Substituted heterocyclic compound and use thereof

Abstract

The present invention relates to a substituted heterocyclic compound and a use thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition thereof, and a use of the compound represented by general formula (I) or the pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a disease mediated by FGFR tyrosine kinase, wherein each substituent in general formula (I) is the same as defined in the description.

Description

Substituted heterocyclic compounds and their uses Technical Field

[0001] This disclosure relates to novel compounds that act on FGFR tyrosine kinases, particularly FGFR1, FGFR2, FGFR3, and / or FGFR4, and includes methods for preparing said compounds and their uses. More specifically, the present invention relates to diseases that can be treated or prevented by FGFR inhibitors. Background Technology

[0002] Mutations or abnormal expression of protein tyrosine kinases (PTKs) are a major cause of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, with four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. Fibroblast growth factors (FGFs) bind to their receptors (FGFRs), activating downstream signaling pathways they regulate. These pathways play crucial roles in both pro-mitotic (embryogenesis, growth and development, etc.) and non-pro-mitotic (neural regulation, metabolic regulation, etc.) biological processes. In the pro-mitotic pathway, high expression or mutations of FGFRs lead to abnormal activation of their signaling pathways. When the pro-mitotic function of the FGFR pathway is uncontrolled, tumors develop.

[0003] FGFR3 is a tyrosine kinase receptor gene located on chromosome 4p16.3, consisting of 19 exons. Its extracellular portion binds to fibroblast growth factor, triggering a cascade of downstream signaling that ultimately affects cell growth, migration, angiogenesis, and differentiation. Mutations in fibroblast growth factor receptor 3 (FGFR3) primarily occur in low-grade non-invasive urothelial tumors. Simultaneously, FGFR3 is a negative regulator of bone growth. It inhibits the proliferation and differentiation of growth plate chondrocytes, leading to impaired long bone growth. Conversely, the CNP signaling pathway stimulates the proliferation and differentiation of growth plate chondrocytes, thereby promoting endochondral ossification and long bone growth.

[0004] Inhibitors targeting FGFR can suppress abnormal activation of the FGF / FGFR signaling pathway and have the potential to treat the aforementioned diseases, making them a hot topic in drug research in recent years. Since 2019, inhibitors such as Erdafitinib, Pemigatinib, and Infigratinib have been launched. Although their development has been successful, because they are pan-FGFR inhibitors or FGFR1-3 inhibitors, these three approved FGFR inhibitors still have some treatment-related adverse events (TRAEs) in clinical trials. For example, FGFR1-mediated hyperphosphatemia is a dose-limiting toxicity of pan-FGFR inhibitors; FGFR2-mediated skin / nail, ocular, and perioral toxicities lead to chronic intolerance to pan-FGFR inhibitors. Therefore, developing highly selective inhibitors targeting precise FGFR subtypes and second-generation FGFR inhibitors that overcome resistance to existing FGFR inhibitors have become a major research direction. Summary of the Invention

[0005] The present invention provides a compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which has good physicochemical properties, such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety and low toxicity.

[0006] This invention relates to compounds of general formulas (I), (I-1A), (I-1B), (I-2A), (I-2B), (I-3A), (I-3B), (I-4A), (I-4B), (I-5A), (I-5B), (I-6A), (I-6B), (Ia), (Ia-1), (Ia-2), (I-7B), (I-8B), (I-9B), (I-10B), (I-1B-1), (Ia-3), (I-1B-2), (I-1B-3), (Ia-4), (Ia-5), (Ia-6), and (Ia-7), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0007] In some implementations, ring A is In some implementations, ring A is

[0008] In some embodiments, ring A1 is a 4-10-membered nitrogen-containing heterocyclic alkyl group or an 11-12-membered nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. ASubstitution; in some embodiments, ring A1 is a 4-10 member nitrogen-containing heterocyclic alkyl group, optionally further replaced by 1-4 R groups. A replace;

[0009] In some embodiments, ring A1 is a 6-10 member nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A replace;

[0010] In some implementations, ring A2 is C 3-8 Cycloalkyl, optionally further surrounded by 1-4 R A replace;

[0011] In some implementations, ring A1 is... * indicates that it is related to R a1 Linkage sites;

[0012] In some implementations, ring A2 is * indicates the link site with L;

[0013] In some implementations, Z is Or it may not exist, in which Connected to Y;

[0014] In some implementation schemes, Z is in Connected to Y; in some implementations, Z is in Connected to Y;

[0015] In some embodiments, alternatively, R3 and the adjacent pyridopyrazol group together with the attached atom form a 5-8 membered heterocycle or a 5-8 membered carbon ring;

[0016] In some embodiments, R3 and the adjacent pyridopyrazol group together with the attached atom form a 5-membered carbon ring, a benzene ring, or an oxa 6-membered heterocycle;

[0017] In some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B Substitution; in some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B Replacement; in some implementations, ring B is In some embodiments, ring B is pyridyl, optionally further surrounded by 1-4 R groups. B Replacement; in some implementations, ring B is

[0018] In some implementations, Y represents bond, -O-, C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -OC 3-6 Cycloalkylene- or -C 3-6 Cycloalkylene-O-, wherein the alkylene, alkenylene, ynylene, or cycloalkylene group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group;

[0019] In some implementations, Y is -O-, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -OC 1-3 alkylene-, -C 1-3 Alkylene-O-, -OC 3-4 Cycloalkylene- or -C 3-4 Cycloalkylene-O-;

[0020] In some embodiments, Y is a bond, -O-, -CH2-, -CH=CH-, -OCH2-, -CH2O-, -O-cyclobutyl, or -cyclobutyl-O-.

