WO2022105908A1 - Egfr inhibitor, preparation method therefor, and pharmaceutical application thereof - Google Patents

Egfr inhibitor, preparation method therefor, and pharmaceutical application thereof 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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French (fr)
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/en
Publication of WO2022105908A1 publication Critical patent/WO2022105908A1/en

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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.

Abstract

The present invention relates to an EGFR inhibitor having a structure of formula (I) and a preparation method therefor, a pharmaceutical composition containing the EGFR inhibitor, a use of the pharmaceutical composition as the EGFR inhibitor, a use of the pharmaceutical composition in treating and/or preventing cancers, tumors, or metastatic diseases at least partially related to an EGFR exon 20 insertion or deletion mutation, and in particular a use of the pharmaceutical composition in treating hyperproliferative diseases and induced cell death disorders. Substituents in formula (I) have the same definitions as those in the description.

Description

EGFR抑制剂及其制备方法与在药学上的应用EGFR inhibitor and its preparation method and its pharmaceutical application 技术领域technical field
本发明属于药物合成领域，具体涉及一种EGFR抑制剂及其制备方法与在药学上的应用。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.
背景技术Background technique
肺癌是全世界癌症死亡的主要原因，其中非小细胞肺癌(NSCLC)占85％。针对表皮生长因子受体(EGFR)突变、间变性淋巴瘤激酶(ALK)易位、ROS1原癌基因受体酪氨酸激酶(ROS1)重排和B-raf原癌基因、丝氨酸/苏氨酸激酶(BRAF)的多靶点治疗已经开发出来并在临床上得到验证。EGFR抑制能显著提高腺癌NSCLC的无进展生存期，其获得性耐药突变后继而被第三代抑制剂靶向。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.
尽管成功地抑制了经典的EGFR激活突变(外显子19和21)和耐药突变(T790M)，外显子20的框内插入也导致了EGFR信号的结构性激活，并与对现有EGFR抑制剂的从头抵抗相关。外显子20突变是异质性的，包括1-7个氨基酸在EGFR蛋白的762-774个氨基酸之间的框内插入或重复。在NSCLC中，EGFR外显子20的突变频率占EGFR所有突变的4-10％。这些突变与其他已知的致癌基因驱动突变相互排斥，并且在女性、非吸烟者、亚洲人群和非小细胞肺癌患者的腺癌中富集。除NSCLC外，EGFR外显子20插入突变还见于一种罕见的头颈部癌，即鼻腔鳞状细胞癌(SNSCC)。此外，在受体酪氨酸激酶(RTK)EGFR家族的另一成员HER2中也发现了结构类似的外显子20插入突变。Despite successful suppression of canonical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M), the in-frame insertion of exon 20 also resulted in a structural activation of EGFR signaling, which is incompatible with existing EGFR De novo resistance to inhibitors is associated. 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. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR. These mutations were mutually exclusive with other known oncogene driver mutations and were enriched in adenocarcinomas in women, non-smokers, Asian populations, and patients with non-small cell lung cancer. In addition to NSCLC, EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
多重回顾性分析显示，目前可用的第1代、第2代和第3代EGFR抑制剂对外显子20插入突变的疗效有限，但A763-Y764insFQEA突变除外。不可逆抑制剂Poziotinib和EGFR/MET双特异性抗体amivantamab正在临床试验中。几种小分子抑制剂包括TAK-788和TAS-6417，在EGFR外显子20非小细胞肺癌患者中显示出临床上有意义的功效，但是，由于对EGFR WT(野生型)的选择性有限，它们的不良反应是不可避免的，并可能导致剂量限制性毒性。因此，对于这些患者而言，迫切需要针对EGFR外显子20插入突变的高选择性小分子抑制剂。Multiple retrospective analyses showed limited efficacy of currently available first-, second-, and third-generation EGFR inhibitors for exon 20 insertion mutations, with the exception of the A763-Y764insFQEA mutation. The irreversible inhibitor Poziotinib and the EGFR/MET bispecific antibody amivantamab are in clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in EGFR exon 20 non-small cell lung cancer patients, however, due to limited selectivity for EGFR WT (wild-type) , their adverse effects are unavoidable and may lead to dose-limiting toxicity. Therefore, highly selective small-molecule inhibitors targeting EGFR exon 20 insertion mutations are urgently needed for these patients.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种EGFR抑制剂及其制备方法与在药学上的应用。本发明系列化合物对EGFR外显子20插入、缺失或其他突变细胞学活性具有很强的抑制作用，并对EGFR野生型具有高选择性，可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，从而有望开发出新一代EGFR抑制剂。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.
本发明第一方面提供式(I)化合物、其立体异构体或其药学上可接受盐：A first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021132029-appb-000001
Figure PCTCN2021132029-appb-000001
其中，X 1和X 2各自独立地为CR 7或N；Y为CR 8或N；Z为NR 9或O； Wherein, X 1 and X 2 are each independently CR 7 or N; Y is CR 8 or N; Z is NR 9 or O;
环A为3-12元含氮杂环基，优选选自以下基团：
Figure PCTCN2021132029-appb-000002
Figure PCTCN2021132029-appb-000003
Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
Figure PCTCN2021132029-appb-000002
Figure PCTCN2021132029-appb-000003
每个R 1独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and - C 0-8 alkyl-N(R 13 )-C(O)R 12 ;
每个R 2独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12，或者，当n≥2时，相邻的两个R 2与其直接相连的部分一起形成一个C 4-8环烷基或5-8元杂环基； Each R2 is independently selected from hydrogen , deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, halo-substituted C1-10 alkyl, deuterium substituted C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and - C 0-8 alkyl-N(R 13 )-C(O)R 12 , or, when n≥2, two adjacent R 2 together with their directly attached moieties form a C 4-8 cycloalkyl or 5-8 membered heterocyclyl;
R 3和R 4各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； 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选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 11、-C(O)R 12、-C(O)-NR 13R 14和-C 0-4烷基-NR 13R 14； 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 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8 烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 Alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 ) R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and -C 0-8 alkyl-N(R 13 )-C(O)R 12 ;
R 6和R 8各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
Figure PCTCN2021132029-appb-000004
时，R 8不为未取代或卤取代C 1-4烷氧基； R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-8 aryl group, 5-8-membered heteroaryl group, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )- C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 , the above-mentioned groups independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, halo-substituted C1-10 alkyl, deuterium substituted C1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, =O , -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O ) OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0 -8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and -C 0-8 alkyl-N(R 13 )-C(O)R 12 substituents, provided that when ring A is
Figure PCTCN2021132029-appb-000004
, R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
R 9选自氢、氘、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基和3-12元杂环基； 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;
每个R 10独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl radicals, 5-10-membered heteroaryl groups and -NR 13 R 14 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 substituted by the substituents of aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 13 R 14 ;
每个R 11独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 11 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 13 R 14 substituents;
每个R 12独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl group, 5-10 membered heteroaryloxy and -NR 13 R 14 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl , C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 13 R 14 ;
每个R 13和R 14各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、 卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each of R 13 and R 14 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-10 alkanoyl, independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3- 12 -cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered Substituted by substituents of heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;
或者，R 13和R 14与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 13 and R 14 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further substituted by one or more selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, Deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy , C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkane substituted by substituents of amino and C 1-10 alkanoyl;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
每个r独立地为0、1或2。Each r is independently 0, 1, or 2.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 1选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, 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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )-C(= NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 ;
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12，或者，当n≥2时，相邻的两个R 2与其直接相连的部分一起形成一个C 4-8环烷基或5-8元杂环基； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain 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 , -C 0-4 alkyl-C(=NR 13 ) R 12 , -C 0-4 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , or, when n≥2, two adjacent R 2 together with their directly attached moieties form a C 4-8 cycloalkyl or 5-8 membered heterocyclic group;
R 3和R 4各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； 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选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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 6和R 8各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、 5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
Figure PCTCN2021132029-appb-000005
时，R 8不为未取代或卤取代C 1-4烷氧基； R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 10 , -OR 11 , -C(O)OR 11 , -C (O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , -N(R 13 )-C(=NR 14 )R 12 , -C(O ) NR 13 R 14 and -N(R 13 )-C(O)R 12 , the above-mentioned groups are independently optionally further selected by one or more groups selected from 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 3-8 cycloalkyl, 3- 8-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 ) Substituents of -C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 substituted, provided that when ring A is
Figure PCTCN2021132029-appb-000005
, R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 9选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基和3-6元杂环基； 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;
其中，X 1、X 2、Y、Z、环A、m、n、R 10、R 11、R 12、R 13、R 14和r如式(I)化合物所述。 wherein X 1 , X 2 , Y, Z, ring A, m, n, R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅱa)化合物：As a preferred solution, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (IIa) below:
Figure PCTCN2021132029-appb-000006
Figure PCTCN2021132029-appb-000006
其中，Z为NR 9或O； Wherein, Z is NR 9 or O;
环A为3-12元含氮杂环基，优选选自以下基团：
Figure PCTCN2021132029-appb-000007
Figure PCTCN2021132029-appb-000008
Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
Figure PCTCN2021132029-appb-000007
Figure PCTCN2021132029-appb-000008
R 1a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 1b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、 -C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 3选自氢、氘、卤素和C 1-4烷基； R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl;
R 5选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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 8选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、-O-R 11、-O-C(O)R 12、-NR 13R 14、-N(R 13)-C(＝NR 14)R 12和-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
Figure PCTCN2021132029-appb-000009
时，R 8不为未取代或卤取代C 1-4烷氧基； R 8 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycle base, -OR 11 , -OC(O)R 12 , -NR 13 R 14 , -N(R 13 )-C(=NR 14 )R 12 and -N(R 13 )-C(O)R 12 , The above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, 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 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl , =O, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-4 alkyl-C( O) NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 substituents, provided that when ring A is
Figure PCTCN2021132029-appb-000009
, R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
R 9选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
其中，R 10、R 11、R 12、R 13、R 14和r如式(I)化合物所述。 wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，Z为NH或O；As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, Z is NH or O;
R 1a选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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 2选自氢、氘、氟、氯、溴和氰基； R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
R 3选自氢、氘和氟； R is selected from hydrogen, deuterium and fluorine;
R 5选自氢、氘和甲基。 R 5 is selected from hydrogen, deuterium and methyl.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，环A选自以下基团：
Figure PCTCN2021132029-appb-000010
As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring A is selected from the following groups:
Figure PCTCN2021132029-appb-000010
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 8选自C 3-6环烷氧基、3-6元杂环烷氧基、C 3-6环烷基C 1-4烷氧基和3-6元杂环烷基C 1-4烷氧基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、 -N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12的取代基所取代；其中，R 10、R 11、R 12、R 13、R 14和r如式(I)化合物所述。 As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 8 is selected from C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy group, C 3-6 cycloalkyl C 1-4 alkoxy and 3-6 membered heterocycloalkyl C 1-4 alkoxy, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, Halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , -N(R 13 ) -C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 substituents; wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for compounds of formula (I).
作为再进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 8选自
Figure PCTCN2021132029-appb-000011
Figure PCTCN2021132029-appb-000012
所述
Figure PCTCN2021132029-appb-000013
Figure PCTCN2021132029-appb-000014
各自独立地任选进一步被一个或多个选自氘、氟、氯、甲基、甲氧基、氰基和硝基的取代基所取代。 As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 8 is selected from
Figure PCTCN2021132029-appb-000011
Figure PCTCN2021132029-appb-000012
said
Figure PCTCN2021132029-appb-000013
Figure PCTCN2021132029-appb-000014
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.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 8选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链炔基、C 1-2烷氧基、C 3-6环烷基、3-6元杂环基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
Figure PCTCN2021132029-appb-000015
时，R 8不为未取代或卤取代C 1-2烷氧基；其中，R 10、R 11、R 12、R 13、R 14和r如式(I)化合物所述。 As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 8 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 1-2 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -NR 13 R 14 , the above groups are independently optionally further modified by one or more selected from deuterium, halogen, cyano, nitro, azido, 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, =O, -SF5 , -S(O) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , -N (R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 substituents, provided that when Ring A is
Figure PCTCN2021132029-appb-000015
, R 8 is not unsubstituted or halo-substituted C 1-2 alkoxy; wherein, R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为再进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 8选自氢、氘、氟、氯、溴、氰基、甲基、二氟甲基、三氟甲基、乙炔基、甲氧基、乙氧基、一氟甲氧基、甲氧基乙氧基、三氟乙氧基、环丙基、吗啉基、3-氯-丙胺基、三氟乙胺基、2-甲氧基乙胺基、
Figure PCTCN2021132029-appb-000016
Figure PCTCN2021132029-appb-000017
所述
Figure PCTCN2021132029-appb-000018
各自独立地任选进一步被一个或多个选自氘、氟、氯、甲基、甲氧基、氰基和硝基的取代基所取代，条件是当环A为
Figure PCTCN2021132029-appb-000019
时，R 8不为甲氧基、乙氧基、一氟甲氧基或三氟乙氧基。 As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, 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,
Figure PCTCN2021132029-appb-000016
Figure PCTCN2021132029-appb-000017
said
Figure PCTCN2021132029-appb-000018
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
Figure PCTCN2021132029-appb-000019
, R 8 is not methoxy, ethoxy, monofluoromethoxy or trifluoroethoxy.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅱb)化合物：As a preferred solution, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of the following formula (IIb):
Figure PCTCN2021132029-appb-000020
Figure PCTCN2021132029-appb-000020
其中，Z为NR 9或O； Wherein, Z is NR 9 or O;
环A为3-12元含氮杂环基，优选选自以下基团：
Figure PCTCN2021132029-appb-000021
Figure PCTCN2021132029-appb-000022
Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
Figure PCTCN2021132029-appb-000021
Figure PCTCN2021132029-appb-000022
R 1a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 1b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
R 3选自氢、氘、卤素和C 1-4烷基； R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl;
R 5选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
其中，R 10、R 11、R 12、R 13、R 14和r如式(I)化合物所述。 wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，Z为O；As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, Z is O;
R 1a选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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 2选自氢、氘、氟、氯、溴和氰基； R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
R 3选自氢、氘和氟； R is selected from hydrogen, deuterium and fluorine;
R 5选自氢、氘和甲基。 R 5 is selected from hydrogen, deuterium and methyl.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，环A选自以下基团：
Figure PCTCN2021132029-appb-000023
As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring A is selected from the following groups:
Figure PCTCN2021132029-appb-000023
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 10独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 13 R 14 , the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C6-8 aryl, C6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and - Substituents of NR 13 R 14 are substituted;
每个R 11独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； Each R 11 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 13 R 14 substituents;
每个R 12独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy and -NR 13 R 14 , the above groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl , C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 13 R 14 ;
每个R 13和R 14各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 13 and R 14 is independently selected from hydrogen, deuterium, hydroxyl, 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, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6 -cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered Substituted by substituents of heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
或者，R 13和R 14与其直接相连的氮原子一起形成一个4-8元杂环基或5-8元杂芳基，所述4-8元杂环基或5-8元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 13 and R 14 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group or 5-8 membered heteroaryl group, said 4-8 membered heterocyclic group or 5-8 membered heteroaryl group being either is further substituted by one or more selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy , C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkane substituted with substituents of amino and C 1-4 alkanoyl groups.
