WO2022166741A1 - Composé macrocyclique contenant un benzohétérocycle et agissant en tant qu'inhibiteur de la kinase egfr et composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé macrocyclique contenant un benzohétérocycle et agissant en tant qu'inhibiteur de la kinase egfr et composition pharmaceutique et utilisation de celui-ci Download PDF

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WO2022166741A1
WO2022166741A1 PCT/CN2022/074255 CN2022074255W WO2022166741A1 WO 2022166741 A1 WO2022166741 A1 WO 2022166741A1 CN 2022074255 W CN2022074255 W CN 2022074255W WO 2022166741 A1 WO2022166741 A1 WO 2022166741A1
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Prior art keywords
alkyl
alternatively
optionally substituted
cycloalkyl
hydrogen
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PCT/CN2022/074255
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English (en)
Chinese (zh)
Inventor
刘飞
彭岩
徐宏江
任成�
严正磊
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正大天晴药业集团股份有限公司
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Priority to CN202280012961.7A priority Critical patent/CN116761603A/zh
Publication of WO2022166741A1 publication Critical patent/WO2022166741A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—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 four or more hetero rings

Definitions

  • the present application relates to a macrocyclic compound containing a benzoheterocycle as an EGFR kinase inhibitor, and specifically discloses a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof, and a preparation method thereof , a pharmaceutical composition containing the compound, and its medical use.
  • EGFR epidermal growth factor receptor
  • TKI tyrosine kinase inhibitor, tyrosine kinase inhibitor
  • Osimertinib (Osimertinib, AZD9291) is a third-generation EGFR-TKI targeted drug. Although it has a high response rate for drug resistance caused by T790M mutation, patients will also develop drug resistance (Clin Cancer Res; 21 (17), 2015). In 2015, "Nature Medicine, 21, 560–562, 2015” reported the resistance analysis of AZD9291 in 15 patients for the first time, in which the third mutation, the EGFR C797S mutation, was one of the main mechanisms leading to drug resistance to Osimertinib, accounting for about 40%. %. It is of great research significance to provide patients with safer and more effective fourth-generation EGFR C797S/T790M inhibitors.
  • the present application relates to compounds of formula I or pharmaceutically acceptable salts, stereoisomers, tautomers thereof,
  • L is selected from O, -C(O)O-, -C(O)N(R a )- or -N(R b )-;
  • R a and R b are each independently selected from hydrogen, C 1-8 alkyl or C 3-6 cycloalkyl;
  • R 1 is selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • the C 1-8 alkyl is optionally substituted with one or more R c selected from hydroxy, halogen, C 1-8 alkoxy, -NH 2 , -N(C 1-8 alkyl ) 2 , -NH(C 1-8 alkyl), or optionally substituted with one or more groups selected from hydroxy, halogen or C 1-6 alkyl, containing 1, 2 or 3 groups selected from N , O or S heteroatom 3-8 membered heterocycloalkyl;
  • the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more R selected from C 1-8 alkyl, C substituted with one or more deuterium 1-8 alkyl, C 1-8 alkyl substituted with one or more halogens, C 1-8 alkyl substituted with one C 3-8 cycloalkyl, C 3-8 cycloalkyl, halogen, cyano group, amino group or hydroxyl group;
  • R b and R 1 are connected to each other to form a 5-membered heterocycloalkyl group; the 5-membered heterocycloalkyl group is optionally substituted by C 1-8 alkyl, halogen, cyano, amino, hydroxyl or oxygen;
  • R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optional is replaced by one or more R';
  • Each R 3 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optionally substituted with one or more R";
  • Each R' and R" is independently selected from halogen, hydroxy, cyano, amino or nitro;
  • n is selected from 0, 1, 2 or 3.
  • the L is selected from O, -C(O)N(R a )- or -N(R b )-.
  • the L is selected from -C(O)N(R a )- or -N(R b )-.
  • the R a and R b are each independently selected from hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • the R a and R b are each independently selected from hydrogen, C 1-5 alkyl, or C 3-6 cycloalkyl.
  • the R a and R b are each independently selected from hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • the R a and R b are each independently selected from hydrogen, C 1-3 alkyl, or C 3-4 cycloalkyl.
  • the R a and R b are each independently selected from hydrogen or C 1-3 alkyl. In some embodiments, the R a and R b are each independently selected from hydrogen, methyl, ethyl, or n-propyl.