[0021] In some embodiments, Y is a bond; in some embodiments, Y is -O-, -CH2-, -CH=CH-, -OCH2-, -CH2O-, -O-cyclobutyl, -cyclobutyl-O-;

[0022] In some embodiments, R1 is a halogen, hydroxyl, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, -OC 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-11 membered heterocycloalkyl), -O- (5-6 membered heteroaryl), -C 1-6 Alkyl-C 3-8 cycloalkyl, -C 2-6 alkenyl-C 3-8cycloalkyl, -OC 1-6 Alkyl-C 3-8 cycloalkyl or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0023] In some embodiments, R1 is a halogen, hydroxyl, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, -OC 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-3 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-6 membered monocyclic heterocyclic alkyl), -O- (7-11 membered polycyclic heterocyclic alkyl), -O- (5-6 membered heteroaryl), -C 1-3 Alkyl-C 3-8 cycloalkyl, -C 2-4 alkenyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-(4-6 membered monocyclic heterocyclic alkyl) or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0024] In some embodiments, R1 is a halogen, hydroxyl, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-3Alkyl, C 3-8 cycloalkyl, -OC 4-8 cycloalkyl, -C 1-3 Alkyl-C 4-8 cycloalkyl, -C 2-4 alkenyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-C 4-8 cycloalkyl or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, ynyl or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0025] In some embodiments, R1 is a halogen, hydroxyl, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-3 Alkyl, C 4-6 cycloalkyl, -OC 4-6 cycloalkyl, -C 1-3 Alkyl-C 4-6 cycloalkyl, -C 2-4 alkenyl-C 4-6 cycloalkyl, -OC 1-3 Alkyl-C 4-6 cycloalkyl or -CH=C 4-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0026] In some embodiments, R1 is a halogen, C 2-4 alkenyl, -O-halogenated C 1-3 Alkyl, C 3-4 cycloalkyl, -OC 2-4 alkenyl, -OC 3-5 Monocyclic cycloalkyl, -OC 5-7Bicyclic cycloalkyl, -C 1-3 Alkyl-C 3-4 cycloalkyl, -OC 1-3 Alkyl-C 3-4 cycloalkyl, -C 2-3 alkenyl-C 3-4 Cycloalkyl, -O- (4-6 membered monocyclic heterocyclic alkyl), -OC 1-3 Alkyl-(4-6 membered monocyclic heterocyclic alkyl), -O-(5 membered heteroaryl), -C 2-4 alkenyl-C 3-4 cycloalkyl, -CH=C 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or alkenyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0027] In some embodiments, R1 is -O-cyclopropyl, -C 1-3 alkyl-cyclopropyl or -OC 1-3 alkyl-cyclopropyl, wherein the alkyl or cyclopropyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0028] In some implementations, R1 is F, Cl, -CH=CH2, -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3, -C≡C-CH3, -OCH2CHF2,

[0029] In some implementations, R1 is -OCF3, -OCH2CF3, -OCD3, -OCH2CD3, or -OCD2CD3;

[0030] In some implementations, R1 is -OC 1-6The alkyl group may optionally be further substituted with 1 to 5 groups selected from deuterium or halogen; in some embodiments, R1 is -OC. 1-3 The alkyl group may optionally be further substituted with 1 to 5 groups selected from deuterium or halogen; in some embodiments, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3,

[0031] In some implementations, R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, -OCH2CHF2, -OCF2CH2CH3;

[0032] In some implementations, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, or -OCD2CF3; in other implementations, R1 is -OC 1-6 Alkyl groups are further replaced by 1-5 deuterium atoms;

[0033] In some implementations, R1 is -OC 1-3 Alkyl groups are further replaced by 1-5 deuterium atoms;

[0034] In some implementations, R1 is -OCD3 or -OCD2CD3;

[0035] In some implementations, R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkyl group substitution; in some embodiments, R2 is C 1-6Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy group substitution;

[0036] In some implementations, R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkyl group substitution; in some embodiments, R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy group substitution;

[0037] In some implementations, R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group;

[0038] In some implementations, R2 is C 1-3Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group;

[0039] In some embodiments, R2 is -CH2OH, -CH2OC(O)NH2, -CH2OC(O)CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)CH(NH2)CH(CH3)2, -OCH2OC(O)-C(CH3)3, -OCH2P(O)(OCH2OC(O)C(CH3)3)2, -OP(CH2OCH3)(O)(NHC(CH3)COOCH(CH3)2), -OP(O)(OH)2, -OCH2OP(O)(OH)2, -C(CH3)2OH, -CH2OCH3; in some embodiments, R2 is -CH2OH, -CH2OC(O)NH2, -CH2OC(O)CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)CH(NH2)CH(CH3)2;

[0040] In some implementations, R2 is C 1-6 Alkyl groups, further substituted with 1-3 hydroxyl groups; in some embodiments, R2 is C. 1-3 Alkyl groups are further substituted with 1-3 hydroxyl groups; in some embodiments, R2 is -CH2OH;

[0041] In some embodiments, R3 is deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Hydroxyalkyl;

[0042] In some embodiments, R3 is deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl group; in some embodiments, R3 is deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl; in some embodiments, R3 is deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, or trifluoromethyl;

[0043] In some implementations, R3 is C 1-6 Alkyl; in some embodiments, R3 is C 1-3 Alkyl; in some embodiments, R3 is methyl;