作为最优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
Figure PCTCN2021132029-appb-000024
Figure PCTCN2021132029-appb-000024
Figure PCTCN2021132029-appb-000025
Figure PCTCN2021132029-appb-000025
Figure PCTCN2021132029-appb-000026
Figure PCTCN2021132029-appb-000026
Figure PCTCN2021132029-appb-000027
Figure PCTCN2021132029-appb-000027
Figure PCTCN2021132029-appb-000028
Figure PCTCN2021132029-appb-000028
本发明第二方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：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:
Figure PCTCN2021132029-appb-000029
Figure PCTCN2021132029-appb-000029
其中，X为卤素，优选选自氟、氯和溴；环A、R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、Y、Z、m和n如式(I)化合物中所定义。 wherein 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).
本发明第三方面提供一种药物组合物，其包含式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途。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.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的用途。本发明还涉及前述式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌药物中的用途。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.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用作药物。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.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的用途。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.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的用途。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.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。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.
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。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.
本发明还涉及一种预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。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.
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。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.
具体实施方式Detailed ways
本申请的发明人经过广泛而深入地研究，首次研发出一种具有如下式(Ⅰ)结构的EGFR抑制剂，本发明系列化合物可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，有望开发成新一代EGFR抑制剂。在此基础上，完成了本发明。After extensive and in-depth research, the inventors of the present application have developed for the first time 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.
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。DETAILED DESCRIPTION: Unless stated to the contrary or specifically stated, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，优选包括1至10个或1至6个碳原子或1至4个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。“C 1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，“C 1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，“C 0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基，“C 0-4烷基”指包括0至4个碳原子的直链烷基和含支链烷基。 "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, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl base, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "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.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0 -8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 ) -C(O)R 12 is substituted with a substituent.
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，环烷基分为单环环烷基、多环环烷基，优选包括3至12个或3至8个或3至6个碳原子的环烷基，例如，“C 3-12环烷基”指包括3至12个碳原子的环烷基，“C 4-8环烷基”指包括4至8个碳原子的环烷基，“C 3-8环烷基”指包括3至8个碳原子的环烷基，“C 3-6环烷基”指包括3至6个碳原子的 环烷基，其中： "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 π 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 cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, in:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：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:
Figure PCTCN2021132029-appb-000030
Figure PCTCN2021132029-appb-000030
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于："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:
Figure PCTCN2021132029-appb-000031
Figure PCTCN2021132029-appb-000031
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于："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:
Figure PCTCN2021132029-appb-000032
Figure PCTCN2021132029-appb-000032
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。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.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8 烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl- OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 ) Substituents of -C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 )-C(O)R 12 replaced.
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，杂环基中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个或3至8个或3至6个环原子的杂环基，例如，“3-6元杂环基”指包含3至6个环原子的杂环基，“3-8元杂环基”指包含3至8个环原子的杂环基，“4-8元杂环基”指包含4至8个环原子的杂环基，“4-10元杂环基”指包含4至10个环原子的杂环基，“5-8元杂环基”指包含5至8个环原子的杂环基，“3-12元杂环基”指包含3至12个环原子的杂环基。 "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.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、氧杂环丁烷基、四氢呋喃基等。Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键(优选1、2或3个)，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于： 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:
Figure PCTCN2021132029-appb-000033
Figure PCTCN2021132029-appb-000033
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个(优选1、2、3或4个)环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于： "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:
Figure PCTCN2021132029-appb-000034
Figure PCTCN2021132029-appb-000034
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于： "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:
Figure PCTCN2021132029-appb-000035
Figure PCTCN2021132029-appb-000035
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：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:
Figure PCTCN2021132029-appb-000036
Figure PCTCN2021132029-appb-000036
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12所取代。 Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl- OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 ) -C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 )-C(O)R 12 .
“芳基”或“芳环”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选含有6-10个或6-8个碳的全碳芳基，例如，“C 6-10芳基”指含有6-10个碳的全碳芳基，包括但不限于苯基和萘基，“C 6-8芳基”指含有6-8个碳的全碳芳基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于： "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:
Figure PCTCN2021132029-appb-000037
Figure PCTCN2021132029-appb-000037
“芳基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC (O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )- C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 )-C(O)R 12 substituents replace.
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，优选含有5-10个或5-8个或5-6个环原子的杂芳族体系，例如，“5-8元杂芳基”指含有5-8个环原子的杂芳族体系，“5-10元杂芳基”指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于："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 parent structure is a heteroaryl ring, including but not limited to:
Figure PCTCN2021132029-appb-000038
Figure PCTCN2021132029-appb-000038
“杂芳基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, Halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C( O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N( R 13 )-C(O)R 12 is substituted with the substituent.
“链烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基， 优选含有2-10个或2-4个碳的直链或含支链烯基，例如，“C 2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C 2-4链烯基”指含有2-4个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "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 For example, "C 2-10 alkenyl" refers to a straight-chain or branched alkenyl containing 2-10 carbons, and "C 2-4 alkenyl" refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
“链烯基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O) R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 )-C(O)R 12 is substituted.
“链炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，优选含有2-10个或2-4个碳的直链或含支链炔基，例如，“C 2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C 2-4链炔基”指含有2-4个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "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, For example, "C 2-10 alkynyl" refers to a straight or branched chain alkynyl group containing 2-10 carbons, and "C 2-4 alkynyl" refers to a straight or branched chain containing 2-4 carbons alkynyl. Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
“链炔基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C(O) R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N(R 13 )-C(O)R 12 is substituted.
“烷氧基”指-O-烷基，其中烷基的定义如上所述，例如，“C 1-10烷氧基”指含1-10个碳的烷基氧基，“C 1-4烷氧基”指含1-4个碳的烷基氧基，“C 1-2烷氧基”指含1-2个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。 "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.
“烷氧基”可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1- 10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 alkyl-C (O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or -C 0-8 alkyl-N (R 13 )-C(O)R 12 is substituted with the substituent.
“环烷氧基”或“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述，例如，“C 3-12环烷氧基”指含3-12个碳的环烷基氧基，“C 3-6环烷氧基”指含3-6个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。 "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.
“环烷氧基”或“环烷基氧基”可以是任选取代的或未取代的，当被取代时，取代 基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less groups independently selected from deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halogen substituted C1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or - Substituents substituted with C 0-8 alkyl-N(R 13 )-C(O)R 12 .
“杂环氧基”或“杂环基氧基”指-O-杂环基，其中杂环基的定义如上所述，包括但不限于氮杂环丁基氧基、氧杂环丁基氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。"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.
“杂环氧基”或“杂环基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14或-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代。 "Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 or - Substituted with the substituent of C 0-8 alkyl-N(R 13 )-C(O)R 12 .
“C 1-10烷酰基”指C 1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-9烷基-C(O)-”，例如，“C 1烷基-C(O)-”是指乙酰基；“C 2烷基-C(O)-”是指丙酰基；“C 3烷基-C(O)-”是指丁酰基或异丁酰基。 "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烷基-S(O) rR 10”指-S(O) rR 10中的硫原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-S(O) r R 10 " means that the sulfur atom in -S(O) r R 10 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above said.
“-C 0-8烷基-O-R 11”指-O-R 11中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OR 11 " means that the oxygen atom in -OR 11 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-C(O)OR 11”指-C(O)OR 11中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)OR 11 " means that the carbonyl group in -C(O)OR 11 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-C(O)R 12”指-C(O)R 12中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-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.
“-C 0-8烷基-O-C(O)R 12”指-O-C(O)R 12中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OC(O)R 12 " means that the oxygen atom in -OC(O)R 12 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above .
“-C 0-8烷基-NR 13R 14”指-NR 13R 14中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-NR 13 R 14 " means that the nitrogen atom in -NR 13 R 14 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-C(＝NR 13)R 12”指-C(＝NR 13)R 12中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(=NR 13 )R 12 " means that the nitrogen atom in -C(=NR 13 )R 12 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group's Definitions are as above.
“-C 0-8烷基-N(R 13)-C(＝NR 14)R 12”指-N(R 13)-C(＝NR 14)R 12中的氮原子连接在C 0-8 烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 " means that the nitrogen atom in -N(R 13 )-C(=NR 14 )R 12 is attached to C 0-8 on alkyl, wherein C 0-8 alkyl is as defined above.
“-C 0-8烷基-C(O)NR 13R 14”指-C(O)NR 13R 14中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)NR 13 R 14 " means that the carbonyl group in -C(O)NR 13 R 14 is attached to C 0-8 alkyl, wherein the definition of C 0-8 alkyl as above.
“-C 0-8烷基-N(R 13)-C(O)R 12”指-N(R 13)-C(O)R 12中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-N(R 13 )-C(O)R 12 " means that the nitrogen atom in -N(R 13 )-C(O)R 12 is attached to the C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.
“卤取代C 1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "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.
“卤取代C 1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 "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.
“氘取代C 1-10烷基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限于一氘甲基、二氘甲基、三氘甲基等。 "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.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合，也即包括取代的或未取代的两种情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"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 . For example, "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 .
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，符合化学上的价键理论，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。"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.
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。"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. Among them, 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. For example: 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. In the present invention, the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和 有机酸盐，这些盐可通过本专业已知的方法制备。"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.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be further described in detail and completely below in conjunction with the examples, but the present invention is by no means limited, and the present invention is not limited to the contents of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 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).
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。An Agilent 6120 mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。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.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。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.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).
一、中间体的制备1. Preparation of intermediates
中间体1：2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯胺的制备Intermediate 1: Preparation of 2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline
Figure PCTCN2021132029-appb-000039
Figure PCTCN2021132029-appb-000039
第一步：叔-丁基-3-羟基-1H-吡唑-1-羧酸酯的合成The first step: synthesis of tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylate
Figure PCTCN2021132029-appb-000040
Figure PCTCN2021132029-appb-000040
将1H-吡唑-3-醇(25.0g，0.30mol)和三乙胺(75mL，0.39mol)溶于DCM(250mL)中，加入二碳酸二叔丁酯(53.7mL，0.33mol)，反应液在室温下搅拌5小时。减压浓缩干燥得到叔-丁基-3-羟基-1H-吡唑-1-羧酸酯(54.8g，收率：100％)。Dissolve 1H-pyrazol-3-ol (25.0 g, 0.30 mol) and triethylamine (75 mL, 0.39 mol) in DCM (250 mL), add di-tert-butyl dicarbonate (53.7 mL, 0.33 mol), and react The solution was stirred at room temperature for 5 hours. It was concentrated and dried under reduced pressure to obtain tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylate (54.8 g, yield: 100%).
MS m/z(ESI):185[M+H] +。 MS m/z (ESI): 185 [M+H] + .
第二步：叔-丁基-3-(3-氟-4-硝基苯氧基)-1H-吡唑-1-羧酸酯的合成The second step: synthesis of tert-butyl-3-(3-fluoro-4-nitrophenoxy)-1H-pyrazole-1-carboxylate
Figure PCTCN2021132029-appb-000041
Figure PCTCN2021132029-appb-000041
将叔丁基-3-羟基-1H-吡唑-1-羧酸酯(8.30g，45.1mmol)和2,4-二氟-1-硝基苯(7.53g，47.4mmol)溶于N,N-二甲基甲酰胺(100mL)中，室温下加入碳酸钾(12.45g，90.2mmol)，反应液室温搅拌24小时，用水稀释后，用乙酸乙酯萃取，有机相用饱和食盐水溶液洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩后用柱层析分离得到粗品，粗品用乙酸乙酯/石油醚(50mL/500mL)重结晶得到叔-丁基-3-(3-氟-4-硝基苯氧基)-1H-吡唑-1-羧酸酯(3.20g，收率：22％)。MS m/z(ESI):268[M-56+H] +。 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 crude product was recrystallized from ethyl acetate/petroleum ether (50 mL/500 mL) to obtain tert-butyl-3-(3-fluoro-4-nitrophenoxy)- 1H-Pyrazole-1-carboxylate (3.20 g, yield: 22%). MS m/z (ESI): 268 [M-56+H] + .
第三步：叔-丁基-3-(4-氨基-3-氟苯氧基)-1H-吡唑-1-羧酸酯的合成The third step: synthesis of tert-butyl-3-(4-amino-3-fluorophenoxy)-1H-pyrazole-1-carboxylate
Figure PCTCN2021132029-appb-000042
Figure PCTCN2021132029-appb-000042
将叔-丁基-3-(3-氟-4-硝基苯氧基)-1H-吡唑-1-羧酸酯(3.00g，9.28mmol)溶于甲醇/二氯甲烷(50mL/50mL)中，加入钯碳(10％，300mg)，反应液在氢气氛围中室温搅拌5小时。抽滤，滤液浓缩，残留物用柱层析分离得到叔-丁基-3-(4-氨基-3-氟苯氧基)-1H-吡唑-1-羧酸酯(2.20g，收率：81％)。MS m/z(ESI):294[M+H] +。 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] + .
第四步：叔-丁基-3-(4-(((苄氧基)羰基)氨基)-3-氟苯氧基)-1H-吡唑-1-羧酸酯的合成The fourth step: synthesis of tert-butyl-3-(4-(((benzyloxy)carbonyl)amino)-3-fluorophenoxy)-1H-pyrazole-1-carboxylate
Figure PCTCN2021132029-appb-000043
Figure PCTCN2021132029-appb-000043
将叔-丁基-3-(4-氨基-3-氟苯氧基)-1H-吡唑-1-羧酸酯(2.20g，7.5mmol)和氯甲酸苄酯(1.92g，11.3mmol)溶于四氢呋喃(50mL)中，室温下加入碳酸钾(2.07g，15.0mmol)，混合物在60℃下搅拌4小时。反应液用水稀释并用乙酸乙酯萃取，有机相浓缩后柱层析分离得到叔-丁基-3-(4-(((苄氧基)羰基)氨基)-3-氟苯氧基)-1H-吡唑-1-羧酸酯(2.4g，收率：75％)。MS m/z(ESI):428[M+H] +。 tert-Butyl-3-(4-amino-3-fluorophenoxy)-1H-pyrazole-1-carboxylate (2.20 g, 7.5 mmol) and benzyl chloroformate (1.92 g, 11.3 mmol) It was dissolved in tetrahydrofuran (50 mL), potassium carbonate (2.07 g, 15.0 mmol) was added at room temperature, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain tert-butyl-3-(4-(((benzyloxy)carbonyl)amino)-3-fluorophenoxy)-1H - Pyrazole-1-carboxylate (2.4 g, yield: 75%). MS m/z (ESI): 428 [M+H] + .
