WO2025051148A1 - Composé hétéroaryle contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Composé hétéroaryle contenant de l'azote, son procédé de préparation et son utilisation Download PDF

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WO2025051148A1
WO2025051148A1 PCT/CN2024/116822 CN2024116822W WO2025051148A1 WO 2025051148 A1 WO2025051148 A1 WO 2025051148A1 CN 2024116822 W CN2024116822 W CN 2024116822W WO 2025051148 A1 WO2025051148 A1 WO 2025051148A1
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group
methyl
membered
ethyl
amino
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薛海
石和鹏
张培龙
李祥秋
兰文丽
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Beijing Avistone Biotechnology Co Ltd
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    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and in particular relates to nitrogen-containing heteroaryl compounds and preparation methods and applications thereof.
  • the epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21). It is one of the four members of the ErbB family (EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB31 and HER4/ErbB4) and has tyrosine kinase activity. No ligand that can directly interact with HER2 has been found. HER2 can form heterodimers with other members of the ErbB family to activate the downstream MEK/ERK/MAPK pathway and PI3K/AKT bypass for signal transduction, ultimately promoting cell growth, proliferation and division.
  • Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been shown to be associated with many cancers, including breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, endometrial cancer and glioblastoma.
  • the detection rates of HER2 overexpression in lung cancer, breast cancer, gastric cancer, bile duct cancer, ovarian cancer and endometrial cancer are approximately 2.5%, 15% to 25%, 20%, 20%, 27% and 18% to 80%, respectively.
  • the detection rate of HER2 mutation in non-small cell lung cancer is about 2%-4%, among which exon 20 insertion mutation accounts for 71% of HER2 mutations, including common subtypes such as A772_G775dup (55.0%), G776delinsVC (8.3%), G778_P780dup (5.6%) and G776delinsLC (2.1%).
  • Other HER2 mutations include exon 19 mutation L755P (1.9%), exon 21 mutation V842I (0.7%), transmembrane domain mutation V659E (4.1%) and G660D (0.9%), and extracellular region mutation D277Y (1.9%), S310F (7.7%), S310Y (1.9%) and A466V (1.4%).
  • mAbs monoclonal antibodies
  • TKIs small molecule tyrosine kinase inhibitors
  • ADCs antibody-drug conjugates
  • Monoclonal antibodies and antibody-drug conjugates have poor selectivity for wild-type EGFR, and are large-molecule drugs that are not easy to penetrate the blood-brain barrier. In addition, some patients will develop drug resistance or relapse after using monoclonal antibodies (mAbs) for a period of time.
  • mAbs monoclonal antibodies
  • Currently approved TKIs include selective TKI (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib) show moderate antitumor activity against wild-type HER2, but have poor effects against the most common HER2 exon 20 insertion mutation.
  • non-selective TKIs have poor selectivity for wild-type EGFR and are prone to adverse reactions such as rash and diarrhea. Therefore, it is of great significance to develop HER2 inhibitors that are selective, can penetrate the blood-brain barrier, and have potential inhibitory effects on HER2 exon 20 insertion mutations.
  • the present invention aims to provide a nitrogen-containing heteroaryl compound and a preparation method and application thereof.
  • the nitrogen-containing heteroaryl compound has good activity in inhibiting HER2 exon 20 insertion mutation and has high selectivity for wild-type EGFR.
  • the present invention is achieved through the following technical solutions.