[0044] In some implementations, R A and R B Each of these can be independently represented as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine or C 1-6 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0045] In some implementations, R A and R B Each of these can be independently classified as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine or C 1-3 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution; in some embodiments, R A and R B Each is independently of deuterium, halogen, and carbon. 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution with haloalkoxy groups; preferably R A and R B Each is independently of deuterium, halogen, and carbon. 1-3Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution of halogenated alkoxy groups;

[0046] In some implementations, R A For deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine group, C 1-3 Alkyl subunits, halogenated C 1-3 Alkyl derivatives;

[0047] In some implementations, R A The following are the radicals: deuterium, F, Cl, hydroxyl, amino, oxo, SF5, SCF3, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, methylamino, dimethylamino, methyl subunit, ethyl subunit, 1-methyl ethyl subunit, fluoromethyl subunit, and difluoromethyl subunit.

[0048] In some implementations, R B C 1-3 Alkyl groups, optionally further composed of 1-5 radicals selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0049] In some implementations, any one R A R3 and its linked ring atoms form a 5-7 membered heterocyclic alkyl group, optionally further bonded by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0050] In some implementations, -L = -C 1-3 Alkyl-CH=, -C 3-6 Cycloalkyl-CH=, wherein the alkyl group or cycloalkyl group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0051] In some implementations, -L = -C 1-3 Alkyl-CH=, -C 3-6 cycloalkyl-CH=;

[0052] In some implementations, -L = -C 1-3 Alkyl-CH=, -C 3-4 cycloalkyl-CH=;

[0053] In some implementations, L b C 1-6 Alkyl, C 1-6 Alkyl group - (4-6 membered heterocyclic alkyl group), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OC(O)NH2, -C 3-6 The cycloalkyl group is substituted, wherein the cycloalkyl group is optionally further replaced by 1-2 groups selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Substitution of haloalkyl groups; in some embodiments, L b C 1-6 Alkyl, C 1-6 Alkyl group (4-6 membered heterocyclic alkyl group), wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl alkyl groups and -OC(O)NH2 groups are substituted;

[0054] In some implementations, L b -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, -CH2-(4-6 membered heterocyclic alkyl), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, -CH(C 3-6 cycloalkyl-OH)-; in some embodiments, L bThe derivatives are -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, and -CH2- (4-6 membered heterocyclic alkyl groups).

[0055] In some implementations, L b C 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl alkyl groups and -OC(O)NH2 groups are substituted;

[0056] In some implementations, L b C 1-3 Alkyl groups, wherein the alkyl group is optionally further composed of 1-3 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyl alkyl groups and -OC(O)NH2 groups are substituted;

[0057] In some implementations, L b C 1-2 Alkyl group, wherein the alkyl group is optionally further composed of 1-2 elements selected from deuterium, F, Cl, hydroxyl, C. 1-2 Alkyl, C 1-2 Hydroxyl alkyl groups and -OC(O)NH2 groups are substituted;

[0058] In some implementations, L b The derivatives are -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, and -CH2-CH(OC(O)NH2)-.

[0059] In some implementations, L b C 1-6 Alkyl groups, further substituted with 1-4 hydroxyl groups; in some embodiments, L b C 1-3 Alkyl groups are further substituted with 1-3 hydroxyl groups; in some embodiments, L b It is -CH2-CH(OH)-;

[0060] In some implementations, R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), -N(CN)(C 3-6 (cycloalkyl), wherein the alkyl group, or cycloalkyl group, is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0061] In some implementations, R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further composed of 1-3 radicals selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0062] In some implementations, R a2 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0063] In some implementations, R a1 R a2 Each is independently -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 Alkyl), -N(CN)(C 1-3 (deuterated alkyl), -N(CN)(C) 1-3 Halogenated alkyl), -N(CN)(C 3-6 cycloalkyl);

[0064] In some implementations, R a1 R a2 Each of these can be independently represented as -CN, -N(CN)(CH3), -CO-(CH3)-N(CN)(CH3), -(CH3)-N(CN)(CH3), -N(CN)(CD3), -N(CN)(CH2CF3), -N(CN)(CH2CHF2), -N(CN)(CH(CH3)2), -N(CN)(cyclopropyl), -N(CN)(cyclobutyl), -N(CN)(cyclopropyl-CH3), -N(CN)(C(CH3)3);

[0065] In some implementations, R a1 -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 alkyl);

[0066] In some implementations, R a1 -CN, -N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further substituted with 1-3 groups selected from deuterium or halogen; in some embodiments, R a1 -CN, -N(CN)(C 1-3 Alkyl); in some embodiments, R a1 For -CN,

[0067] In some implementations, R a2 -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 alkyl);

[0068] In some implementations... for

[0069] In some implementations... for

[0070] In some implementations... for

[0071] In some implementations... for

[0072] In some implementations... for

[0073] The specific first technical solution involves a compound represented by general formulas (I) and (Ia), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0074] in:

[0075] Ring A is In some implementations, ring A is

[0076] Ring A1 is a 4-10-membered nitrogen-containing heterocyclic alkyl group or an 11-12-membered nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A Substitution; in some embodiments, ring A1 is a 4-10 membered nitrogen-containing heterocyclic alkyl group, optionally further replaced by 1-4 R groups. A replace;

[0077] Ring A2 is C 3-8 Cycloalkyl, optionally further surrounded by 1-4 R A replace;