第五步：(4-(((1H-吡唑-3-基)氧基)-2-氟苯基)氨基甲酸苄酯的合成The fifth step: the synthesis of (4-(((1H-pyrazol-3-yl)oxy)-2-fluorophenyl)carbamic acid benzyl ester
Figure PCTCN2021132029-appb-000044
Figure PCTCN2021132029-appb-000044
将叔-丁基-3-(4-(((苄氧基)羰基)氨基)-3-氟苯氧基)-1H-吡唑-1-羧酸酯(2.40g，5.6mmol)溶于二氯甲烷(15mL)中，室温下加入三氟醋酸(5mL)，混合物在室温下搅拌2小时。反应液用二氯甲烷(150mL)稀释，加入饱和碳酸氢钠水溶液(100mL)中和，分液，饱和食盐水(50mL)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得到(4-(((1H-吡唑-3-基)氧基)-2-氟苯基)氨基甲酸苄酯(1.80g，收率：98％)。MS m/z(ESI):328[M+H] +。 tert-Butyl-3-(4-(((benzyloxy)carbonyl)amino)-3-fluorophenoxy)-1H-pyrazole-1-carboxylate (2.40 g, 5.6 mmol) was dissolved in To dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (150 mL), neutralized by adding saturated aqueous sodium bicarbonate solution (100 mL), separated, washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain ( Benzyl 4-(((1H-pyrazol-3-yl)oxy)-2-fluorophenyl)carbamate (1.80 g, yield: 98%). MS m/z (ESI): 328 [M +H] + .
第六步：苄基(2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基氨基甲酸酯的合成The sixth step: benzyl (2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenylcarbamic acid Synthesis of Esters
Figure PCTCN2021132029-appb-000045
Figure PCTCN2021132029-appb-000045
将(4-(((1H-吡唑-3-基)氧基)-2-氟苯基)氨基甲酸苄酯(1.80g，5.50mmol)和2-甲基-3-氟-5-溴吡啶置于干燥甲苯(60mL)中，加入反式-N,N'-二甲基-1,2-环己二胺(312mg，2.2mmol)、碘化亚铜(210mg，1.1mmol)和碳酸钾(1.52g，11.0mmol)，混合物在120℃搅拌反应20小时。反应液直接浓缩，残留物柱层析分离得到苄基(2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基氨基甲酸酯(355mg，收率：36％)。MS m/z(ESI):437[M+H] +。 Benzyl (4-(((1H-pyrazol-3-yl)oxy)-2-fluorophenyl)carbamate (1.80 g, 5.50 mmol) and 2-methyl-3-fluoro-5-bromo Pyridine was placed in dry toluene (60 mL), trans-N,N'-dimethyl-1,2-cyclohexanediamine (312 mg, 2.2 mmol), cuprous iodide (210 mg, 1.1 mmol) and carbonic acid were added Potassium (1.52 g, 11.0 mmol), the mixture was stirred and reacted at 120°C for 20 hours. The reaction solution was directly concentrated, and the residue was separated by column chromatography to obtain benzyl (2-fluoro-4-((1-(5-fluoro-6- Methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenylcarbamate (355 mg, yield: 36%). MS m/z (ESI): 437 [M+H ] + .
第七步：2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯胺的合成The seventh step: the synthesis of 2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline
Figure PCTCN2021132029-appb-000046
Figure PCTCN2021132029-appb-000046
将苄基(2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基氨基甲酸酯(850mg，1.95mmol)溶于甲醇/二氯甲烷(20mL/20mL)中，加入氢氧化钯(10％，85mg)，反应液在氢气氛围中室温搅拌4小时。抽滤，滤液浓缩得到2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯胺(588mg，收率：100％)。MS m/z(ESI):303[M+H] +。 Benzyl (2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenylcarbamate (850 mg , 1.95mmol) was dissolved in methanol/dichloromethane (20mL/20mL), palladium hydroxide (10%, 85mg) was added, and the reaction solution was stirred at room temperature for 4 hours in a hydrogen atmosphere. Suction filtration, and the filtrate was concentrated to obtain 2-fluoro- 4-((1-(5-Fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline (588 mg, yield: 100%). MS m/z ( ESI): 303[M+H] + .
中间体2可参照中间体1全部或部分合成方法选择相应的原料进行制备:Intermediate 2 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of Intermediate 1:
Figure PCTCN2021132029-appb-000047
Figure PCTCN2021132029-appb-000047
中间体3：1-(3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮的制备Intermediate 3: Preparation of 1-(3-((4-Chloro-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTCN2021132029-appb-000048
Figure PCTCN2021132029-appb-000048
第一步：叔-丁基-3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-羧酸酯的合成The first step: synthesis of tert-butyl-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-1-carboxylate
Figure PCTCN2021132029-appb-000049
Figure PCTCN2021132029-appb-000049
将4-氯-7-甲氧基喹唑啉-6-醇(700mg，3.33mmol)、叔-丁基-3-羟基吖丁啶-1-羧酸酯(865mg，5.0mmol)和三苯基膦(1.32g，5.0mmol)置于干燥二氯甲烷(20mL)中，冰浴冷却下加入偶氮二甲酸二异丙酯(1.01g，5.0mmol)，反应液室温搅拌过夜。反应液直接浓缩，残留物经柱层析分离得到叔-丁基-3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-羧酸酯粗品(2.2g)，直接用于下一步反应。MS m/z(ESI):366[M+H] +。 4-Chloro-7-methoxyquinazolin-6-ol (700 mg, 3.33 mmol), tert-butyl-3-hydroxyazetidine-1-carboxylate (865 mg, 5.0 mmol) and triphenyl Phosphine (1.32 g, 5.0 mmol) was placed in dry dichloromethane (20 mL), diisopropyl azodicarboxylate (1.01 g, 5.0 mmol) was added under ice cooling, and the reaction solution was stirred at room temperature overnight. The reaction solution was directly concentrated, and the residue was separated by column chromatography to obtain tert-butyl-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-1-carboxylic acid The crude ester (2.2 g) was used directly in the next reaction. MS m/z (ESI): 366 [M+H] + .
第二步：6-(吖丁啶-3-氧基)-4-氯-7-甲氧基喹唑啉盐酸的合成The second step: the synthesis of 6-(azetidine-3-oxy)-4-chloro-7-methoxyquinazoline hydrochloride
Figure PCTCN2021132029-appb-000050
Figure PCTCN2021132029-appb-000050
将叔-丁基-3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-羧酸酯粗品(2.2g)置于氯化氢/1,4-二氧六环溶液(5mL)中，反应液室温搅拌1小时。反应液加入四氢呋喃(10mL)，产生的白色固体过滤后，滤饼干燥得到6-(吖丁啶-3-氧基)-4-氯-7-甲氧基喹唑啉盐酸(300mg)，直接用于下一步反应。MS m/z(ESI):266[M+H] +。 The crude product of tert-butyl-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidine-1-carboxylate (2.2g) was placed in hydrogen chloride/1, 4-dioxane solution (5 mL), the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added with tetrahydrofuran (10 mL), the resulting white solid was filtered, and the filter cake was dried to obtain 6-(azetidine-3-oxy)-4-chloro-7-methoxyquinazoline hydrochloric acid (300 mg), which was directly used for the next reaction. MS m/z (ESI): 266 [M+H] + .
第三步：1-(3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮的合成The third step: synthesis of 1-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one
Figure PCTCN2021132029-appb-000051
Figure PCTCN2021132029-appb-000051
将6-(吖丁啶-3-氧基)-4-氯-7-甲氧基喹唑啉盐酸(300mg，1.0mmol)和三乙胺(404mg，44.0mmol)置于二氯甲烷(40mL)中，冰浴冷却下加入丙烯酰氯(136mg，1.5mmol)，反应液冰浴冷却搅拌1小时。反应液直接浓缩，残留物柱层析分离得到1-(3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮(57mg，收率：18％)。MS m/z(ESI):320[M+H] +。 6-(azetidine-3-oxy)-4-chloro-7-methoxyquinazoline hydrochloride (300 mg, 1.0 mmol) and triethylamine (404 mg, 44.0 mmol) were placed in dichloromethane (40 mL) ), acryloyl chloride (136 mg, 1.5 mmol) was added under ice-cooling, and the reaction solution was ice-cooled and stirred for 1 hour. The reaction solution was directly concentrated, and the residue was separated by column chromatography to obtain 1-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)propan-2 -en-1-one (57 mg, yield: 18%). MS m/z (ESI): 320 [M+H] + .
中间体4-6可参照中间体3全部或部分合成方法选择相应的原料进行制备:Intermediates 4-6 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 3:
Figure PCTCN2021132029-appb-000052
Figure PCTCN2021132029-appb-000052
Figure PCTCN2021132029-appb-000053
Figure PCTCN2021132029-appb-000053
中间体7：1-(4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的制备Intermediate 7: Preparation of 1-(4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTCN2021132029-appb-000054
Figure PCTCN2021132029-appb-000054
第一步：5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-氟-2-硝基苯甲酸的合成The first step: Synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-fluoro-2-nitrobenzoic acid
Figure PCTCN2021132029-appb-000055
Figure PCTCN2021132029-appb-000055
冰浴冷却下，向4,5-二氟-2-硝基苯甲酸(20.0g，98.5mmol)和4-羟基哌啶-1-甲酸叔丁酯(39.64g，196.9mmol)的N,N-二甲基甲酰胺(100mL)溶液中分批加入氢化钠(60％，于油中，7.88g，196.9mmol)，将反应混合物逐渐升至室温，并在室温搅拌19小时。向反应溶液中加入冰水淬灭，1mol/L盐酸调节pH约为2-3，用乙酸乙酯萃取反应溶液。有机层用饱和盐水洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩，得到5-((1-(叔丁氧基羰基)哌啶-4-基)氧基)-4-氟-2-硝基苯甲酸粗产物(50g粗品)。将粗产物直接用于下一步反应。MS m/z(ESI):329[M-56+H] +。 Under ice-cooling, a N,N solution of 4,5-difluoro-2-nitrobenzoic acid (20.0 g, 98.5 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (39.64 g, 196.9 mmol) was added. - To a solution of dimethylformamide (100 mL) was added sodium hydride (60% in oil, 7.88 g, 196.9 mmol) portionwise, the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 19 hours. Add ice water to the reaction solution to quench, adjust the pH to about 2-3 with 1 mol/L hydrochloric acid, and extract the reaction solution with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-fluoro-2-nitrobenzoic acid (50 g crude product). The crude product was used directly in the next reaction. MS m/z (ESI): 329 [M-56+H] + .
第二步：叔-丁基4-(2-氟-5-(甲酯基(甲氧基羰基))-4-硝基苯氧基)哌啶-1-羧酸酯的合成The second step: Synthesis of tert-butyl 4-(2-fluoro-5-(carbomethoxy(methoxycarbonyl))-4-nitrophenoxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000056
Figure PCTCN2021132029-appb-000056
向5-((1-(叔丁氧基羰基)哌啶-4-基)氧基)-4-氟-2-硝基苯甲酸(50g粗品，98.5mmol)的N,N-二甲基甲酰胺(200mL)溶液中加入碘甲烷(12.3mL，197.7mmol)和碳酸钾(27.33g，197.7mmol)，并将混合物在室温搅拌2小时。反应溶液用乙酸乙酯稀释，用饱和盐水洗涤，有机相减压浓缩，残留物柱层析分离得到叔-丁基4-(2-氟-5-(甲酯基(甲氧基羰基))-4-硝基苯氧基)哌啶-1-羧酸酯(39.0g，收率：99％)。MS m/z(ESI):343[M-56+H] +。 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 reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain tert-butyl 4-(2-fluoro-5-(carbomethoxy(methoxycarbonyl)) -4-Nitrophenoxy)piperidine-1-carboxylate (39.0 g, yield: 99%). MS m/z (ESI): 343[M-56+H] + .
第三步：5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基-2-硝基苯甲酸的合成The third step: synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxy-2-nitrobenzoic acid
Figure PCTCN2021132029-appb-000057
Figure PCTCN2021132029-appb-000057
冰浴冷却下向叔-丁基4-(2-氟-5-(甲酯基(甲氧基羰基))-4-硝基苯氧基)哌啶-1-羧酸酯(10.0g，25.1mmol)和环丙醇(2.92g，50.2mmol)的N,N-二甲基甲酰胺(100mL)溶液中分批加入氢化钠(60％，于油中，2.01g，50.2mmol)，反应混合物逐渐温热至室温，并室温搅拌3小时。向反应溶液中加入冰水淬灭，用1mol/L盐酸调节pH约为2-3并搅拌30分钟，沉淀物抽滤，水洗涤，干燥得到5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基-2-硝基苯甲酸(10.8g，纯度：69％，收率：70.3％)粗产物。将粗产物直接用于下一步反应而不经进一步纯化。MS m/z(ESI):367[M-56+H] +。 Under ice bath cooling, 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. Add ice water to the reaction solution to quench, adjust pH to be about 2-3 with 1mol/L hydrochloric acid and stir for 30 minutes, the precipitate is suction filtered, washed with water, and dried to obtain 5-((1-(tert-butoxycarbonyl )piperidin-4-yl)oxy)-4-cyclopropoxy-2-nitrobenzoic acid (10.8 g, purity: 69%, yield: 70.3%) crude product. The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 367[M-56+H] + .
