WO2024152995A1 - Inhibiteurs macrocycliques de la cycline ainsi que leur procédé de préparation et leur utilisation - Google Patents

Inhibiteurs macrocycliques de la cycline ainsi que leur procédé de préparation et leur utilisation Download PDF

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WO2024152995A1
WO2024152995A1 PCT/CN2024/071915 CN2024071915W WO2024152995A1 WO 2024152995 A1 WO2024152995 A1 WO 2024152995A1 CN 2024071915 W CN2024071915 W CN 2024071915W WO 2024152995 A1 WO2024152995 A1 WO 2024152995A1
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cycloalkyl
group
alkyl
alkoxy
hydrogen
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Chinese (zh)
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孙海丰
刘杨
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Shanghai Highslab Therapeutics Inc
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Shanghai Highslab Therapeutics Inc
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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

Definitions

  • the present invention relates to compounds for treating tumors or cancers, and in particular to a macrocyclic compound and a preparation method thereof, a pharmaceutical composition containing the macrocyclic compound, and medical uses thereof.
  • CDKs Cyclin-dependent kinases
  • CDK2 is a key cell cycle regulator that is active from the late G1 phase to the entire S phase.
  • CDK2 binds to cyclin E to form the proteasome complex CDK2-cyclinE and activates it, which promotes further phosphorylation of Rb and induces the continuous expression of transcription factor E2F, thereby regulating the smooth passage of cells from the G1 phase to the S phase (Henley et al., Cell Div, 2012, 7(1): p.10).
  • CDK2 After entering the S phase, CDK2 combines with cyclin A to form a complex CDK2-cyclinA, which participates in the S phase of the cell cycle and completes DNA replication (Ekholm et al. Curr Opin Cell Biol, 2000. 12(6): 676-84).
  • CCNE1 amplification and overexpression make HER2+ breast cancer resistant to trastuzumab treatment; estrogen receptor-positive breast cancer is resistant to CDK4/6 inhibitors (Herrera-Abreu et al., Cancer Res, 2016.76(8):2301-13).
  • Inhibiting CDK2 activity can not only inhibit tumor growth by blocking the cell cycle (Mendoza et al., Cancer Res, 2003.63(5):1020-4), but also increase the sensitivity of related tumors to anti-tumor drugs, thereby enhancing the therapeutic effect.
  • inhibition of CDK2 can restore the sensitivity of CCNE1-overexpressing tumor cells that are resistant to tamoxifen to tamoxifen or CDK4 inhibitors (Caldon et al., Mol Cancer Ther 2012, 11(7): 1488–1499.). Therefore, CDK2 has been valued as a potential new anti-cancer drug target and has been developed for drug development.
  • CDK multi-target inhibitors related to CDK2 or CDK2 inhibitors with certain selectivity have entered clinical trials.
  • development of new CDK2 inhibitors with high efficiency, low toxicity and unique selectivity is still an unmet need.
  • the present invention is a new CDK2 inhibitor developed to meet this need. It provides a new treatment option for patients with related tumor diseases.
  • the present invention provides a compound represented by formula (I) or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts,
  • Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl, and the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more Q 1 ;
  • Ring B is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl, and the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more Q 2 ;
  • X is selected from a bond, O, S, NH, alkylene, alkenylene, and alkynylene;
  • L is selected from *-WYZG-**, wherein * represents the connection site between L and ring A, and ** represents the connection site between L and the N atom in -NR 1 -;
  • W is selected from a bond, O, NR"', S, carbonyl, sulfone, sulfoxide, alkylene, alkenylene, alkynylene, carbamoyl, cycloalkyl and heterocyclyl, wherein the alkylene, alkenylene, carbamoyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Q 3 ;
  • Y is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more Q4 ;
  • Z is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R3 ;
  • G is selected from a bond, an alkylene group, a cycloalkyl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group and the heterocyclyl group are optionally substituted with one or more R 4 ;
  • Q 1 is selected from hydrogen, halogen, cyano, hydroxy, NR'(R"), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • Oxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R2 ;
  • Q 2 is selected from hydrogen, halogen, cyano, hydroxy, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 5 ;
  • R" is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R6 ;
  • R' and R" and the atoms to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally substituted with one or more R 7 ;
  • each R 5 , R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R 7 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R"' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 8 ;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R1 is selected from hydrogen, alkyl and haloalkyl
  • R 1 and Z or the carbon atoms in R 1 and Z and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 9 ;
  • R 9 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 10 ;
  • R 10 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • n is selected from 0 and 1.
  • the compounds provided by the present invention have good inhibitory activity on cyclin-dependent kinases (CDKs), specifically, they have strong inhibitory activity on CDK2, and weak inhibitory activity on other subtypes of CDK (such as CDK1, etc.), thereby achieving the effect of selectively inhibiting CDK2 and improving safety and effectiveness.
  • CDKs cyclin-dependent kinases
  • the compounds provided by the present application can be used to prevent and treat diseases related to CDKs, especially diseases related to CDK2, such as inflammation, tumors or cancer.
  • the present invention provides a compound represented by formula (I) or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts,
  • Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl, and the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more Q 1 ;
  • Ring B is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl, and the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more Q 2 ;
  • X is selected from a bond, O, S, NH, alkylene, alkenylene, and alkynylene;
  • L is selected from *-WYZG-**, wherein * represents the connection site between L and ring A, and ** represents the connection site between L and the N atom in -NR 1 -;
  • W is selected from a bond, O, NR"', S, carbonyl, sulfone, sulfoxide, alkylene, alkenylene, alkynylene, carbamoyl, cycloalkyl and heterocyclyl, wherein the alkylene, alkenylene, carbamoyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Q 3 ;
  • Y is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more Q4 ;
  • Z is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R3 ;
  • G is selected from a bond, an alkylene group, a cycloalkyl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group and the heterocyclyl group are optionally substituted with one or more R 4 ;
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R"), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ;
  • Q2 is selected from hydrogen, halogen, cyano, hydroxy, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 5 ;
  • R" is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R6 ;
  • R' and R" and the atoms to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally substituted with one or more R 7 ;
  • each R 5 , R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R 7 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R"' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 8 ;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R1 is selected from hydrogen, alkyl and haloalkyl
  • R 1 and Z or the carbon atoms in R 1 and Z and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 9 ;
  • R 9 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 10 ;
  • R 10 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • n is selected from 0 and 1.
  • the ring A is selected from C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl, and the C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted with one or more Q 1 .
  • the ring A is selected from C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 1 .
  • the ring A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • the heteroaryl contains 1-4 heteroatoms selected from N, O and S
  • the C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more Q 1 .
  • the ring A is selected from phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, thienopyridinyl and imidazo[4,5-c]pyridinyl, and the phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrimidinyl
  • the ring A is selected from phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, and the phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, and pyrimidopyrrolyl are optionally substituted with one or more Q 1 .
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R " ), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl are optionally substituted with one or more R.
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl are optionally substituted with one or more R 2 .
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 2 .
  • the Q 1 is selected from hydrogen, hydroxy, NR'(R"), methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl are optionally substituted with one or more R 2 .
  • the R 2 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, halogen, hydroxy, oxo, SO 2 R′, NR′(R′′), COR′, COOR′, and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, oxo, SO 2 R′, NR′(R′′), COR′, COOR′ and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylamino, oxo, SO 2 R′ and NR′(R′′).
  • the R 2 is selected from hydrogen, methoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, dimethylamino, oxo, SO 2 R′, and NR′(R′′).
  • the ring B is selected from C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl, and the C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted with one or more Q 2 .
  • the ring B is selected from C 3-7 cycloalkyl and 3-10 membered heterocyclyl, and the C 3-7 cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more Q 2 .
  • the ring B is selected from C 3-6 cycloalkyl and 4-6 membered heterocyclyl
  • the heterocyclyl contains 1-4 heteroatoms selected from N, O and S
  • the C 3-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted by one or more Q 2 .
  • the ring B is selected from C 4-5 cycloalkyl and 4-6 membered heterocyclyl
  • the heterocyclyl contains 1-2 heteroatoms selected from N and O
  • the C 4-5 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted by one or more Q 2 .
  • the ring B is selected from cyclopentyl, tetrahydrofuranyl, and cyclobutyl, and the cyclopentyl, tetrahydrofuranyl, and cyclobutyl are optionally substituted with one or more Q 2 .
  • Q 2 is selected from hydrogen, halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, Haloalkyl, haloalkoxy and hydroxyalkyl.
  • Q 2 is selected from hydrogen, halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl.
  • Q 2 is selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 hydroxyalkyl.
  • said Q 2 is selected from hydrogen.
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl and cycloalkyl, and the alkylene, alkenylene, carbamoyl and cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, and the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, and the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, and the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl.
  • Y is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen , halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • Y is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more Q 4 , wherein Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more R3 , wherein the R3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl, or two R3 and The atoms to which they are attached form a cycloalkyl group or a heterocyclic group.
  • Z is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more R 3 , and the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • Z is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and C 3-5 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-5 cycloalkyl or 4-6-membered heterocyclyl.
  • the G is selected from a bond, O, NR"' and alkylene
  • the alkylene is optionally substituted with one or more R4
  • the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms to which they are attached form a cycloalkyl or heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms to which they are attached form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the X is selected from a bond, O, S, NH, and alkylene.
  • said X is selected from a bond and a C 1-3 alkylene group.
  • said X is selected from a bond and a methylene group.
  • the R 1 is selected from hydrogen and alkyl.
  • the R 1 is selected from hydrogen and C 1-3 alkyl.
  • said R 1 is selected from hydrogen and methyl.