  • the present invention provides a compound having a structure as shown in the following formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof:
  • M is N or CR 3 ;
  • X is N or CR 4 ;
  • A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, 6-10-membered aryl, 5-10-membered heteroaryl, C 1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl-C 1-6 alkylene-oxy, 3-12-membered heterocyclyl-C 1-6 alkylene-oxy, C 1-6 alkylthiol, 3-12 -membered cycloalkylthiol, 3-12-membered heterocyclylthiol, 3-12-membered cycloalkyl-C 1-6 alkylene-thiol or 3-12-membered heterocyclyl-C 1-6 alkylene-thiol, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 al
  • Y 1 is a chemical bond, CR 5 R 6 , a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R′;
  • Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , wherein the 3-12 membered heterocyclic group is optionally substituted by one or more R′;
  • Z is C( ⁇ O) or S(O) 2 ;
  • L 1 is NR 8 , O, CR 5 R 6 , S, S(O) or S(O) 2 ;
  • L 2 is a chemical bond, O, NR 8 , CR 5 R 6 , C( ⁇ O), S, S(O) or S(O) 2 ;
  • E is a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are optionally substituted by one or more Re ;
  • G is Said optionally substituted with one or more R′;
  • Ring B is a 5-6 membered heteroaryl, a 5-7 membered heterocyclyl or a 5-7 membered cycloalkyl;
  • X1 is a chemical bond, N, CH, CH2 , O, S, S(O) or S(O) 2 ;
  • X2 is N, CH, CH2 , O, S, S(O) or S(O) 2 ;
  • X3 and X4 are each independently N or C, and X3 and X4 are not N at the same time, and X1 , X2 and X3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O, S, S(O) or S(O) 2 ;
  • R1 is a halomethyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, an oxetane group or a C4-6 cycloalkenyl group, wherein the C2-4 alkenyl group, the C2-4 alkynyl group, the oxetane group and the C4-6 cycloalkenyl group are optionally substituted with one or more halogen, cyano, C1-4 alkyl group, a halo-substituted C1-4 alkyl group, a 3-12-membered cycloalkyl group, a deuterium atom, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, a 6-12-membered aryl group, a C1-3 alkoxy- C1-3 alkyl group, or NRaRb , wherein the C1-4 alkyl group, the halo-substituted C1-4 alkyl group, the
  • R2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the hydroxyl group, the amino group, the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R's;
  • R3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12 -membered heterocyclyloxy group, RcRdNC1-6alkylene -oxy group, a 3-12 -membered cycloalkyl-C1-6alkylene-oxy group, a 3-12 -membered heterocyclyl-C1-6alkylene-oxy group, a C1-6 alkylthiol group, a C1-6 alkylamino group,
  • R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 alkoxy group, a 3-12-membered cycloalkyl group, a 3-12 -membered heterocyclyl group, a C1-6 alkoxy group, a 3-12- membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 alkylthiol group, a C1-6 alkylamino group or a di( C1-6 alkyl)amino group, wherein the amino group, the C1-6 alkyl group, the C2-4 alkenyl group, the C2-4 alkynyl group, the 3-12-membered cycloalkyl group, the 3-12
  • R5 and R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, a 6-10- membered aryl group, a C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12 -membered heterocyclyloxy group, a C1-6 alkylmercapto group, a C1-6 alkylamino group, a di( C1-6 alkyl)amino group, a cyano- C1-6 alkyl-, a C1-6 alkoxy-C1-6 al
  • R 5 together with R 6 and the C atom to which they are attached form a 3-12 membered cycloalkyl or a 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and the 3-12 membered heterocyclyl are optionally substituted by one or more R′;
  • R7 is a hydrogen atom, a C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 haloalkyl group, a 5-12-membered heteroaryl group or a 6-12-membered aryl group, wherein the C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the C1-6 haloalkyl group, the 5-12-membered heteroaryl group and the 6-12-membered aryl group are optionally substituted by one or more R's;
  • R 8 is a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a cyano-C 1-6 alkyl group or a hydroxy C 1-6 alkyl group;
  • Ra and Rb are each independently a hydrogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl- C1-4 alkyl group, a 3-12-membered heterocyclyl group, a 3-12 -membered cycloalkyl- C1-4 alkyl group, a 3-12-membered heterocyclyl group- C1-4 alkyl group, a C1-4 alkoxy- C1-4 alkyl group, or a deuterated C1-4 alkyl group, wherein the C1-4 alkyl group, the C1-4 haloalkyl group, the 3-12 -membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl-C1-4 alkyl group, the 3-12-membered heterocyclyl
  • Ra , Rb and the N atom to which they are attached together form a 3-12 membered heterocyclic group, which is optionally substituted by one or more R';
  • R c and R d are each independently a hydrogen atom, a C 1-6 alkyl group, a C 2-4 alkenyl group, a C 2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl group-C 1-6 alkyl group, or a 3-12-membered heterocyclyl group-C 1-6 alkyl group, wherein the C 1-6 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl group-C 1-6 alkyl group, and the 3-12-membered heterocyclyl group-C 1-6 alkyl group are optionally substituted with one or more R′;
  • Re1 and Re2 are each independently a hydrogen atom, a deuterium atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, or Re1 and Re2 together with the connected N atom form a 3-12-membered heterocyclic group;
  • R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogenated C 1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a halogenated C 1-6 alkoxy group or an oxo group ( ⁇ O).
  • M is N or CR 3 ;
  • R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a C1-6 alkyl group, a halogenated C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12- membered heterocyclyl group, a C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12- membered heterocyclyloxy group, RcRdN - C1-6 alkylene-oxy group, a 3-12-membered cycloalkyl- C1-6 alkylene-oxy group, a 3-12-membered heterocyclyl- C1-6 alkylene-oxy group, a C1-6 alkylthiol group, a C1-6 alkylamino group,
  • R c and R d are each independently a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group, optionally substituted by one or more R ′;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or oxo ( ⁇ O);
  • M is N or CR 3 ;
  • M is N or CR 3 ;
  • R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin
  • X is N or CR 4 ;
  • R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R';
  • R' is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy.