第四步：2-氨基-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基苯甲酸的合成The fourth step: the synthesis of 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxybenzoic acid
Figure PCTCN2021132029-appb-000058
Figure PCTCN2021132029-appb-000058
向5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基-2-硝基苯甲酸(10.8g粗品，69％纯度，17.6mmol)的甲醇(100mL)和二氯甲烷(100mL)溶液中加入10％湿钯碳(540mg)，将反应混合物在氢气氛围下室温搅拌过夜。反应液抽滤，甲醇洗涤，滤液减压旋蒸浓缩得到2-氨基-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基苯甲酸(9.5g)。将粗产物直接用于下一步反应。MS m/z(ESI):393[M+H] +。 To 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxy-2-nitrobenzoic acid (10.8 g crude, 69% pure, 17.6 mmol ) in methanol (100 mL) and dichloromethane (100 mL) was added 10% wet palladium on carbon (540 mg), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was suction filtered, washed with methanol, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxy Benzoic acid (9.5 g). The crude product was used directly in the next reaction. MS m/z (ESI): 393 [M+H] + .
第五步：叔-丁基4-((7-环丙氧基-4-羟基喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The fifth step: the synthesis of tert-butyl 4-((7-cyclopropoxy-4-hydroxyquinazolin-6-yl)oxy) piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000059
Figure PCTCN2021132029-appb-000059
向2-氨基-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-环丙氧基苯甲酸(7.7g粗品，70％纯度，13.7mmol)的乙二醇单甲醚(100mL)溶液中加入醋酸甲脒(5.72g，54.9mmol)，将反应混合物在130℃下搅拌反应1小时。反应液冷却至室温，加入水(300mL)，室温搅拌1小时，沉淀物抽滤，水洗涤，干燥得到将叔-丁基4-((7- 环丙氧基-4-羟基喹唑啉-6-基)氧基)哌啶-1-羧酸酯粗产物(6.5g粗品)。粗产物直接用于下一步反应。MS m/z(ESI):402[M+H] +。 To 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-cyclopropoxybenzoic acid (7.7 g crude, 70% pure, 13.7 mmol) To the ethylene glycol monomethyl ether (100 mL) solution was added formamidine acetate (5.72 g, 54.9 mmol), and the reaction mixture was stirred at 130° C. for 1 hour. The reaction solution was cooled to room temperature, water (300 mL) was added, stirred at room temperature for 1 hour, the precipitate was suction filtered, washed with water, and dried to obtain tert-butyl 4-((7-cyclopropoxy-4-hydroxyquinazoline- Crude 6-yl)oxy)piperidine-1-carboxylate (6.5 g crude). The crude product was directly used in the next reaction. MS m/z (ESI): 402 [M+H] + .
第六步：叔-丁基4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The sixth step: the synthesis of tert-butyl 4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy) piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000060
Figure PCTCN2021132029-appb-000060
向叔-丁基4-((7-环丙氧基-4-羟基喹唑啉-6-基)氧基)哌啶-1-羧酸酯(2.3g，5.16mmol)二氯乙烷(50mL)溶液中加入N,N-二异丙基乙胺(5.11mL，30.94mmol)和三氯氧磷(1.92mL，20.62mmol)，将反应混合物在80℃下搅拌反应3小时。反应液冷却至室温，倒入冰水中，饱和碳酸氢钠溶液碱化，二氯甲烷萃取。有机相旋蒸浓缩，残留物柱层析分离[展开剂:石油醚/乙酸乙酯＝0～20％]得到叔-丁基4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-羧酸酯(1.60g，收率：74％)。MS m/z(ESI):420[M+H] +。 To tert-butyl 4-((7-cyclopropoxy-4-hydroxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (2.3 g, 5.16 mmol) dichloroethane ( N,N-diisopropylethylamine (5.11 mL, 30.94 mmol) and phosphorus oxychloride (1.92 mL, 20.62 mmol) were added to the solution in 50 mL), and the reaction mixture was stirred at 80° C. for 3 hours. The reaction solution was cooled to room temperature, poured into ice water, basified with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was concentrated by rotary evaporation, and the residue was separated by column chromatography [developing solvent: petroleum ether/ethyl acetate=0～20%] to obtain tert-butyl 4-((4-chloro-7-cyclopropoxyquinazoline -6-yl)oxy)piperidine-1-carboxylate (1.60 g, yield: 74%). MS m/z (ESI): 420 [M+H] + .
第七步：4-氯-7-环丙氧基-6-(哌啶-4-氧基)喹唑啉盐酸的合成The seventh step: the synthesis of 4-chloro-7-cyclopropoxy-6-(piperidine-4-oxy) quinazoline hydrochloride
Figure PCTCN2021132029-appb-000061
Figure PCTCN2021132029-appb-000061
向叔-丁基4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-羧酸酯(1.60g，3.81mmol)的1,4-二氧六环(10mL)溶液中加入氯化氢/1,4-二氧六环溶液(20mL，80mmol，4mol/L)，反应混合物室温搅拌反应3小时。反应液减压旋蒸浓缩得到4-氯-7-环丙氧基-6-(哌啶-4-氧基)喹唑啉盐酸(1.35g)。粗产物直接用于下一步反应。MS m/z(ESI):320[M+H] +。 To tert-butyl 4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (1.60 g, 3.81 mmol) in 1,4- Hydrogen chloride/1,4-dioxane solution (20 mL, 80 mmol, 4 mol/L) was added to the dioxane (10 mL) solution, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain 4-chloro-7-cyclopropoxy-6-(piperidin-4-oxy)quinazoline hydrochloride (1.35 g). The crude product was directly used in the next reaction. MS m/z (ESI): 320 [M+H] + .
第八步：1-(4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成The eighth step: synthesis of 1-(4-((4-chloro-7-cyclopropoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
Figure PCTCN2021132029-appb-000062
Figure PCTCN2021132029-appb-000062
向4-氯-7-环丙氧基-6-(哌啶-4-氧基)喹唑啉盐酸(1.35g粗品，纯度：75％，2.84mmol)的四氢呋喃(30mL)溶液中加入水(15mL)和碳酸氢钠(1.19g，14.2mmol)，反应混合物冷却至0℃，逐滴加入丙烯酰氯(386mg，4.26mmol)。反应液0℃搅拌反应30分钟。反应液加入乙酸乙酯和饱和食盐水稀释，分液，有机相减压旋蒸浓缩，残留物柱层析分离得到1-(4-((4-氯-7-环丙氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮(980mg，收率：89.5％)。MS m/z(ESI):374[M+H] +。 To a solution of 4-chloro-7-cyclopropoxy-6-(piperidin-4-oxy)quinazoline hydrochloride (1.35 g crude, purity: 75%, 2.84 mmol) in tetrahydrofuran (30 mL) was added water ( 15 mL) and sodium bicarbonate (1.19 g, 14.2 mmol), the reaction mixture was cooled to 0 °C and acryloyl chloride (386 mg, 4.26 mmol) was added dropwise. The reaction solution was stirred at 0°C for 30 minutes. The reaction solution was diluted with ethyl acetate and saturated brine, the layers were separated, the organic phase was concentrated by rotary evaporation under reduced pressure, and the residue was separated by column chromatography to obtain 1-(4-((4-chloro-7-cyclopropoxyquinazoline -6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (980 mg, yield: 89.5%). MS m/z (ESI): 374 [M+H] + .
中间体8-37可参照中间体7全部或部分合成方法选择相应的原料进行制备:Intermediates 8-37 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 7:
Figure PCTCN2021132029-appb-000063
Figure PCTCN2021132029-appb-000063
Figure PCTCN2021132029-appb-000064
Figure PCTCN2021132029-appb-000064
Figure PCTCN2021132029-appb-000065
Figure PCTCN2021132029-appb-000065
中间体38：叔-丁基4-((4-氯-7-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸酯的制备Intermediate 38: Preparation of tert-butyl 4-((4-chloro-7-methylquinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000066
Figure PCTCN2021132029-appb-000066
第一步：4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基苯甲酸的合成The first step: Synthesis of 4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitrobenzoic acid
Figure PCTCN2021132029-appb-000067
Figure PCTCN2021132029-appb-000067
将叔-丁基4-羟基哌啶-1-羧酸酯(6.63g，33mmol)置于干燥N,N-二甲基甲酰胺(100mL)中，冰浴冷却下加入钠氢(1.32g，33mmol)搅拌30分钟，然后加入4-溴-5-氟-2-硝基苯甲酸(4.35g，16.48mmol)，反应液室温搅拌过夜。反应液用水淬灭，二氯甲烷萃取，然后水相用稀盐酸调节至pH值接近2左右，再用乙酸乙酯萃取，有机相直接浓缩，得到4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基苯甲酸(7.3g)，粗品直接用于下一步反应。MS m/z(ESI):345/347[M-100+H] +。 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. -Butoxycarbonyl)piperidin-4-yl)oxy)-2-nitrobenzoic acid (7.3g), the crude product was directly used in the next reaction. MS m/z (ESI): 345/347[M-100+H] + .
第二步：2-氨基-4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)苯甲酸的合成The second step: the synthesis of 2-amino-4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid
Figure PCTCN2021132029-appb-000068
Figure PCTCN2021132029-appb-000068
将4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基苯甲酸(4.45g，10.00mmol)置于水(100mL)和甲醇(100mL)中，加入氯化铵(6.41g，119.9mmol)以及铁粉(4.47g，79.95mmol)，反应液加热到60℃搅拌18小时。反应液过滤，滤液浓缩得到2-氨基-4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)苯甲酸(5.2g)，直接用于下一步反应。MS m/z(ESI):416/418[M+H] +。 4-Bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitrobenzoic acid (4.45 g, 10.00 mmol) was dissolved in water (100 mL) and Ammonium chloride (6.41 g, 119.9 mmol) and iron powder (4.47 g, 79.95 mmol) were added to methanol (100 mL), and the reaction solution was heated to 60° C. and stirred for 18 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain 2-amino-4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid (5.2g), which was directly used in the following one-step reaction. MS m/z (ESI): 416/418 [M+H] + .
第三步：叔-丁基4-((7-溴-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The third step: synthesis of tert-butyl 4-((7-bromo-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000069
Figure PCTCN2021132029-appb-000069
将2-氨基-4-溴-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)苯甲酸(5.2g，12.52mmol)置于乙二醇单甲醚(30mL)中，加入醋酸甲咪(5.21g，50.09mmol)，反应液加热到100℃搅拌1小时。反应液旋干溶剂，加入水析出固体，过滤，滤饼干燥后得到叔-丁基4-((7-溴-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(4.2g，收率79％)。MS m/z(ESI):424/426[M+H] +。 2-Amino-4-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid (5.2 g, 12.52 mmol) was placed in ethylene glycol monomethyl ether (30 mL), methyl imidate acetate (5.21 g, 50.09 mmol) was added, and the reaction solution was heated to 100° C. and stirred for 1 hour. The 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). MS m/z (ESI): 424/426 [M+H] + .
第四步：叔-丁基4-((7-甲基-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The fourth step: the synthesis of tert-butyl 4-((7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy) piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000070
Figure PCTCN2021132029-appb-000070
将叔-丁基4-((7-溴-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(212mg，0.50mmol)，四甲基锡烷(0.14mL，1.00mmol)，三(2-甲基苯基)磷(15.2mg，0.05mmol)，三((1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮)二钯(22.88mg，0.03mmol)置于N,N-二甲基甲酰胺(5mL)，在氮气保护下，将反应液加热到90℃搅拌2小时。反应液浓缩然后柱层析分离得到叔-丁基4-((7-甲基-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(180mg)。MS m/z(ESI):360[M+H] +。 tert-Butyl 4-((7-bromo-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (212 mg, 0.50 mmol), Tetramethylstannane (0.14 mL, 1.00 mmol), tris(2-methylphenyl)phosphorus (15.2 mg, 0.05 mmol), tris((1E,4E)-1,5-diphenylpentane-1, 4-Dien-3-one)dipalladium (22.88 mg, 0.03 mmol) was placed in N,N-dimethylformamide (5 mL), and the reaction solution was heated to 90°C and stirred for 2 hours under nitrogen protection. The reaction solution was concentrated and separated by column chromatography to obtain tert-butyl 4-((7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxyl acid ester (180 mg). MS m/z (ESI): 360 [M+H] + .
第五步：叔-丁基4-((4-氯-7-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The fifth step: the synthesis of tert-butyl 4-((4-chloro-7-methylquinazolin-6-yl)oxy) piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000071
Figure PCTCN2021132029-appb-000071
将叔-丁基4-((7-甲基-4-氧代-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(180mg，0.50mmol)，置于二氯乙烷(10mL)，加入二异丙基乙胺(0.50mL，3.01mmol)以及三氯氧磷(0.19mL，2.00mmol)，将反应液加热到80℃搅拌18小时。反应液浓缩然后用柱层析分离得到叔-丁基4-((4-氯-7-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸酯(90mg，收率50％)。MS m/z(ESI):379[M+H] +。 tert-Butyl 4-((7-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (180 mg, 0.50 mmol) , placed in dichloroethane (10 mL), added diisopropylethylamine (0.50 mL, 3.01 mmol) and phosphorus oxychloride (0.19 mL, 2.00 mmol), and the reaction solution was heated to 80 °C and stirred for 18 hours. The reaction solution was concentrated and separated by column chromatography to obtain tert-butyl 4-((4-chloro-7-methylquinazolin-6-yl)oxy)piperidine-1-carboxylate (90 mg, yield 50%). MS m/z (ESI): 379 [M+H] + .
中间体39-41可参照中间体38全部或部分合成方法选择相应的原料进行制备:Intermediates 39-41 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 38:
Figure PCTCN2021132029-appb-000072
Figure PCTCN2021132029-appb-000072
中间体42：叔-丁基4-((4-氯-7-(三氟甲基)喹唑啉-6-基)氧基)哌啶-1-羧酸酯的制备Intermediate 42: Preparation of tert-butyl 4-((4-chloro-7-(trifluoromethyl)quinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000073
Figure PCTCN2021132029-appb-000073
第一步：甲基5-氟-2-硝基-4-(三氟甲基)苯酸酯的合成The first step: the synthesis of methyl 5-fluoro-2-nitro-4-(trifluoromethyl) benzoate
Figure PCTCN2021132029-appb-000074
Figure PCTCN2021132029-appb-000074
将甲基4-溴-5-氟-2-硝基苯酸酯(1.2g，4.32mmol)置于干燥N,N-二甲基甲酰胺(2mL)中，加入碘化亚铜(740mg，3.89mmol)，以及甲基2,2-二氟-2-(氟磺酰)乙酸酯(4.94mL，38.83mmol)，反应液90℃搅拌过夜。过滤，滤液浓缩，残留物柱层析分离得到甲基5-氟-2-硝基-4-(三氟甲基)苯酸酯(900mg，收率：16％)。Methyl 4-bromo-5-fluoro-2-nitrobenzoate (1.2 g, 4.32 mmol) was placed in dry N,N-dimethylformamide (2 mL), and cuprous iodide (740 mg, 3.89 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (4.94 mL, 38.83 mmol), the reaction solution was stirred at 90°C overnight. After filtration, the filtrate was concentrated, and the residue was separated by column chromatography to obtain methyl 5-fluoro-2-nitro-4-(trifluoromethyl)benzoate (900 mg, yield: 16%).
