WO2023241618A1 - Composés aminopyrimidines et leur utilisation - Google Patents

Composés aminopyrimidines et leur utilisation Download PDF

Info

Publication number
WO2023241618A1
WO2023241618A1 PCT/CN2023/100166 CN2023100166W WO2023241618A1 WO 2023241618 A1 WO2023241618 A1 WO 2023241618A1 CN 2023100166 W CN2023100166 W CN 2023100166W WO 2023241618 A1 WO2023241618 A1 WO 2023241618A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
add
μmol
ethyl acetate
reaction
Prior art date
Application number
PCT/CN2023/100166
Other languages
English (en)
Chinese (zh)
Inventor
陈正霞
戴美碧
张杨
陈曙辉
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2023241618A1 publication Critical patent/WO2023241618A1/fr

Links

Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to a series of aminopyrimidine compounds and their applications, specifically to the compounds represented by formula (XI), their stereoisomers and their pharmaceutically acceptable salts and their applications.
  • EGFR Epidermal Growth Factor Receptor, referred to as EGFR, ErbB-1 or HER1
  • EGFR is a member of the epidermal growth factor receptor (HER) family.
  • EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells.
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Mutated EGFR exists in many tumors, and many EGFR mutant types have been discovered.
  • EGFR mutations More than 80% of EGFR mutations are 19Del and L858R mutations, and the rest are rare mutations, mainly including G719X, E709X, and Del18 in exon 18, Ins19 in exon 19, and Ins20 in exon 20. , S768I, L861Q on exon 21.
  • Targeted therapy has shown excellent efficacy for patients with driver mutations in genes such as EGFR.
  • first-generation EGFR-TKIs such as gefitinib and erlotinib
  • first-generation EGFR-TKIs use competitive non-covalent binding to ATP to inhibit EGFR with deletion mutations in exon 19 and point mutations in exon 21.
  • first-generation EGFR-TKIs can also inhibit the EGFR function of normal cells, leading to side effects such as rash, diarrhea, and loss of appetite.
  • Second-generation EGFR-TKIs such as afatinib and dacomitinib, competitively and irreversibly bind to ATP through covalent bonding.
  • the inhibitory effect is stronger and the progression-free survival period mPFS is improved.
  • the disadvantage is that the side effects are stronger due to irreversible inhibition.
  • the T790M mutation occurs in the amino acid fragment bound to EGFR-TKIs, leading to drug resistance, accounting for about 50-70%.
  • the third-generation EGFR-TKIs AstraZeneca's AZD9291 (osimertinib) has become the first inhibitor to target the EGFRT790M mutation, targeting EGFR gene mutations in non-small cell lung cancer (including Exon18, 19, and 21 mutations). After 10 months of medication, the exon 20C797 mutation will occur, resulting in resistance to the third-generation drug AZD9291, and insufficient efficacy against the EGFR del19/L858R T790M C797S triple mutation. Therefore, the development of drugs that are selective for EGFR del19/L858R T790M C797S triple mutations while also targeting wild-type EGFR has huge clinical and market value.
  • the compound of the present invention has excellent inhibitory activity against the EGFR del19/L858R T790M C797S triple mutation, and at the same time has good selectivity for wild-type EGFT, and is expected to be used in patients with EGFR abnormal diseases.
  • the present invention provides the compound represented by formula (XI), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- dihydrobenzofuryl, phthalyl, 2,3-dihydropyridofuryl and isoindolinyl;
  • Ring B is selected from pyrazolyl, piperidinyl, tetrahydropyridinyl, dihydropyranyl, cyclohexyl, cyclohexenyl and 7-10 membered heterocycloalkyl;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optionally substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino groups are each independently optionally substituted by 1, 2 or 3 halogens;
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 8 is selected from H and halogen
  • T 3 is selected from C(R c ) 2 , NR c and O;
  • n 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • r is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and C 1-3 alkyl
  • ring A is selected from 2,3-dihydrobenzofuryl, phthalyl, 2,3 -Dihydropyridofuranyl and isoindolinyl;
  • Ring B is not selected from pyrazolyl.
  • the present invention also provides the compound represented by formula (XI), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- dihydrobenzofuryl, phthalyl, 2,3-dihydropyridofuryl and isoindolinyl;
