WO2022105908A1 - Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2022105908A1
WO2022105908A1 PCT/CN2021/132029 CN2021132029W WO2022105908A1 WO 2022105908 A1 WO2022105908 A1 WO 2022105908A1 CN 2021132029 W CN2021132029 W CN 2021132029W WO 2022105908 A1 WO2022105908 A1 WO 2022105908A1
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alkyl
deuterium
substituted
membered
halogen
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PCT/CN2021/132029
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English (en)
Chinese (zh)
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邓海兵
杨飞
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN202180049014.0A priority Critical patent/CN115803326B/zh
Publication of WO2022105908A1 publication Critical patent/WO2022105908A1/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
    • A61K31/495—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
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to an EGFR inhibitor, a preparation method thereof and its pharmaceutical application.
  • Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
  • Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multitargeted therapy has been developed and clinically validated.
  • EGFR inhibition can significantly improve progression-free survival in adenocarcinoma NSCLC, whose acquired resistance mutations are subsequently targeted by third-generation inhibitors.
  • exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein.
  • NSCLC the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR.
  • EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC).
  • SNSCC nasal squamous cell carcinoma
  • a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
  • the purpose of the present invention is to provide an EGFR inhibitor and its preparation method and its pharmaceutical application.
  • the series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation, and have high selectivity for EGFR wild type, and can be widely used in the preparation of treatment and/or prevention at least partially related to EGFR Drugs for cancers, tumors or metastatic diseases associated with exon 20 insertions, deletions or other mutations, especially for hyperproliferative diseases and cell death-inducing disorders, are expected to lead to the development of a new generation of EGFR inhibitors.
  • a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 and X 2 are each independently CR 7 or N; Y is CR 8 or N; Z is NR 9 or O;
  • Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl;
  • R 5 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered Heterocyclyl, -C(O)OR 11 , -C(O)R 12 , -C(O)-NR 13 R 14 and -C 0-4alkyl -NR 13 R 14 ;
  • R 9 is selected from hydrogen, deuterium, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, or 4;
  • Each r is independently 0, 1, or 2.
  • R 1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1 -4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 Membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 10 , -C 0 -4 alkyl-OR 11 , -C 0-4 alkyl-C(O)OR 11 , -C 0-4 alkyl-C(O)R 12 , -C 0-4 alkyl-OC(O) R 12 , -C 0-4 alkyl-NR 13 R 14 ,
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl;
  • R 5 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0-4 alkyl-NR 13 R 14 ;
  • R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • the compound of formula (I) is the compound of formula (IIa) below:
  • Z is NR 9 or O
  • Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
  • R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl
  • R 5 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -C 0-4 alkyl-NR 13 R 14 ;
  • R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • Z is NH or O
  • R 1a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl ;
  • R 1b is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl ;
  • R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
  • R is selected from hydrogen, deuterium and fluorine
  • R 5 is selected from hydrogen, deuterium and methyl.
  • ring A is selected from the following groups:
  • R 8 is selected from said Each independently is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, methyl, methoxy, cyano and nitro.
  • R 8 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, Difluoromethyl, trifluoromethyl, ethynyl, methoxy, ethoxy, monofluoromethoxy, methoxyethoxy, trifluoroethoxy, cyclopropyl, morpholinyl, 3- Chloro-propylamino, trifluoroethylamino, 2-methoxyethylamino, said are each independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, methyl, methoxy, cyano and nitro, provided that when Ring A is , R 8 is not methoxy, ethoxy, monofluoromethoxy or trifluoroethoxy.
  • the compound of formula (I) is the compound of the following formula (IIb):
  • Z is NR 9 or O
  • Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
  • R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl
  • R 5 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -C 0-4 alkyl-NR 13 R 14 ;
  • R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • Z is O
  • R 1a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl ;
  • R 1b is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl ;
  • R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
  • R is selected from hydrogen, deuterium and fluorine
  • R 5 is selected from hydrogen, deuterium and methyl.