第二步：叔-丁基4-(5-(甲酯基(甲氧羰基))-4-硝基-2-(三氟甲基)苯氧基)哌啶-1-羧酸酯的合成The second step: tert-butyl 4-(5-(methoxycarbonyl(methoxycarbonyl))-4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate synthesis
Figure PCTCN2021132029-appb-000075
Figure PCTCN2021132029-appb-000075
将叔-丁基4-羟基哌啶-1-羧酸酯(1.36g，6.74mmol)置于干燥N,N-二甲基甲酰胺(10mL)中，冰浴冷却下加入钠氢(269mg，6.74mmol)搅拌一个小时，然后加入甲基5-氟-2-硝基-4-(三氟甲基)苯酸酯(900mg，0.67mmol)，反应液室温搅拌过夜，得到叔-丁基4-(5-(甲酯基(甲氧羰基))-4-硝基-2-(三氟甲基)苯氧基)哌啶-1-羧酸酯。反应液直接用于下一步反应。MS m/z(ESI):393[M-56+H] +。 The tert-butyl 4-hydroxypiperidine-1-carboxylate (1.36g, 6.74mmol) was placed in dry N,N-dimethylformamide (10mL), and sodium hydrogen (269mg, 6.74 mmol) was stirred for one hour, then methyl 5-fluoro-2-nitro-4-(trifluoromethyl) benzoate (900 mg, 0.67 mmol) was added, and the reaction solution was stirred at room temperature overnight to obtain tert-butyl 4 -(5-(Carbomethoxy(methoxycarbonyl))-4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate. The reaction solution was directly used in the next reaction. MS m/z (ESI): 393 [M-56+H] + .
第三步：5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基-4-(三氟甲基)苯甲酸的合成The third step: Synthesis of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitro-4-(trifluoromethyl)benzoic acid
Figure PCTCN2021132029-appb-000076
Figure PCTCN2021132029-appb-000076
将叔-丁基4-(5-(甲酯基(甲氧羰基))-4-硝基-2-(三氟甲基)苯氧基)哌啶-1-羧酸酯反应液(1.51g，3.37mmol)中依次加入水(100mL)，氢氧化钠(673.5mg，16.84mmol)，室温搅拌三个小时，反应液二氯甲烷萃取，水相用稀盐酸调节至pH值接近2左右，乙酸乙酯萃取，有机相直接浓缩，得到5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基-4-(三氟甲基)苯甲酸(1.46g)，直接用于下一步反应。MS m/z(ESI):379[M-56+H] +。 The tert-butyl 4-(5-(methoxycarbonyl(methoxycarbonyl))-4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate reaction solution (1.51 g, 3.37mmol) in turn, add water (100mL), sodium hydroxide (673.5mg, 16.84mmol), stir at room temperature for three hours, the reaction solution is extracted with dichloromethane, and the aqueous phase is adjusted to about pH 2 with dilute hydrochloric acid, Ethyl acetate extraction, the organic phase was directly concentrated to obtain 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitro-4-(trifluoromethyl)benzene Formic acid (1.46 g) was used directly in the next reaction. MS m/z (ESI): 379 [M-56+H] + .
第四步：2-氨基-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-(三氟甲基)苯甲酸的合成The fourth step: the synthesis of 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-(trifluoromethyl)benzoic acid
Figure PCTCN2021132029-appb-000077
Figure PCTCN2021132029-appb-000077
将5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-2-硝基-4-(三氟甲基)苯甲酸(1.46g，3.37mmol)置于甲醇(50mL)中，加入氯化铵(1.44g，26.94mmol)以及铁粉(940.51mg，16.840mmol)，反应液加热到60℃搅拌3小时。反应液过滤，滤液浓缩得到2-氨基-5-((1-(叔-丁氧基羰基)哌啶-4-基)氧基)-4-(三氟甲基)苯甲酸(1.36g)。粗品直接用于下一步反应。MS m/z(ESI):349[M-56+H] +。 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-nitro-4-(trifluoromethyl)benzoic acid (1.46 g, 3.37 mmol) was placed in To methanol (50 mL), ammonium chloride (1.44 g, 26.94 mmol) and iron powder (940.51 mg, 16.840 mmol) were added, and the reaction solution was heated to 60°C and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain 2-amino-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4-(trifluoromethyl)benzoic acid (1.36g) . The crude product was directly used in the next reaction. MS m/z (ESI): 349 [M-56+H] + .
第五步：叔-丁基4-((4-氧代-7-(三氟甲基)-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The fifth step: tert-butyl 4-((4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylic acid Synthesis of Esters
Figure PCTCN2021132029-appb-000078
Figure PCTCN2021132029-appb-000078
将叔-丁基4-((4-氧代-7-(三氟甲基)-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(1.36g，3.368mmol)置于乙二醇单甲醚(30mL)中，加入醋酸甲咪(1.40g，13.47mmol)，然后反应液加热到90℃搅拌18小时。反应液旋干，柱层析分离得到叔-丁基4-((4-氧代-7-(三氟甲基)-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(350mg粗品，纯度：16％，收率：4.02％)。MS m/z(ESI):414[M+H] +。 tert-Butyl 4-((4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (1.36 g, 3.368 mmol) was placed in ethylene glycol monomethyl ether (30 mL), methyl imidate acetate (1.40 g, 13.47 mmol) was added, and the reaction solution was heated to 90°C and stirred for 18 hours. The reaction solution was spin-dried and separated by column chromatography to obtain tert-butyl 4-((4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)oxy)piperidine Pyridin-1-carboxylate (350 mg crude, purity: 16%, yield: 4.02%). MS m/z (ESI): 414 [M+H] + .
第六步：叔-丁基4-((4-氯-7-(三氟甲基)喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The sixth step: synthesis of tert-butyl 4-((4-chloro-7-(trifluoromethyl)quinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000079
Figure PCTCN2021132029-appb-000079
将叔-丁基4-((4-氧代-7-(三氟甲基)-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-羧酸酯(50mg，0.12mmol)，置于二氯乙烷(5mL)，加入二异丙基乙胺(0.12mL，0.73mmol)以及三氯氧磷(0.05mL，0.48mmol)，将反应液加热到搅拌18小时。反应液浓缩然后用柱层析分离得到叔-丁基4-((4-氯-7-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸酯(20mg，收率：38％)。MS m/z(ESI):432.3[M+H] +。 tert-Butyl 4-((4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg , 0.12mmol), placed in dichloroethane (5mL), added diisopropylethylamine (0.12mL, 0.73mmol) and phosphorus oxychloride (0.05mL, 0.48mmol), the reaction solution was heated to stirring for 18 hours . The reaction solution was concentrated and then separated by column chromatography to obtain tert-butyl 4-((4-chloro-7-methylquinazolin-6-yl)oxy)piperidine-1-carboxylate (20 mg, yield : 38%). MS m/z (ESI): 432.3 [M+H] + .
中间体43：叔丁基-4-((4-氯喹唑啉-6-基)氧基)哌啶-1-羧酸酯的制备Intermediate 43: Preparation of tert-butyl-4-((4-chloroquinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000080
Figure PCTCN2021132029-appb-000080
第一步：喹唑啉-4,6-二醇的合成The first step: synthesis of quinazoline-4,6-diol
Figure PCTCN2021132029-appb-000081
Figure PCTCN2021132029-appb-000081
将2-氨基-5-羟基苯甲酸(15g，98mmol)溶于甲酰胺(150mL)中，200℃搅拌1小时后，冷却至室温加入水(50mL)，过滤，滤饼用水洗数次，最后用甲基叔丁基醚洗涤1次，干燥得到喹唑啉-4,6-二醇(12g，收率：75％)。MS m/z(ESI):163[M+H] +。 2-Amino-5-hydroxybenzoic acid (15 g, 98 mmol) was dissolved in formamide (150 mL), stirred at 200° C. for 1 hour, cooled to room temperature, added water (50 mL), filtered, and the filter cake was washed with water several times, and finally It was washed once with methyl tert-butyl ether, and dried to obtain quinazoline-4,6-diol (12 g, yield: 75%). MS m/z (ESI): 163 [M+H] + .
第二步：4-羟基喹唑啉-6-基乙酸酯的合成The second step: the synthesis of 4-hydroxyquinazolin-6-yl acetate
Figure PCTCN2021132029-appb-000082
Figure PCTCN2021132029-appb-000082
将喹唑啉-4,6-二醇(2g，12.33mmol)溶于乙酸酐(15mL)中，加入吡啶(3mL)，100℃搅拌5小时，浓缩反应液，加入适量水，析出固体，过滤，干燥得到4-羟基喹唑啉-6-基乙酸酯(1.3g，收率：51％)。MS m/z(ESI):205[M+H] +。 Dissolve quinazoline-4,6-diol (2 g, 12.33 mmol) in acetic anhydride (15 mL), add pyridine (3 mL), stir at 100°C for 5 hours, concentrate the reaction solution, add an appropriate amount of water, precipitate out solid, filter , and dried to obtain 4-hydroxyquinazolin-6-yl acetate (1.3 g, yield: 51%). MS m/z (ESI): 205 [M+H] + .
第三步：4-氯喹唑啉-6-基乙酸酯的合成The third step: the synthesis of 4-chloroquinazolin-6-yl acetate
Figure PCTCN2021132029-appb-000083
Figure PCTCN2021132029-appb-000083
将4-羟基喹唑啉-6-基乙酸酯(800mg，3.92mmol)溶于氯化亚砜(10mL)中，滴加DMF(1mL)，85℃搅拌过夜，浓缩后加入适量乙酸乙酯，冰浴下加入碳酸氢钠饱和溶液，分离乙酸乙酯，食盐水洗涤，无水硫酸钠干燥，过滤后浓缩，柱层析分离得到4-氯喹唑啉-6-基乙酸酯(700mg，收率：80％)。MS m/z(ESI):223[M+H] +。 4-Hydroxyquinazolin-6-yl acetate (800 mg, 3.92 mmol) was dissolved in thionyl chloride (10 mL), DMF (1 mL) was added dropwise, stirred at 85°C overnight, concentrated and then added an appropriate amount of ethyl acetate , a saturated solution of sodium bicarbonate was added under an ice bath, ethyl acetate was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 4-chloroquinazolin-6-yl acetate (700 mg, Yield: 80%). MS m/z (ESI): 223 [M+H] + .
第四步：4-氯喹唑啉-6-醇的合成The fourth step: the synthesis of 4-chloroquinazolin-6-ol
Figure PCTCN2021132029-appb-000084
Figure PCTCN2021132029-appb-000084
将4-氯喹唑啉-6-基乙酸酯(700mg，3.144mmol)溶于甲醇(5mL)中，加入7N氨甲醇溶液(15mL)，室温搅拌3小时，加入甲基叔丁基醚，析出沉淀产物，过滤，滤饼用适量甲基叔丁基醚洗涤，干燥后得到4-氯喹唑啉-6-醇(600mg，收率：95％)。MS m/z(ESI):179[M+H] +。 Dissolve 4-chloroquinazolin-6-yl acetate (700 mg, 3.144 mmol) in methanol (5 mL), add 7N ammonia methanol solution (15 mL), stir at room temperature for 3 hours, add methyl tert-butyl ether, and precipitate The product was precipitated, filtered, and the filter cake was washed with an appropriate amount of methyl tert-butyl ether, and dried to obtain 4-chloroquinazolin-6-ol (600 mg, yield: 95%). MS m/z (ESI): 179 [M+H] + .
第五步：叔丁基-4-((4-氯喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The fifth step: the synthesis of tert-butyl-4-((4-chloroquinazolin-6-yl)oxy) piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000085
Figure PCTCN2021132029-appb-000085
将4-氯喹唑啉-6-醇(600mg，3.32mmol)，叔丁基4-羟基哌啶-1-羧酸酯(1g，4.98mmol)，三苯基磷(1.3g，4.98mmol)，偶氮二甲酸二异丙酯(1g，4.98mmol)溶于干燥二氯甲烷(20mL)中，氮气保护下室温搅拌过夜，加入硅胶浓缩后柱层析得到叔丁基-4-((4-氯喹唑啉-6-基)氧基)哌啶-1-羧酸酯(800mg，收率：66％)。MS m/z(ESI):364[M+H] +。 4-Chloroquinazolin-6-ol (600 mg, 3.32 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.98 mmol), triphenylphosphine (1.3 g, 4.98 mmol), Diisopropyl azodicarboxylate (1 g, 4.98 mmol) was dissolved in dry dichloromethane (20 mL), stirred overnight at room temperature under nitrogen protection, added silica gel and concentrated, and then column chromatography gave tert-butyl-4-((4- Chloroquinazolin-6-yl)oxy)piperidine-1-carboxylate (800 mg, yield: 66%). MS m/z (ESI): 364 [M+H] + .
中间体44-53可参照中间体43全部或部分合成方法选择相应的原料进行制备:Intermediates 44-53 can be prepared with reference to all or part of the synthesis methods of intermediate 43 by selecting corresponding raw materials:
Figure PCTCN2021132029-appb-000086
Figure PCTCN2021132029-appb-000086
Figure PCTCN2021132029-appb-000087
Figure PCTCN2021132029-appb-000087
二、具体实施例的制备Two, the preparation of specific embodiment
实施例1：1-(4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的制备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
Figure PCTCN2021132029-appb-000088
Figure PCTCN2021132029-appb-000088
第一步：叔丁基-4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-羧酸酯的合成The first step: tert-butyl-4-((4-((2-fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy) Synthesis of Phenyl)amino)quinazolin-6-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2021132029-appb-000089
Figure PCTCN2021132029-appb-000089
将叔丁基-4-((4-氯喹唑啉-6-基)氧基)哌啶-1-羧酸酯(50mg，0.137mmol)，2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯胺(30mg，0.106mmol)溶于异丙醇(10mL)中，80℃搅拌过夜，浓缩后柱层析得到叔丁基-4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-羧酸酯(50mg，收率：77％)。MS m/z(ESI):612[M+H] +。 tert-Butyl-4-((4-chloroquinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg, 0.137 mmol), 2-fluoro-4-(((1-(6- Methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline (30 mg, 0.106 mmol) was dissolved in isopropanol (10 mL), stirred at 80°C overnight, concentrated and subjected to column chromatography to obtain tertiary Butyl-4-((4-((2-Fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenyl)amino) Quinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg, yield: 77%). MS m/z (ESI): 612 [M+H] + .