[0078] Z is Or it may not exist; in some implementations, Z is in Connected to Y;

[0079] Alternatively, R3 and the adjacent pyridopyrazol group together with the attached atom form a 5-8 membered heterocycle or a 5-8 membered carbon ring;

[0080] Ring B can be phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B Substitution; in some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B Substitution; in some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R BSubstitution; in some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B Substitution; in some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B replace;

[0081] Y represents a bond, -O-, or C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -OC 3-6 Cycloalkylene- or -C 3-6 Cycloalkylene-O-, wherein the alkylene, alkenylene, ynylene, or cycloalkylene group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group;

[0082] R1 is a halogen, hydroxyl, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, -OC 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-11 membered heterocycloalkyl), -O- (5-6 membered heteroaryl), -C 1-6 Alkyl-C 3-8 cycloalkyl, -C 2-6 alkenyl-C 3-8 cycloalkyl, -OC 1-6 Alkyl-C 3-8 cycloalkyl or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl, or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0083] R2 is C1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkyl group substitution; in some embodiments, R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl or C 2-4 Alkyne group substitution; in some embodiments, R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Alkyne group substitution; in some embodiments, R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, C 2-4 alkenyl or C 2-4Group substitution of the alkynyl group;

[0084] R3 can be deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Hydroxyalkyl; in some embodiments, R3 is deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Hydroxyalkyl;

[0085] R A and R B Each of these can be independently classified as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine or C 1-6 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0086] Or, any R A R3 and its linked ring atoms form a 5-7 membered heterocyclic alkyl group, optionally further bonded by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0087] -L = -C 1-3 Alkyl-CH=, -C 3-6Cycloalkyl-CH=, wherein the alkyl group or cycloalkyl group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0088] L b C 1-6 Alkyl, C 1-6 Alkyl group - (4-6 membered heterocyclic alkyl group), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OC(O)NH2, C 3-6 The cycloalkyl group is substituted, wherein the cycloalkyl group is optionally further replaced by 1-2 groups selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Substitution of haloalkyl groups; in some embodiments, L b C 1-6 Alkyl, C 1-6 Alkyl group - (4-6 membered heterocyclic alkyl group), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl groups, -OC(O)NH2 group substitution; in some embodiments, L b C 1-6 Alkyl, C 1-6 Alkyl group (4-6 membered heterocyclic alkyl group), wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl groups, -OC(O)NH2 group substitution; in some embodiments, L b C 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyl alkyl groups and -OC(O)NH2 groups are substituted;

[0089] R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), -N(CN)(C 3-6 (cycloalkyl), wherein the alkyl group, or cycloalkyl group, is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; in some embodiments, R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further composed of 1-3 radicals selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; in some embodiments, R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further composed of 1-3 radicals selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0090] R a2 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; in some embodiments, R a2-CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution;

[0091] Furthermore, the invention relates to a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, provided that one or more of the following conditions are met:

[0092] (1) When Y is the bond and Z is the bond, R2 is -CH2OH, -CH(OH)CH2OH, -CH2F, -CF3, -OCHF2, -OCF3, -OCH2CF3, R a1 When R1 is -CN or -N(CN)(CH3), it is not a halogen.

[0093] (2) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... R a1 When R1 is -CN or -N(CN)(CH3), R1 is not...

[0094] (3) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... R a1 When R1 is -CN, it is not -OCHF2, -OCF3, or -OCH2CF3.

[0095] (4) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... R a1 When R1 is -N(CN)(CH3), R1 is not... -OCF2CH3, -OCF2CH2CH3, -OCF2CH(CH3)2, -OCF2CH=CH2;

[0096] (5) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... R a1 For -CN, R1 is At that time, ring A is not

[0097] (6) When Y is CH2, -CH=CH-, Z is R2 is -CH2OH, and ring B is... R a1 When -CN is used, R1 is not a halogen.

[0098] Alternatively, further, it relates to a compound of general formula (I) as described in the first technical solution, its stereoisomer, or a pharmaceutically acceptable salt thereof, provided that one or more of the following conditions are met:

[0099] (1) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... When R1 is OCHF2, OCF3, or OCH2CF3, ring A is not...

[0100] (2) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... When R1 is OCH2CF3, ring A is not...

[0101] (3) When Y is the bond and Z is the bond, R2 is -CH2OH, and ring B is... When R1 is OCF2CH3, OCF2CH2CH3, or OCF2CH(CH3)2, ring A is not...

[0102] Specifically, in the second technical solution, the compound represented by general formula (I) or (Ia) of any of the aforementioned technical solutions, its stereoisomer, or its pharmaceutically acceptable salt, wherein:

[0103] Ring A is

[0104] Ring A1 is a 4-10 member nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A Substitution; preferably, ring A1 is a 6-10 membered nitrogen-containing heterocyclic alkyl group, optionally further replaced by 1-4 R groups. A Replacement; more preferably ring A1 is * indicates that it is related to R a1 Linkage sites; more preferably for

[0105] Z is

[0106] Ring B is pyridyl, optionally further bonded by 1-4 R groups. B Replacement; preferred ring B is

[0107] Y represents the bond;

[0108] R1 is -OC 1-6 The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; preferably R1 is -OC. 1-3 The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; more preferably, R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, -OCH2CHF2, -OCF2CH2CH3; even more preferably, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3; or R1 is -OC 1-6 Alkyl groups, further substituted with 1-5 deuterium atoms; preferably R1 is -OC. 1-3 Alkyl groups are further substituted with 1-5 deuterium atoms; more preferably, R1 is -OCD3 or -OCD2CD3;

