyl, or (C3-C14)cycloalkyl;
  • R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 6 and R 7 and the N atom to which they are connected can together form one (3-11 member) Heterocycloalkyl, which can be optionally substituted by one or more of the following groups: -H, -CD 3 , halogen, -R 4 and -OR 4 ;
  • R 0 is (C1-C6)alkyl or (C3-C14)cycloalkyl
  • p is an integer of 0, 1, or 2
  • n is an integer of 0, 1, 2, or 3
  • m is an integer of 1, 2, or 3.
  • Y is (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) heteroaryl, wherein said heterocycloalkyl , Phenyl and heteroaryl groups can be optionally substituted by one or more of the following groups: -H, -F, -Cl, -Br, -CN, -OH, -OCH 3 , -NH 2 , -N( CH 3 ) 2 , -NHCOCH 3 , -NHSO2CH 3 , -CH 3 , -CONH 2 , -CH 2 OH and -O-CH 2 -O-.
  • Y is:
  • X is a phenylene group or a 6-membered heteroarylene group, wherein the phenylene group and heteroarylene group may optionally be substituted by one or more The following groups are substituted: -H, -F, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCF 2 H and -OCF 3 .
  • X is:
  • R 1 is: -H, -N(CH 3 ) 2 , -CH 2 -(6-11 membered) heterocycloalkyl or (6- 11-membered) heterocycloalkyl, wherein the heterocycloalkyl is:
  • the heterocycloalkyl group may be optionally substituted by one or more of the following groups: -H, -CH 3 , -N(CH 3 ) 2 , And -CD 3 .
  • R 1 is:
  • R 2 is:
  • the representative compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable excipient or carrier, and a compound of the general formula (1) of the present invention, or each of its isomers, crystal forms, and pharmaceuticals.
  • a pharmaceutical composition which contains a pharmaceutically acceptable excipient or carrier, and a compound of the general formula (1) of the present invention, or each of its isomers, crystal forms, and pharmaceuticals.
  • the above acceptable salt, hydrate or solvate is used as the active ingredient.
  • Another object of the present invention is to provide the above-mentioned compound of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the above-mentioned pharmaceutical composition for preparing and treating EGFR mutation related Application of disease drugs.
  • Another object of the present invention is to provide a method for treating, regulating and/or preventing a disease related to EGFR mutein, which comprises administering to the subject a therapeutically effective amount of the above-mentioned compound, or each of its isomers, crystal forms, and pharmacologically.
  • the inventors found that in the compound of general formula (1), when Y is a heterocycloalkyl, aromatic heterocycle, or aryl group, the compound unexpectedly has very Strong EGFR del19/T790M/C797S and EGFR L858R/T790M/C797S inhibitory activity, and high selectivity for wild-type EGFR WT.
  • Fig. 1 is the result of tumor growth inhibition rate in the in vivo pharmacodynamic study of mice in Example 4 of the present invention
  • Fig. 2 is the result of tumor growth inhibition rate in the in vivo pharmacodynamic study of mice in Example 5 of the present invention.
  • the compound of general formula (1) described above can be synthesized using standard synthesis techniques or well-known techniques and methods combined in the text.
  • the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials used for the synthesis of the compounds can be synthesized or obtained from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction scheme 1 or general reaction scheme 2:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , X, Y, L 1 and L 2 are as defined above, H represents hydrogen, and B represents boric acid, boric acid ester or Trifluoroborate.
  • R 1 , R 2 , X, Y, L 1 and L 2 are as defined above, H represents hydrogen, and B represents boric acid, boric acid ester or Trifluoroborate.
  • compound 1-1 reacts with formamide to form compound 1-2
  • compound 1-2 and R 1 -XL 1 -H react under basic conditions to form compound 1-3
  • compound 1-3 Coupling reaction with YB produces compound 1-4, compound 1-4 and R 2 -L 2 -H react under basic conditions to produce target compound 1-5.
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , X, Y, L 1 and L 2 are as defined above, and H represents hydrogen.
  • compound 2-1 reacts with formamide to form compound 2-2
  • compound 2-2 and R 1 -XL 1 -H react under basic conditions to form compound 2-3
  • compound 2-3 It reacts with R 2 -L 2 -H under basic conditions to produce 2-4
  • compound 2-4 and YH react under basic conditions to produce target compound 2-5.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or a diluent, that does not make the biological activity or properties of the compound disappear, and is relatively non-toxic, for example, when a substance is administered to an individual, it will not cause unwanted biological effects or Interacts with any components it contains in a harmful way.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause important irritation to the administered organism and does not cause the biological activity and properties of the compound to disappear.
  • pharmaceutically acceptable salts are obtained by reacting compounds of formula (1) with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, Propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • Organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents, and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc.
  • a hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol.