第二步：N-(2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)-6-(哌啶-4-氧基)喹唑啉-4-胺的合成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
Figure PCTCN2021132029-appb-000090
Figure PCTCN2021132029-appb-000090
将叔丁基-4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-羧酸酯(50mg，0.0818mmol)溶于二氯甲烷(5mL)中，加 入三氟乙酸(1mL)，室温搅拌1小时后浓缩干燥得到粗品N-(2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)-6-(哌啶-4-氧基)喹唑啉-4-胺的三氟乙酸盐(100mg，收率：100％)，直接用于下一步反应。MS m/z(ESI):512[M+H] +。 tert-Butyl-4-((4-((2-fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenyl) Amino)quinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg, 0.0818 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and after stirring at room temperature for 1 hour Concentrate and dry to obtain crude N-(2-fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenyl)-6-(piperidine -4-Oxy)quinazolin-4-amine trifluoroacetate salt (100 mg, yield: 100%), which was directly used in the next reaction. MS m/z (ESI): 512 [M+H] + .
第三步：1-(4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成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
Figure PCTCN2021132029-appb-000091
Figure PCTCN2021132029-appb-000091
将N-(2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)-6-(哌啶-4-氧基)喹唑啉-4-胺的三氟乙酸盐(100mg，0.0818mmol)溶于四氢呋喃(4mL)和饱和碳酸氢钠水溶液(1mL)中，置于冰浴下后加入烯丙酰氯(11mg，0.121mmol)，搅拌10分钟后反应完成，直接反相柱分离得到1-(4-((4-((2-氟-4-((1-(6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮(24mg，收率：52％)。MS m/z(ESI):566[M+H] +。 N-(2-Fluoro-4-((1-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)phenyl)-6-(piperidine-4- The trifluoroacetate salt of oxy)quinazolin-4-amine (100 mg, 0.0818 mmol) was dissolved in tetrahydrofuran (4 mL) and saturated aqueous sodium bicarbonate (1 mL), placed under an ice bath and added with allyl chloride ( 11 mg, 0.121 mmol), the reaction was completed after stirring for 10 minutes, and 1-(4-((4-((2-fluoro-4-((1-(6-methylpyridin-3-yl) was then obtained by direct reverse-phase column separation. )-1H-pyrazol-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (24 mg, received rate: 52%). MS m/z (ESI): 566 [M+H] + .
1H NMR(400MHz,MeOH-d 4)δ8.73(d,J＝2.6Hz,1H),8.34(s,1H),8.19(d,J＝2.6Hz,1H),7.97(dd,J＝8.5,2.7Hz,1H),7.80(d,J＝2.5Hz,1H),7.69(d,J＝9.1Hz,1H),7.58-7.51(m,1H),7.51-7.44(m,1H),7.32(d,J＝8.5Hz,1H),7.15-7.01(m,2H),6.78-6.66(m,1H),6.19-6.08(m,2H),5.66(dd,J＝10.5,2.0Hz,1H),4.83-4.76(m,1H),3.96-3.80(m,2H),3.63-3.50(m,2H),2.48(s,3H),2.11-1.97(m,2H),1.87-1.69(m,2H)。 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.73 (d, J=2.6 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J=2.6 Hz, 1H), 7.97 (dd, J= 8.5,2.7Hz,1H),7.80(d,J=2.5Hz,1H),7.69(d,J=9.1Hz,1H),7.58-7.51(m,1H),7.51-7.44(m,1H), 7.32(d,J=8.5Hz,1H),7.15-7.01(m,2H),6.78-6.66(m,1H),6.19-6.08(m,2H),5.66(dd,J=10.5,2.0Hz, 1H), 4.83-4.76(m, 1H), 3.96-3.80(m, 2H), 3.63-3.50(m, 2H), 2.48(s, 3H), 2.11-1.97(m, 2H), 1.87-1.69( m, 2H).
实施例2～10，30～34可参照实施例1全部或部分合成方法选择相应的原料进行制备: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:
Figure PCTCN2021132029-appb-000092
Figure PCTCN2021132029-appb-000092
Figure PCTCN2021132029-appb-000093
Figure PCTCN2021132029-appb-000093
Figure PCTCN2021132029-appb-000094
Figure PCTCN2021132029-appb-000094
实施例11：1-(3-((4-((2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮的制备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
Figure PCTCN2021132029-appb-000095
Figure PCTCN2021132029-appb-000095
将1-(3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮(28mg，0.087mmol)和2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯胺(26mg，0.087mmol)置于异丙醇(3mL)中，加入三氟醋酸(1滴)，反应液50℃搅拌反应3小时。反应液直接浓缩，残留物经反相柱层析分离得到1-(3-((4-((2-氟-4-((1-(5-氟-6-甲基吡啶-3-基)-1H-吡唑-3-基)氧基)苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)吖丁啶-1-基)丙-2-烯-1-酮(23mg，收率：45％)。MS m/z(ESI):586[M+H] +。 1-(3-((4-Chloro-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one (28 mg, 0.087 mmol ) and 2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)aniline (26 mg, 0.087 mmol) were placed in iso To propanol (3 mL), trifluoroacetic acid (1 drop) was added, and the reaction solution was stirred at 50°C for 3 hours. The reaction solution was directly concentrated, and the residue was separated by reverse-phase column chromatography to obtain 1-(3-((4-((2-fluoro-4-((1-(5-fluoro-6-methylpyridin-3-yl) )-1H-pyrazol-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-ene- 1-keto (23 mg, yield: 45%). MS m/z (ESI): 586 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.81(d,J＝2.0Hz,1H),8.62(d,J＝2.6Hz,1H),8.36(s,1H),8.10(d,J＝10.7Hz,1H),7.58-7.48(m,2H),7.32-7.22(m,2H),7.13(dd,J＝8.7,2.6Hz,1H),6.44-6.32(m,2H),6.14(dd,J＝17.0,2.1Hz,1H),5.70(dd,J＝10.1,2.1Hz,1H),5.22-5.17(m,1H),4.80(t,J＝8.2Hz,1H),4.57(dd,J＝11.0,6.6Hz,1H),4.29(d,J＝10.0Hz,1H),3.98-3.94(m,4H),2.48(d,J＝2.5Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.46(s, 1H), 8.81(d, J=2.0Hz, 1H), 8.62(d, J=2.6Hz, 1H), 8.36(s, 1H) ,8.10(d,J＝10.7Hz,1H),7.58-7.48(m,2H),7.32-7.22(m,2H),7.13(dd,J＝8.7,2.6Hz,1H),6.44-6.32(m ,2H),6.14(dd,J＝17.0,2.1Hz,1H),5.70(dd,J＝10.1,2.1Hz,1H),5.22-5.17(m,1H),4.80(t,J＝8.2Hz, 1H), 4.57 (dd, J=11.0, 6.6Hz, 1H), 4.29 (d, J=10.0Hz, 1H), 3.98-3.94 (m, 4H), 2.48 (d, J=2.5Hz, 3H).
实施例12～24、26～29和35～54可参照实施例11全部或部分合成方法选择相应的原料进行制备: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:
Figure PCTCN2021132029-appb-000096
Figure PCTCN2021132029-appb-000096
Figure PCTCN2021132029-appb-000097
Figure PCTCN2021132029-appb-000097
Figure PCTCN2021132029-appb-000098
Figure PCTCN2021132029-appb-000098
Figure PCTCN2021132029-appb-000099
Figure PCTCN2021132029-appb-000099
Figure PCTCN2021132029-appb-000100
Figure PCTCN2021132029-appb-000100
Figure PCTCN2021132029-appb-000101
Figure PCTCN2021132029-appb-000101
Figure PCTCN2021132029-appb-000102
Figure PCTCN2021132029-appb-000102
上述实施例制备得到的化合物的核磁数据如下：The NMR data of the compounds prepared in the above examples are as follows:
Figure PCTCN2021132029-appb-000103
Figure PCTCN2021132029-appb-000103
Figure PCTCN2021132029-appb-000104
Figure PCTCN2021132029-appb-000104
Figure PCTCN2021132029-appb-000105
Figure PCTCN2021132029-appb-000105
Figure PCTCN2021132029-appb-000106
Figure PCTCN2021132029-appb-000106
Figure PCTCN2021132029-appb-000107
Figure PCTCN2021132029-appb-000107
生物学测试评价Biological Test Evaluation
一、细胞增殖实验1. Cell proliferation experiment
(一)试剂和耗材(1) Reagents and consumables
胎牛血清FBS(GBICO,Cat#10099-141)；Fetal bovine serum FBS (GBICO, Cat#10099-141);
Figure PCTCN2021132029-appb-000108
发光法细胞活力检测试剂盒(Promega,Cat#G7572)；
Figure PCTCN2021132029-appb-000108
Luminescence cell viability detection kit (Promega, Cat#G7572);
黑色透明平底96孔板，(
Figure PCTCN2021132029-appb-000109
Cat#3603)。 Black transparent flat bottom 96-well plate, (
Figure PCTCN2021132029-appb-000109
Cat#3603).
(二)仪器(2) Instruments
SpectraMax多标记微孔板检测仪MD,2104-0010A；SpectraMax Multi-label Microplate Detector MD, 2104-0010A;
二氧化碳培养箱，Thermo Scientific 3100系列；CO2 incubator, Thermo Scientific 3100 series;
生物安全柜，Thermo Scientific，1300系列A2型；Biological Safety Cabinet, Thermo Scientific, 1300 Series Type A2;
倒置显微镜，Olympus,CKX41SF；Inverted microscope, Olympus, CKX41SF;
西门子冰箱KK25E76TI。Siemens refrigerator KK25E76TI.
(三)细胞系和培养条件(3) Cell lines and culture conditions
No.No. 细胞系cell line 细胞培养基cell culture medium 细胞密度Cell density
11 A431A431 DMEM+15％FBSDMEM+15%FBS 50005000
22 Ba/F3 EGFR-D770-N771ins_SVDBa/F3 EGFR-D770-N771ins_SVD RPMI1640+10％FBSRPMI1640+10%FBS 30003000
33 Ba/F3 EGFR-V769_D770insASVBa/F3 EGFR-V769_D770insASV RPMI1640+10％FBSRPMI1640+10%FBS 30003000
(四)实验步骤(4) Experimental steps
1、细胞培养和接种：1. Cell culture and inoculation:
(1)收获处于对数生长期的细胞，并使用血小板计数器对细胞进行计数。通过锥虫蓝排除法检测细胞活力，以确保细胞活力在90％以上。(1) Harvest cells in logarithmic growth phase and count the cells using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability was above 90%.
(2)调整细胞浓度以达到最终密度；将90μL细胞悬液添加到96孔板中。(2) Adjust the cell concentration to reach the final density; add 90 μL of the cell suspension to a 96-well plate.
(3)将细胞在96孔板中于37℃，5％CO 2和95％湿度下孵育过夜。 (3) Incubate the cells in a 96-well plate overnight at 37°C, 5% CO2 and 95% humidity.
2、T0基准数据：2. T0 benchmark data:
(1)在装有细胞的T0平板的每个孔中加入10μL PBS。(1) Add 10 μL of PBS to each well of the T0 plate containing cells.
(2)解冻CTG试剂，并将细胞板平衡至室温30分钟。(2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(3)向每个孔中添加等体积的CTG溶液。(3) Add an equal volume of CTG solution to each well.
(4)在定轨振荡器上振动5分钟以裂解细胞。(4) Shake for 5 minutes on an orbital shaker to lyse cells.
(5)将细胞板在室温下放置20分钟以稳定发光信号。(5) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.
(6)读取T0发光信号值。(6) Read the T0 light-emitting signal value.
3、化合物稀释和添加3. Compound dilution and addition
(1)根据化合物信息表，将相应体积的DMSO加入相应的化合物粉末中，以 制备10mM储备液。(1) According to the compound information table, the corresponding volume of DMSO was added to the corresponding compound powder to prepare a 10 mM stock solution.
(2)准备1000倍，3.16倍稀释的化合物溶液。(2) Prepare a 1000-fold, 3.16-fold diluted compound solution.
(3)用PBS将1000×稀释的化合物溶液稀释100倍，以制备10倍的化合物溶液，最高浓度为10μM，9种浓度，稀释3.16倍，在接种有96孔板的每个孔中加入10μL药物溶液，接种细胞。每个化合物的浓度设置三个重复孔，DMSO的最终浓度为0.1％。(3) Dilute the 1000× diluted compound solution 100 times with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μM, 9 concentrations, diluted 3.16 times, and add 10 μL to each well inoculated with a 96-well plate Drug solution, seeded cells. Three replicate wells were set up for each compound concentration and the final concentration of DMSO was 0.1%.
(4)将细胞置于装有药物的96孔板中，温度为37℃，5％CO 2和95％湿度，继续培养72小时，然后进行CTG分析。 (4) 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.
4、发光信号读取4, luminous signal reading
(1)解冻CTG试剂，并将细胞板平衡至室温30分钟。(1) Thaw CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(2)向每个孔中添加等体积的CTG溶液。(2) Add an equal volume of CTG solution to each well.
(3)在定轨振荡器上振动5分钟以裂解细胞。(3) Shake on an orbital shaker for 5 minutes to lyse cells.
(4)将细胞板在室温放置20分钟以稳定发光信号。(4) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.
(5)读取发光值。(5) Read the luminous value.
5、数据处理5. Data processing
使用GraphPad Prism 7.0软件分析数据，并使用非线性S曲线回归拟合数据以获得剂量效应曲线，并据此计算IC 50值(单位：nM)，具体实验结果见表1： Use GraphPad Prism 7.0 software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-response curve, and calculate the IC 50 value (unit: nM) accordingly. The specific experimental results are shown in Table 1:
细胞存活率(％)＝(Lum试验药物-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%)=(Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control)×100%.