  • ring A is selected from the following groups:
  • the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
  • the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • X is halogen, preferably selected from fluorine, chlorine and bromine; rings A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , Y, Z, m and n are such as as defined in compounds of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of the treatment and/or prevention of cancers, tumors at least partially associated with EGFR exon 20 insertions, deletions or other mutations or the use of drugs in metastatic disease.
  • the present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in.
  • the present invention also relates to the preparation of the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of lung cancer and colon cancer at least partially associated with EGFR exon 20 insertion, deletion or other mutation , Pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors , breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma or nasal and paranasal inversion papilloma-related nasal squamous cell carcinoma use in the drug.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations , tumor or metastatic disease.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of tumors, cancers and/or metastases caused by hyperproliferative and cell death-inducing disorders use of sexually transmitted diseases.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of lung cancer at least partially associated with EGFR exon 20 insertion, deletion or other mutation , colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors , endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma.
  • the present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method for the treatment and/or prevention of lung, colon, pancreatic, head and neck, breast, ovarian, uterine, gastric, non- Small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, intranasal and paranasal tumors
  • a method for inverted papilloma or naso-inverted papilloma-associated squamous cell carcinoma of the paranasal sinuses comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof or Its pharmaceutically acceptable salts.
  • an EGFR inhibitor with the structure of the following formula (I). 20 Drugs for cancers, tumors or metastatic diseases associated with insertions, deletions or other mutations, especially for hyperproliferative and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl,
  • C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group
  • C 0-8 alkyl refers to a straight-chain alkyl group containing 0 to 8 carbon atoms and a branched alkyl group
  • C 0-4 alkyl refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, “C 4-8 cycloalkyl” refers to cycloalkyl groups including 4 to 8 carbon atoms atomic cycloalkyl, “C 3-8 cycloalkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atoms, "C 3-6
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2) heteroatoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • a heterocyclyl group including 3 to 12 or 3 to 8 or 3 to 6 ring atoms is preferred, for example, "3-6 membered heterocyclyl” refers to a heterocyclyl group containing 3 to 6 ring atoms, “3- “8-membered heterocyclyl” refers to a heterocyclyl containing 3 to 8 ring atoms, “4-8 membered heterocyclyl” refers to a heterocyclyl containing 4 to 8 ring atoms, “4-10 membered heterocyclyl” refers to a heterocyclyl group containing 4 to 10 ring atoms, “5-8 membered heterocyclyl” refers to a heterocyclyl group containing 5 to 8 ring atoms, “3-12 membered heterocyclyl” refers to a heterocyclyl group containing 3 to 12 ring atoms Heterocyclyl of ring atoms.
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • Spiroheterocyclyl groups include, but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, “C 6-10 aryl” refers to all-carbon aryl groups containing 6-10 carbons, Including but not limited to phenyl and naphthyl, "C 6-8 aryl” refers to an all-carbon aryl group containing 6-8 carbons.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl” means containing 5-8 ring atoms Heteroaromatic systems of ring atoms, "5-10 membered heteroaryl” refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight or branched chain alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight or branched chain containing 2-4 carbons alkynyl.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, "C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons, “C 1-2 alkoxy” refers to an alkyloxy group containing 1-2 carbons, including but not limited to methoxy, ethoxy , propoxy, butoxy, etc.
  • Cycloalkoxy or “cycloalkyloxy” refers to -O-cycloalkyl, wherein cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a group containing 3-12 Carbon cycloalkyloxy, “C 3-6 cycloalkoxy” refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , cyclohexyloxy, etc.
  • Heterocyclyloxy or “heterocyclyloxy” refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy group, azacyclopentyloxy, nitrogen, oxanyloxy and the like.
  • C 1-10 alkanoyl refers to the monovalent atomic group remaining after C 1-10 alkyl acid removes the hydroxyl group, usually also expressed as “C 0-9 alkyl-C(O)-", for example, “C 1 "Alkyl-C(O)-” means acetyl; “ C2alkyl -C(O)-” means propionyl; “ C3alkyl -C(O)-” means butyryl or isobutyl Acyl.