  • the solvate of the compound of general formula (1) is conveniently prepared or formed according to the method 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 here can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.
  • the compound of general formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form, and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, 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.
  • the compound of general formula (1) may have a chiral center and/or axial chirality, and therefore can be used as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the forms of enantiomers, and cis-trans isomers appear.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included in the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs generally have lower toxic and side effects and increase drugs. Stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 14 carbon atoms. It is preferably a lower alkyl group 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.
  • a lower alkenyl group containing 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl.
  • 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. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.
  • cycloalkyl refers to a 3- to 14-membered all-carbon monocyclic aliphatic hydrocarbon group, in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system .
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like are examples of the like.
  • alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those with 1-6 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.
  • the aryl group is monocyclic or polycyclic, for example, a monocyclic aryl ring is fused with one or more carbocyclic aromatic groups.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • arylene refers to a divalent aryl group as defined above.
  • examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), and a heteroaryl group is monocyclic or polycyclic, such as a monocyclic heteroaryl ring and one Or multiple carbocyclic aromatic groups or other monocyclic heterocyclic groups are condensed.
  • 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 and pyrrolopyrimidinyl.
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S, or N), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom Optionally quaternized as ring atoms.
  • heterocycloalkyl ring system can be a monocyclic, bicyclic, spirocyclic or polycyclic ring system.
  • Heterocycloalkyl can be attached to the rest of the molecule through more than one ring carbon or heteroatom.
  • heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, Dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorph Phinoline-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-Azaspiro[3.3]heptane and so on.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing in front of the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Replaced by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • acceptable refers to a prescription component or active ingredient that does not have unduly harmful effects on the health of the general treatment target.
  • treatment include alleviating, inhibiting, or ameliorating the symptoms or conditions of diseases; inhibiting the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of diseases or symptoms, Such as controlling the development of diseases or conditions; reducing diseases or symptoms; reducing diseases or symptoms; reducing complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the situation of administration.
  • Active ingredient refers to the compound represented by the general formula (1) and the pharmaceutically acceptable inorganic or organic salt 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 therefore presented as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. Appears in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and 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 refers to when administered to an individual (human or medicament).
  • agent a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
  • administered 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 using the compounds or pharmaceutical compositions of the present invention to treat diseases, including but not limited to conditions involving EGFR mutations (such as cancer).
  • cancer is mediated by EGFR mutations.
  • the cancer is lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, breast cancer, urothelial cancer, prostate cancer, ovarian cancer, head and neck cancer, stomach cancer, mesothelioma, or all cancer metastases.
  • the compound of the present invention and its pharmaceutically acceptable salt can be prepared into various preparations, which contain a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. .
  • 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 amount of the compound is determined according to the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity . "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmacologically acceptable excipients or carriers include 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, 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 compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), or locally.
  • 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 mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous 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.
  • the dosage forms of the compound of the present invention for topical administration 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 can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are all within the skill range of a skilled physician.
  • CDCl 3 stands for deuterated chloroform
  • CD 3 OD stands for deuterated methanol
  • DMSO-d6 stands for deuterated dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • Hexane stands for n-hexane
  • MeCN stands for acetonitrile
  • DCM stands for dichloromethane
  • DIPEA stands for diisopropylethylamine
  • NMP stands for 1-methylpyrrolidin-2-one
  • Dioxane stands for 1,4-dioxane
  • DMF stands for N,N-dimethylformaldehyde amide
  • Representative DMSO dimethylsulfoxide H for hour
  • K 3 PO 4 potassium phosphate Representative; min for minutes; MS mass spectrum; representatives of NaH sodium hydride; NMR nuclear magnetic resonance Representative; Pd 2 (dba) 3 Representative tris (dimethylene Benzylacetone)dipalladium; Pd(dppf
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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 5-chloro-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-phenylpyrazine-2 -Synthesis of carboxamide (compound int_4):
  • Step 4 Compound 5-((3-hydroxycyclopentyl)amino)-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino ) Synthesis of-6-phenylpyrazine-2-carboxamide (Compound 135):
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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 5-chloro-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-(pyridin-4-yl ) Synthesis of pyrazine-2-carboxamide (compound int_6):
  • Step 4 Compound 3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-(pyridin-4-yl)-5- Synthesis of ((Tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound 39)
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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 5-chloro-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-(1H-pyrazole- Synthesis of 3-yl)pyrazine-2-carboxamide (compound int_7):
  • Step 4 Compound 3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-(1H-pyrazol-3-yl) Synthesis of -5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound 55)
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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 5-chloro-6-(1H-indol-4-yl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene Synthesis of yl)amino)pyrazine-2-carboxamide (compound int_8):
  • Step 4 Compound 6-(1H-indol-4-yl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Synthesis of -5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound 511)
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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 5-chloro-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-phenylpyrazine-2 -Synthesis of carboxamide (compound int_4):
  • Step 4 Compound 5-methoxy-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-phenylpyrazine Synthesis of -2-carboxamide (Compound 19):
  • Step 1 Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):
  • Step 2 The 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-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H Synthesis of -pyran-4-yl)amino)pyrazine-2-carboxamide (compound int_5):
  • Step 4 Compound 3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-(piperidin-1-yl)-5 Synthesis of -((Tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound 116):
  • the LC-MS analysis method is as follows:
  • Example 2 Detection of the inhibitory activity of the compound of the present invention on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzyme
  • the HTRF method was used to determine the inhibitory effect of the compound on the enzymatic activity of EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT). details as follows.