  • the R a and R b are each independently selected from hydrogen.
  • the R 1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C 1-6 alkyl is optionally substituted by one or more R c , and the C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more an R substitution.
  • the R 1 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C 1-4 alkyl is optionally substituted by one or more R c , and the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more an R substitution.
  • the R 1 is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C 1-3 alkyl is optionally substituted by one or more R c , and the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more an R substitution.
  • the R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, oxetanyl, azetidine, thietanyl, tetrahydrofuranyl, tetrahydro pyranyl, piperidinyl or tetrahydropyrrolyl, the methyl, ethyl or propyl optionally substituted with one or more R c , the cyclopropyl, oxetanyl, azetidine , thietanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or tetrahydropyrrolyl optionally substituted with one or more Rs.
  • the R 1 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl, the methyl, ethyl or propyl is optionally substituted with one or more R c , the cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl is optionally substituted with one or more R.
  • the R 1 is selected from hydrogen, methyl, ethyl, cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl, the methyl or ethyl optionally being Substituted with one or more R c , the cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl is optionally substituted with one or more R.
  • the R 1 is selected from hydrogen, C 1-6 alkyl optionally substituted by hydroxy or halogen, C 3-8 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-8 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.
  • the R 1 is selected from hydrogen, C 1-4 alkyl optionally substituted by hydroxy or halogen, C 3-6 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-6 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.
  • the R 1 is selected from hydrogen, C 1-3 alkyl optionally substituted by hydroxy or halogen, C 3-6 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-6 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.
  • the R 1 is selected from C 3-6 cycloalkyl or a 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, the Cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.
  • the heterocycloalkyl of R 1 is selected from 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, containing 1, 2 or 3 heteroatoms selected from N, O or S. 8-, 9- or 10-membered heterocycloalkyl optionally substituted with one or more Rs.
  • the heterocycloalkyl group of R 1 is selected from 3-9 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl group of R 1 is selected from 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl group of R 1 is selected from 3-7 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl group of R 1 is selected from 3-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl group of R 1 is selected from 4-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl group of R 1 is selected from 5-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.
  • the heterocycloalkyl for R is selected from 5-membered heterocycloalkyl containing 1 , 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl optionally is substituted with one or more Rs.
  • the heterocycloalkyl of R 1 is selected from 6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl optionally is substituted with one or more Rs.
  • the R b and R 1 are linked to each other to form a tetrahydropyrrole, the tetrahydropyrrole is optionally surrounded by one or more selected from the group consisting of C 1-6 alkyl, halogen, cyano, amino, hydroxyl or oxygen group substitution.
  • the R b and R 1 are connected to each other to form said Optionally substituted with one or more groups selected from C1-3 alkyl, fluoro, chloro, cyano, amino, hydroxy or oxygen. In some embodiments, the R b and R 1 are interconnected to form a substituted with one or more oxygens
  • the R c is selected from hydroxy, halogen, C 1-6 alkoxy, -NH 2 , -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl) , or a 3-8 membered heteroatom containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted by one or more groups selected from hydroxy, halogen or C 1-6 alkyl Cycloalkyl.
  • the R c is selected from hydroxy, halogen, C 1-4 alkoxy, -NH 2 , -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl) , or a 4-6 membered heteroatom containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted with one or more groups selected from hydroxy, halogen or C 1-4 alkyl Cycloalkyl.
  • the R c is selected from the group consisting of hydroxy, fluoro, chloro, C 1-3 alkoxy, -NH 2 , -N(C 1-3 alkyl) 2 , -NH(C 1-3 alkane group), or 5-6 containing 1, 2 or 3 heteroatoms selected from N, O or S optionally substituted with one or more groups selected from hydroxy, halogen or C 1-3 alkyl Membered heterocycloalkyl.
  • the R c is selected from hydroxy, fluoro, methoxy, -N(CH 3 ) 2 , tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, or 1,4-dioxane ring base.
  • the R is selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkyl substituted with one or more halo C 3-6 cycloalkyl substituted C 1-6 alkyl, C 3-6 cycloalkyl, halogen, cyano, amino or hydroxy.