  • A is selected from the following groups:
  • R 5 and R 6 together with the C atom to which they are attached form a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and the 3-12 membered heterocyclyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;
  • Y 1 is a chemical bond, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;
  • R 5 and R 6 together with the C atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl or oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl and oxetanyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy.
  • R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;
  • Y 2 is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or NR 7 , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group; and R 7 is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a
  • Z is C( ⁇ O) or S(O) 2 .
  • L 1 is NR 8 or O
  • R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxy C 1-6 ethyl group;
  • L 1 is NR 8 ;
  • L 2 is a chemical bond, O, CH or C( ⁇ O).
  • E is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more Re ;
  • R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH 3 , SO 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , SO 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl,
  • E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted by one or more Re ;
  • R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH 3 , SO 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , SO2NCH3 , P(O)( CH3 ) 2 or P(O) ( CH2CH3 ) 2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, triflu
  • G is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;
  • Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;
  • X2 is N, CH, CH2 , O, S, S(O) or S(O) 2 ;
  • X3 and X4 are each independently N or C, and X3 and X4 are not N at the same time, and X1 , X2 and X3 are not N at the same time;
  • X 5 is a chemical bond, N, CH, CH 2 , O or S;
  • X6 is N, O, S or CH;
  • G is selected from the following groups:
  • G is selected from the following groups:
  • R a and R b are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl or acridinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl and acridinylethyl are optionally substituted with one or more R ′;
  • R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo ( ⁇ O);
  • R 1 is selected from the following groups:
  • R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • M is N or CR 3 ;
  • R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R';
  • A is C 2-4 alkenyl, C 2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, C 1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl-C 1-6 alkylene-oxy or 3-12-membered heterocyclyl-C 1-6 alkylene-oxy, the C 2-4 alkenyl, C 2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, Phenyl, 5-6 membered heteroaryl, C 1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 alkylene-oxy and 3-12 membered heterocyclyl-C 1-6
  • Y 1 is a chemical bond, CR 5 R 6 , a 3-12 membered cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the 3-12 membered cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;
  • R5 and R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, a 5-12-membered heteroaryl group, a 6-10 -membered aryl group, a cyano- C1-6 alkyl group, a C1-6 alkoxy- C1-6 alkyl group, a C1-6 alkylamino group or a 3-12-membered cycloalkyl- C1-6 alkyl group; the hydroxyl group, the amino group, the C1-6 alkyl group, the halogenated C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclic group, the 5-12-membered heteroaryl group, the 6-10-membered
  • R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;
  • L 1 is NR 8 or O
  • R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxy C 1-6 ethyl group;
  • E is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by one or more Re ;
  • R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH 3 , SO 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , SO 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl,
  • X2 is N, CH, CH2 , O, S, S(O) or S(O) 2 ;
  • X3 and X4 are each independently N or C, and X3 and X4 are not N at the same time, and X1 , X2 and X3 are not N at the same time;
  • X6 is N, O, S or CH;
  • R 1 is a halomethyl group, a vinyl group, a propenyl group, a ethynyl group, a propynyl group, a butynyl group, a glycidyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group, wherein the halomethyl group, the vinyl group, the propenyl group, the ethynyl group, the propynyl group, the butynyl group, the glycidyl group, the cyclobutenyl group, the cyclopentenyl group or the cyclohexenyl group are optionally substituted with one or more F, Cl, a methyl group, an ethyl group, a cyclopropyl group, an acridinyl group, a pyrrolidinyl group, a piperidinyl group, a glycidyl
  • R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo ( ⁇ O);
  • M is N or CR 3 ;
  • R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;
  • Y 1 is a chemical bond, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;
  • R 5 and R 6 are each independently a hydrogen atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one
  • R 5 and R 6 together with the C atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy;
  • Z is C( ⁇ O) or S(O) 2 ;
  • R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group;
  • E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, wherein the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted with one or more Re ;
  • R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH 3 , SO 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , SO 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl,
  • G is selected from the following groups:
  • deuterium atoms F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;
  • R1 is selected from the following groups:
  • R2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • M is N or CR 3 ;
  • R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin
  • X is N or CR 4 ;
  • R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;
  • R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy;
  • A is selected from the following groups:
  • Y 1 is a chemical bond, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;
  • R 5 and R 6 are each independently a hydrogen atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one
  • R 5 and R 6 together with the C atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy;
  • Y 2 is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or a NR 7 , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group;
  • R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;
  • L 1 is NR 8 ;
  • R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group;
  • E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, wherein the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted with one or more Re ;
  • R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH 3 , SO 2 CH 3 , C( ⁇ O)CH 3 , C( ⁇ O)NCH 3 , NHC( ⁇ O)CH 3 , SO 2 NCH 3 , P(O)(CH 3 ) 2 or P(O)(CH 2 CH 3 ) 2 , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl,
  • G is selected from the following groups:
  • R1 is selected from the following groups:
  • R2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • the compound represented by formula I is selected from the following compounds:
  • the present invention provides a method for preparing a compound of formula I, comprising the following reaction steps:
  • Compound I-1 undergoes coupling or substitution reaction with Compound I-2 to form Compound I-3;
  • the present invention provides another method for preparing a compound of formula I, comprising the following reaction steps:
  • the present invention provides another method for preparing compound I-3, comprising the following reaction steps:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient;
  • Suitable dosage forms include (but are not limited to) dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories.