  • -C 0-8 alkyl-C(O)R 12 means that the carbonyl group in -C(O)R 12 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
  • Halo-substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium-substituted C1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
  • Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
  • the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
  • geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
  • “Pharmaceutically acceptable salts” as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS internal standard For tetramethylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step synthesis of tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylate
  • the second step synthesis of tert-butyl-3-(3-fluoro-4-nitrophenoxy)-1H-pyrazole-1-carboxylate
  • tert-Butyl-3-hydroxy-1H-pyrazole-1-carboxylate (8.30 g, 45.1 mmol) and 2,4-difluoro-1-nitrobenzene (7.53 g, 47.4 mmol) were dissolved in N, In N-dimethylformamide (100 mL), potassium carbonate (12.45 g, 90.2 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 24 hours, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After filtering, the filtrate was concentrated and separated by column chromatography to obtain the crude product.
  • the third step synthesis of tert-butyl-3-(4-amino-3-fluorophenoxy)-1H-pyrazole-1-carboxylate
  • tert-Butyl-3-(3-fluoro-4-nitrophenoxy)-1H-pyrazole-1-carboxylate (3.00 g, 9.28 mmol) was dissolved in methanol/dichloromethane (50 mL/50 mL) ), palladium on carbon (10%, 300 mg) was added, and the reaction solution was stirred at room temperature for 5 hours under a hydrogen atmosphere. Suction filtration, the filtrate was concentrated, and the residue was separated by column chromatography to obtain tert-butyl-3-(4-amino-3-fluorophenoxy)-1H-pyrazole-1-carboxylate (2.20 g, yield : 81%). MS m/z (ESI): 294 [M+H] + .
  • the fourth step synthesis of tert-butyl-3-(4-(((benzyloxy)carbonyl)amino)-3-fluorophenoxy)-1H-pyrazole-1-carboxylate
  • the fifth step the synthesis of (4-(((1H-pyrazol-3-yl)oxy)-2-fluorophenyl)carbamic acid benzyl ester
  • the seventh step the synthesis of 2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline
  • Intermediate 2 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of Intermediate 1:
  • the first step synthesis of tert-butyl-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-1-carboxylate
  • the second step the synthesis of 6-(azetidine-3-oxy)-4-chloro-7-methoxyquinazoline hydrochloride
  • the third step synthesis of 1-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Intermediates 4-6 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 3:
  • the first step Synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-fluoro-2-nitrobenzoic acid
  • the second step Synthesis of tert-butyl 4-(2-fluoro-5-(carbomethoxy(methoxycarbonyl))-4-nitrophenoxy)piperidine-1-carboxylate
  • N,N-dimethyl to 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-fluoro-2-nitrobenzoic acid 50 g crude, 98.5 mmol
  • To the formamide (200 mL) solution was added iodomethane (12.3 mL, 197.7 mmol) and potassium carbonate (27.33 g, 197.7 mmol), and the mixture was stirred at room temperature for 2 hours.
  • the third step synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxy-2-nitrobenzoic acid
  • tert-butyl 4-(2-fluoro-5-(carbomethoxy(methoxycarbonyl))-4-nitrophenoxy)piperidine-1-carboxylate (10.0 g, 25.1 mmol) and cyclopropanol (2.92 g, 50.2 mmol) in N,N-dimethylformamide (100 mL) solution was added in portions sodium hydride (60% in oil, 2.01 g, 50.2 mmol), the reaction was The mixture was gradually warmed to room temperature and stirred at room temperature for 3 hours.
  • the fourth step the synthesis of 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxybenzoic acid
  • the fifth step the synthesis of tert-butyl 4-((7-cyclopropoxy-4-hydroxyquinazolin-6-yl)oxy) piperidine-1-carboxylate
  • the sixth step the synthesis of tert-butyl 4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy) piperidine-1-carboxylate
  • the seventh step the synthesis of 4-chloro-7-cyclopropoxy-6-(piperidine-4-oxy) quinazoline hydrochloride
  • the eighth step synthesis of 1-(4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Intermediates 8-37 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 7:
  • the first step Synthesis of 4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitrobenzoic acid
  • the tert-butyl 4-hydroxypiperidine-1-carboxylate (6.63g, 33mmol) was placed in dry N,N-dimethylformamide (100mL), and sodium hydrogen (1.32g, 33 mmol) and stirred for 30 minutes, then 4-bromo-5-fluoro-2-nitrobenzoic acid (4.35 g, 16.48 mmol) was added, and the reaction solution was stirred at room temperature overnight.