  • the carbon atoms in R 1 and Z and the atoms attached thereto form a heterocyclic group, which is optionally substituted with one or more R 9 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-
  • the 10-membered heterocyclyl is optionally substituted with one or more R 9 selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R 9 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • the carbon atom in R 1 and Z and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group, which is optionally substituted with one or more R 10 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 10 , wherein the R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R1 and G and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R10 selected from hydrogen, C1-3 alkyl, C1-3 alkoxy and halogen.
  • R 1 and the carbon atom in G and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • the R' is selected from hydrogen, alkyl and alkoxy, the alkyl and alkoxy being optionally substituted with one or more R5 .
  • the R′ is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more R 5 .
  • the R′ is selected from hydrogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with one or more R 5 .
  • the R' is selected from methyl, which is optionally substituted with one or more R5 .
  • the R" is selected from hydrogen, alkyl and alkoxy, and the alkyl and alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-6 alkyl and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-3 alkyl and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from methyl, which is optionally substituted with one or more R6 .
  • the R' and R" and the atoms to which they are attached form a heterocyclic group, which is optionally substituted with one or more R7 .
  • the R′ and R′′ and the atoms to which they are attached form a 3-10 membered heterocyclyl, which is optionally substituted with one or more R 7 .
  • the R' and R" and the atoms to which they are attached form a 4-6 membered heterocyclic group
  • the heterocyclic group contains 1-2 heteroatoms selected from N, O and S
  • the 4-6 membered heterocyclic group is optionally substituted by one or more R7 .
  • said R′ and R′′ and the atoms to which they are attached form azetidinylmorpholinyl or piperazinyl, said azetidinylmorpholinyl or piperazinyl being optionally substituted with one or more R 7 .
  • the R 5 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 5 is selected from hydrogen.
  • the R 6 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 6 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 6 is selected from hydrogen.
  • the R 7 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl, and oxo.
  • said R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halogen.
  • the R 7 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 7 is selected from hydrogen, methyl, and fluoro.
  • the R'' is selected from hydrogen, hydroxy, alkyl, alkoxy and cycloalkyl, and the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, hydroxy, C 1-6 alkyl and C 3-7 cycloalkyl, and the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, methyl and cyclopropyl, the methyl and cyclopropyl being optionally substituted with one or more R 8 .
  • R 8 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl, carboxylate, and 4-6 membered heterocyclic groups, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S.
  • the R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, oxo, and pyrrolidinyl.
  • said R 8 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 8 is selected from hydrogen.
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl, and cycloalkyl, the alkylene, alkenylene, carbamoyl, and cycloalkyl being optionally substituted with one or more Q 3 , the Q 3 being selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl;
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted with one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl;
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted by one or more R3 , wherein the R3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R3 and the atoms connected thereto form a cycloalkyl group or a heterocyclyl group;
  • the G is selected from a bond, O, NR"' and an alkylene group, the alkylene group is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms connected thereto form a cycloalkyl or heterocyclyl group.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Y is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more Q 4 , the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Z is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more R 3 , the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms connected thereto form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl;
  • the G is selected from a bond, O, NR"' and C 1-6 alkylene, the C 1-6 alkylene is optionally substituted by one or more R 4 ,
  • the R 4 is selected from hydrogen, halogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C 3-7 cycloalkyl, or two R 4 and the atoms connected thereto form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl;
  • the Y is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 hydroxyalkyl group and C 3-5 cycloalkyl group;
  • the Z is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group and C 3-5 cycloalkyl group, or two R
  • the G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl , 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the *-WYZG-** is selected from
  • *-WYZG-NR 1 - is selected from
  • the present invention provides a compound represented by formula (I-1), (I-2), (I-3) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof.
  • Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclic groups, wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally replaced by one or more Q 1 ;
  • X is selected from a bond, O, S, NH, alkylene, alkenylene, and alkynylene;
  • L is selected from *-WYZG-**, wherein * represents the connection site between L and ring A, and ** represents the connection site between L and the N atom in -NR 1 -;
  • W is selected from a bond, O, NR"', S, carbonyl, sulfone, sulfoxide, alkylene, alkenylene, alkynylene, carbamoyl, cycloalkyl and heterocyclyl, wherein the alkylene, alkenylene, carbamoyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Q 3 ;
  • Y is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more Q4 ;
  • Z is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R3 ;
  • G is selected from a bond, an alkylene group, a cycloalkyl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group and the heterocyclyl group are optionally substituted with one or more R 4 ;
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R"), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R;
  • R' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 5 ;
  • R" is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R6 ;
  • R' and R" and the atoms to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally substituted with one or more R 7 ;
  • each R 5 , R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R 7 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R"' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 8 ;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R1 is selected from hydrogen, alkyl and haloalkyl
  • R 1 and Z or the carbon atoms in R 1 and Z and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 9 ;
  • R 9 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 10 ;
  • R 10 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • n is selected from 0 and 1.
  • the ring A is selected from C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclic
  • the C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by one or more Q 1 .
  • the ring A is selected from C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 1 .
  • the ring A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • the heteroaryl contains 1-4 heteroatoms selected from N, O and S
  • the C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more Q 1 .
  • the ring A is selected from phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, thienopyridinyl and imidazo[4,5-c]pyridinyl, and the phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrimidinyl
  • the ring A is selected from phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, and the phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, and pyrimidopyrrolyl are optionally substituted with one or more Q 1 .
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R " ), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl are optionally substituted with one or more R.
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl are optionally substituted with one or more R 2 .
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 2 .
  • the Q 1 is selected from hydrogen, hydroxy, NR'(R"), methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl are optionally substituted with one or more R 2 .
  • the R 2 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, halogen, hydroxy, oxo, SO 2 R′, NR′(R′′), COR′, COOR′, and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, oxo, SO 2 R′, NR′(R′′), COR′, COOR′ and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylamino, oxo, SO 2 R′ and NR′(R′′).
  • the R 2 is selected from hydrogen, methoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, dimethylamino, oxo, SO 2 R′, and NR′(R′′).
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl and cycloalkyl, and the alkylene, alkenylene, carbamoyl and cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, and the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, and the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, and the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl.
  • Y is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen , halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • Y is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more Q 4 , wherein Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R 3 and the atoms to which they are attached form a cycloalkyl or heterocyclic group.
  • Z is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more R 3 , and the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • Z is selected from a bond, C 1-3 alkylene, O, NR′′′, S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and C 3-5 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-5 cycloalkyl or 4-6-membered heterocyclyl.
  • the G is selected from a bond, O, NR"' and alkylene
  • the alkylene is optionally substituted with one or more R4
  • the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms to which they are attached form a cycloalkyl or heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms to which they are attached form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the X is selected from a bond, O, S, NH, and alkylene.
  • said X is selected from a bond and a C 1-3 alkylene group.
  • said X is selected from a bond and a methylene group.
  • the R 1 is selected from hydrogen and alkyl.
  • the R 1 is selected from hydrogen and C 1-3 alkyl.
  • said R 1 is selected from hydrogen and methyl.
  • the carbon atoms in R 1 and Z and the atoms attached thereto form a heterocyclic group, which is optionally substituted with one or more R 9 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 9 , wherein R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R 9 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • the carbon atom in R 1 and Z and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group, which is optionally substituted with one or more R 10 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 10 , wherein the R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R1 and G and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R10 selected from hydrogen, C1-3 alkyl, C1-3 alkoxy and halogen.
  • R 1 and the carbon atom in G and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • the R' is selected from hydrogen, alkyl and alkoxy, the alkyl and alkoxy being optionally substituted with one or more R5 .
  • the R′ is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more R 5 .
  • the R′ is selected from hydrogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with one or more R 5 .
  • the R' is selected from methyl, which is optionally substituted with one or more R5 .
  • the R" is selected from hydrogen, alkyl and alkoxy, and the alkyl and alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-6 alkyl and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-3 alkyl and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from methyl, which is optionally substituted with one or more R6 .
  • the R' and R" and the atoms to which they are attached form a heterocyclic group, which is optionally One or more R7 are substituted.
  • the R′ and R′′ and the atoms to which they are attached form a 3-10 membered heterocyclyl, which is optionally substituted with one or more R 7 .
  • the R' and R" and the atoms to which they are attached form a 4-6 membered heterocyclic group
  • the heterocyclic group contains 1-2 heteroatoms selected from N, O and S
  • the 4-6 membered heterocyclic group is optionally substituted by one or more R7 .
  • said R′ and R′′ and the atoms to which they are attached form azetidinylmorpholinyl or piperazinyl, said azetidinylmorpholinyl or piperazinyl being optionally substituted with one or more R 7 .
  • the R 5 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 5 is selected from hydrogen.
  • the R 6 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 6 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 6 is selected from hydrogen.
  • the R 7 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl, and oxo.
  • said R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halogen.
  • the R 7 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 7 is selected from hydrogen, methyl, and fluoro.
  • the R'' is selected from hydrogen, hydroxy, alkyl, alkoxy and cycloalkyl, and the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, hydroxy, C 1-6 alkyl and C 3-7 cycloalkyl, and the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, methyl and cyclopropyl, the methyl and cyclopropyl being optionally substituted with one or more R 8 .
  • the R 8 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, NR'(R"), nitro, cyano, Oxo, carboxyl, carboxylate and 4-6 membered heterocyclic groups, wherein the heterocyclic groups contain 1-2 heteroatoms selected from N, O and S.
  • the R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, oxo, and pyrrolidinyl.
  • said R 8 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 8 is selected from hydrogen.