  • These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and the preparation methods and processes are well known, such as those provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
  • the compound or pharmaceutical composition of the present invention can be administered simultaneously with one or more other pharmacologically active substances, so that an additive or even synergistic effect can be achieved in vivo.
  • the compound of the present invention can be combined with other pharmacologically active substances into a pharmaceutical composition, or administered simultaneously as a separate composition, or administered sequentially as a separate composition.
  • the process is carried out under conventional conditions or conditions recommended by the manufacturer.
  • the raw materials or excipients used, as well as the reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be obtained commercially.
  • the minimum and maximum carbon atom content of the hydrocarbon group is indicated by a prefix, for example, the prefix (C ab ) alkyl represents any alkyl group containing from "a" to "b” carbon atoms.
  • (C 1-6 ) alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
  • the alkyl group may be branched or straight chain.
  • the atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.
  • Alkyl refers to a linear or branched, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and other similar groups.
  • the alkyl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, a cyano group, a nitro group, an azido group, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10-membered aryl group, a 5-10-membered heteroaryl group, an oxo ( ⁇ O), a —C 0-6 alkyl-OR
  • Cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon group that can be combined with other groups.
  • Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a 3-8-membered cycloalkyl group More preferably, a 3-6-membered cycloalkyl group. More preferably, a 3-4-membered cycloalkyl group.
  • Polycyclic hydrocarbon groups include linked rings, spiro rings, condensed rings, or bridged ring cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:
  • Cycloalkenyl refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated ⁇ electron system and can be combined with other groups.
  • Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc.
  • 3-8-membered cycloalkenyls More preferably, 3-6-membered cycloalkenyls.
  • Polycyclic cycloalkenyls include linked rings, spiro rings, condensed rings or bridged ring cycloalkenyls. Including but not limited to the following groups:
  • the cycloalkyl or cycloalkenyl group may be fused with an aryl group, a heteroaryl group or a heterocyclic group, including but not limited to a tetrahydronaphthyl group and the like.
  • Alkenyl refers to a straight chain, branched or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl.
  • Alkynyl refers to a straight chain, branched or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. Preferably C2-6 alkynyl. More preferably C2-4 alkynyl.
  • Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
  • Haloalkyl refers to an alkyl group as defined herein, wherein one or more hydrogens have been replaced by the same or different halogens, including but not limited to -CH2Cl , -CHF2 , -CH2CF3 , -CH2CC13 , perfluoroalkyl (eg, -CF3 ), and the like.
  • Alkylamino refers to NH 3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino and the like.
  • Dialkylamino refers to a group having the structure N(C 1-6 alkyl) 2 , including but not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, and the like.
  • Aryl refers to a monocyclic or polycyclic carbon ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, indenyl. Preferably, it is a 6-10 membered monocyclic or bicyclic aromatic group. More preferably, it is phenyl or naphthyl. Most preferably, it is phenyl.
  • Polycyclic systems include fused, bridged or spirocyclic systems.
  • monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc.
  • the heteroaryl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, a cyano group, a nitro group, an azido group, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a deuterated C 1-10 alkyl group, a deuterated C 1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, an oxo ( ⁇ O), a —C 0-6 alkyl-OR e
  • “Pharmaceutically acceptable salt” refers to conventional acid addition salts or base addition salts, which retain the biological effectiveness and properties of the compound of formula I, and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid.
  • N-oxide means that when a compound contains an amine functional group or a heteroaryl compound containing N atoms, one or more N atoms can be oxidized to form a compound containing N + , preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl compound containing N.