  • the R is selected from C 1-4 alkyl, per-deuterated C 1-4 alkyl, C 1 substituted with one or more groups selected from fluorine, chlorine, bromine or iodine -4 alkyl, C 1-4 alkyl substituted with one C 3-6 cycloalkyl, C 3-6 cycloalkyl, fluorine, chlorine, bromine, iodine, cyano, amino or hydroxy.
  • the R is selected from C 1-3 alkyl, per-deuterated C 1-3 alkyl, C 1 substituted with one or more groups selected from fluorine, chlorine, bromine or iodine -3 alkyl, C 1-3 alkyl substituted with one C 3-5 cycloalkyl, C 3-5 cycloalkyl, fluoro, chloro, bromo, cyano, amino or hydroxy.
  • the R is selected from methyl, ethyl, n - propyl , isopropyl, -CD3 , -C2D5 , -C3D7 , -CF3 , -CH2CH2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -C 2 F 5 , -C 3 F 7 , methyl substituted with one C 3-5 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentane group, fluorine, chlorine, bromine, cyano, amino or hydroxyl.
  • the R is selected from methyl, ethyl , -CD3 , -C2D5 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -C 2 F 5 , cyclopropylmethyl, cyclopropyl, fluoro, chloro, bromo, cyano, amino or hydroxy.
  • the R is selected from methyl, ethyl, -CD3 , -CF3 , cyclopropyl, cyclopropylmethyl, cyano, amino, or hydroxy.
  • the R is selected from methyl.
  • the heterocycloalkyl group of R 1 is selected from azetidine, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, azacyclo Heptyl, imidazolinyl, pyrazolinyl, piperazinyl, hexahydropyrimidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, morpholinyl or tetrahydropyranyl , the heterocycloalkyl is optionally substituted with one or more Rs.
  • the heterocycloalkyl of R 1 is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, azepanyl, imidazolinyl, pyrazolinyl, piperazine , hexahydropyrimidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, morpholinyl or tetrahydropyranyl, said heterocycloalkyl optionally being replaced by one or more an R substitution.
  • the heterocycloalkyl of R 1 is selected from The heterocycloalkyl is optionally substituted with one or more Rs.
  • the R 1 is selected from hydrogen, cyclopropyl, methyl, ethyl, propyl, The methyl, ethyl or propyl is optionally substituted with one or more R; the cyclopropyl, optionally substituted with one or more R.
  • the R b and R 1 are connected to each other to form
  • the R 1 is selected from hydrogen, cyclopropyl, methyl, ethyl, propyl, or The methyl, ethyl or propyl is optionally substituted with one or more R; the cyclopropyl, optionally substituted with one or more R.
  • the R 1 is selected from hydrogen, cyclopropyl, methyl, ethyl, or The methyl or ethyl is optionally substituted with one or more R; the cyclopropyl, optionally substituted with one or more R.
  • the R 1 is selected from hydrogen, cyclopropyl, The cyclopropyl, optionally substituted with one or more R.
  • the R1 is selected from cyclopropyl optionally substituted with one or more Rs.
  • the R 1 is selected from optionally substituted with one or more R
  • the R 1 is selected from optionally substituted with one or more R
  • the R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted with one or more R'.
  • the R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy, wherein C 1 -4Alkyl or C1-4alkoxy is optionally substituted with one or more R'.
  • the R 2 is selected from hydrogen, fluorine, chlorine, bromine, hydroxy, cyano, amino, nitro, C 1-3 alkyl or C 1-3 alkoxy, wherein C 1-3 Alkyl or C1-3alkoxy is optionally substituted with one or more R'.
  • the R 2 is selected from hydrogen, fluorine, chlorine, bromine, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R'.
  • the R 2 is selected from hydrogen, fluoro, chloro, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R'.
  • the R 2 is selected from fluoro or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more fluoro.
  • the R 2 is selected from fluoro or methyl optionally substituted with one or more fluoro. In some embodiments, the R 2 is selected from fluoro, methyl or trifluoromethyl.
  • the R' is selected from fluoro, chloro, bromo, hydroxy, cyano, amino, or nitro.
  • the R' is selected from fluoro, chloro or bromo.
  • the R' is selected from fluoro or chloro.
  • the R' is selected from fluoro.
  • each of said R 3 is independently selected from halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy, wherein C 1-6 alkoxy or C 1-6 alkoxy optionally substituted with one or more R".
  • each of said R 3 is independently selected from halogen, hydroxy, cyano, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy, wherein C 1-4 alkoxy or C 1-4 alkoxy optionally substituted with one or more R".