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl, and cycloalkyl, the alkylene, alkenylene, carbamoyl, and cycloalkyl being optionally substituted with one or more Q 3 , the Q 3 being selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl;
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted with one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl;
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted by one or more R3 , wherein the R3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R3 and the atoms connected thereto form a cycloalkyl group or a heterocyclyl group;
  • the G is selected from a bond, O, NR"' and an alkylene group, the alkylene group is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms connected thereto form a cycloalkyl or heterocyclyl group.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Y is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more Q 4 , the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Z is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more R 3 , the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms connected thereto form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl;
  • the G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms connected thereto form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl;
  • the Y is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 hydroxyalkyl group and C 3-5 cycloalkyl group;
  • the Z is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group and C 3-5 cycloalkyl group, or two R
  • the G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl , 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the *-WYZG-** is selected from
  • *-WYZG-NR 1 - is selected from
  • the present invention provides a compound represented by formula (I-1-1), (I-2-1), (I-3-1) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof.
  • Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclic groups, wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally replaced by one or more Q 1 ;
  • X is selected from a bond, O, S, NH, alkylene, alkenylene, and alkynylene;
  • L is selected from *-WYZG-**, wherein * represents the connection site between L and ring A, and ** represents the connection site between L and the N atom in -NR 1 -;
  • W is selected from a bond, O, NR"', S, carbonyl, sulfone, sulfoxide, alkylene, alkenylene, alkynylene, carbamoyl, cycloalkyl and heterocyclyl, wherein the alkylene, alkenylene, carbamoyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Q 3 ;
  • Y is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more Q4 ;
  • Z is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R3 ;
  • G is selected from a bond, an alkylene group, a cycloalkyl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group and the heterocyclyl group are optionally substituted with one or more R 4 ;
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R"), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R;
  • R' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 5 ;
  • R" is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R6 ;
  • R' and R" and the atoms to which they are attached form a heterocyclic group or a heteroaryl group, the heterocyclic group or the heteroaryl group being optionally substituted with one or more R 7 ;
  • each R 5 , R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R 7 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R"' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 8 ;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R1 is selected from hydrogen, alkyl and haloalkyl
  • R 1 and Z or the carbon atoms in R 1 and Z and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 9 ;
  • R 9 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 10 ;
  • R 10 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • n is selected from 0 and 1.
  • the ring A is selected from C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclic
  • the C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by one or more Q 1 .
  • the ring A is selected from C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 1 .
  • the ring A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • the heteroaryl contains 1-4 heteroatoms selected from N, O and S
  • the C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more Q 1 .
  • the ring A is selected from phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, thienopyridinyl and imidazo[4,5-c]pyridinyl, and the phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrimidinyl
  • the ring A is selected from phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, and the phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, and pyrimidopyrrolyl are optionally substituted with one or more Q 1 .
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R " ), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl are optionally substituted with one or more R.
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl are optionally substituted with one or more R 2 .
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 2 .
  • the Q 1 is selected from hydrogen, hydroxy, NR'(R"), methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl are optionally substituted with one or more R 2 .
  • the R 2 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, halogen, hydroxy, oxo, SO 2 R′, NR′(R′′), COR′, COOR′, and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, oxo, SO 2 R′, NR′(R′′), COR′, COOR′ and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylamino, oxo, SO 2 R′ and NR′(R′′).
  • the R 2 is selected from hydrogen, methoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, dimethylamino, oxo, SO 2 R′, and NR′(R′′).
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl and cycloalkyl, and the alkylene, alkenylene, carbamoyl and cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, and the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, and the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, and the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl.
  • Y is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen , halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • Y is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more Q 4 , wherein Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R 3 and the atoms to which they are attached form a cycloalkyl or heterocyclic group.
  • Z is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more R 3 , and the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • Z is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and C 3-5 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-5 cycloalkyl or 4-6-membered heterocyclyl.
  • the G is selected from a bond, O, NR"' and alkylene
  • the alkylene is optionally substituted with one or more R4
  • the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms to which they are attached form a cycloalkyl or heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms to which they are attached form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the X is selected from a bond, O, S, NH, and alkylene.
  • said X is selected from a bond and a C 1-3 alkylene group.
  • said X is selected from a bond and a methylene group.
  • the R 1 is selected from hydrogen and alkyl.
  • the R 1 is selected from hydrogen and C 1-3 alkyl.
  • said R 1 is selected from hydrogen and methyl.
  • the carbon atoms in R 1 and Z and the atoms attached thereto form a heterocyclic group, which is optionally substituted with one or more R 9 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 9 , wherein R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R 9 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • the carbon atom in R 1 and Z and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group, which is optionally substituted with one or more R 10 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 10 , wherein the R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R1 and G and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R10 selected from hydrogen, C1-3 alkyl, C1-3 alkoxy and halogen.
  • R 1 and the carbon atom in G and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • the R' is selected from hydrogen, alkyl and alkoxy, the alkyl and alkoxy being optionally substituted with one or more R5 .
  • the R′ is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more R 5 .
  • the R′ is selected from hydrogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with one or more R 5 .
  • the R' is selected from methyl, which is optionally substituted with one or more R5 .
  • the R" is selected from hydrogen, alkyl and alkoxy, and the alkyl and alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-6 alkyl and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-3 alkyl and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from methyl, which is optionally substituted with one or more R6 .
  • the R' and R" and the atoms to which they are attached form a heterocyclic group, which is optionally One or more R7 are substituted.
  • the R′ and R′′ and the atoms to which they are attached form a 3-10 membered heterocyclyl, which is optionally substituted with one or more R 7 .
  • the R' and R" and the atoms to which they are attached form a 4-6 membered heterocyclic group
  • the heterocyclic group contains 1-2 heteroatoms selected from N, O and S
  • the 4-6 membered heterocyclic group is optionally substituted by one or more R7 .
  • said R′ and R′′ and the atoms to which they are attached form azetidinylmorpholinyl or piperazinyl, said azetidinylmorpholinyl or piperazinyl being optionally substituted with one or more R 7 .
  • the R 5 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 5 is selected from hydrogen.
  • the R 6 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 6 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 6 is selected from hydrogen.
  • the R 7 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl, and oxo.
  • said R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halogen.
  • the R 7 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 7 is selected from hydrogen, methyl, and fluoro.
  • the R'' is selected from hydrogen, hydroxy, alkyl, alkoxy and cycloalkyl, and the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, hydroxy, C 1-6 alkyl and C 3-7 cycloalkyl, and the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, methyl and cyclopropyl, the methyl and cyclopropyl being optionally substituted with one or more R 8 .
  • the R 8 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, NR'(R"), nitro, cyano, Oxo, carboxyl, carboxylate and 4-6 membered heterocyclic groups, wherein the heterocyclic groups contain 1-2 heteroatoms selected from N, O and S.
  • the R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, oxo, and pyrrolidinyl.
  • said R 8 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 8 is selected from hydrogen.
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl, and cycloalkyl, the alkylene, alkenylene, carbamoyl, and cycloalkyl being optionally substituted with one or more Q 3 , the Q 3 being selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl;
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted with one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl;
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted by one or more R3 , wherein the R3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R3 and the atoms connected thereto form a cycloalkyl group or a heterocyclyl group;
  • the G is selected from a bond, O, NR"' and an alkylene group, the alkylene group is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms connected thereto form a cycloalkyl or heterocyclyl group.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Y is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more Q 4 , the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Z is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more R 3 , the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms connected thereto form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl;
  • the G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms connected thereto form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl;
  • the Y is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 hydroxyalkyl group and C 3-5 cycloalkyl group;
  • the Z is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group and C 3-5 cycloalkyl group, or two R
  • the G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl , 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the *-WYZG-** is selected from
  • *-WYZG-NR 1 - is selected from
  • the present invention provides a compound represented by formula (I-1-2), (I-2-2) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof.
  • Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclic groups, wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally replaced by one or more Q 1 ;
  • X is selected from a bond, O, S, NH, alkylene, alkenylene, and alkynylene;
  • L is selected from *-WYZG-**, wherein * represents the connection site between L and ring A, and ** represents the connection site between L and the N atom in -NR 1 -;
  • W is selected from a bond, O, NR"', S, carbonyl, sulfone, sulfoxide, alkylene, alkenylene, alkynylene, carbamoyl, cycloalkyl and heterocyclyl, wherein the alkylene, alkenylene, carbamoyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Q 3 ;
  • Y is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more Q4 ;
  • Z is selected from a bond, alkylene, alkenylene, alkynylene, O, NR"', S, carbonyl, sulfone, sulfoxide, cycloalkyl, aryl, heteroaryl and heterocyclyl; said alkylene, alkenylene, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R3 ;
  • G is selected from a bond, an alkylene group, a cycloalkyl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group and the heterocyclyl group are optionally substituted with one or more R 4 ;
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R"), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; said alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ;
  • R' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 5 ;
  • R" is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R6 ;
  • R' and R" and the atoms to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally substituted with one or more R 7 ;
  • each R 5 , R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R 7 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R"' is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 8 ;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate;
  • R1 is selected from hydrogen, alkyl and haloalkyl
  • R 1 and Z or the carbon atoms in R 1 and Z and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 9 ;
  • R 9 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group or a heteroaryl group, and the heterocyclic group or the heteroaryl group is optionally substituted by one or more R 10 ;
  • R 10 is selected from hydrogen, alkyl, alkoxy, halogen, mercapto, hydroxy, NR'(R"), nitro, cyano, oxo, carboxyl and carboxylate;
  • n is selected from 0 and 1.
  • the ring A is selected from C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclic
  • the C 3-7 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by one or more Q 1 .
  • the ring A is selected from C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 5-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 1 .
  • the ring A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • the heteroaryl contains 1-4 heteroatoms selected from N, O and S
  • the C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more Q 1 .
  • the ring A is selected from phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, thienopyridinyl and imidazo[4,5-c]pyridinyl, and the phenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, triazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrimidinyl
  • the ring A is selected from phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, pyrimidopyrrolyl, and the phenyl, pyrazolyl, pyridinyl, triazolyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, and pyrimidopyrrolyl are optionally substituted with one or more Q 1 .