  • Ring B is selected from pyrazolyl, piperidinyl, tetrahydropyridinyl, dihydropyranyl, cyclohexyl, cyclohexenyl and 7-10 membered heterocycloalkyl;
  • the C 1-3 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogens;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optionally substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino groups are each independently optionally substituted by 1, 2 or 3 halogens;
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 8 is selected from H and halogen
  • T 3 is selected from CR c , NR c and O;
  • n 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • r is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and C 1-3 alkyl
  • the present invention also provides the compound represented by formula (XI), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- dihydrobenzofuryl, phthalyl, 2,3-dihydropyridofuryl and isoindolinyl;
  • Ring B is selected from pyrazolyl, piperidinyl, tetrahydropyridinyl, dihydropyranyl, cyclohexyl, cyclohexenyl and 7-10 membered heterocycloalkyl;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optionally substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino groups are each independently optionally substituted by 1, 2 or 3 halogens;
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 8 is selected from H and halogen
  • T 3 is selected from CR c , NR c and O;
  • n 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • r is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and C 1-3 alkyl
  • ring A is selected from 2,3-dihydrobenzofuryl, phthalyl, 2,3 -Dihydropyridofuranyl and isoindolinyl;
  • Ring B is not selected from pyrazolyl.
  • the present invention also provides the compound represented by formula (V), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- dihydrobenzofuryl, phthalyl, 2,3-dihydropyridofuryl and isoindolinyl;
  • Ring B is selected from pyrazolyl, piperidinyl, tetrahydropyridinyl, dihydropyranyl, cyclohexyl, cyclohexenyl and 7-10 membered heterocycloalkyl;
  • the C 1-3 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogens;
  • T 3 is selected from NR c and O;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optionally substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, CH 3 , OCH 3 , CH 2 CH 3 and N(CH 3 ) 2 ;
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • n 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • r is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and C 1-3 alkyl
  • R b is selected from H
  • T 1 is selected from N
  • T 2 is selected from N
  • T 4 is selected from C
  • the structural unit Selected from Where T 7 and T 8 are independently selected from N and CR
  • R is selected from H, halogen and CH 3 ,
  • Ring B is selected from pyrazolyltetrahydropyridyl, dihydropyranyl, cyclohexyl and cyclohexenyl, or;
  • R 2 is selected from H and R 6 is selected from H, R 7 is not H and not CH 3 , or;
  • R 6 is not H and is not CH 3 .
  • the present invention provides the compound represented by formula (V), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- dihydrobenzofuryl, phthalyl, 2,3-dihydropyridofuryl, and isoindoline;
  • Ring B is selected from pyrazolyl and piperidinyl
  • the C 1-3 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogens;
  • T 3 is selected from NR c and O;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optionally substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, CH 3 , OCH 3 and
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • n is selected from 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • r is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and C 1-3 alkyl
  • T 1 is selected from N
  • T 2 is selected from N
  • T 4 is selected from C
  • the structural unit Selected from Where T 7 and T 8 are independently selected from N and CR
  • R is selected from H, halogen and CH 3 ,
  • Ring B is selected from pyrazolyl, or
  • R 2 is selected from H and R 6 is selected from H, R 7 is not H and not CH 3 , or;
  • R 6 is not H and is not CH 3 .
  • the present invention also provides the compound represented by formula (V), its stereoisomer or its pharmaceutically acceptable salt,
  • T 1 and T 2 are independently selected from CH and N;
  • T 4 is selected from C and N;
  • T 5 is selected from CH and N;
  • Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidinonyl, tetrahydropyridinyl, tetrahydropyrazinyl, dihydropyrazinonyl, 2,3- Dihydrobenzofuryl, phthalyl and 2,3-dihydropyridofuranyl;