  • the reaction solution was quenched with water, extracted with dichloromethane, then the aqueous phase was adjusted to about pH 2 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was directly concentrated to obtain 4-bromo-5-((1-(tert.
  • the second step the synthesis of 2-amino-4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid
  • the third step synthesis of tert-butyl 4-((7-bromo-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate
  • reaction solution was spin-dried to dry the solvent, water was added to separate out the solid, filtered, and the filter cake was dried to obtain tert-butyl 4-((7-bromo-4-oxo-3,4-dihydroquinazolin-6-yl)oxygen yl)piperidine-1-carboxylate (4.2 g, 79% yield).
  • the fourth step the synthesis of tert-butyl 4-((7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy) piperidine-1-carboxylate
  • the fifth step the synthesis of tert-butyl 4-((4-chloro-7-methylquinazolin-6-yl)oxy) piperidine-1-carboxylate
  • the first step the synthesis of methyl 5-fluoro-2-nitro-4-(trifluoromethyl) benzoate
  • the third step Synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitro-4-(trifluoromethyl)benzoic acid
  • the fourth step the synthesis of 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-(trifluoromethyl)benzoic acid
  • the sixth step synthesis of tert-butyl 4-((4-chloro-7-(trifluoromethyl)quinazolin-6-yl)oxy)piperidine-1-carboxylate
  • the second step the synthesis of 4-hydroxyquinazolin-6-yl acetate
  • the third step the synthesis of 4-chloroquinazolin-6-yl acetate
  • the fourth step the synthesis of 4-chloroquinazolin-6-ol
  • the fifth step the synthesis of tert-butyl-4-((4-chloroquinazolin-6-yl)oxy) piperidine-1-carboxylate
  • Example 1 1-(4-((4-((2-Fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)benzene Preparation of yl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Step 2 N-(2-Fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenyl)-6-(piperidine Synthesis of -4-Oxy)quinazolin-4-amine
  • the third step 1-(4-((4-((2-Fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)benzene Synthesis of yl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Embodiments 2-10, 30-34 can be prepared by selecting the corresponding raw materials with reference to all or part of the synthetic methods of Example 1:
  • Example 11 1-(3-((4-((2-Fluoro-4-((1-(5-Fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl) Preparation of oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
  • Embodiments 12-24, 26-29 and 35-54 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 11:
  • Luminescence cell viability detection kit Promega, Cat#G7572
  • cell line cell culture medium Cell density 1 A431 DMEM+15%FBS 5000 2 Ba/F3 EGFR-D770-N771ins_SVD RPMI1640+10%FBS 3000 3 Ba/F3 EGFR-V769_D770insASV RPMI1640+10%FBS 3000
  • the cells were placed in a 96-well plate filled with drugs at a temperature of 37°C, 5% CO 2 and 95% humidity, and cultured for 72 hours, followed by CTG analysis.
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion mutation at the cellular level, and have strong selectivity for EGFR WT.
  • the selectivity of some compounds in Ba/F3EGFR-V769_D770insASV cells relative to EGFR WT (wild-type) cells in inhibiting proliferation activity was increased by more than 50%, such as Examples 1, 11, 12, 13 and 48 , especially the selectivity of Examples 1 and 12 is as high as more than 60 times; the most surprising is that the compound of Example 12 has the activity of inhibiting proliferation relative to EGFR WT (wild-type) cells in Ba/F3EGFR-V769_D770insASV cells.
  • the compounds used in this test are derived from the compounds of specific examples of the present invention.
  • ICR mice male N 3Original source: Shanghai Sipple-Bike Laboratory Animal Co., Ltd.