  • Q is selected from hydrogen, halogen, cyano, hydroxy, NR'(R " ), nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl, and the alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyl are optionally substituted with one or more R.
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-6 cycloalkyl are optionally substituted with one or more R 2 .
  • Q 1 is selected from hydrogen, halogen, hydroxyl, NR'(R"), C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 2 .
  • the Q 1 is selected from hydrogen, hydroxy, NR'(R"), methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxymethyl and cyclopropyl are optionally substituted with one or more R 2 .
  • the R 2 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, halogen, hydroxy, oxo, SO 2 R′, NR′(R′′), COR′, COOR′, and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamino, oxo, SO 2 R′, NR′(R′′), COR′, COOR′ and CONR′(R′′).
  • the R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylamino, oxo, SO 2 R′ and NR′(R′′).
  • the R 2 is selected from hydrogen, methoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, dimethylamino, oxo, SO 2 R′, and NR′(R′′).
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl and cycloalkyl, and the alkylene, alkenylene, carbamoyl and cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, and the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, and the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , and the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, and the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl.
  • Y is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more Q 4 , and the Q 4 is selected from hydrogen , halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl.
  • Y is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more Q 4 , wherein Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl.
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group, and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group, and the heterocyclyl group are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, cyano, hydroxy, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R 3 and the atoms to which they are attached form a cycloalkyl or heterocyclic group.
  • Z is selected from a bond, C 1-6 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, and the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted with one or more R 3 , and the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • Z is selected from a bond, C 1-3 alkylene, O, NR"', S, sulfone, sulfoxide, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 4-6-membered heterocyclyl contain 1-4 heteroatoms selected from N, O and S, and the C 1-3 alkylene, C 3-5 cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclyl are optionally substituted with one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl and C 3-5 cycloalkyl, or two R 3 and the atoms to which they are attached form a C 3-5 cycloalkyl or 4-6-membered heterocyclyl.
  • the G is selected from a bond, O, NR"' and alkylene
  • the alkylene is optionally substituted with one or more R4
  • the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms to which they are attached form a cycloalkyl or heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms to which they are attached form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the X is selected from a bond, O, S, NH, and alkylene.
  • said X is selected from a bond and a C 1-3 alkylene group.
  • said X is selected from a bond and a methylene group.
  • the R 1 is selected from hydrogen and alkyl.
  • the R 1 is selected from hydrogen and C 1-3 alkyl.
  • said R 1 is selected from hydrogen and methyl.
  • the carbon atoms in R 1 and Z and the atoms attached thereto form a heterocyclic group, which is optionally substituted with one or more R 9 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 9 , wherein R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R 1 and Z and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R 9 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • the carbon atom in R 1 and Z and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a heterocyclic group, which is optionally substituted with one or more R 10 selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl and oxo.
  • R 1 and the carbon atoms in G and the atoms connected thereto form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by one or more R 10 , wherein the R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the carbon atoms in R1 and G and the atoms connected thereto form a 4-6 membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O and S, and the 4-6 membered heterocyclic group is optionally substituted by one or more R10 selected from hydrogen, C1-3 alkyl, C1-3 alkoxy and halogen.
  • R 1 and the carbon atom in G and the atoms to which they are attached form an azetidinyl or pyrrolidinyl group.
  • the R' is selected from hydrogen, alkyl and alkoxy, the alkyl and alkoxy being optionally substituted with one or more R5 .
  • the R′ is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more R 5 .
  • the R′ is selected from hydrogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with one or more R 5 .
  • the R' is selected from methyl, which is optionally substituted with one or more R5 .
  • the R" is selected from hydrogen, alkyl and alkoxy, and the alkyl and alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-6 alkyl and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from hydrogen, C1-3 alkyl and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy are optionally substituted with one or more R6 .
  • the R" is selected from methyl, which is optionally substituted with one or more R6 .
  • the R' and R" and the atoms to which they are attached form a heterocyclic group, which is optionally One or more R7 are substituted.
  • the R′ and R′′ and the atoms to which they are attached form a 3-10 membered heterocyclyl, which is optionally substituted with one or more R 7 .
  • the R' and R" and the atoms to which they are attached form a 4-6 membered heterocyclic group
  • the heterocyclic group contains 1-2 heteroatoms selected from N, O and S
  • the 4-6 membered heterocyclic group is optionally substituted by one or more R7 .
  • said R′ and R′′ and the atoms to which they are attached form azetidinylmorpholinyl or piperazinyl, said azetidinylmorpholinyl or piperazinyl being optionally substituted with one or more R 7 .
  • the R 5 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 5 is selected from hydrogen.
  • the R 6 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, cyano, oxo, carboxyl, and carboxylate.
  • the R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl and oxo.
  • the R 6 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 6 is selected from hydrogen.
  • the R 7 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxyl, and oxo.
  • said R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halogen.
  • the R 7 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 7 is selected from hydrogen, methyl, and fluoro.
  • the R'' is selected from hydrogen, hydroxy, alkyl, alkoxy and cycloalkyl, and the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, hydroxy, C 1-6 alkyl and C 3-7 cycloalkyl, and the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with one or more R 8 .
  • the R'' is selected from hydrogen, methyl and cyclopropyl, the methyl and cyclopropyl being optionally substituted with one or more R 8 .
  • the R 8 is selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, NR'(R"), nitro, cyano, Oxo, carboxyl, carboxylate and 4-6 membered heterocyclic groups, wherein the heterocyclic groups contain 1-2 heteroatoms selected from N, O and S.
  • the R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, oxo, and pyrrolidinyl.
  • said R 8 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy and halogen.
  • said R 8 is selected from hydrogen.
  • the W is selected from a bond, O, sulfone, sulfoxide, alkylene, alkenylene, carbamoyl, and cycloalkyl, the alkylene, alkenylene, carbamoyl, and cycloalkyl being optionally substituted with one or more Q 3 , the Q 3 being selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl, and cycloalkyl;
  • the Y is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted with one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl;
  • the Z is selected from a bond, an alkylene group, O, NR"', S, a sulfone group, a sulfoxide group, a cycloalkyl group, a heteroaryl group and a heterocyclyl group, wherein the alkylene group, the cycloalkyl group, the heteroaryl group and the heterocyclyl group are optionally substituted by one or more R3 , wherein the R3 is selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, hydroxyalkyl and cycloalkyl, or two R3 and the atoms connected thereto form a cycloalkyl group or a heterocyclyl group;
  • the G is selected from a bond, O, NR"' and an alkylene group, the alkylene group is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, cyano, oxo, alkyl, alkoxy, hydroxyalkyl, heterocyclyl and cycloalkyl, or two R4 and the atoms connected thereto form a cycloalkyl or heterocyclyl group.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl, the C 1-6 alkylene, C 2-10 alkenylene, carbamoyl and C 3-7 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Y is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more Q 4 , the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl;
  • the Z is selected from a bond, C 1-6 alkylene, O, NR "', S, sulfone, sulfoxide, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, the C 1-6 alkylene, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are optionally substituted by one or more R 3 , the R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-7 cycloalkyl, or two R 3 and the atoms connected thereto form a C 3-7 cycloalkyl or a 5-10 membered heterocyclyl;
  • the G is selected from a bond, O, NR"' and C1-6 alkylene, the C1-6 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, 5-10 membered heterocyclyl and C3-7 cycloalkyl, or two R4 and the atoms connected thereto form a C3-7 cycloalkyl or a 5-10 membered heterocyclyl.
  • the W is selected from a bond, O, sulfone, sulfoxide, C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl, the C 1-3 alkylene, C 2-5 alkenylene, carbamoyl and C 3-5 cycloalkyl are optionally substituted with one or more Q 3 , the Q 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-5 cycloalkyl;
  • the Y is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more Q 4 , wherein the Q 4 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 hydroxyalkyl group and C 3-5 cycloalkyl group;
  • the Z is selected from a bond, a C 1-3 alkylene, O, NR"', S, a sulfone group, a sulfoxide group, a C 3-5 cycloalkyl group, a 5-6-membered heteroaryl group and a 4-6-membered heterocyclyl group, wherein the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group contain 1-4 heteroatoms, wherein the heteroatoms are selected from N, O and S, and the C 1-3 alkylene group, the C 3-5 cycloalkyl group, the 5-6-membered heteroaryl group and the 4-6-membered heterocyclyl group are optionally substituted by one or more R 3 , wherein R 3 is selected from hydrogen, halogen, hydroxyl, oxo, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group and C 3-5 cycloalkyl group, or two R
  • the G is selected from a bond, O, NR"' and C1-3 alkylene, the C1-3 alkylene is optionally substituted by one or more R4 , the R4 is selected from hydrogen, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl , 5-6 membered heterocyclyl and C3-5 cycloalkyl, the heterocyclyl contains 1-2 heteroatoms, the heteroatoms are selected from N and O, or two R4 and the atoms connected thereto form a C3-5 cycloalkyl or a 4-6 membered heterocyclyl.
  • the *-WYZG-** is selected from
  • *-WYZG-NR 1 - is selected from
  • the compound of formula (I) is any of the following:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the aforementioned compounds or stereoisomers thereof, Tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents or excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.
  • All compounds involved in the present invention and mixtures and compositions containing the compounds disclosed herein can be administered to a living body via any administration route.
  • the administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.
  • All compounds involved in the present invention and mixtures, compositions, etc. containing the disclosed compounds can be formulated into a single dose, which contains the active compound of the present invention and carriers, excipients, etc., and the dosage form can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc.
  • These dosage forms can contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonicity adjusters, anti-adhesive agents, etc.
  • Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press published in 2005. Therefore, those skilled in the art can easily prepare them.