  • each of said R 3 is independently selected from fluoro, chloro, hydroxy, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein C 1-3 alkyl or C 1-3 alkoxy optionally substituted with one or more R".
  • the R" is selected from fluoro, chloro, bromo, or hydroxy.
  • the R" is selected from fluoro, chloro or bromo.
  • the R" is selected from fluoro or chloro.
  • the R" is selected from fluoro.
  • the n is selected from 0, 1 or 2.
  • the n is selected from 0 or 1.
  • the n is zero.
  • the n is 1.
  • the R 3 is selected from hydrogen, fluorine, chlorine, bromine, or C 1-6 alkyl optionally substituted with one or more halogens. In some embodiments, the R 3 is selected from hydrogen, fluorine, chlorine, bromine, or C 1-4 alkyl optionally substituted with one or more atoms selected from fluorine or chlorine. In other embodiments, the R 3 is selected from hydrogen, fluorine, chlorine, or C 1-3 alkyl optionally substituted with one or more fluorine atoms. In other embodiments, the R3 is selected from hydrogen, fluorine, chlorine, or methyl optionally substituted with one or more fluorine atoms. In other embodiments, the R3 is selected from hydrogen, fluoro, chloro or trifluoromethyl.
  • the L is selected from -C(O)N(R a )-, and R 1 is selected from cyclopropyl optionally substituted with one or more R; alternatively, the R 1 is selected from from optionally substituted with one or more R or R 1 is selected from optionally substituted with one or more R
  • the L is selected from -N(R b )-, and R 1 is selected from cyclopropyl optionally substituted with one or more R; or, the R 1 is selected from optionally substituted by one or more R or R 1 is selected from optionally substituted with one or more R
  • the heteroatom of the heterocycloalkyl described herein is N; in some embodiments, the heteroatom of the heterocycloalkyl described herein is O.
  • the present application encompasses the above-defined variables and embodiments thereof, as well as any combination thereof.
  • the compound of formula I of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, is selected from the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer thereof , tautomers,
  • L, R 1 , R 2 and R 3 are as described above.
  • the R 1 is selected from hydrogen, C 1-8 alkyl optionally substituted with hydroxy or halo, C 3-10 cycloalkyl or contains 1, 2 or 3 selected from N, O or A 3-10 membered heterocycloalkyl of a heteroatom of S, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs selected from C 1-8 alkyl, substituted by one or Multiple deuterium substituted C 1-8 alkyl, C 1-8 alkyl substituted with one or more halogens, C 1-8 alkyl substituted with one C 3-8 cycloalkyl, C 3-8 ring Alkyl, halogen, cyano, amino or hydroxyl;
  • the R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy optionally substituted with one or more R' selected from halogen, hydroxy, cyano, amino or nitro;
  • Said R3 is selected from hydrogen, halogen or C1-8 alkyl optionally substituted with one or more halogens.
  • the compound of formula I of the present application is selected from the group consisting of formula II, formula III, formula IV, formula V, formula VI, formula VII or a compound of formula VIII or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,
  • R 1 , R 2 , R 3 or n are the same as those defined above in this application.
  • the application provides the following compounds or pharmaceutically acceptable salts, stereoisomers, tautomers thereof:
  • the application provides the following compounds or pharmaceutically acceptable salts, stereoisomers, tautomers thereof:
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof.
  • the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.
  • the present application relates to a method of treating an EGFR-mediated disease in an individual, comprising administering to an individual in need of such treatment, preferably a mammal, more preferably a human, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable amount thereof
  • a mammal preferably a mammal, more preferably a human
  • a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable amount thereof
  • the salts, stereoisomers, tautomers, or pharmaceutical compositions thereof preferably a mammal, more preferably a human.
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of EGFR-mediated diseases the use of.
  • the present application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, in the prevention or treatment of EGFR-mediated diseases.
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof for the prevention or treatment of EGFR-mediated diseases.
  • the EGFR-mediated diseases described herein are selected from EGFR mutant-mediated diseases. wherein the mutant is selected from one, two, three, or four of L858R, T790M, d19 (eg, d746-750, which is one of exon 19 deletion mutations), C797S; in some embodiments , wherein the mutant is selected from two mutants of L858R and T790M; in some embodiments, wherein the mutant is selected from two mutants of d19 and T790M.