  • Ring B is selected from pyrazolyl and piperidinyl
  • the C 1-3 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogens;
  • T 3 is selected from NR c and O;
  • R 2 is selected from H, halogen and OH, or is absent;
  • T 4 is selected from C, R 1 and R 2 form a double bond such that the structural unit form
  • R 1 and R 2 form a ring with the connected atom to form a tetrahydropyranyl group
  • R 3 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are independently optional Substituted by 1, 2 or 3 halogens;
  • R 4 is selected from F, OH, CH 3 , OCH 3 and
  • R 6 and R 7 are each independently selected from H, halogen and C(R a ) 3 ;
  • R 6 and R 7 form a double bond, making the structural unit form
  • R 6 and R 7 form a ring with the connected atom to form a tetrahydropyranyl group
  • n is selected from 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • s is selected from 1 and 2;
  • t is selected from 1 and 2;
  • Each R a is independently selected from H and halogen
  • Each R b is independently selected from H and halogen
  • R c is selected from H and CH 3 ;
  • Ring B is selected from pyrazolyl, or
  • R 2 , R 6 , R 7 and R a are not selected from H at the same time, or
  • T 2 is selected from CH.
  • T 3 is selected from CH 2 , NH, NCH 3 , NCH 2 CH 3 , NCH(CH 3 ) 2 and O, and other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • R 2 is selected from H, F and OH, or does not exist, and other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • R 6 and R 7 are independently selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 6 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 7 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 8 is selected from H and F, and other variables are as defined in the present invention.
  • R 3 is selected from F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and cyclopropyl, and other variables are as defined in the present invention.
  • R 3 is selected from F, CH 3 , CH(CH 3 ) 2 , OCH 3 and cyclopropyl, and other variables are as defined in the present invention.
  • the above-mentioned Ring A is selected from 2,3-dihydrobenzofuranyl, phenyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from phenyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from piperidyl, tetrahydropyridyl, dihydropyranyl, cyclohexenyl and 7-10 membered heterocycloalkyl, and other variables are as defined in the invention.
  • R 4 is selected from F, OH, CH 3 , OCH 3 , CH 2 CH 3 , N(CH 3 ) 2 and Other variables are as defined in the present invention.
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from,
  • R 1 is selected from
  • Ring A, Ring B, R2 , R3 , R4, R6 , R7 , R8 , T1 , T2 , T3 , T4 , T5 , m, n and r are as defined herein.
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from,
  • R 1 is selected from Rings A, R2 , R3 , R4 , R6 , R7 , T3 , m, n and r are as defined herein.
  • the present invention provides the following compounds, their stereoisomers or their pharmaceutically acceptable salts,
  • the compound, its stereoisomer or its pharmaceutically acceptable salt, the compound thereof is selected from,
  • the compound, its stereoisomer or its pharmaceutically acceptable salt, the compound thereof is selected from,
  • the present invention also provides a pharmaceutical composition, including a therapeutically effective amount of a compound as defined in the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier and diluent. or excipients.
  • the present invention also provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned composition in the preparation of drugs for treating solid tumors.
  • the solid tumor refers to solid tumors such as non-small cell lung cancer.
  • the present invention also provides the following synthesis methods of the above compounds:
  • the present invention also provides the following test methods for the above compounds:
  • Test method 1 Kinase inhibitory activity of compounds against EGFR (T790M/C797S/L858R)
  • reaction buffer (20mM hydroxyethyl piperazine ethyl sulfonic acid (Hepes) (pH 7.5), 10mM magnesium chloride (MgCl 2 ), 1mM ethylene glycol bisaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene ten Dialkyl ether (Brij35), 0.02mg/mL BSA, 0.1mM sodium vanadate (Na 3 VO 4 ), 2mM dithiothreitol (DTT), 1% DMSO) and then add a certain concentration of substrate and coenzyme factor , kinase and test compound (10 doses, 3-fold serial dilution, 2% DMSO final concentration) and mix well, incubate the mixture at room temperature for 20 minutes, add a certain concentration of 33 P-ATP to the reaction mixture to start the reaction , followed by incubation at room temperature for 120 minutes.