  • Different dosages can be selected according to the nature and intensity of the disease suffered by different individuals, the age, gender, weight of the patient, the route of administration and other factors.
  • the dosage of the compound disclosed herein can be 0.01 to 500 mg/kg per day, preferably 1-100 mg/kg per day, and can be administered once or multiple times.
  • the present invention also provides the compound of the present invention or its stereoisomers, tautomers, solvates, Hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, their use in regulating cyclin-dependent kinases (CDKs), or their use in preparing drugs for regulating cyclin-dependent kinases (CDKs).
  • CDKs cyclin-dependent kinases
  • CDKs cyclin-dependent kinases
  • the cyclin-dependent kinases are CDK2-related.
  • the present invention also provides the compounds described in the present invention or their stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, their use in treating and/or preventing inflammation, tumors or cancer, or their use in preparing drugs for treating and/or preventing inflammation, tumors or cancer.
  • the inflammation, tumor or cancer is cyclin-dependent kinases (CDKs) related.
  • CDKs cyclin-dependent kinases
  • the inflammation, tumor or cancer is CDK2-related.
  • the present invention also provides a method for treating and/or preventing inflammation, tumors or cancer, comprising administering to a patient a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or the aforementioned pharmaceutical composition;
  • the inflammation, tumor or cancer is cyclin-dependent kinases (CDKs) related;
  • the inflammation, tumor or cancer is CDK2-related.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms ( C1-20 ), preferably an alkyl group containing 1 to 12 carbon atoms ( C1-12 ), and more preferably an alkyl group containing 1 to 6 carbon atoms ( C1-6 ).
  • Non-limiting examples include 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-methylpropyl, 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,
  • Alkylene refers to a saturated straight or branched aliphatic hydrocarbon radical having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane radical, which is a straight or branched chain radical containing from 1 to 20 carbon atoms.
  • the alkylene group preferably contains 1 to 12 carbon atoms, and more preferably contains 1 to 6 carbon atoms.
  • alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the alkylene group may be optionally substituted independently with one or more substituents described herein.
  • Alkenylene refers to a radical having two hydrogen atoms derived from a parent alkene by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms.
  • Alkynyl refers to a straight or branched monovalent hydrocarbon group having 2-20 carbon atoms and at least one unsaturated site (i.e., a carbon-carbon sp triple bond), wherein the alkynyl group may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (propargyl, -CH2C ⁇ CH ), and the like.
  • Alkyne refers to a radical having two hydrogen atoms derived from the same carbon atom or from two different carbon atoms of a parent alkyne.
  • Carbocycle or “cycloalkyl” used interchangeably herein refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls. Wherein the cycloalkyl may be optionally substituted independently by one or more substituents described herein.
  • “Spirocycloalkyl” refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic.
  • fused cycloalkyl groups include:
  • Bridged cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl group as described above (e.g., a monocyclic ring, a spirocyclic ring, a fused ring, and a bridged ring) fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
  • Alkoxy refers to (alkyl)-O-, wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy and butoxy. Wherein the alkoxy may be optionally substituted independently with one or more substituents described herein, such as deuterated alkoxy, haloalkoxy.
  • Heterocycle or “heterocyclyl” as used interchangeably herein refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms being carbon.
  • 1, 2, 3 and 4 are heteroatoms; more preferably containing 3 to 10 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms.
  • monocyclic heterocyclic groups include oxetane, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. Wherein the heterocyclic group may be optionally substituted independently by one or more substituents described herein.
  • “Spiro heterocyclic group” refers to a 5-20 membered polycyclic heterocyclic group, wherein the single rings share one atom (called spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxidized (i.e., forming sulfoxide or sulfone), wherein The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14, more preferably 7 to 10 (e.g., 7, 8, 9 or 10).
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group.
  • spiral heterocyclic groups include:
  • fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic. Non-limiting examples of fused heterocyclic groups include:
  • “Bridged heterocyclic group” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes a heterocyclic group as described above (e.g., a monocyclic ring, a spiro heterocyclic ring, a fused heterocyclic ring, and a bridged heterocyclic ring) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:
  • Aromatic ring or “aryl” used interchangeably herein refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:
  • the aryl groups may be optionally substituted independently with one or more substituents described herein.
  • Heteroaromatic ring and “heteroaryl” used interchangeably herein refer to heteroaromatic systems containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, or 10 members), more preferably 5 or 6 members, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
  • the heteroaryl group may be optionally substituted independently with one or more substituents described herein, and when substituted, it may be substituted at any available point of attachment.
  • cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", “divalent heterocyclic", "arylene” and "heteroarylene".
  • Amino refers to -NH2 , which is optionally substituted with one or more substituents described herein, to form, for example, -NHC1-6alkyl , -N( C1-6alkyl ) C1-6alkyl , wherein alkyl is as defined above.
  • Ester group refers to a carboxyl group in which the H is replaced by a substituent as described herein, for example, -COOC 1-6 alkyl, wherein alkyl is as defined above.
  • Alkylamino refers to an -NH-alkyl group optionally substituted with one or more substituents described herein, for example, -N(alkyl)alkyl, where alkyl is as defined above.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Hydrophill refers to -OH.
  • the compounds of the present application include isotopic derivatives thereof.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • compounds having the structure disclosed herein, replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with 18 F-fluorine labeling ( 18 F isotope), or replacing carbon atoms with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 C-isotope) are within the scope of the present disclosure.
  • Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the various deuterated forms of the compounds disclosed herein refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature.
  • deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, Deuterated compounds usually retain the same activity as undeuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.
  • Optional 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.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • Each independently means that at least two groups (or ring systems) with the same or similar value ranges in the structure can have the same or different meanings under specific circumstances.
  • X and Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl; similarly, when Y is hydrogen, X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
  • Substituted means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents.
  • substituents Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.
  • substitution means that a certain group is completely replaced by another group, such as a methylene group being replaced by a heteroatom such as an oxygen atom or a nitrogen atom.
  • the term "therapeutically effective amount” refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” or “acceptable salts” refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • Solvate refers to a physical combination of a compound of the present application with one or more, preferably 1-3, solvent molecules, whether organic or inorganic.
  • the physical combination includes hydrogen bonding.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • “Hydrate” refers to a substance formed by the compound of the present application or its pharmaceutically acceptable salt and water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrate, monohydrate, dihydrate, trihydrate, etc.
  • Prodrug refers to a compound that can be transformed in vivo under physiological conditions, for example, by hydrolysis in the blood, to yield the active prodrug.
  • “Pharmaceutically acceptable” means that these compounds, materials, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
  • Stereoisomers refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, etc.
  • Tautomers refer to isomers of compounds that differ from one another in proton position and/or electron distribution.
  • In vitro refers to biological entities, biological processes or biological reactions under artificial conditions outside the body.
  • cells grown in vitro are understood to be cells grown in an environment outside the body, such as a test tube, culture dish or microtiter plate.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations. Key Can be Although all the above structural formulas are drawn as certain isomers for the sake of simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers.
  • the bond No configuration is specified, i.e., the bond The configuration can be E-type or Z-type, or include both E and Z configurations.
  • the reactions in the examples are generally carried out under nitrogen protection.
  • the LC-MS liquid chromatography-mass spectrometry chromatograph uses Waters ACQUITY Arc or equivalent equipment.
  • the mass spectrum (MS) uses an ESI source, indicating only the molecular weight M of the parent molecule, and usually reports [M+H] + .
  • the NMR spectrum uses a Varian 400MHz nuclear magnetic resonance spectrometer or equivalent equipment to obtain data, usually using CDCl 3 , DMSO-d 6 as solvents, and reporting chemical shifts in ppm.
  • the descriptions of various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet). Coupling constants are expressed in Hz.
  • acetonitrile (10.03 g, 244.39 mmol, 12.86 mL) was added dropwise to a tetrahydrofuran solution (600 mL) containing n-butyl lithium (2.5 M, 97.76 mL), and the reaction solution was stirred at -70°C for 1 hour. Then, a tetrahydrofuran solution of compound B was added dropwise to the reaction solution at -65°C, and stirring was continued at -70°C for 1 hour. After the reaction was completed by monitoring the reaction on a TLC plate, the reaction solution was returned to room temperature and an aqueous solution of ammonium chloride (1000 mL) was added thereto to quench the reaction.
  • lithium triethylborohydride (1M, 104.00mL) was added dropwise to a tetrahydrofuran solution (500mL) containing compound E (26g, 73.15mmol), and the reaction solution was stirred at -70°C for 2 hours.
  • 1000mL of aqueous ammonium chloride solution was added to the reaction solution to quench the reaction.
  • 500mL of water was added to dilute and extracted with ethyl acetate (700mL*3), the organic phases were mixed, the solution was removed under reduced pressure, and the crude yellow oil compound F (40g) was directly used in the next step.
  • Step 1 Synthesis of compound ii-B
  • Triethylamine (131g, 1.30mol) was slowly added dropwise to the reaction, and after the addition was completed, the temperature of the reaction solution was naturally restored to -20°C, and the reaction mixture was stirred at this temperature for 1h. After the reaction was completed, water (300mL) was added to the reaction mixture to quench it, and it was extracted with dichloromethane (200ml*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to remove the solid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound ii-E (40 g, yield: 80%).
  • intermediate D-1 refers to the synthesis of intermediate 1, except that tert-butylhydrazine hydrochloride in step 3 is replaced by 4-methoxybenzylhydrazine and the protecting group is removed.
  • N-methylimidazole (3.75 g, 45.72 mmol) was added to an acetonitrile solution (100 mL) containing compound D-1 (7.3 g, 15.24 mmol) and 1-1 (3.27 g, 16.76 mmol) and stirred at room temperature for 10 minutes.