[0109] R2 is C 1-6 Alkyl groups, further substituted with 1-3 hydroxyl groups; preferably R2 is C. 1-3 Alkyl groups are further substituted with 1-3 hydroxyl groups; more preferably, R2 is -CH2OH;

[0110] R3 is C 1-6 Alkyl group; preferably R3 is C 1-3 Alkyl; more preferably R3 is methyl;

[0111] R A and R B Each is independently of deuterium, halogen, and carbon. 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution with haloalkoxy groups; preferably R A and R B Each is independently of deuterium, halogen, and carbon. 1-3Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution of halogenated alkoxy groups;

[0112] L b C 1-6 Alkyl groups, further substituted with 1-4 hydroxyl groups; preferably L b C 1-3 Alkyl groups, further substituted with 1-3 hydroxyl groups; more preferably L b It is -CH2-CH(OH)-;

[0113] R a1 -CN, -N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further substituted with 1-3 groups selected from deuterium or halogen; preferably R a1 -CN, -N(CN)(C 1-3 Alkyl); more preferably R a1 For -CN, -N(CN)(CH3);

[0114] In some embodiments, provided that in general formulas (I) and (Ia), R3 is methyl and R2 is -CH2OH or L b It is -CH2-CH(OH)-, and ring B is When one or more of the following conditions are met: (1) When R1 is OCHF2, OCF3, or OCH2CF3, ring A is not (2) When R1 is OCH2CF3, ring A is not... (3) When R1 is OCF2CH3, OCF2CH2CH3, or OCF2CH(CH3)2, ring A is not...

[0115] Specifically, in the third technical solution, the compound represented by general formula (I) or (Ia) of any of the aforementioned technical solutions, its stereoisomer, or its pharmaceutically acceptable salt, wherein general formula (I) or (Ia) is further represented as general formula (I-1A), general formula (I-1B), general formula (I-2A), general formula (I-2B), general formula (I-3A), general formula (I-3B), general formula (I-4A), general formula (I-4B), general formula (I-5A), general formula (I-5B), general formula (I-6A), general formula (I-6B), general formula (Ia-1), general formula (Ia-6), and general formula (Ia-7):

[0116] in:

[0117] Y is -O-, C1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -OC 1-3 alkylene-, -C 1-3 Alkylene-O-, -OC 3-4 Cycloalkylene- or -C 3-4 Cycloalkylene-O-;

[0118] R1 is a halogen, hydroxyl, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, -O-(5-6 membered heteroaryl), C 2-4 alkynyl group, -OC 1-3 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-6 membered monocyclic heterocyclic alkyl), -O- (7-11 membered polycyclic heterocyclic alkyl), -O- (5-6 membered heteroaryl), -C 1-3 Alkyl-C 3-8 cycloalkyl, -C 2-4 alkenyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-(4-6 membered monocyclic heterocyclic alkyl) or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl, or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0119] L b -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, -CH2-(4-6 membered heterocyclic alkyl)-, -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, -CH(C 3-6 cycloalkyl-OH)-; in some embodiments, L bThe derivatives are -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, -CH2-(4-6 membered heterocyclic alkyl), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-; in some embodiments, L b -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, -CH2- (4-6 membered heterocyclic alkyl); in some embodiments, L b The derivatives are -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, and -CH2-CH(OC(O)NH2)-; in some embodiments, L b The forms are -CH2-C(CF3)(OH)- and -CH2-C(CH3)(OH)-.

[0120] The remaining definitions are the same as those in the specific first technical solution.

[0121] Specifically, in the fourth technical solution, the compound represented by general formula (Ia), its stereoisomer, or a pharmaceutically acceptable salt thereof as described in any of the foregoing technical solutions, wherein general formula (Ia) is further shown as general formula (Ia-2):

[0122] in:

[0123] The ring C is a 5-7 membered heterocyclic alkyl group, optionally further divided by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0124] L b The possible values ​​are -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, and -CH2-CH(OH)-CH2-.

[0125] In some implementations... for In some implementations... for

[0126] The remaining definitions are the same as those in the specific first technical solution.

[0127] Specifically, in the fifth technical solution, the compound represented by general formula (I) of any of the aforementioned technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further shown as general formula (I-7B), general formula (I-8B), general formula (I-9B), and general formula (I-10B):

[0128] in:

[0129] R3 can be deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 In some embodiments, R3 is a haloalkyl group, a halogen, a hydroxyl group, an amino group, or a C-aryl group. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 In some embodiments, R3 is a haloalkyl group, wherein R3 is deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, or trifluoromethyl; in other embodiments, R3 is deuterium, halogen, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 In some embodiments, R3 is a haloalkyl group, a halogen, a hydroxyl group, an amino group, or a C-aryl group. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 In some embodiments, R3 is a haloalkyl group, and in some embodiments, R3 is deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, or trifluoromethyl.

[0130] The remaining definitions are the same as those in the specific first technical solution.

[0131] Specifically, in the sixth technical solution, the compounds, their stereoisomers, or pharmaceutically acceptable salts of the general formulas (I), (I-1A), (I-1B), (I-2A), (I-2B), (I-3A), (I-3B), (I-4A), (I-4B), (I-5A), (I-5B), (I-6A), (I-6B), (Ia), (Ia-1), (Ia-2), (I-7B), (I-8B), (I-9B), (I-10B), (Ia-6), and (Ia-7) described in any of the aforementioned technical solutions, are included.