  • the mutant comprises a C797S mutant; further, wherein the mutant is selected from three mutants of L858R, T790M and C797S; or wherein the mutant is selected from three mutants of d19, T790M and C797S.
  • the EGFR-mediated disease described herein is selected from cancer.
  • the EGFR-mediated disease described herein is selected from lung cancer.
  • the EGFR-mediated disease described herein is selected from non-small cell lung cancer.
  • the compounds of the present application have good kinase and cellular activities (including wild-type and mutant types such as d19, T790M, C797S and L858R). It has stable metabolism in vitro and in vivo, and has excellent efficacy in vivo.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • one or more refers to an integer from one to ten.
  • “one or more” means one, two, three, four, five, six, seven, eight, nine or ten; alternatively, “one or more” means one, two , three, four, five or six; alternatively, “one or more” means one, two or three.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • Cmn in this context is that the moiety has an integer number of carbon atoms in the given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent single bond.
  • substituents When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH2 group.
  • nitro refers to the -NO 2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n+1 .
  • the alkyl group can be straight or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio ie, alkyl
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • alkylsulfonyl refers to -SO2 -alkyl.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring (eg, 3, 4, 5, 6, 7, 8, 9, 10 membered rings).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, oxiranyl, ethylene oxide
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetine
  • Examples of cyclyl, thibutanyl, 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of yl, imidazolidinyl, tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, especially when such When a mammal is predisposed to the disease state, but has not been diagnosed with the disease state.
  • the term "effective amount” means (i) treatment or prevention of a particular disease, condition or disorder, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay herein
  • the amount of a compound of the present application that constitutes an "effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to their own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • the word "comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, ie, "including but not limited to”.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • non-limiting examples of tautomers include, but are not limited to
  • the present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • isotopically-labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium (ie 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dose is from 0.01 to 200 mg/kg body weight, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.
  • Pd(dppf) CH2Cl2 is [1,1' - bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; TBTU stands for O-benzotriazole-N,N ,N',N'-tetramethylurea tetrafluoroboric acid; Pd 2 (dba) 3 represents tris(dibenzylidene-BASE acetone) dipalladium; Pd(OAc) 2 represents palladium acetate; Xantphos represents 4,5-bis (diphenylphosphine)-9,9-dimethylxanthene; DMF stands for N,N-dimethylformamide; SEM-Cl stands for 2-(trimethylsilyl)ethoxymethyl chloride.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Test Example 1 In vitro kinase activity
  • EGFR EGFR
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • the working solution final concentration is 0.003ng/ ⁇ L
  • different compounds dissolved in DMSO were added to the wells with a nanoliter sampler, so that the final concentration of the compounds was 100nM-0.0244nM, 4-fold gradient, a total of 7 concentrations, while A blank control well (without enzyme) and a negative control well (with enzyme, with DMSO as a solvent) were set, and two duplicate wells were set.
  • EGFR L858R/T790M, Carna
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • 6 ⁇ L of 1.67 ⁇ 0.004175 ng was added to each well.
  • EGFR 50 ng/ ⁇ L of EGFR (d746-750/T790M, Carna) stock solution was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 ⁇ L of 1.67 ⁇ EGFR was added to each well.
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • EGFR L858R/T790M/C797S, BPS
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • EGFR dilute 50 ng/ ⁇ L of EGFR (d746-750/T790M/C797S, BPS) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20) and add 6 ⁇ L of 1.67 to each well 0.05ng/ ⁇ L working solution of ⁇ (final concentration is 0.03ng/ ⁇ L), different compounds dissolved in DMSO were added to the wells with a nanoliter dispenser, so that the final compound concentration was 10nM-0.0024nM, 4-fold gradient, A total of 7 concentrations were set, and blank control wells (without enzyme) and negative control wells (with enzyme and DMSO added) were set simultaneously, and 2 duplicate wells were set.
  • kinase buffer 50 mM HEPES, 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20
  • the 300 ⁇ L final incubation system contains 30 ⁇ L liver microsomes (protein concentration: 0.15 mg/mL), 30 ⁇ L NADPH+MgCl 2 , 3 ⁇ L test compound (prepared in acetonitrile), and 237 ⁇ L PBS buffer (pH 7.4). The proportion of organic solvent (acetonitrile) is 1%. Make 2 servings of each species, 0.3 mL each. Pre-incubate with NADPH for 5 min at 37°C, add 30 ⁇ L NADPH + MgCl 2 to mix, and take out 50 ⁇ L at 0, 15, 30, and 60 min. The reaction was stopped with 300 ⁇ L of ice acetonitrile containing internal standard.