  • Hepes hydroxyethyl piperazine
  • the radioactivity of the reactants is detected by filtration-binding method.
  • the final kinase activity is expressed as the ratio of the remaining kinase activity in the test sample to the kinase activity in the DMSO control group.
  • the dose-response relationship curve was fitted and IC 50 was calculated using GraphPad software.
  • Test method 2 Inhibitory activity of compounds on Ba/F3-FL-EGFR (T790M/C797S/L858R) cell proliferation
  • Adenosine Tri-Phosphate is a common energy carrier in various life activities in nature and is the smallest unit of energy storage and transfer.
  • CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase requires the participation of ATP during the luminescence process.
  • the cell line was Ba/F3-FL-EGFR (T790M/C797S/L858R) stably transfected cell line.
  • the cell lines were cultured in an incubator with culture conditions of 37°C and 5% CO2 . Passage regularly and use cells in the logarithmic growth phase for plating.
  • Inhibition Rate(Inh%) 100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key and straight dotted keys like generation surface like represent mixture.
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton migration tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-3 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 7-10-membered heterocycloalkyl group includes 7-10-membered, 7-9-membered, 7-8-membered, 8-10-membered, 8-9-membered, 8-membered, 9-membered and 10-membered heterocycloalkyl groups, etc. Examples of 7-10 membered heterocycloalkyl groups include, but are not limited to wait.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent replacement method, preferred Implementations include, but are not limited to, embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation, and the scanning mode is: ⁇ / ⁇ scanning. After collecting relevant data, the direct method is further used. (Shelxs97)
  • the absolute configuration can be confirmed by analyzing the crystal structure.
  • TMSOTf represents trimethylsilyl triflate
  • NaBH 4 represents sodium borohydride
  • Cs 2 CO 3 represents cesium carbonate
  • NBS represents bromosuccinimide
  • PE represents petroleum ether
  • EtOAc represents ethyl acetate
  • DCM dichloromethane
  • MeOH represents methanol
  • EtOH represents ethanol
  • TFA trifluoroacetic acid
  • Pd(dppf)Cl 2 represents 1,1-bis(diphenylphosphorus)ferrocene chloride Palladium
  • K 2 CO 3 represents potassium carbonate
  • PtO 2 represents platinum dioxide
  • NaH represents sodium hydrogen
  • THF represents tetrahydrofuran
  • Boc represents tert-butyl
  • DMF represents N,N-dimethylformamide
  • KOH represents potassium hydroxide
  • Xantphos-Pd-G4 represents palladium methanesulfonate [4,5-bisdiphenylphosphin
  • the compound of the present invention exhibits high kinase inhibitory activity against del19/L858R T790M C797S mutated EGFR, and is highly selective compared with the wild type. It has good proliferation inhibitory activity against EGFR triple mutant cells and has good proliferation inhibitory activity against EGFR wild type cells. Significantly weakened, with better selectivity.
  • the compound of the invention has good in vivo metabolic stability, excellent oral absorption drug exposure and good oral absorption bioavailability, and has good stability in human and mouse liver microsomes.
  • Figure 10 Binding mode diagram of compound J and EGFR mutant protein.
  • the molecular docking process was performed using Maestro ( Performed with Glide SP[1] in version 2020-1) and default options.
  • the co-crystal structure of mutant EGFR (PDB ID: 5HCY) was selected as the docking template.
  • hydrogen atoms were added using the Protein Preparation Wizard module of Maestro [2] and the OPLS3e force field was used.
  • the LigPrep module was used to generate the three-dimensional structure of the molecule and energy minimization was performed [3], and the ConfGen module was used to search for small molecule conformations [4].
  • Receptor Grid Generation module in Glide to generate the grid file required for docking, with the ligand in the crystal structure as the center of the docking box. Analyze the interaction type between the protein receptor and the ligand, and then select molecules with high potential for synthesis testing based on the calculated docking score and binding mode selection.