[0132] Ring A1 is * indicates that it is related to R a1 Linkage sites;

[0133] Ring A2 is * indicates the link site with L;

[0134] Y represents the following: -O-, -CH2-, -CH=CH-, -OCH2-, -CH2O-, -O-cyclobutyl, -cyclobutyl-O-;

[0135] R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkyl group substitution; in some embodiments, R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl or C 2-4 Alkyne group substitution; in some embodiments, R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Alkyne group substitution; in some embodiments, R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group;

[0136] R A and R B Each of these can be independently classified as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine or C 1-3 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution;

[0137] -L = -C 1-3 Alkyl-CH=, -C 3-4 cycloalkyl-CH=;

[0138] R a1 R a2 Each is independently -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 Alkyl), -N(CN)(C 1-3 (deuterated alkyl), -N(CN)(C) 1-3 Halogenated alkyl), -N(CN)(C 3-6 (cycloalkyl), wherein the alkyl group, or cycloalkyl group, is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; in some embodiments, R a1 R a2Each is independently -CN, -N(CN)(CH3), -CO-(CH3)-N(CN)(CH3), -(CH3)-N(CN)(CH3), -N(CN)(CD3), -N(CN)(CH2CF3), -N(CN)(CH2CHF2), -N(CN)(CH(CH3)2), -N(CN)(cyclopropyl), -N(CN)(cyclobutyl), -N(CN)(cyclopropyl-CH3), -N(CN)(C(CH3)3); in some embodiments, R a1 R a2 Each is independently -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 Alkyl group), wherein the alkyl group is optionally further composed of 1-3 radicals selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; in some embodiments, R a1 R a2 Each can be independently represented as -CN, -N(CN)(CH3), -CO-(CH3)-N(CN)(CH3), or -(CH3)-N(CN)(CH3);

[0139] The remaining definitions are the same as those for the specific first, second, third, fourth, or fifth technical solutions.

[0140] Specifically, in the seventh technical solution, the compounds, their stereoisomers, or pharmaceutically acceptable salts of the general formulas (I), (I-1A), (I-1B), (I-2A), (I-2B), (I-3A), (I-3B), (I-4A), (I-4B), (I-5A), (I-5B), (I-6A), (I-6B), (Ia), (Ia-1), (Ia-2), (I-7B), (I-8B), (I-9B), (I-10B), (Ia-6), and (Ia-7) described in any of the aforementioned technical solutions, are included.

[0141] R1 is F, Cl, -CH=CH2, -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3, -C≡C-CH3, -OCH2CHF2, -OCHF2, -OCH2F , -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCH2CD3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, In some implementations, R1 is F, Cl, -CH=CH2, -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3, -C≡C-CH3, -OCH2CHF2,

[0142] The remaining definitions are the same as those for the specific first, second, third, fourth, fifth, or sixth technical solutions.

[0143] Specifically, in the eighth technical solution, the compounds, their stereoisomers, or pharmaceutically acceptable salts of the general formulas (I), (I-1A), (I-1B), (I-2A), (I-2B), (I-3A), (I-3B), (I-4A), (I-4B), (I-5A), (I-5B), (I-6A), (I-6B), (Ia), (Ia-1), (Ia-2), (I-7B), (I-8B), (I-9B), (I-10B), (Ia-6), and (Ia-7) described in any of the aforementioned technical solutions, are included.

[0144] R2 is -CH2OH, -CH2OC(O)NH2, -CH2OC(O)CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)CH(NH2)CH(CH3)2, -OCH2OC(O)-C(CH3)3, -OCH2P (O)(OCH2OC(O)C(CH3)3)2, -OP(CH2OCH3)(O)(NHC(CH3)COOCH(CH3)2), -OP(O)(OH)2, -OCH2OP(O)(OH)2, -C(CH3)2OH, -CH2O CH3; in some embodiments, R2 is -CH2OH, -CH2OC(O)NH2, -CH2OC(O)CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)CH(NH2)CH(CH3)2, -OCH2OC(O)-C(CH3)3, -OCH2P(O)(OCH2OC(O)C(CH3)3)2, -OP(CH2OCH3)(O)(NHC(CH3)COOCH(CH3)2), -OP(O)(OH)2, -OCH2OP(O)(OH)2; and / or,

[0145] Ring B is In some implementations, ring B is And / or,

[0146] for In some implementations... for And / or,

[0147] for And / or,

[0148] for

[0149] The remaining definitions are the same as those for the specific first, second, third, fourth, fifth, sixth, or seventh technical solutions.

[0150] Specifically, in the ninth technical solution, the compound represented by general formula (I-1B) or (Ia-6) of any of the aforementioned technical solutions, its stereoisomer, or its pharmaceutically acceptable salt, wherein:

[0151] Ring A1 is a 4-10 member nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A Substitution; preferably, ring A1 is a 6-10 membered nitrogen-containing heterocyclic alkyl group, optionally further replaced by 1-4 R groups. A Replacement; more preferably ring A1 is * indicates that it is related to R a1 Linkage sites; more preferably for

[0152] Ring B is pyridyl, optionally further bonded by 1-4 R groups. B Replacement; preferred ring B is

[0153] R1 is -OC 1-6 The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; preferably R1 is -OC. 1-3 The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; more preferably, R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, -OCH2CHF2, -OCF2CH2CH3; even more preferably, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3; or R1 is -OC 1-6 Alkyl groups, further substituted with 1-5 deuterium atoms; preferably R1 is -OC. 1-3 Alkyl groups are further substituted with 1-5 deuterium atoms; more preferably, R1 is -OCD3 or -OCD2CD3;