  • Tetramethyl chlorourea hexafluorophosphate (8.55 g, 30.48 mmol) was then added to the reaction solution and stirred for 16 hours. After the reaction was completed by LCMS monitoring, 100 mL of aqueous solution was added to the reaction solution to quench the reaction.
  • the mixture was extracted with ethyl acetate (100 mL*2), the organic phases were mixed and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was removed under reduced pressure.
  • Iron powder (3.86 g, 69.19 mmol) and ammonium chloride (2.22 g, 41.51 mmol) were added to a mixture of an ethanol solution (60 mL) containing compound 1-2 (6.4 g, 13.84 mmol) and water (60 mL), and stirred at 80°C for 16 hours. After the reaction was completed by LCMS monitoring, 100 mL of aqueous solution was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (100 mL*2).
  • N-methylimidazole (227.78 mg, 2.77 mmol) was added to an acetonitrile solution (10 mL) containing compound 1-3 (0.4 g, 924.83 umol) and Boc-5-aminovaleric acid (200.93 mg, 924.83 umol) and stirred at room temperature for 10 minutes. Tetramethyl chlorouronium hexafluorophosphate (518.98 mg, 1.85 mmol) was then added to the reaction solution and stirred for 16 hours. After the reaction was completed by LCMS monitoring, 10 mL of aqueous solution was added to the reaction solution to quench the reaction.
  • Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a dichloromethane solution (12 mL) containing compound 1-6 (0.9 g, 1.24 mmol) at room temperature and stirred for 1 hour. After the reaction was completed by LCMS monitoring, the solution was removed under reduced pressure to obtain a crude yellow oil compound 1-7 (2 g) which was directly used in the next step.
  • Compound 1-7 (ESI+) m/z 628.4 (M+H) + .
  • Potassium carbonate (1.32 g, 9.56 mmol) was added to a DMF solution (30 mL) containing compound 1-7 (2 g, 3.19 mmol) and the mixture was heated to 70°C and stirred for 12 hours. After the reaction was completed by LCMS monitoring, 30 mL of aqueous solution was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (30 mL*2). The organic phases were mixed and washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the solution was removed under reduced pressure.
  • Example 1 compound as a white solid (38.10 mg, 85.05 umol, yield: 28.00%).
  • Example 1 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.07 (br s,1H),10.92-10.45(m,1H),10.39-9.68(m,1H),8.04-7.62(m,1H),7.16-6.99(m,2H),6.85-6.58(m,1H),6.44-6.30(m,1H),5.10-4.82(m,1H), 3.73-3.60(m,2H),3.28-3.13(m,2H),2.86-2.72(m,1H),2.36-2.18(m,6H),2.14-2.00(m,1H),1.97-1.85(m,1H),1.82-1.59(m,5H),1.56-1.35 (m,2H); (ESI+)m/z 440.4(M+H) + .
  • Example 2 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 10.95-10.57 (m, 1H), 10.37-9.68 (m, 1H), 7.98-7.59 (m, 1H), 7.16-7.10 (m, 1H), 7.06-7.00 (m, 1H), 6.93-6.61 (m, 1H), 6.35-6.28 (m, 1H), 5.08-4.81 (m, 1H), 3.76-3.71 (m, 2H), 3.27-3.05 (m, 2H), 3.00-2.69 (m, 2H), 2.33-2.24 (m, 5H), 2.12-1.98 (m, 1H), 1.86-1.22 (m, 11H); (ESI+) m/z 454.4(M+H) + .
  • Example 3 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 11.05-10.52 (m, 1H), 10.14-9.83 (m, 1H), 7.79-7.65 (m, 1H), 7.17-7.09 (m, 1H), 7.06-7.00 (m, 1H), 6.93-6.65 (m, 1H), 6.32-6.25 (m, 1H), 5.07-4.84 (m, 1H), 4 .53-4.33(m,2H),3.71-3.61(m,2H),3.26-3.02(m,2H),2.86-2.70(m,1H),2.34-2.22(m,5H),2.07-1.96(m,1H),1.80-1.56(m,6H),1.42-1.21( m,6H); (ESI+)m/z 468.4(M+H) + .
  • Example 4 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.32-11.87 (m, 1H), 10.78-10.24 (m, 1H), 9.99-9.31 (m, 1H), 7.85-7.54 (m, 1H), 7.17-7.07 (m, 1H), 7.05-7.00 (m, 1H), 6.96-6.66 (m, 1H), 6.35-6.20 (m, 1H), 5 .11-4.81(m,1H),3.73-3.56(m,2H),3.22-3.05(m,2H),2.99-2.69(m,2H),2.34-2.24(m,5H),2.06-1.94(m,1H),1.84-1.57(m,6H),1.40-1.20( m,8H); (ESI+)m/z 482.3(M+H) + .
  • N-methylimidazole (534.23 mg, 6.51 mmol) was added to an acetonitrile solution (10 mL) containing compound 5-1 (0.6 g, 2.91 mmol) and the deprotected intermediate compound D (0.6 g, 2.17 mmol) and stirred at room temperature for 10 minutes. Tetramethyl chlorourea hexafluorophosphate (1.22 g, 4.34 mmol) was then added to the reaction solution and stirred for 16 hours. After the reaction was completed by LCMS monitoring, 10 mL of aqueous solution was added to the reaction solution to quench the reaction.
  • tetrakistriphenylphosphine palladium 141.09 mg, 122.09 umol
  • morpholine 212.74 mg, 2.44 mmol
  • 10 mL of aqueous solution was added to the reaction solution for quenching and dilution.
  • Potassium carbonate (448.90 mg, 3.25 mmol) was added to a DMF solution (10 mL) containing compound 5-3 (0.4 g, 1.08 mmol) and (7-bromoheptyl)carbamic acid tert-butyl ester (318.55 mg, 1.08 mmol), and the temperature was raised to 90°C and stirred for 12 hours. After the reaction was completed by LCMS monitoring, 10 mL of aqueous solution was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (10 mL*2).
  • Example 5 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 10.70-10.29 (m, 1H), 7.04-6.93 (m, 2H), 6.66 (br s, 2H), 6.22-6.15 (m, 1H), 5.05-4.83 (m, 1H), 3.93-3.85 (m, 2H), 3.19-3.08 (m, 2H), 2.88-2.70 (m, 2H), 2.40-2.31 (m, 1H), 2.25-2.17 (m, 3H), 2.15-2.05 (m, 1H), 1.89-1.49 (m, 7H), 1.46-0.96 (m, 9H); (ESI+) m/z 455.4 (M+H) + .
  • Acetic acid (223 mg, 3.70 mmol) was added to a DMF solution (10 mL) containing compound 1-3 (1.60 g, 3.70 mmol) and tert-butyl 7-oxoheptylcarbamate (849 mg, 3.70 mmol) and stirred at room temperature for 1 hour. The reaction solution was then cooled to zero degrees, sodium acetate borohydride (1.38 g, 6.51 mmol) was added, and stirring was continued at zero degrees for 1 hour.
  • Example 3 Refer to the synthesis of Example 3: the difference is that the starting compound 1-1 is replaced by (5-methoxy-2-nitro-phenyl)-acetic acid.
  • Synthesis of compound 10-1 Refer to the synthesis of intermediate 1-3 in Example 1, except that the intermediate compound D-1 in step 1 is replaced by the deprotected intermediate compound D.
  • Lithium hydroxide (0.81 g, 19.3 mmol) was added to a mixed solution of tetrahydrofuran (20 mL) and water (5 mL) containing compound 11-2 (2 g, 6.4 mmol) and stirred at room temperature for 16 hours. After the reaction was completed by LCMS monitoring, the mixture was filtered, and the filtrate was adjusted to pH 5 with 2N hydrochloric acid, extracted with ethyl acetate (50 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solution was removed under reduced pressure to obtain a white solid compound 11-3 (1.9 g, 6.4 mmol, yield: 99.48%).
  • 1,1-Carbonyldiimidazole (467.75 mg, 2.89 mmol) was added to a tetrahydrofuran solution (8 mL) containing compound 11-5 (290 mg, 0.58 mmol) at room temperature and stirred for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was evaporated under reduced pressure, 50 mL of ethyl acetate was added, and washed with saturated brine (15 mL*5), dried over anhydrous magnesium sulfate, and the solution was removed under reduced pressure to obtain a crude yellow oil compound 11-6 (340 mg, 0.57 mmol, yield: 98.27%), which was directly used in the next step.
  • Compound 11-6 (ESI+) m/z 597.4 (M+H) + .
  • Trifluoroacetic acid (1.091 mL, 14.250 mmol) was added to a dichloromethane solution (4 mL) containing compound 11-6 (340 mg, 0.57 mmol) at room temperature and stirred for 2 hours. After the reaction was completed by LCMS monitoring, the solution was removed under reduced pressure to obtain a crude yellow oil compound 11-7 (280 mg, 0.56 mmol, yield: 98.24%) which was directly used for the next step.
  • Compound 11-7 (ESI+) m/z 497.4 (M+H) + .
  • the trifluoroacetic acid solution (1.5 mL) containing compound 11-8 (60 mg, 0.14 mmol) was heated to 70 ° C and stirred for 16 hours. After the reaction was completed by LCMS monitoring, the solution was removed under reduced pressure, ethyl acetate (5 mL) was added, and the pH value was adjusted to about 7-8 with saturated sodium bicarbonate solution. The mixed solution was extracted with ethyl acetate (5 mL * 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solution was removed under reduced pressure.
  • Example 12 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.16 (br s, 1H), 10.75 (s, 1H), 7.49 (s, 1H), 7.20-6.95 (m, 1H), 6.80-6.45 (m, 2H), 5.10-4.85 (m, 1H), 4.80-4.38 (m, 2H), 3.31-3.13 (m, 2H), 2.81 (br s, 1H), 2.35-2.12 (m, 2H), 2.11-1.97 (m, 1H), 1.96-1.59 (m, 6H), 1.53 (br s, 1H), 1.42-1.21 (m, 4H); (ESI+) m/z 387.4 (M+H) + .