  • the compound of the present invention binds well to EGFR mutant protein.
  • reaction solution was concentrated under reduced pressure, and subjected to preparative HPLC chromatography (chromatographic column: Phenomenex luna C18 250 ⁇ 80mm ⁇ 10 ⁇ m; mobile phase: [H 2 O (NH 3 H 2 O+NH 4 HCO 3 )-acetonitrile]; acetonitrile %: 0%-20%, 20min) to separate the product for 1 hour, and then separate it through chiral preparation (chromatographic column: DAICEL CHIRALCEL OJ (250mm ⁇ 50mm, 10 ⁇ m); mobile phase: supercritical CO 2 - [ethanol solution containing 0.1% ammonia] ; Containing 0.1% ammonia in ethanol solution%: 40%-40%) to obtain compounds 1h-1, 1h-2, 1h-3 and 1h-4.
  • Potassium monopersulfate (8.91g, 14.49mmol) was added to a solution of compound 1a (2.1g, 9.66mmol) in THF (20mL)/EtOH (20mL)/H 2 O (20mL), and the mixture was stirred at 25°C for 2 hours.
  • Methyl Grignard reagent (3.32g, 27.88mmol) was added dropwise to N-Boc-azetidine-3-carboxylic acid methyl ester (2.0g, 9.29mmol) in THF (25mL) at 0°C, and the temperature was raised to room temperature. , reaction 16hr. Add saturated ammonium chloride solution dropwise to quench the reaction, extract with 3 ⁇ 15 mL ethyl acetate, combine the organic layers, and concentrate under reduced pressure to obtain intermediate 2a.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 3.72 (br s, 4H) 2.38-2.47 (m, 1H) 1.36 (s, 9H) 0.99 (s, 6H).
  • NBS (257.23 mg, 1.45 mmol) was added to the acetonitrile (5 mL) solution containing intermediate 2c (0.4 g, 1.45 mmol), and the reaction was carried out at 25°C for 2 hours.
  • Add 2 mL of water to the reaction solution to quench the reaction, evaporate the organic solvent under reduced pressure, extract with 2 ⁇ 10 mL of ethyl acetate, dry and concentrate the organic phase and perform silica gel column chromatography (DCM:MeOH 100:1) to obtain compound 2d.
  • MS m/z:356.8[M+3] + MS m/z:356.8[M+3] + .
  • Triethylamine (19.05g, 188.24mmol, 26.20mL) was added to a solution of compound 5a (30g, 125.36mmol) in DCM (300mL), cooled to -20°C, and then methanesulfonyl chloride (17.76g, 155.04mmol) , 12.00 mL) was added dropwise to the reaction solution, raised to 0°C and stirred for 1 hour.
  • the reaction solution was slowly poured into ice water (300 mL), the organic phase was collected in layers, and then washed with 10% sodium bicarbonate solution. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 5b.
  • Diethyl malonate (28.86g, 180.21mmol, 27.23mL) was added dropwise to a solution of sodium hydrogen (6.54g, 163.50mmol, 60%) in N,N-dimethylformamide (180mL) at 0°C. Stir below 25°C for 1 hour, then add compound 5b (26g, 81.92mmol) in N,N-dimethylformamide (40mL), and stir at 70°C for 16 hours. Add the reaction liquid to ice water (400mL), add ethyl acetate for extraction (200mL ⁇ 3), combine the organic phases, wash with water (300mL ⁇ 3), and extract with saturated sodium chloride aqueous solution (300mL).
  • Trifluoroacetic acid (775.75 mg, 6.80 mmol, 503.73 ⁇ L) was added to a solution of compound 5h (0.1 g, 382.65 ⁇ mol) in DCM (2 mL) at 0°C, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 5i.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 7.81-9.30 (m, 1H), 4.31 (br s, 4H), 3.62-4.08 (m, 4H), 2.92-3.55 (m, 2H).
  • the crude compound 7 was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: A (acetonitrile) and B (water, containing 0.05% ammonia water and 0.01mol ammonium bicarbonate); gradient: B% :5%-45%) to obtain compound 7.
  • methanol methanol
  • n-heptane n-heptane
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (40 mL ⁇ 3), washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • Dissolve compound 14d (350 mg, 1.40 mmol) in dichloromethane (5 mL), add N,N-diisopropylethylamine (541.33 mg, 4.19 mmol, 729.56 ⁇ L), cool to 0°C, and add trifluoromethanesulfonate acid anhydride (787.85 mg, 2.79 mmol, 460.73 ⁇ L), and then reacted at 20°C for 0.5 hr. Add 5 mL of saturated ammonium chloride, extract with ethyl acetate (3 mL ⁇ 3), separate the liquids and combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product.
  • reaction solution was slowly poured into 120 mL of saturated ammonium chloride solution, and then extracted with ethyl acetate (50 mL Concentrate under reduced pressure to obtain crude product.