[0154] R2 is C 1-6 Alkyl groups, further substituted with 1-3 hydroxyl groups; preferably R2 is C. 1-3 Alkyl groups are further substituted with 1-3 hydroxyl groups; more preferably, R2 is -CH2OH;

[0155] R A and R B Each is independently of deuterium, halogen, and carbon. 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution with haloalkoxy groups; preferably R A and R BEach is independently of deuterium, halogen, and carbon. 1-3 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution of halogenated alkoxy groups;

[0156] L b C 1-6 Alkyl groups, further substituted with 1-4 hydroxyl groups; preferably L b C 1-3 Alkyl groups, further substituted with 1-3 hydroxyl groups; more preferably L b It is -CH2-CH(OH)-;

[0157] R a1 -CN, -N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further substituted with 1-3 groups selected from deuterium or halogen; preferably R a1 -CN, -N(CN)(C 1-3 Alkyl); more preferably R a1 For -CN, -N(CN)(CH3);

[0158] In some implementations, provided that in general formulas (I-1B) and (Ia-6), R2 is -CH2OH or L b It is -CH2-CH(OH)-, and ring B is When, one or more of the following conditions are met: (1) When R1 is OCHF2, OCF3, or OCH2CF3, Not for (2) When R1 is OCH2CF3 Not for (3) When R1 is OCF2CH3, OCF2CH2CH3, or OCF2CH(CH3)2 Not for

[0159] Specifically, the tenth technical solution refers to the compound represented by general formula (I) of any of the foregoing technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further shown as general formula (I-1B-1):

[0160] Among them: ring A1, R a1 The definition is the same as that of the specific first, second, sixth, eighth, or ninth technical solutions;

[0161] The definition of R1 is the same as that of the specific first, second, third, seventh, or ninth technical solutions;

[0162] Furthermore, the compound represented by general formula (I-1B-1), its stereoisomers, or its pharmaceutically acceptable salts as described in the aforementioned tenth technical solution are further represented by general formulas (I-1B-2) and (I-1B-3):

[0163] The rings A1 and R are described a1 The definitions of R1 and R1 are the same as those of the tenth technical solution.

[0164] Specifically, in the eleventh technical solution, the compound represented by general formula (I) of any of the foregoing technical solutions, its stereoisomers, or its pharmaceutically acceptable salts, wherein general formula (I) is further represented as general formula (Ia-3):

[0165] Among them: ring A1, R a1 The definition is the same as that of the specific first, second, sixth, eighth, or ninth technical solutions;

[0166] The definition of R1 is the same as that of the specific first, second, third, seventh, or ninth technical solutions;

[0167] Furthermore, the compound represented by general formula (Ia-3), its stereoisomers, or its pharmaceutically acceptable salts as described in the aforementioned eleventh technical solution are further represented by general formulas (Ia-4) and (Ia-5):

[0168] The rings A1 and R are described a1 The definitions of R1 and R1 are the same as those of the eleventh technical solution.

[0169] Specifically, in the twelfth technical solution, the compounds represented by general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5) of any of the aforementioned technical solutions, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0170] R1 is -OC 1-6 The alkyl group may optionally be further substituted with 1 to 5 groups selected from deuterium or halogen; preferably R1 is -OC. 1-3 The alkyl group may optionally be further substituted with 1-5 groups selected from deuterium or halogen; more preferably, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3.

[0171] Furthermore, the general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5), their stereoisomers, or pharmaceutically acceptable salts thereof, described in the aforementioned twelfth technical solution, satisfy the following conditions:

[0172] (1) When R1 is OCHF2, OCF 33 When OCH2CF3, Not for

[0173] (2) When R1 is OCH2CF3, Not for

[0174] (3) When R1 is OCF2CH3, OCF2CH2CH3, or OCF2CH(CH3)2, Not for

[0175] Specifically, in the thirteenth technical solution, the compounds, their stereoisomers, or pharmaceutically acceptable salts represented by general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5) described in any of the foregoing technical solutions, are included.

[0176] Ring A1 is a 4-10 member nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A Substitution; preferably, ring A1 is a 6-10 membered nitrogen-containing heterocyclic alkyl group, optionally further replaced by 1-4 R groups. A Replacement; more preferably ring A1 is * indicates that it is related to R a1 Linkage sites; more preferably for

[0177] R1 is -OC 1-6 The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; preferably R1 is -OC. 1-3The alkyl group is further substituted with 1-5 groups selected from deuterium or halogen; more preferably, R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, -OCH2CHF2, -OCF2CH2CH3; even more preferably, R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3; or R1 is -OC 1-6 Alkyl groups, further substituted with 1-5 deuterium atoms; preferably R1 is -OC. 1-3 Alkyl groups are further substituted with 1-5 deuterium atoms; more preferably, R1 is -OCD3 or -OCD2CD3;

[0178] R A For deuterium, halogens, C 1-6 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution with haloalkoxy groups; preferably R A For deuterium, halogens, C 1-3 Alkyl groups, wherein the alkyl group is optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Group substitution of halogenated alkoxy groups;

[0179] R a1 -CN, -N(CN)(C 1-6 Alkyl group), wherein the alkyl group is optionally further substituted with 1-3 groups selected from deuterium or halogen; preferably R a1 -CN, -N(CN)(C 1-3 Alkyl); more preferably R a1 For -CN, -N(CN)(CH3);