  • Example 14 The compound of Example 14 was further resolved by chiral SFC to give the compound of Example 16.
  • Example 14 was further resolved by chiral SFC to give the compound of Example 17.
  • Lithium hydroxide (1.69 g, 40.16 mmol) was added to a mixed solution of tetrahydrofuran (24 mL) and water (6 mL) containing compound 18-2 (2.6 g, 13.39 mmol) and stirred at room temperature for 16 hours. After the reaction was completed by LCMS monitoring, the mixture was filtered, and the filtrate was adjusted to pH 5 with 2N hydrochloric acid, extracted with ethyl acetate (50 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solution was removed under reduced pressure to obtain a yellow oil compound 18-3 (2.4 g, 13.32 mmol, yield: 99.5%).
  • N-methylimidazole (729.62 mg, 8.89 mmol, 708.37 uL) was added to an acetonitrile solution (100 mL) containing compound 18-3 (640.58 mg, 3.55 mmol) and intermediate 1 (1 g, 2.96 mmol) and stirred at room temperature for 30 minutes.
  • Tetramethyl chlorouronium hexafluorophosphate (1.25 g, 4.44 mmol) was then added to the reaction solution and stirred at room temperature for 16 hours.
  • Tetrabutylammonium fluoride (1M, 7.28mL) was added to a tetrahydrofuran solution (10mL) containing compound 18-4 (1.3g, 1.46mmol), and stirred at room temperature for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was evaporated under reduced pressure, 100mL of ethyl acetate was added, and washed with saturated brine (30mL*4), dried over anhydrous magnesium sulfate, and the solution was removed under reduced pressure to obtain a crude yellow oil compound 18-5 (1.05g, 1.23mmol, yield: 84.24%), which was directly used for the next step reaction.
  • Compound 18-5 (ESI+) m/z 386.0 (M+H) + .
  • 1,1-Carbonyldiimidazole (946.39 mg, 5.84 mmol) was added to a tetrahydrofuran solution (20 mL) containing compound 18-5 (1 g, 1.17 mmol) at room temperature and stirred for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was evaporated under reduced pressure, 150 mL of ethyl acetate was added, and washed with saturated brine (50 mL*4), dried over anhydrous magnesium sulfate, and the solution was removed under reduced pressure.
  • Example 19 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.19 (br s, 1H), 10.74-10.33 (m, 1H), 6.97-6.69 (m, 2H), 6.41 (br s, 1H), 5.08-4.79 (m, 1H), 4.63-4.32 (m, 2H), 3.25-2.97 (m, 1H), 2.72 (br s, 1H), 2.22-1.94 (m, 5H), 1.92-1.55 (m, 7H), 1.37-1.16 (m, 10H); (ESI+) m/z 429.1 (M+H) + .
  • Example 22 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.21 (br s, 1H), 10.63-10.55 (m, 1H), 6.73-6.64 (m, 1H), 6.98 (br s, 1H), 6.53 (br s,1H),6.47-6.37(m,1H),5.06-4.93(m,1H),3.90(s,3H),4.08-3.83(m,1H),3.23-3.03(m,2H),2.95-2.74(m,2H),2.11-2.01(m,1H),1.89-1.7 0(m,4H),1.67-1.61(m,1H),1.57-1.49(m,1H),1.39-1.11(m,10H); (ESI+)m/z 445.4(M+H) + .
  • Example 12 was further resolved by chiral SFC to give the compound of Example 23.
  • Example 23 compound (ESI+) m/z 387.2 (M+H) + .
  • Example 12 was further resolved by chiral SFC to give the compound of Example 24.
  • Example 25 The synthesis was carried out in accordance with Example 18, except that the compound 5-bromo-1-pentene in step 1 and the compound 4-pentene-1-amine in step 6 were replaced by the compounds 4-bromo-1-butene and 3-butene-1-amine, respectively, and the compound of Example 25 was obtained by preparative liquid separation.
  • Example 25 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.30-11.95 (m, 1H), 10.96-10.41 (m, 1H), 7.51 (br s, 1H), 7.18-6.88 (m, 1H), 6.73-6.37 (m, 2H), 5.84-4.36 (m, 5H), 3.33-2.90 (m, 2H), 2.85-2.70 (m, 1H), 2.39-1.80 (m, 10H); (ESI+) m/z 385.4 (M+H) + .
  • Example 26 The synthesis was carried out in accordance with Example 18, except that the compound 5-bromo-1-pentene in step 1 and the compound 4-pentene-1-amine in step 6 were replaced by the compounds 4-bromo-1-butene and 3-butene-1-amine, respectively, and the compound of Example 26 was obtained by preparative liquid separation.
  • Example 25 was further resolved by chiral SFC to give the compound of Example 27.
  • Example 27 compound (ESI+) m/z 385.4 (M+H) + .
  • Example 25 was further resolved by chiral SFC to give the compound of Example 28.
  • Example 28 compound (ESI+) m/z 385.4 (M+H) + .
  • Example 29 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.13 (br s, 1H), 10.64 (s, 1H), 6.92-6.42 (m, 3H), 5.05-4.82 (m, 1H), 4.74-4.30 (m, 2H), 3.30-3.00 (m, 2H), 2.86-2.71 (m, 1H), 2.30-2.05 (m, 5H), 2.04-1.40 (m, 8H), 1.39-0.97 (m, 4H); (ESI+) m/z 401.2 (M+H) + .
  • reaction solution was removed under reduced pressure, ethyl acetate (500 mL) was added, and washed with saturated brine (100 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solution was removed under reduced pressure.
  • the synthesis of reference example 34 is as follows: the difference is that the compound N-Boc-ethanolamine in step 2 of the side chain synthesis is replaced by compound The starting compound 3-pyrazolecarboxylic acid methyl ester was replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester.
  • Example 34 Refer to the synthesis of Example 34: the differences are that the compound N-Boc-ethanolamine in the second step of the side chain synthesis is replaced by the compound N-Boc-D-alaninol; the starting compound 3-pyrazolecarboxylic acid methyl ester is replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester.
  • N-Boc-3-aminopropyl bromide (4.53 g, 19.03 mmol) and potassium carbonate (6.58 g, 47.58 mmol) were added to an acetonitrile solution (300 mL) containing 3-pyrazolecarboxylic acid methyl ester 11-1 (2 g, 15.86 mmol) and stirred at 80°C for 16 hours.
  • the reaction was completed after LCMS monitoring, filtered, and the solution was removed under reduced pressure.
  • Triethylamine (4.3 mL, 31.0 mmol) was added to a DMF solution (70 mL) containing 37-2 (1.42 g, 7.75 mmol) and BOC-glycine (1.63 g, 9.30 mmol) and stirred for 5 minutes, then HATU (3.54 g, 9.3 mmol) was added and stirred at room temperature for 1 hour.
  • ethyl acetate 500 mL was added, and the mixture was washed with saturated brine (50 mL*4), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solution was removed under reduced pressure.
  • Example 37 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.23 (br s, 1H), 11.08 (s, 1H), 8.02 (br s, 1H), 7.57 (s, 1H), 7.41 (br s, 1H), 7.24 (s, 1H), 6.74 (s, 1H), 5.00 (br s, 1H), 4.90-4.78 (m, 1H), 4.49-4.39 (m, 1H), 3.94-3.44 (m, 2H), 3.33-3.19 (m, 3H), 2.30-2.13 (m, 2H), 1.93-1.73 (m, 6H); (ESI+) m/z 402.1 (M+H) + .
  • Triethylamine (6.94 mL, 49.96 mmol) and HATU (5.7 g, 15 mmol) were added to a DMF solution (40 mL) containing 38-2 (2.3 g, 12.5 mmol) and N-tert-butyloxycarbonyl-1,3-propylenediamine (2.18 g, 12.5 mmol), and stirred at room temperature for 1 hour.
  • ethyl acetate 500 mL was added, and the mixture was washed with saturated brine (50 mL*4). The organic phase was washed with anhydrous The mixture was dried over sodium sulfate, filtered, and the solution was removed under reduced pressure.
  • Example 35 was further resolved by chiral SFC to give the compound of Example 39.
  • Example 35 was further resolved by chiral SFC to give the compound of Example 40.
  • Example 40 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.18 (br s, 1H), 10.98-10.72 (m, 1H), 7.25-5.89 (m, 3H), 5.26-4.82 (m, 2H), 4.41 (s, 3H), 3.80-3.46 (m, 2H), 3.38-3.19 (m, 6H), 3.18-2.84 (m, 1H), 2.22-1.77 (m, 8H), 1.24-1.00 (m, 3H); (ESI+) m/z 447.3 (M+H) + .
  • Example 44 The compound of Example 44 was further resolved by chiral SFC.
  • Example 44 The compound of Example 44 was further resolved by chiral SFC.
  • Example 34 Refer to the synthesis of Example 34: the differences are that the compound 3-bromo-1-propanol in the first step of the side chain synthesis is replaced by the compound 2-bromoethanol; the compound N-Boc-ethanolamine in the second step is replaced by the compound 3-(BOC-amino)-1-propanol.
  • Example 47 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.14 (br s, 1H), 10.77-10.55 (m, 1H), 7.52 (br s, 1H), 7.18-6.90 (m, 1H), 6.80-6.40 (m, 2H), 5.10-4.81 (m, 2H), 4.72-4.49 (m, 1H), 3.74-3.37 (m, 4H), 3.33-3.17 (m, 2H), 2.97-2.71 (m, 1H), 2.28-1.76 (m, 6H), 1.66-1.32 (m, 2H); (ESI+) m/z 389.2 (M+H) + .