  • Hydrophillipate refers to an association formed with a certain amount of water.
  • Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutically acceptable carriers, excipients or diluents.
  • the purpose of a pharmaceutical composition is to facilitate the process of administration to an animal.
  • a pharmaceutical composition may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH regulators and buffers, toxicity regulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which participates in loading or delivering the compounds of the present invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part.
  • a pharmaceutically acceptable carrier can be a medium, diluent, excipient or other material that is not excessively toxic or has side effects and can be used to contact animal tissues.
  • Some pharmaceutically acceptable carrier materials include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) (11) glycols, such as propylene glycol; (12) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) lipids, such as ethyl oleate and ethyl laurate; (14) agarose; (15) buffers, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid
  • Each pharmaceutically acceptable carrier should be compatible with other components, for example, forming a preparation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs of organisms, and with a reasonable benefit-risk ratio.
  • the pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage form (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage form (e.g., aqueous solution, emulsion, elixir, syrup, etc.).
  • solid dosage form e.g., tablets, capsules, powders, granules, etc.
  • liquid dosage form e.g., aqueous solution, emulsion, elixir, syrup, etc.
  • it can be prepared according to conventional techniques, for example, as provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
  • 5-(2-chloro-4-nitrophenoxy)-1-methyl-1H-benzimidazole (1.8 g, 5.9 mmol) was dissolved in a mixed solution of methanol (10 mL) and water (2 mL), iron powder (1.6 g, 29.5 mmol) and ammonium chloride (3.2 g, 59.0 mmol) were added in sequence, nitrogen was replaced, the temperature was raised to 60°C and stirred for 1 h. The reaction solution was cooled to room temperature.
  • Step 3 5-bromo-6-difluoromethyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine
  • Step 1 Under nitrogen protection, 7-bromoimidazole [1,2-a] pyridine (2 g, 10.2 mmol) was dissolved in a mixed solution of dimethyl sulfoxide/water (30 mL, 4/1 v/v), and lithium hydroxide monohydrate (899.6 mg, 21.4 mmol), N, N'-bis (4-hydroxy-2,6-dimethylphenyl) oxamide (BHMPO, 66.9 mg, 0.2 mmol) and copper acetylacetonate (53.2 mg, 0.2 mmol) were added in sequence, and the temperature was raised to 80 ° C and stirred for 2 h.
  • lithium hydroxide monohydrate 899.6 mg, 21.4 mmol
  • BHMPO N, N'-bis (4-hydroxy-2,6-dimethylphenyl) oxamide
  • copper acetylacetonate 53.2 mg, 0.2 mmol
  • Step 2 Dissolve imidazo[1,2-a]pyridine-7-ol (1.0 g, 7.45 mmol) in N,N-dimethylformamide (20 mL), add cesium carbonate (4.9 g, 14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g, 7.45 mmol) in turn. Heat to 80°C and stir for 3 h. After the reaction is complete, cool to room temperature, add water (30 mL) to the reaction solution, extract the mixture with ethyl acetate (30 mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 3 Dissolve 7-(2-methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (1.0 g, 3.71 mmol) in acetonitrile (15 mL), add N-chlorosuccinimide (595.1 mg, 4.46 mmol). Stir at room temperature for 16 h. After the reaction is complete, add water (30 mL) to the reaction solution, extract the mixture with ethyl acetate (40 mL ⁇ 3), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • tert-butyl 2-formylazetidine-1-carboxylate 2.4g, 13.0mmol
  • methanol 10.5mL
  • potassium carbonate 3.6g, 26.0mmol
  • dimethyl (1-diazo-2-oxo-propanol)-phosphonate 3.7g, 19.5mmol
  • Intermediate B2 was prepared using commercially available methyl 2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetate as raw material and the synthetic method of intermediate B1.
  • tert-butyl 2-formyl-5-methylpiperidine-1-carboxylate as raw material, tert-butyl 2-ethynyl-5-methylpiperidine-1-carboxylate (yellow oil, 280 mg, 64.0%) was prepared according to the second step synthesis method of intermediate B1.
  • tert-butyl 2-methylpiperidine-1-carboxylate as raw material, tert-butyl 2-ethynyl-6-methylpiperidine-1-carboxylate (colorless transparent liquid, 398 mg, 81.0%) was prepared according to the synthetic method of intermediate B17.
  • tert-butyl (1-ethynylcyclopropyl)carbamate as raw material, tert-butyl (1-ethynylcyclopropyl)(methyl)carbamate (colorless oil) was prepared according to the synthetic method of intermediate B19.