表1：生物学测试结果Table 1: Biological Test Results
Figure PCTCN2021132029-appb-000110
Figure PCTCN2021132029-appb-000110
Figure PCTCN2021132029-appb-000111
Figure PCTCN2021132029-appb-000111
从具体实施例化合物生物活性数据来看，本发明系列化合物在细胞水平上对EGFR外显子20插入突变具有很强的抑制作用，且对EGFR WT具有很强的选择性。与阳性化合物相比，部分化合物在Ba/F3EGFR-V769_D770insASV细胞中相对于EGFR WT(野生型)细胞抑制增殖的活性的选择性提高了50％以上，例如实施例1、11、12、13和48，尤其是实施例1和12的选择性高达60倍以上；最令人意外的是实施例12化合物除了具有在Ba/F3EGFR-V769_D770insASV细胞中相对于EGFR WT(野生型)细胞抑制增殖的活性的高选择性之外，同时还具有在Ba/F3EGFR-D770-N771ins_SVD细胞中相对于EGFR WT(野生型)细胞抑制增殖的活性的高选择性，选择性高达75倍。Judging from the biological activity data of the compounds in the specific examples, 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. Compared with the positive compounds, 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. In addition to high selectivity, it also has high selectivity in Ba/F3EGFR-D770-N771ins_SVD cells relative to EGFR WT (wild-type) cells in inhibiting proliferation activity, with a selectivity of up to 75 times.
二、小鼠药代动力学实验2. Pharmacokinetic Experiments in Mice
1.试验药品1. Test drug
本试验用化合物来自本发明具体实施例化合物。The compounds used in this test are derived from the compounds of specific examples of the present invention.
2.试验动物2. Experimental animals
ICR小鼠雄性N＝3原始来源：上海西普尔-必凯实验动物有限公司。ICR mice male N=3Original source: Shanghai Sipple-Bike Laboratory Animal Co., Ltd.
3.药物配制与给药3. Drug formulation and administration
称取化合物分别溶于0.5％SDS+0.5％CMCNa的溶媒中，摇匀、超声，配成无色澄清溶液。3只小鼠，禁食一夜后口服。给药剂量为10mg/kg。给药方式分别为ICR小鼠经单次口服(PO)。The compounds 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.
4.样品采集：4. Sample collection:
约90μL/时间点经眼眶取血，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。采血时间点为0,0.25,0.5,1,2,4,6,8,24小时。样品放于负20℃冰箱保存。小鼠安乐死后，取3-5μL脑脊液(CSF)干冰保存。心脏灌流后取脑组织0.1-0.2g，干冰保存，采集时间点均为1h，4h，24h。About 90 μL/time point blood was collected from the orbit, anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). Blood collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The samples were stored in a refrigerator at minus 20°C. After the mice were euthanized, 3-5 μL of cerebrospinal fluid (CSF) was taken and stored on dry ice. After cardiac perfusion, 0.1-0.2 g of brain tissue was collected and stored on dry ice. The collection time points were 1h, 4h, and 24h.
血浆样品40μL，加入160μL含有内标的冰冷乙腈，2)脑组织1：5重量比加入生理盐水进行匀浆，然40μL脑匀浆加入160uL含有内标的冰冷乙腈；3)脑脊液稀释到40μL，加入160μL含有内标的冰冷乙腈乙腈。涡旋3分钟，11000转/分钟离心5分钟。取上清液100μL加入到100μL水中，取5μL进样到LC/MS/MS进行分析。40 μL of plasma sample was added with 160 μL of ice-cold acetonitrile containing internal standard; 2) Brain tissue was homogenized by adding physiological saline at a weight ratio of 1:5, then 40 μL of brain homogenate was added with 160 μL of ice-cold acetonitrile containing internal standard; 3) CSF was diluted to 40 μL, and 160 μL was added Ice-cold acetonitrile acetonitrile with internal standard. Vortex for 3 minutes and centrifuge at 11,000 rpm for 5 minutes. 100 μL of the supernatant was added to 100 μL of water, and 5 μL was injected into LC/MS/MS for analysis.
三、血浆和脑蛋白结合率实验3. Plasma and brain protein binding rate experiments
1.试验步骤1. Test procedure
1.1配制50mM磷酸钠缓冲溶液，pH7.4。1.1 Prepare 50 mM sodium phosphate buffer solution, pH 7.4.
用磷酸二氢钠(NaH 2PO 4)，磷酸氢二钠(Na 2HPO 4)，氯化钠(NaCl)配制50mM磷酸钠缓冲溶液，用NaOH或H 3PO4调节pH至7.4+/-0.1。 Prepare 50 mM sodium phosphate buffer solution with sodium dihydrogen phosphate (NaH 2 PO 4 ), disodium hydrogen phosphate (Na 2 HPO 4 ), sodium chloride (NaCl), adjust pH to 7.4+/-0.1 with NaOH or H 3 PO 4 .
1.2受试化合物以及对照品分别溶于DMSO，配成10mM储备液。1.2 The test compound and the reference substance were respectively dissolved in DMSO to prepare a 10 mM stock solution.
1.3给药溶液的配制：1.3 Preparation of dosing solution:
10mM待测化合物和阳性化合物逐步稀释，稀释成终浓度的20×溶液(20μM)：Stepwise dilutions of 10 mM test compound and positive compound to a final concentration of 20X solution (20 μM):
500μM溶液:将10μL的10mM储备液加入到190μL DMSO中；500 μM solution: Add 10 μL of 10 mM stock to 190 μL DMSO;
20μM溶液:将8μL的500μM溶液加入到192μL的50mM磷酸钠缓冲溶液中。使其DMSO的终浓度为4％。20 μM solution: Add 8 μL of 500 μM solution to 192 μL of 50 mM sodium phosphate buffer solution. Its final concentration of DMSO was 4%.
1.4 1μM待测化合物和阳性化合物给药基质的配制：1.4 Preparation of 1 μM test compound and positive compound administration matrix:
将20μL的20μM基质加入到380μL血浆或者脑中，配成最终给药基质。20 μL of 20 μM matrix was added to 380 μL of plasma or brain to form the final dosing matrix.
1.5收集0小时样品：取25μL含化合物的基质加入到空白的96孔收集板中，储存于-20℃。1.5 Collect 0-hour samples: Add 25 μL of compound-containing matrix to a blank 96-well collection plate and store at -20°C.
1.6准备平衡透析装置1.6 Preparing the Equilibrium Dialysis Set
将100μL缓冲液加入到平衡透析板的接收侧。Add 100 μL of buffer to the receiving side of the equilibrated dialysis plate.
再将100μL含受试化合物或阳性化合物的给药基质(见步骤1.4)加入到平衡透析板的给药侧。An additional 100 μL of the dosing matrix containing the test compound or positive compound (see step 1.4) was added to the dosing side of the equilibrated dialysis plate.
将准备好的平衡透析板置于37℃摇床中以60转/分钟速度振摇5小时。The prepared equilibrated dialysis plate was placed in a shaker at 37°C for 5 hours at 60 rpm.
1.7在孵育结束时(5小时)，样品制备：1.7 At the end of the incubation (5 hours), sample preparation:
1.7.1制备接收侧(Receiver)样品：1.7.1 Prepare Receiver samples:
由接收侧的样品取出25μL，置于96孔样品收集板中，加入相同体积的基质(空白血浆)混合。25 μL 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).
加入200μL含内标的ACN，样品涡旋振荡10分钟，然后5594×g离心15分钟。200 μL of ACN containing internal standard was added, the samples were vortexed for 10 minutes, and then centrifuged at 5594×g for 15 minutes.
1.7.2制备给药侧(Donor)样品：1.7.2 Prepare the sample on the administration side (Donor):
1μM受试化合物及1μM阳性化合物给药侧样品：取25μL给药侧样品，加入25μL空白缓冲溶液混合。1 μM test compound and 1 μM positive compound dosing side sample: Take 25 μL dosing side sample, add 25 μL blank buffer solution and mix.
加入200μL含内标的ACN，于600转/分钟振荡10分钟，然后在离心机(Thermo，Multifuge×3R)上采用5594×g离心15分钟。200 μL of ACN containing internal standard was added, shaken at 600 rpm for 10 minutes, and then centrifuged at 5594×g for 15 minutes in a centrifuge (Thermo, Multifuge×3R).
1.7.3制备0小时样品：1.7.3 Prepare 0-hour samples:
0小时样品37℃复融，样品制备同给药侧样品。The samples were thawed at 37°C for 0 hours, and the sample preparation was the same as that of the dosing side samples.
1.7.4所有样品离心后，制备样品送至LC-MS/MS分析。1.7.4 After centrifugation of all samples, prepare samples for LC-MS/MS analysis.
1.8通过以下公式计算血浆或者脑蛋白结合率：1.8 Calculate the plasma or brain protein binding rate by the following formula:
结合率％＝([给药侧] 5h-[接收侧] 5h)/[给药侧] 5h×100％ Binding rate % = ([administration side] 5h - [receiving side] 5h )/[administration side] 5h × 100%
Fu％＝100％-结合率％，Fu是未结合分数。Fu%=100%-% bound, Fu is the unbound fraction.
四、小鼠中的血脑屏障穿透分析4. Analysis of blood-brain barrier penetration in mice
通过上述方法测得的脑或血浆中的AUC或者浓度和Fu来计算Kp,uu脑。Kp,uu脑是指脑和血液中未结合药物浓度之间的关系，用于评估药物穿透血脑屏障的能力。给药后的Kpu,uu脑通过以下的公式进行计算：Kp,uubrain 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,uu脑＝[AUC(脑)/AUC(血浆)]×[Fu(脑)/Fu(血浆)]。或者Kp,uuBrain=[AUC(brain)/AUC(plasma)]×[Fu(brain)/Fu(plasma)]. or
Kp,uu脑＝[药物浓度(脑)/药物浓度(血浆)]×[Fu(脑)/Fu(血浆)。Kp,uuBrain=[Drug Concentration(Brain)/Drug Concentration(Plasma)]×[Fu(Brain)/Fu(Plasma).
表2：示例性化合物的Kp,uu脑的数据Table 2: Kp,uu Brain Data for Exemplary Compounds
   Kp,uu脑(给药1h)Kp, uu brain (administration 1h) Kp,uu脑(给药4h)Kp, uu brain (administration 4h)
实施例12Example 12 0.100.10 0.060.06
阳性化合物positive compound 0.010.01 <0.01<0.01
由上述数据可知，阳性化合物是一个基本不入脑的化合物，本发明实施例12化合物具有一定的入脑效果。从入脑测试数据来看，本发明实施例12化合物与阳性化合物相比具有更高的Kp,uu脑，试验证明本发明实施例12化合物具有更优异的脑屏障穿透特性。It can be seen from the above data that 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. From the data of the brain penetration test, 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.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (20)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021132029-appb-100001
    Figure PCTCN2021132029-appb-100001
    其中，X 1和X 2各自独立地为CR 7或N；Y为CR 8或N；Z为NR 9或O； Wherein, X 1 and X 2 are each independently CR 7 or N; Y is CR 8 or N; Z is NR 9 or O;
    环A为3-12元含氮杂环基，优选选自以下基团：
    Figure PCTCN2021132029-appb-100002
    Figure PCTCN2021132029-appb-100003
    Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
    Figure PCTCN2021132029-appb-100002
    Figure PCTCN2021132029-appb-100003
    每个R 1独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and - C 0-8 alkyl-N(R 13 )-C(O)R 12 ;
    每个R 2独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12，或者，当n≥2时，相邻的两个R 2与其直接相连的部分一起形成一个C 4-8环烷基或5-8元杂环基； Each R2 is independently selected from hydrogen , deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, halo-substituted C1-10 alkyl, deuterium substituted C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , - C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl- C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and - C 0-8 alkyl-N(R 13 )-C(O)R 12 , or, when n≥2, two adjacent R 2 together with their directly attached moieties form a C 4-8 cycloalkyl or 5-8 membered heterocyclyl;
    R 3和R 4各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； 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选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 11、-C(O)R 12、-C(O)-NR 13R 14和-C 0-4烷基-NR 13R 14； 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 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10 芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O)OR 11 , -C 0-8 Alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0-8 alkyl-C(=NR 13 ) R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and -C 0-8 alkyl-N(R 13 )-C(O)R 12 ;
    R 6和R 8各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 10、-C 0-8烷基-O-R 11、-C 0-8烷基-C(O)OR 11、-C 0-8烷基-C(O)R 12、-C 0-8烷基-O-C(O)R 12、-C 0-8烷基-NR 13R 14、-C 0-8烷基-C(＝NR 13)R 12、-C 0-8烷基-N(R 13)-C(＝NR 14)R 12、-C 0-8烷基-C(O)NR 13R 14和-C 0-8烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
    Figure PCTCN2021132029-appb-100004
    时，R 8不为未取代或卤取代C 1-4烷氧基；     R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-8 aryl group, 5-8-membered heteroaryl group, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )- C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 , the above-mentioned groups independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, halo-substituted C1-10 alkyl, deuterium substituted C1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, =O , -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 10 , -C 0-8 alkyl-OR 11 , -C 0-8 alkyl-C(O ) OR 11 , -C 0-8 alkyl-C(O)R 12 , -C 0-8 alkyl-OC(O)R 12 , -C 0-8 alkyl-NR 13 R 14 , -C 0 -8 alkyl-C(=NR 13 )R 12 , -C 0-8 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-8 alkyl-C(O)NR 13 R 14 and -C 0-8 alkyl-N(R 13 )-C(O)R 12 substituents, provided that when ring A is
    Figure PCTCN2021132029-appb-100004
    , R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
    R 9选自氢、氘、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基和3-12元杂环基； 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;
    每个R 10独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl radicals, 5-10-membered heteroaryl groups and -NR 13 R 14 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 substituted by the substituents of aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 13 R 14 ;
    每个R 11独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 11 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 13 R 14 substituents;
    每个R 12独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 13R 14的取代基所取代； Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl group, 5-10 membered heteroaryloxy and -NR 13 R 14 , the above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl , C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 13 R 14 ;
    每个R 13和R 14各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺 酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each of R 13 and R 14 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-10 alkanoyl, the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3- 12 -cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered Substituted by substituents of heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;
    或者，R 13和R 14与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 13 and R 14 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further substituted by one or more selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, Deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy , C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkane substituted by substituents of amino and C 1-10 alkanoyl;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
    每个r独立地为0、1或2。Each r is independently 0, 1, or 2.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12； The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein 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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )-C (=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 ;
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12，或者，当n≥2时，相邻的两个R 2与其直接相连的部分一起形成一个C 4-8环烷基或5-8元杂环基； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain 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 , -C 0-4 alkyl-C(=NR 13 ) R 12 , -C 0-4 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 Alkyl-N(R 13 )-C(O)R 12 , or, when n≥2, two adjacent R 2 together with their directly attached moieties form a C 4-8 cycloalkyl or 5-8 membered heterocyclic group;
    R 3和R 4各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； 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选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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 6和R 8各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、 -O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
    Figure PCTCN2021132029-appb-100005
    时，R 8不为未取代或卤取代C 1-4烷氧基；     R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 10 , -OR 11 , -C(O)OR 11 , -C (O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , -N(R 13 )-C(=NR 14 )R 12 , -C(O ) NR 13 R 14 and -N(R 13 )-C(O)R 12 , the above-mentioned groups are independently optionally further selected by one or more groups selected from 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 3-8 cycloalkyl, 3- 8-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 ) Substituents of -C(=NR 14 )R 12 , -C 0-4 alkyl-C(O)NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 substituted, provided that when ring A is
    Figure PCTCN2021132029-appb-100005
    , R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
    R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 9选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基和3-6元杂环基； 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;
    其中，X 1、X 2、Y、Z、环A、m、n、R 10、R 11、R 12、R 13、R 14和r如权利要求1所定义。 wherein X 1 , X 2 , Y, Z, Ring A, m, n, R 10 , R 11 , R 12 , R 13 , R 14 and r are as defined in claim 1 .