Abstract

L'invention concerne une série de composés aminopyrimidines et leur utilisation, et spécifiquement un composé représenté par la formule (XI), un stéréoisomère de celui-ci et un sel pharmaceutiquement acceptable de celui-ci, et son utilisation.
PCT/CN2023/100166 2022-06-14 2023-06-14 Composés aminopyrimidines et leur utilisation WO2023241618A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
CN202210673201 2022-06-14
CN202210673201.2 2022-06-14
CN202211242420 2022-10-11
CN202211242420.1 2022-10-11
CN202211414875.7 2022-11-11
CN202211414875 2022-11-11
CN202211478036.1 2022-11-23
CN202211478036 2022-11-23
CN202310042008.3 2023-01-12
CN202310042008 2023-01-12
CN202310277897.1 2023-03-21
CN202310277897 2023-03-21

Publications (1)

Publication Number Publication Date
WO2023241618A1 true WO2023241618A1 (fr) 2023-12-21

Family

ID=89192323

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/100166 WO2023241618A1 (fr) 2022-06-14 2023-06-14 Composés aminopyrimidines et leur utilisation

Country Status (1)

Country Link
WO (1) WO2023241618A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210354A1 (fr) * 2013-06-28 2014-12-31 Genentech, Inc. Composés d'azaindazole en tant qu'inhibiteurs de la t790m contenant des mutants de l'egfr
CN104955824A (zh) * 2012-11-20 2015-09-30 基因泰克公司 作为含t790m的egfr突变体的抑制剂的氨基嘧啶化合物
WO2021133809A1 (fr) * 2019-12-23 2021-07-01 Blueprint Medicines Corporation Inhibiteurs de formes mutantes de l'egfr
WO2022271612A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2023025320A1 (fr) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 Inhibiteur de dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023071998A1 (fr) * 2021-10-26 2023-05-04 杭州德睿智药科技有限公司 Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
CN116262741A (zh) * 2021-12-14 2023-06-16 杭州紫晶医药科技有限公司 作为突变型egfr抑制剂的化合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104955824A (zh) * 2012-11-20 2015-09-30 基因泰克公司 作为含t790m的egfr突变体的抑制剂的氨基嘧啶化合物
WO2014210354A1 (fr) * 2013-06-28 2014-12-31 Genentech, Inc. Composés d'azaindazole en tant qu'inhibiteurs de la t790m contenant des mutants de l'egfr
WO2021133809A1 (fr) * 2019-12-23 2021-07-01 Blueprint Medicines Corporation Inhibiteurs de formes mutantes de l'egfr
WO2022271612A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2023025320A1 (fr) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 Inhibiteur de dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023071998A1 (fr) * 2021-10-26 2023-05-04 杭州德睿智药科技有限公司 Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
CN116262741A (zh) * 2021-12-14 2023-06-16 杭州紫晶医药科技有限公司 作为突变型egfr抑制剂的化合物

Similar Documents

Publication Publication Date Title
WO2021180181A1 (fr) Composés pyrimidohétérocycliques et leur application
CN111247151B (zh) 2,3-二氢-1h-吡咯嗪-7-甲酰胺类衍生物及其应用
CN108137607A (zh) 适用于治疗与ntrk相关的病症的化合物和组合物
CN115702156A (zh) 吡啶酰胺类化合物
CN112533916B (zh) 一种作用于crbn蛋白的三并环类化合物
JP2023517393A (ja) タンパク質分解調整剤およびその使用方法
WO2020200316A1 (fr) Composé de pyrazolopyridine utilisé comme inhibiteur de ret et son application
WO2020048546A1 (fr) Composé de pipéridine dione substitué tricyclique
WO2022218442A1 (fr) Composé de peptide court de proline à cycle modifié et son utilisation
WO2021047674A1 (fr) Composé bicyclique qui agit comme régulateur de la protéine crbn
WO2020239076A1 (fr) DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION
KR20220059517A (ko) 소분자 pd-1/pd-l1 억제제로서의 화합물 및 이의 용도
WO2022134642A1 (fr) Composé hétérocyclique aromatique, et composition pharmaceutique et application de celui-ci
WO2023036175A1 (fr) Composé de glutarimide et son utilisation
WO2023208127A1 (fr) Composé bicyclique substitué par hétéroaryle et son utilisation
CN112469718A (zh) 氮杂吲哚衍生物及其作为FGFR和C-Met抑制剂的应用
WO2023217045A1 (fr) Dérivé de fluoroquinoxalinone pour l'inhibition selective de parp1
CN113874379B (zh) 作为Cdc7抑制剂的四并环类化合物
CN115667258A (zh) 氟代吡咯并吡啶类化合物及其应用
CN114761407A (zh) 作为高选择性ros1抑制剂的化合物及其应用
WO2020063965A1 (fr) Dérivé de pyrazolopyrimidine en tant qu'inhibiteur de trk sélectif
CN111315750B (zh) 作为mTORC1/2双激酶抑制剂的吡啶并嘧啶类化合物
WO2023241618A1 (fr) Composés aminopyrimidines et leur utilisation
WO2023001069A1 (fr) Composés amides macrocycliques et leur application
WO2022166721A1 (fr) Dérivés cycliques fusionnés contenant du 1,4-oxazépane

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23823184

Country of ref document: EP

Kind code of ref document: A1