  • the crude product is separated and purified by high performance liquid chromatography (column type: XBridge Prep Amide OBD, 19 mm ⁇ 150 mm, 5 ⁇ m; mobile phase: water (10 mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 25 mL/min; gradient: 95%-50% acetonitrile 8 min; wavelength: 254/220 nm) to obtain 4-(dimethylamino)but-2-ynoic acid (yellow oil, 100 mg, 16.4%).
  • MS(ESI + )m/z 128.3[M+H] + .
  • tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.0g, 5.7mmol) was dissolved in dichloromethane (10mL), triethylamine (1.7g, 17.1mmol) was added, and then methylsulfonyl chloride (1.3g, 11.4mmol) was added dropwise, and stirred at 0°C for 2h.
  • Water (10mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50mL ⁇ 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Step 2 tert-Butyl (2-((4-aminopyrimidin-5-yl)oxy)ethyl)(methyl)carbamate
  • Step 2 Ethyl 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate
  • Step 3 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid
  • Step 4 (4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester
  • Step 5 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylic acid methyl ester
  • Step 6 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid methyl ester
  • Step 1 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)aminopyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester
  • Step 2 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid
  • Step 3 (7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonyl)serine methyl ester
  • Step 4 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-4,5-dihydrooxazole-4-carboxylic acid methyl ester
  • Step 5 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazole-4-carboxylic acid methyl ester
  • Step 1 Dissolve intermediate A25 (1.4 g, 3.42 mmol) in DMF (30 mL), add DIEA (1.3 g, 10.25 mmol) and methyl 2-amino-3-hydroxypropionate (610.4 mg, 5.12 mmol) in turn, cool to 0°C, slowly add HATU (2.6 g, 6.8 mmol) in DMF (5 mL), warm to room temperature and stir for 1 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane/methanol (10/1 v/v, 60 mL ⁇ 3).
  • Step 2 Dissolve (4-chloro-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (1.4 g, 2.74 mmol) in isopropanol (50 mL) and add p-methoxybenzylamine (563.8 mg, 4.11 mmol). Heat to 60°C and stir for 2 h.
  • Step 3 and Step 4 Using (4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester as starting material, 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid methyl ester (light yellow solid, 620 mg, 57.0%) was prepared according to the method of Step 5 and Step 6 of Synthesis Intermediate E1.
  • MS (ESI + ) m/z 592.3 [M+H] + .
  • Step 1 Dissolve 5-bromo-4-chloropyrimidine (10.0 g, 51.70 mmol) in N,N-dimethylformamide (100 mL), add sodium thiomethoxide (4.3 g, 62.04 mmol). Stir at room temperature for 12 h. After the reaction is complete, add water (100 mL) to the reaction solution, extract the mixed solution with ethyl acetate (200 mL ⁇ 3), wash the combined organic phases with a saturated sodium chloride solution (200 mL ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 2 Under nitrogen protection, 5-bromo-4-(methylthio)pyrimidine (5.0 g, 24.38 mmol) was dissolved in 1,4-dioxane (70 mL), and Pd(dppf)Cl 2 (5.4 g, 7.31 mmol), bis-pinacol borate (18.6 g, 73.15 mmol) and potassium acetate (12.0 g, 121.91 mmol) were added in sequence. The temperature was raised to 90°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 3 Under nitrogen protection, 4-methylthio-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (6.0 g, 23.80 mmol) was dissolved in a mixture of 1,4-dioxane and water (4/1 v/v, 62.5 mL), and Xphos Pd G3 (2.0 g, 2.38 mmol), Xphos (1.1 g, 2.38 mmol), potassium carbonate (8.2 g, 59.49 mmol) and ethyl 2-bromo-1,3-oxazole-4-carboxylate (5.2 g, 23.80 mmol). Heat to 80 °C and stir for 3 h.
  • Step 5 Dissolve ethyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate (473.4 mg, 1.87 mmol) in isopropanol (20 mL), add intermediate F4 (359.5 mg, 1.33 mmol). Heat to 90°C and stir for 1 h.
  • intermediates E8-E10 were prepared according to the method for synthesizing intermediate E7, as shown in Table 4.
  • Step 1 In a 100 mL reaction bottle, dissolve the compound 2-(4-(methylthio)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester (384.0 mg, 1.45 mmol) in dichloromethane (40 mL), add m-chloroperbenzoic acid (mCPBA, 3.40 mmol), stir at room temperature for 1.5 h, add sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (5 mL) after the reaction is complete, extract the mixture with ethyl acetate (100 mL ⁇ 3), combine the organic phases, dry them with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(4-(methylsulfonyl)pyrimidin-5-yl)oxazole-4-carboxylic acid ethyl ester (light yellow solid, 228.0 mg, 63.0%). MS (ESI +
  • intermediates F1-F7 were prepared using the first and second step methods of intermediate A1, as shown in Table 5.