  3. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅱa)化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of the following formula (IIa):
    Figure PCTCN2021132029-appb-100006
    Figure PCTCN2021132029-appb-100006
    其中，Z为NR 9或O； Wherein, Z is NR 9 or O;
    环A为3-12元含氮杂环基，优选选自以下基团：
    Figure PCTCN2021132029-appb-100007
    Figure PCTCN2021132029-appb-100008
    Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
    Figure PCTCN2021132029-appb-100007
    Figure PCTCN2021132029-appb-100008
    R 1a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、 5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 1b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 3选自氢、氘、卤素和C 1-4烷基； R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl;
    R 5选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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 8选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、-O-R 11、-O-C(O)R 12、-NR 13R 14、-N(R 13)-C(＝NR 14)R 12和-N(R 13)-C(O)R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 10、-C 0-4烷基-O-R 11、-C 0-4烷基-C(O)OR 11、-C 0-4烷基-C(O)R 12、-C 0-4烷基-O-C(O)R 12、-C 0-4烷基-NR 13R 14、-C 0-4烷基-C(＝NR 13)R 12、-C 0-4烷基-N(R 13)-C(＝NR 14)R 12、-C 0-4烷基-C(O)NR 13R 14和-C 0-4烷基-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
    Figure PCTCN2021132029-appb-100009
    时，R 8不为未取代或卤取代C 1-4烷氧基；     R 8 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycle base, -OR 11 , -OC(O)R 12 , -NR 13 R 14 , -N(R 13 )-C(=NR 14 )R 12 and -N(R 13 )-C(O)R 12 , The above groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, 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 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl , =O, -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 , -C 0-4 alkyl-C(=NR 13 )R 12 , -C 0-4 alkyl-N(R 13 )-C(=NR 14 )R 12 , -C 0-4 alkyl-C( O) NR 13 R 14 and -C 0-4 alkyl-N(R 13 )-C(O)R 12 substituents, provided that when ring A is
    Figure PCTCN2021132029-appb-100009
    , R 8 is not unsubstituted or halogen-substituted C 1-4 alkoxy;
    R 9选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
    其中，R 10、R 11、R 12、R 13、R 14和r如权利要求1所定义。 wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as defined in claim 1 .
  4. 根据权利要求3所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Z为NH或O；The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, wherein Z is NH or O;
    R 1a选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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 2选自氢、氘、氟、氯、溴和氰基； R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
    R 3选自氢、氘和氟； R is selected from hydrogen, deuterium and fluorine;
    R 5选自氢、氘和甲基。 R 5 is selected from hydrogen, deuterium and methyl.
  5. 根据权利要求3所述的式(I)化合物、其立体异构体或其药学上可接受盐， 其特征在于，环A选自以下基团：
    Figure PCTCN2021132029-appb-100010
    The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 3, wherein ring A is selected from the following groups:
    Figure PCTCN2021132029-appb-100010
  6. 根据权利要求3所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 8选自C 3-6环烷氧基、3-6元杂环烷氧基、C 3-6环烷基C 1-4烷氧基和3-6元杂环烷基C 1-4烷氧基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12的取代基所取代；其中，R 10、R 11、R 12、R 13、R 14和r如权利要求1所定义。 The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, wherein R 8 is selected from C 3-6 cycloalkoxy, 3-6 membered heterocycloalkane oxy, C 3-6 cycloalkyl C 1-4 alkoxy and 3-6 membered heterocycloalkyl C 1-4 alkoxy, independently optionally further selected by one or more groups selected from deuterium , halogen, cyano, nitro, azido, 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, =O, -SF 5 , -S(O) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , -N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 substituents; wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as defined in claim 1 .
  7. 根据权利要求6所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 8选自
    Figure PCTCN2021132029-appb-100011
    Figure PCTCN2021132029-appb-100012
    所述
    Figure PCTCN2021132029-appb-100013
    Figure PCTCN2021132029-appb-100014
    各自独立地任选进一步被一个或多个选自氘、氟、氯、甲基、甲氧基、氰基和硝基的取代基所取代。     The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 6, wherein R 8 is selected from
    Figure PCTCN2021132029-appb-100011
    Figure PCTCN2021132029-appb-100012
    said
    Figure PCTCN2021132029-appb-100013
    Figure PCTCN2021132029-appb-100014
    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.
  8. 根据权利要求3所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 8选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链炔基、C 1-2烷氧基、C 3-6环烷基、3-6元杂环基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12的取代基所取代，条件是当环A为
    Figure PCTCN2021132029-appb-100015
    时，R 8不为未取代或卤取代C 1-2烷氧基；其中，R 10、R 11、R 12、R 13、R 14和r如权利要求1所定义。     The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, wherein R 8 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 1-2 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -NR 13 R 14 , the above-mentioned groups are independently optionally further substituted by one or more one is selected from deuterium, halogen, cyano, nitro, azido, 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, =O, -SF5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - Substituents of N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 , provided that when Ring A is
    Figure PCTCN2021132029-appb-100015
    , R 8 is not unsubstituted or halo-substituted C 1-2 alkoxy; wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as defined in claim 1 .
  9. 根据权利要求8所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 8选自氢、氘、氟、氯、溴、氰基、甲基、二氟甲基、三氟甲基、乙炔基、甲氧基、乙氧基、一氟甲氧基、甲氧基乙氧基、三氟乙氧基、环丙基、吗啉基、3-氯-丙胺基、三氟乙胺基、2-甲氧基乙胺基、
    Figure PCTCN2021132029-appb-100016
    Figure PCTCN2021132029-appb-100017
    所述
    Figure PCTCN2021132029-appb-100018
    各自独立地任选进一步被一个或多个选自氘、氟、氯、甲基、甲氧基、氰基和硝基的取代基所取代，条件是当环A为
    Figure PCTCN2021132029-appb-100019
    时，R 8不为甲氧基、乙氧基、一氟甲氧基或三氟乙氧基。     The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 8, wherein 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,
    Figure PCTCN2021132029-appb-100016
    Figure PCTCN2021132029-appb-100017
    said
    Figure PCTCN2021132029-appb-100018
    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
    Figure PCTCN2021132029-appb-100019
    , R 8 is not methoxy, ethoxy, monofluoromethoxy or trifluoroethoxy.
  10. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅱb)化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of the following formula (IIb):
    Figure PCTCN2021132029-appb-100020
    Figure PCTCN2021132029-appb-100020
    其中，Z为NR 9或O； Wherein, Z is NR 9 or O;
    环A为3-12元含氮杂环基，优选选自以下基团：
    Figure PCTCN2021132029-appb-100021
    Figure PCTCN2021132029-appb-100022
    Ring A is a 3-12 membered nitrogen-containing heterocyclic group, preferably selected from the following groups:
    Figure PCTCN2021132029-appb-100021
    Figure PCTCN2021132029-appb-100022
    R 1a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 1b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 1b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(＝NR 13)R 12、-N(R 13)-C(＝NR 14)R 12、-C(O)NR 13R 14和-N(R 13)-C(O)R 12； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 10 , -OR 11 , -C(O)OR 11 , -C(O)R 12 , -OC(O)R 12 , -NR 13 R 14 , -C(=NR 13 )R 12 , - N(R 13 )-C(=NR 14 )R 12 , -C(O)NR 13 R 14 and -N(R 13 )-C(O)R 12 ;
    R 3选自氢、氘、卤素和C 1-4烷基； R is selected from hydrogen, deuterium, halogen and C 1-4 alkyl;
    R 5选自氢、氘、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 13R 14； 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选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 9 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
    其中，R 10、R 11、R 12、R 13、R 14和r如权利要求1所定义。 wherein R 10 , R 11 , R 12 , R 13 , R 14 and r are as defined in claim 1 .
  11. 根据权利要求10所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Z为O；The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 10, wherein Z is O;
    R 1a选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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选自氢、氘、氟、氯、溴、氰基、环丙基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； 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 2选自氢、氘、氟、氯、溴和氰基； R is selected from hydrogen , deuterium, fluorine, chlorine, bromine and cyano;
    R 3选自氢、氘和氟； R is selected from hydrogen, deuterium and fluorine;
    R 5选自氢、氘和甲基。 R 5 is selected from hydrogen, deuterium and methyl.
  12. 根据权利要求10所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自以下基团：
    Figure PCTCN2021132029-appb-100023
    The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 10, wherein ring A is selected from the following groups:
    Figure PCTCN2021132029-appb-100023
  13. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 10独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 13 R 14 , the above groups are independent optionally further selected by one or more selected from deuterium, halogen, hydroxyl, =O, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy base, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 13 R 14 substituents are substituted;
    每个R 11独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； Each R 11 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 13 R 14 substituents;
    每个R 12独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 13R 14的取代基所取代； Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy and -NR 13 R 14 , the above groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl , C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 13 R 14 ;
    每个R 13和R 14各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷 基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 13 and R 14 is independently selected from hydrogen, deuterium, hydroxyl, 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, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6 -cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered Substituted by substituents of heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
    或者，R 13和R 14与其直接相连的氮原子一起形成一个4-8元杂环基或5-8元杂芳基，所述4-8元杂环基或5-8元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、＝O、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 13 and R 14 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group or 5-8 membered heteroaryl group, said 4-8 membered heterocyclic group or 5-8 membered heteroaryl group being either is further substituted by one or more selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy , C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkane substituted with substituents of amino and C 1-4 alkanoyl groups.
  14. 根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, characterized in that, it is selected from the following compounds:
    Figure PCTCN2021132029-appb-100024
    Figure PCTCN2021132029-appb-100024
    Figure PCTCN2021132029-appb-100025
    Figure PCTCN2021132029-appb-100025
    Figure PCTCN2021132029-appb-100026
    Figure PCTCN2021132029-appb-100026
    Figure PCTCN2021132029-appb-100027
    Figure PCTCN2021132029-appb-100027
    Figure PCTCN2021132029-appb-100028
    Figure PCTCN2021132029-appb-100028
  15. 一种根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：A preparation method of the compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, comprises the steps:
    Figure PCTCN2021132029-appb-100029
    Figure PCTCN2021132029-appb-100029
    Figure PCTCN2021132029-appb-100030
    Figure PCTCN2021132029-appb-100030
    其中，X为卤素，优选选自氟、氯和溴；环A、R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、Y、Z、m和n如权利要求1中所定义。 wherein 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 claim 1.
  16. 一种药物组合物，其包含根据权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  17. 根据权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分由与EGFR外显子20插入或缺失突变相关的癌症、肿瘤或转移性疾病的药物中的用途。A compound of formula (I) according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of therapeutic and/or prophylactic at least in part by insertion or deletion with EGFR exon 20 Use in the medicament of mutation-related cancers, tumors or metastatic disease.
  18. 根据权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的用途。The compound of formula (I) according to any one of claims 1-14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is used in the manufacture of preventing and/or treating tumors caused by hyperproliferation and inducing cell death disorders, Use in the medicament of cancer and/or metastatic disease.
  19. 根据权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗至少部分由与EGFR外显子20插入或缺失突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的药物中的用途。A compound of formula (I) according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of prophylactic and/or therapeutic at least in part by insertion or deletion with EGFR exon 20 Mutation-related lung cancer, 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 tumor, thoracic tumor, Drugs for gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, naso-inverted papilloma, or naso-inverted papilloma-related squamous cell carcinoma use in.
  20. 根据权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分由与EGFR外显子20插入或缺失突变相关的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 14, for use in therapy and/or prophylaxis, at least in part by insertion with EGFR exon 20 Lung cancer, 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 cancer, thoracic cavity Neoplasms, gastrointestinal neoplasms, endocrine neoplasms, breast and other gynecological neoplasms, urological neoplasms, skin neoplasms, sarcomas, naso-inverted papilloma or nasosinus-associated squamous cell carcinoma the use of.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567466A (en) * 2024-01-16 2024-02-20 成都金瑞基业生物科技有限公司 Preparation method of quinazoline derivative

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882573A (en) * 2003-09-16 2006-12-20 阿斯利康(瑞典)有限公司 Quinazoline derivatives as tyrosine kinase inhibitors
CN101679384A (en) * 2007-06-05 2010-03-24 韩美药品株式会社 Novel amide derivative for inhibiting the growth of cancer cells
WO2020009156A1 (en) * 2018-07-04 2020-01-09 第一三共株式会社 Biaryl ether-type quinazoline derivative
WO2020061470A1 (en) * 2018-09-21 2020-03-26 Spectrum Pharmaceuticals, Inc. Novel quinazoline egfr inhibitors
WO2021231400A1 (en) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl ethers containing n-acyl azetidine as egfr/her2 inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882573A (en) * 2003-09-16 2006-12-20 阿斯利康(瑞典)有限公司 Quinazoline derivatives as tyrosine kinase inhibitors
CN101679384A (en) * 2007-06-05 2010-03-24 韩美药品株式会社 Novel amide derivative for inhibiting the growth of cancer cells
WO2020009156A1 (en) * 2018-07-04 2020-01-09 第一三共株式会社 Biaryl ether-type quinazoline derivative
WO2020061470A1 (en) * 2018-09-21 2020-03-26 Spectrum Pharmaceuticals, Inc. Novel quinazoline egfr inhibitors
WO2021231400A1 (en) * 2020-05-12 2021-11-18 Accutar Biotechnology, Inc. Bis-aryl ethers containing n-acyl azetidine as egfr/her2 inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567466A (en) * 2024-01-16 2024-02-20 成都金瑞基业生物科技有限公司 Preparation method of quinazoline derivative
CN117567466B (en) * 2024-01-16 2024-04-16 成都金瑞基业生物科技有限公司 Preparation method of quinazoline derivative

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