  • +++ means the inhibition rate is greater than 50%.
  • N.D means the activity has not been tested
  • the compound of the present invention has good inhibitory activity on the enzymatic activity of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S), and has good selectivity for EGFR (WT).
  • Example 3 Anti-proliferative activity of the compound of the present invention on Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells and A431 (EGFR WT) cells
  • Ba/F3 cells carrying EGFR (del19/T790M/C797S) or 2000 A431 cells were planted in a 384-well plate. After one day of growth, add gradient dilution compounds (Ba/F3 cells up to 500nM, A431 cells up to 10uM ). Three days after the compound was added, Cell Titer Glow was added to evaluate cell growth, and the percentage and IC 50 value of the compound's inhibition of cell growth were calculated. The results are shown in Table 5 below.
  • the vast majority of compounds of the invention Ba / F3 (EGFR del19 / T790M / C797S) antiproliferative activity of triple mutant cells are less than 10OnM, and Gilteritinib for Ba / F3 (EGFR del19 / T790M / C797S) three
  • the anti-proliferation activity of the mutant cells is greater than 500 nM. It can be seen that when Y is an aryl group, a heteroaryl group or a heterocycloalkyl group, the compound has a strong anti-proliferation activity of the Ba/F3 (EGFR del19/T790M/C797S ) triple mutant cells.
  • Example 4 In vivo drug efficacy study-mouse H1975 subcutaneous xenograft tumor model
  • mice BALB / c nude mice were inoculated subcutaneously with the left dorsal 5 * 10 6 H1975 cells carrying the EGFR T790M mutation, the tumors grew to 100-150mm 3, after randomization, are administered orally, Group 1: vehicle control; Group 2: Compound 511 (60 mg/kg); Group 3: Compound 511 (80 mg/kg), once a day. Tumor volume was measured twice a week and at the end of dosing.
  • TGI tumor growth rate inhibition rate
  • compound 511 at 60 mg/kg and 80 mg/kg doses can inhibit tumor growth in the H1975 mouse subcutaneous xenograft model carrying the EGFR T790M mutation.
  • Example 5 In vivo drug efficacy study-mouse PC9 (EGFR Del19/T790M/C797S) subcutaneous xenograft tumor model
  • mice were subcutaneously inoculated with 5x10 6 PC9 cells carrying over-expressing EGFR Del19/T790M/C797S after the tumor grew to 100-150mm 3 , and after random grouping, they were given intragastric administration respectively.
  • Group 1 Vehicle control Group;
  • Group 2 Compound 511 (60 mg/kg);
  • Group 3 Compound 511 (80 mg/kg), once a day. Tumor volume was measured twice a week and at the end of dosing.
  • TGI tumor growth rate inhibition rate
  • compound 511 at 60 mg/kg and 80 mg/kg doses can inhibit tumor growth in the PC9 mouse subcutaneous xenograft tumor model that overexpresses EGFR Del19/T790M/C797S mutation.

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EP21817710.3A EP4159731A4 (en) 2020-06-01 2021-06-01 New pyrazine compound
BR112022022220A BR112022022220A2 (pt) 2020-06-01 2021-06-01 Composto, composição farmacêutica, uso do composto, e método para tratar, regular e/ou prevenir uma doença relacionada a uma proteína mutante de egfr
JP2022574270A JP7777544B2 (ja) 2020-06-01 2021-06-01 新規ピラジン化合物
MX2022013397A MX2022013397A (es) 2020-06-01 2021-06-01 Nuevo compuesto de pirazina.
KR1020227044988A KR20230019444A (ko) 2020-06-01 2021-06-01 신규한 피라진 화합물
CN202180039487.2A CN115698000B (zh) 2020-06-01 2021-06-01 新型吡嗪化合物
US17/917,435 US12600714B2 (en) 2020-06-01 2021-06-01 Substituted pyrazinecarboxamide compounds for treating diseases related to EGFR mutation
AU2021284676A AU2021284676A1 (en) 2020-06-01 2021-06-01 New pyrazine compound
CA3179395A CA3179395A1 (en) 2020-06-01 2021-06-01 New pyrazine compound

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