  • the samples were incubated with 50 ⁇ L, 300 ⁇ L of ice acetonitrile containing the internal standard (diazepam 20 ng/mL) was added for precipitation, vortexed for 5 min, and centrifuged (12000 rpm, 4° C.) for 10 min. Aspirate 75 ⁇ L of the supernatant, add 75 ⁇ L of ultrapure water to dilute and mix, and inject 0.5 ⁇ L for analysis.
  • the internal standard diazepam 20 ng/mL
  • ICR mice weighing 18-20 g, were randomly divided into groups after 3-5 days of adaptation, 9 mice in each group, and the corresponding compounds were administered by gavage at a dose of 10 mg/kg.
  • test animals ICR mice were fasted for 12 hours before administration, given food for 4 hours after administration, and had free access to water before and after the experiment and during the experiment.

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Abstract

L'invention concerne un composé macrocyclique contenant un benzohétérocycle et agissant en tant qu'inhibiteur de la kinase EGFR. L'invention concerne plus particulièrement un composé représenté par la formule I ou un sel pharmaceutiquement acceptable, un stéréoisomère et un tautomère de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant le composé et son utilisation médicale.
PCT/CN2022/074255 2021-02-06 2022-01-27 Composé macrocyclique contenant un benzohétérocycle et agissant en tant qu'inhibiteur de la kinase egfr et composition pharmaceutique et utilisation de celui-ci WO2022166741A1 (fr)

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WO2024046221A1 (fr) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Inhibiteurs d'egfr et leurs utilisations
WO2024078263A1 (fr) * 2022-10-09 2024-04-18 药雅科技(上海)有限公司 Préparation et utilisation d'un composé hétérocyclique macrocyclique en tant qu'inhibiteur d'egfr

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WO2002076438A2 (fr) * 2001-03-23 2002-10-03 Chugai Seiyaku Kabushiki Kaisha Ligands flt-1 et utilisations de ceux-ci
WO2007129183A2 (fr) * 2006-05-02 2007-11-15 Pfizer Products Inc. Composés d'hétéroaryle bicyclique utilisés comme inhibiteurs de la pde10
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WO2020132582A1 (fr) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Agonistes de sting et leurs utilisations
CN111741954A (zh) * 2018-02-21 2020-10-02 勃林格殷格翰国际有限公司 用作egfr抑制剂的新型苯并咪唑化合物及衍生物
WO2020260252A1 (fr) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh Nouveaux composés macrocycliques et leurs dérivés utilisés en tant qu'inhibiteurs d'egfr

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WO2001051456A2 (fr) * 2000-01-13 2001-07-19 Tularik Inc. Agents antibacteriens
WO2002076438A2 (fr) * 2001-03-23 2002-10-03 Chugai Seiyaku Kabushiki Kaisha Ligands flt-1 et utilisations de ceux-ci
WO2007129183A2 (fr) * 2006-05-02 2007-11-15 Pfizer Products Inc. Composés d'hétéroaryle bicyclique utilisés comme inhibiteurs de la pde10
WO2010029300A1 (fr) * 2008-09-12 2010-03-18 Biolipox Ab Composés bis-aromatiques pour utilisation dans le traitement de l’inflammation
CN111741954A (zh) * 2018-02-21 2020-10-02 勃林格殷格翰国际有限公司 用作egfr抑制剂的新型苯并咪唑化合物及衍生物
WO2020132582A1 (fr) * 2018-12-21 2020-06-25 Nimbus Titan, Inc. Agonistes de sting et leurs utilisations
WO2020260252A1 (fr) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh Nouveaux composés macrocycliques et leurs dérivés utilisés en tant qu'inhibiteurs d'egfr

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046221A1 (fr) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Inhibiteurs d'egfr et leurs utilisations
WO2024078263A1 (fr) * 2022-10-09 2024-04-18 药雅科技(上海)有限公司 Préparation et utilisation d'un composé hétérocyclique macrocyclique en tant qu'inhibiteur d'egfr

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