  • Step 1 Under nitrogen protection, 5-bromo-1,2-difluoro-3-nitrobenzene (2.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (4.3 g, 33.61 mmol) and methylamine hydrochloride (2.8 g, 42.02 mmol) were added in sequence. The temperature was raised to 60 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (70 mL ⁇ 3).
  • Step 2 4-bromo-2-fluoro-N-methyl-6-nitroaniline (1.8 g, 7.23 mmol) was dissolved in a mixture of tetrahydrofuran and water (5/1 v/v, 24 mL), iron powder (4.0 g, 72.28 mmol) and ammonium chloride (3.9 g, 72.28 mmol) were added in sequence, and the mixture was heated to 60°C and stirred for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 3 Under nitrogen protection, dissolve 4-bromo-6-fluoro-N 1 -methyl-1,2-phenylenediamine (1.1 g, 5.02 mmol) in toluene (20 mL), cool to 0°C, and add p-toluenesulfonamide (86.0 mg, 0.50 mmol) and triethyl orthoformate (1.5 g, 10.04 mmol) in sequence. Heat to 120°C and stir for 16 h. After the reaction is complete, cool to room temperature and add water (50 mL) to the reaction solution.
  • Step 4 Under nitrogen protection, 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole (1.0 g, 4.37 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (4/1 v/v, 10 mL), and Cu(acac) 2 (114.3 mg, 0.44 mmol) and BHMPO (143.4 mg, 0.44 mmol) were added in sequence, and then lithium hydroxide monohydrate (769.4 mg, 18.34 mmol) was slowly added. The mixture was heated to 80°C and stirred for 2 h.
  • Step 1 Under nitrogen protection, 7-chloroimidazo[1,2-c]pyrimidine (500.0 mg, 3.26 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (900.0 mg, 6.51 mmol) and 2-methyl-4-nitrophenol (598.3 mg, 3.91 mmol) were added. The temperature was raised to 80°C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 Dissolve 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-c]pyrimidine (170.0 mg, 0.63 mmol) in a mixture of methanol and water (3/1 v/v, 4 mL), and add iron powder (281.1 mg, 5.03 mmol) and ammonium chloride (269.2 mg, 5.03 mmol) in turn. Heat to 80°C and stir for 2 h.
  • Step 1 tert-Butyl 2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidine-1-carboxylate
  • the condensation method in this step also includes: 1) using a commercially available olefin/alkyne acid compound or intermediate C1-C6 as a raw material, EDCI as a catalyst, pyridine as a solvent, and reacting at room temperature; 2) using an olefin/alkyne acid chloride compound as a raw material, triethylamine as a catalyst, THF as a solvent, and reacting at room temperature.
  • the preparation method of the final product 1 is adopted, and the intermediates A1-A28, intermediates B1-B22, intermediates C1-C6 or commercially available alkynyl compounds and other commercially available compounds are used as raw materials to prepare final products 2-25, 27-29, 31-32, 34-36, 38-41, 43, 47, 49-51, 54, 57, 60-61, 63-66, 68-73, 76-77, 79-80, 124-125, 133, 138-139, 143-144, 152-153, 158-163, as shown in Table 6.
  • Step 1 (R,Z/E)-2-(2-fluoro-3-((3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)amino)-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 2 (R,Z/E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)-3-(pyrrolidin-2-yl)acrylamide
  • Step 3 (R,Z)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide and (R,E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide
  • Step 1 (2E)-4-bromo-N-(1-((4-((3-methyl-4-(1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-enamide
  • Step 2 (2E)-N-(1-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-4-morpholinobut-2-enamide
  • (2E)-4-bromo-N-(1-((4-((3-methyl-4-(1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-enamide (446 mg, 0.8 mmol) was dissolved in acetonitrile (4 mL), and morpholine (104.5 mg, 1.2 mmol) and potassium carbonate (331.7 mg, 2.4 mmol) were added in sequence, nitrogen was replaced, and the temperature was raised to 60°C and stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product.
  • Step 1 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one
  • N-(3-methyl-4-((1-methyl-1H-benzimidazole-5-oxy)phenyl)-5-(piperidin-2-ylethynyl)pyrimidin-4-amine 150 mg, 0.3 mmol
  • pyridine 3 mL
  • 3-(trimethylsilyl)prop-2-ynoic acid 43.8 mg, 0.3 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI, 131.1 mg, 0.6 mmol
  • Step 2 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)prop-2-yn-1-one
  • the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • the pH was adjusted to alkaline with sodium bicarbonate solution.