  • mice were weighed and dissolved in a solvent of 0.5% SDS + 0.5% CMCNa, shaken, and sonicated to prepare a colorless and clear solution. 3 mice were orally administered after an overnight fast. The dose administered was 10 mg/kg. The modes of administration were single oral (PO) in ICR mice.
  • test compound and the reference substance were respectively dissolved in DMSO to prepare a 10 mM stock solution.
  • 500 ⁇ M solution Add 10 ⁇ L of 10 mM stock to 190 ⁇ L DMSO;
  • the prepared equilibrated dialysis plate was placed in a shaker at 37°C for 5 hours at 60 rpm.
  • 25 ⁇ L was taken from the sample on the receiving side, placed in a 96-well sample collection plate, and mixed with the same volume of matrix (blank plasma).
  • 1 ⁇ M test compound and 1 ⁇ M positive compound dosing side sample Take 25 ⁇ L dosing side sample, add 25 ⁇ L blank buffer solution and mix.
  • the samples were thawed at 37°C for 0 hours, and the sample preparation was the same as that of the dosing side samples.
  • Binding rate % ([administration side] 5h - [receiving side] 5h )/[administration side] 5h ⁇ 100%
  • Fu% 100%-% bound, Fu is the unbound fraction.
  • Kp,ubrain was calculated from AUC or concentration and Fu in brain or plasma measured as above.
  • Kp,uuBrain refers to the relationship between the concentration of unbound drug in the brain and blood and is used to assess the ability of a drug to penetrate the blood-brain barrier.
  • the Kpu,uu brain after administration is calculated by the following formula:
  • Kp,uuBrain [AUC(brain)/AUC(plasma)] ⁇ [Fu(brain)/Fu(plasma)].
  • Kp,uuBrain [Drug Concentration(Brain)/Drug Concentration(Plasma)] ⁇ [Fu(Brain)/Fu(Plasma).
  • the positive compound is a compound that does not penetrate the brain, and the compound of Example 12 of the present invention has a certain effect of penetrating the brain.
  • the compound of Example 12 of the present invention has higher Kp,uu brain compared with the positive compound, and the test proves that the compound of Example 12 of the present invention has more excellent brain barrier penetration properties.

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Abstract

La présente invention concerne un inhibiteur d'EGFR ayant une structure de formule (I) et son procédé de préparation, une composition pharmaceutique contenant l'inhibiteur d'EGFR, une utilisation de la composition pharmaceutique en tant qu'inhibiteur d'EGFR, une utilisation de la composition pharmaceutique dans le traitement et/ou la prévention de cancers, des tumeurs ou des maladies métastatiques au moins partiellement associées à une mutation d'insertion ou de délétion de l'exon 20 d'EGFR, et en particulier une utilisation de la composition pharmaceutique dans le traitement de maladies hyperprolifératives et de troubles de la mort cellulaire induite. Les substituants dans la formule (I) ont les mêmes définitions que celles données dans la description.
PCT/CN2021/132029 2020-11-23 2021-11-22 Inhibiteur d'egfr, son procédé de préparation et son utilisation pharmaceutique WO2022105908A1 (fr)

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CN101679384A (zh) * 2007-06-05 2010-03-24 韩美药品株式会社 用于抑制癌细胞生长的新酰胺衍生物
WO2020009156A1 (fr) * 2018-07-04 2020-01-09 第一三共株式会社 Dérivé de quinazoline de type éther de biaryle
WO2020061470A1 (fr) * 2018-09-21 2020-03-26 Spectrum Pharmaceuticals, Inc. Nouveaux inhibiteurs de l'egfr quinazoline
WO2021231400A1 (fr) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl éthers contenant de la n-acyl azétidine en tant qu'inhibiteurs de l'egfr/her2

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CN101679384A (zh) * 2007-06-05 2010-03-24 韩美药品株式会社 用于抑制癌细胞生长的新酰胺衍生物
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CN117567466A (zh) * 2024-01-16 2024-02-20 成都金瑞基业生物科技有限公司 一种喹唑啉衍生物的制备方法
CN117567466B (zh) * 2024-01-16 2024-04-16 成都金瑞基业生物科技有限公司 一种喹唑啉衍生物的制备方法

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