  • Example 55 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.08 (br s, 1H), 10.58 (br s, 1H), 7.09-6.75 (m, 1H), 6.63-6.27 (m, 2H), 5.35-4.08 (m, 5H), 3.66-3.39 (m, 6H), 3.27 (s, 3H), 2.19-1.76 (m, 6H), 1.08-0.55 (m, 3H); (ESI+) m/z 433.2 (M+H) + .
  • Example 56 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.28-11.89 (m, 1H), 10.89-10.43 (m, 1H), 7.18-6.84 (m, 1H), 6.75-6.33 (m, 1H), 5.64-4.09 (m, 5H), 3.59-3.40 (m, 6H), 3.28 (s, 3H), 2.30-1.41 (m, 6H), 0.87-0.60 (m, 3H); (ESI+) m/z 433.2 (M+H) + .
  • Example 47 Refer to the synthesis of Example 47: the differences are that the compound 3-(BOC-amino)-1-propanol in the second step of the side chain synthesis is replaced by the compound BOC-(S)-3-amino-1-butanol; the starting compound 3-pyrazolecarboxylic acid methyl ester is replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester; and finally the product is separated by chiral SFC.
  • Example 47 Refer to the synthesis of Example 47: the differences are that the compound 3-(BOC-amino)-1-propanol in the second step of the side chain synthesis is replaced by the compound BOC-(S)-3-amino-1-butanol; the starting compound 3-pyrazolecarboxylic acid methyl ester is replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester; and finally the product is separated by chiral SFC.
  • Example 59 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.08 (br s, 1H), 10.58 (br s, 1H), 7.05-6.77 (m, 1H), 6.64-6.30 (m, 2H), 5.14-4.16 (m, 5H), 3.54 (br s, 4H), 3.28 (s, 5H), 2.15-1.75 (m, 6H), 1.05-0.63 (m, 3H); (ESI+) m/z 433.2 (M+H) + .
  • Example 60 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.22-11.90 (m, 1H), 10.88-10.38 (m, 1H), 7.10-6.39 (m, 2H), 5.72-5.03 (m, 2H), 4.88 (br s, 1H), 4.46-4.10 (m, 3H), 3.61-3.37 (m, 4H), 3.29 (s, 4H), 2.26-1.57 (m, 6H), 0.87-0.61 (m, 3H); (ESI+) m/z 433.3 (M+H) + .
  • the synthesis was performed in accordance with Example 34, except that the compound 3-bromo-1-propanol in the first step of the side chain synthesis was replaced by the compound 2-bromoethanol; the compound N-Boc-ethanolamine in the second step was replaced by the compound (S)-(3-hydroxy-2-methylpropyl)carbamic acid tert-butyl ester; the starting compound 3-pyrazolecarboxylic acid methyl ester was replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester. The product was finally obtained by chiral SFC separation.
  • the synthesis was performed in accordance with Example 34, except that the compound 3-bromo-1-propanol in the first step of the side chain synthesis was replaced by the compound 2-bromoethanol; the compound N-Boc-ethanolamine in the second step was replaced by the compound (S)-(3-hydroxy-2-methylpropyl)carbamic acid tert-butyl ester; the starting compound 3-pyrazolecarboxylic acid methyl ester was replaced by the compound 5-methoxymethylene-1H-pyrazole-3-carboxylic acid methyl ester. The product was finally obtained by chiral SFC separation.
  • Example 63 Refer to the synthesis of Example 63 and finally obtain it by chiral SFC separation.
  • Example 63 Refer to the synthesis of Example 63 and finally obtain it by chiral SFC separation.
  • Example 69 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.13 (br s,1H),10.85-10.72(m,1H),7.55-7.47(m,1H),7.18-6.50(m,2H),6.46-5.90(m,1H),5.18-4.91(m,2H),4.41-4.25(m,1H),3.69-3.53(m,1H),3 .48-3.37(m,2H),3.30-3.16(m,2H),3.08-2.93(m,1H),2.22-2.11(m,1H),2.09-1.95(m,2H),1.94-1.82(m,5H),1.81-1.69(m,1H),0.90-0.69( m,6H); (ESI+)m/z 431.2(M+H) + .
  • Example 62 Refer to the synthesis of Example 62 and finally obtain it by chiral SFC separation.
  • Example 62 Refer to the synthesis of Example 62 and finally obtain it by chiral SFC separation.
  • Example 72 compound (ESI+) m/z 473.3 (M+H) + .
  • Example 57 Refer to the synthesis of Example 57 and finally obtain it by chiral SFC separation.
  • Example 57 Refer to the synthesis of Example 57 and finally obtain it by chiral SFC separation.
  • Example 74 Compound 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 12.14 (br s, 1H), 10.88-10.62 (m, 1H), 7.24-6.30 (m, 3H), 5.21-4.96 (m, 1H), 4.95-4.59 (m, 2H), 4.35 (s, 2H), 3.92-3.37 (m, 3H), 3.36-3.27 (m, 6H), 2.18 (br s, 2H), 2.00-1.72 (m, 4H), 1.63-1.31 (m, 3H), 0.83-0.62 (m, 6H); (ESI+) m/z 475.1 (M+H) + .
  • the synthesis was carried out in accordance with Example 35, except that the compound N-Boc-ethanolamine in the second step of the side chain synthesis was replaced by the compound N-Boc-L-valinol; and the starting compound 3-pyrazolecarboxylic acid methyl ester was replaced by the compound 5-dimethylaminomethylene-1H-pyrazole-3-carboxylic acid ethyl ester.
  • Example 76 Compound 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 12.16 (br s, 1H), 10.94-10.60 (m, 1H), 7.22-6.36 (m, 3H), 5.20-4.48 (m, 3H), 4.39-4.28 (m, 2H), 3.98-3.51 (m, 1H), 3.31-3.09 (m, 8H), 2.24-1.69 (m, 9H), 0.85-0.74 (m, 6H); (ESI+) m/z 523.2 (M+H) + .
  • Example 76 Refer to the synthesis of Example 76 and finally obtain it by chiral SFC separation.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des inhibiteurs ciblant CDK représentés par la formule (I), leur procédé de préparation, une composition pharmaceutique les comprenant, et leur utilisation médicale. Les composés ont une excellente activité inhibitrice de CDK et une excellente activité inhibitrice sélective.
PCT/CN2024/071915 2023-01-20 2024-01-12 Inhibiteurs macrocycliques de la cycline ainsi que leur procédé de préparation et leur utilisation Ceased WO2024152995A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2020125513A1 (fr) * 2018-12-19 2020-06-25 凯复制药有限公司 Composé macrocyclique servant d'inhibiteur de cdk, son procédé de préparation et son utilisation en médecine
CN113330000A (zh) * 2019-01-31 2021-08-31 辉瑞公司 具有对cdk2的抑制活性的3-羰基氨基-5-环戊基-1fi-吡咯化合物
CN113603708A (zh) * 2021-07-27 2021-11-05 中国药科大学 一种具有大环骨架结构的新型cdk9抑制剂的制备及其应用
WO2022135365A1 (fr) * 2020-12-22 2022-06-30 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Inhibiteurs de kinase de cyclopentane disubstitués
WO2022135442A1 (fr) * 2020-12-22 2022-06-30 上海拓界生物医药科技有限公司 Inhibiteur de cdk2 et son procédé de préparation
WO2022174031A1 (fr) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation
CN116023367A (zh) * 2021-10-25 2023-04-28 优领医药科技(香港)有限公司 含四氢呋喃多环类衍生物、其药学上可接受的盐及其制备方法和应用
WO2023141852A1 (fr) * 2022-01-27 2023-08-03 益方生物科技(上海)股份有限公司 Inhibiteurs de la cdk2, leur procédé de préparation et leur utilisation
WO2023154426A1 (fr) * 2022-02-11 2023-08-17 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation
WO2024046443A1 (fr) * 2022-09-01 2024-03-07 Nutshell Biotech (Shanghai) Co., Ltd. Composés macrocycliques utilisés en tant qu'inhibiteurs sélectifs de cdk

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020125513A1 (fr) * 2018-12-19 2020-06-25 凯复制药有限公司 Composé macrocyclique servant d'inhibiteur de cdk, son procédé de préparation et son utilisation en médecine
CN113330000A (zh) * 2019-01-31 2021-08-31 辉瑞公司 具有对cdk2的抑制活性的3-羰基氨基-5-环戊基-1fi-吡咯化合物
WO2022135365A1 (fr) * 2020-12-22 2022-06-30 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Inhibiteurs de kinase de cyclopentane disubstitués
WO2022135442A1 (fr) * 2020-12-22 2022-06-30 上海拓界生物医药科技有限公司 Inhibiteur de cdk2 et son procédé de préparation
WO2022174031A1 (fr) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation
CN113603708A (zh) * 2021-07-27 2021-11-05 中国药科大学 一种具有大环骨架结构的新型cdk9抑制剂的制备及其应用
CN116023367A (zh) * 2021-10-25 2023-04-28 优领医药科技(香港)有限公司 含四氢呋喃多环类衍生物、其药学上可接受的盐及其制备方法和应用
WO2023141852A1 (fr) * 2022-01-27 2023-08-03 益方生物科技(上海)股份有限公司 Inhibiteurs de la cdk2, leur procédé de préparation et leur utilisation
WO2023154426A1 (fr) * 2022-02-11 2023-08-17 Relay Therapeutics, Inc. Inhibiteurs de cdk et leurs procédés d'utilisation
WO2024046443A1 (fr) * 2022-09-01 2024-03-07 Nutshell Biotech (Shanghai) Co., Ltd. Composés macrocycliques utilisés en tant qu'inhibiteurs sélectifs de cdk

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