  • the mixed solution was extracted with ethyl acetate (30 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 tert-Butyl 2-((2-chloro-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate
  • Signal Ave_VC The average signal of the negative control of the entire plate
  • Measured resistance value (ohms) x membrane area (cm 2 ) TEER value (ohm ⁇ cm 2 )
  • HBSS 10mM HEPES, pH 7.4
  • HBSS 10mM HEPES, pH 7.4
  • the membrane area in the formula is the Transwell-96 well plate membrane area (0.143 cm 2 ); the incubation time unit is seconds (s).
  • the efflux rate is calculated using the following formula:
  • mice Using ICR mice as test subjects, the LC/MS/MS method was used to determine the compound administered by oral gavage (PO), and the drug concentration of the compound in plasma was detected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h, to study the pharmacokinetic behavior of the compound of the present invention in mice and evaluate its pharmacokinetic characteristics.
  • PO oral gavage
  • Drug preparation The compounds were prepared into clear solutions with 10% DMSO + 10% Solutol HS 15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as solvents for PO administration using cassette dosing. The dosage of the compounds was 10 mg/kg. The pharmacokinetic parameters are shown in Table 13.

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Abstract

La présente invention concerne un composé cyclique hétéroaromatique contenant de l'azote, son procédé de préparation et son utilisation. Le composé cyclique hétéroaromatique contenant de l'azote présente une structure telle que représentée dans la formule I, les définitions de M, X, a, E, G, Z, L1, L2, Y1, Y2, R1 et R2 étant telles que décrites dans la description. Le composé cyclique hétéroaromatique contenant de l'azote a un effet inhibiteur efficace et hautement sélectif sur le récepteur 2 du facteur de croissance épidermique (HER2), et peut ainsi être utilisé dans le traitement de maladies associées induites par des anomalies de HER2, en particulier dans le traitement de maladies cancéreuses.
PCT/CN2024/116822 2023-09-05 2024-09-04 Composé hétéroaryle contenant de l'azote, son procédé de préparation et son utilisation Pending WO2025051148A1 (fr)

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WO2026007878A1 (fr) * 2024-07-01 2026-01-08 北京鞍石生物科技股份有限公司 Composé cyclique condensé, son procédé de préparation et son utilisation

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CN115052878A (zh) * 2020-02-03 2022-09-13 勃林格殷格翰国际有限公司 作为HER2抑制剂的[1,3]二嗪并[5,4-d]嘧啶
WO2022221227A1 (fr) * 2021-04-13 2022-10-20 Nuvalent, Inc. Hétérocycles amino-substitués pour le traitement de cancers avec des mutations egfr
WO2022269531A1 (fr) * 2021-06-26 2022-12-29 Array Biopharma Inc. Inhibiteurs de mutation her2
CN116003406A (zh) * 2021-12-29 2023-04-25 北京鞍石生物科技有限责任公司 杂芳环氮氧化合物及其制备方法和应用
WO2023081637A1 (fr) * 2021-11-02 2023-05-11 Enliven Therapeutics, Inc. Dérivés de quinazoline tétracycliques fusionnés utilisés en tant qu'inhibiteurs d'erbb2
WO2023154124A1 (fr) * 2022-02-09 2023-08-17 Enliven Therapeutics, Inc. Dérivés de quinazoline hétérocycliques acylés utilisés en tant qu'inhibiteurs de erbb2

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CN106103446A (zh) * 2014-03-26 2016-11-09 豪夫迈·罗氏有限公司 作为自分泌运动因子(atx)和溶血磷脂酸(lpa)生产抑制剂的二环化合物
CN112266384A (zh) * 2018-05-08 2021-01-26 迪哲(江苏)医药股份有限公司 ErbB受体抑制剂
CN115052878A (zh) * 2020-02-03 2022-09-13 勃林格殷格翰国际有限公司 作为HER2抑制剂的[1,3]二嗪并[5,4-d]嘧啶
WO2022221227A1 (fr) * 2021-04-13 2022-10-20 Nuvalent, Inc. Hétérocycles amino-substitués pour le traitement de cancers avec des mutations egfr
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WO2023154124A1 (fr) * 2022-02-09 2023-08-17 Enliven Therapeutics, Inc. Dérivés de quinazoline hétérocycliques acylés utilisés en tant qu'inhibiteurs de erbb2

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