[0180] In some implementations, the prerequisite is that one or more of the following conditions are met in general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5): (1) When R1 is OCHF2, OCF3, or OCH2CF3, Not for (2) When R1 is OCH2CF3 Not for (3) When R1 is OCF2CH3, OCF2CH2CH3, or OCF2CH(CH3)2 Not for

[0181] In some embodiments, general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5) are used, and ring A1 is... * indicates that it is related to R a1 Linkage sites;

[0182] R a1 -N(CN)(C) 1-6 Alkyl group), wherein the alkyl group is optionally further substituted with 1-3 groups selected from deuterium or halogen; R a1 -N(CN)(C) 1-3 Alkyl); preferably R a1 It is -N(CN)(CH3);

[0183] R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2; preferably R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3; more preferably R1 is -OCD3, -OCD2CD3.

[0184] In some embodiments, general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5) are used.

[0185] for R1 is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCD3, -OCD2CD3, -OCH2CD3, -OCD2CF3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2; preferably R1 is -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3; more preferably R1 is -OCD3, -OCD2CD3.

[0186] Specifically, in the fourteenth technical solution, the general formulas (I) and (Ia) are selected from the compounds in Tables 1 and 2 below:

[0187] Table 1:

[0188] Table 2:

[0189] Secondly, the present invention also provides a pharmaceutical composition comprising any of the compounds described in any of the foregoing technical solutions, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0190] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0191] Furthermore, the present invention also provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in any of the foregoing embodiments in the preparation of a medicament, preferably a medicament for the prevention and / or treatment of FGFR-mediated diseases.

[0192] In some embodiments, the disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0193] This invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer Selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0194] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammals described in the present invention include humans.

[0195] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound, conjugate, or pharmaceutically acceptable salt thereof disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0196] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of any of the compounds shown above, their stereoisomers, or their pharmaceutically acceptable salts.

[0197] The present invention further relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of any of the compounds shown above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, in any of the above amounts of 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0198] The present invention further relates to a method for treating a disease in mammals, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or multiple doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day; in some embodiments, the daily dose includes, but is not limited to, 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0199] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims of this invention, wherein the amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is the same as that in the preceding pharmaceutical composition.

[0200] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0201] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0202] Synthetic route

[0203] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0204] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals in the catalogue can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services to standard chemical supply plants (such as those listed above).

[0205] the term

[0206] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0207] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). 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, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. When the alkyl group is substituted with a substituent, the substituent is no longer subject to further substitution.

[0208] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0209] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0210] The term "alkenyl" refers to divalent straight-chain and branched alkenyl groups. Examples of alkenyl groups include, but are not limited to, -CH=CH-, -CH=C(CH3)-, etc.

[0211] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically comprising 2 to 18 carbon atoms, further comprising 2 to 8 carbon atoms, further comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable linker. When the alkynyl group is substituted by a substituent, the substituent is not further substituted.

[0212] The term "ynynyl" refers to divalent straight-chain and branched ynynyl groups. Examples of ynynyl groups include, but are not limited to, -C≡C-.

[0213] The term "heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring. Unless otherwise specified, it contains one to four heteroatoms selected from N, O, P, S, Se, or Si and their oxidation states, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl groups and heteroaryl groups. The N and S atoms in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylcycloyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl, etc.

[0214] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C ... 3-8 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0215] The term "spirocycloalkyl" refers to a polycyclic group in which the monocyclic rings share a single carbon atom (called the spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Spirocycloalkyl. The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C14). 6-14 Spirocycloalkyl, more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Spirocycloalkyl. Based on the number of spiroatoms shared between rings, spirocycloalkyl is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocycloalkyl.

[0216] The term "fused-cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Fused cyclic alkyl groups. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cyclic alkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Fused cyclic alkyl groups, more preferably fused cyclic alkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Fused cyclic alkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups based on the number of constituent rings. Bicyclic or tricyclic fused cyclic alkyl groups are preferred, and ternary / quadrivalent, ternary / quinary, ternary / sixary, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / sixary, quinary / trivalent, quinary / quadrivalent, quinary / quinary, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, or quinary / sixary bicyclic fused cyclic alkyl groups are more preferred.

[0217] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20Bridged cycloalkyl groups. They contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Bridged cycloalkyl groups, more preferably bridged cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Bridged cycloalkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups based on the number of rings, with bicyclic or tricyclic bridged cycloalkyl groups being preferred.

[0218] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, for example including C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, C 5-6 The cycloalkyl group is preferably a 5-6 membered heterocycloalkyl group, such as cyclopentyl 5-membered heterocycloalkyl, cyclopentyl 6-membered heterocycloalkyl, cyclopentyl 5-membered heteroaryl, cyclopentyl 6-membered heteroaryl, cyclohexyl 5-membered heterocycloalkyl, cyclohexyl 6-membered heterocycloalkyl, cyclohexyl 5-membered heteroaryl, or cyclohexyl 6-membered heteroaryl. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point. When the cycloalkyl group is substituted by a substituent, the substituent is not further substituted.

[0219] The term "cycloalkylene" refers to divalent straight-chain and branched cycloalkyl groups. Examples of cycloalkylene groups include, but are not limited to, those mentioned above. wait.

[0220] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic alkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic alkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, se, Si, and p(o). m and S(O) nThe heterocyclic alkyl group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic alkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocyclic alkyl groups), containing 1 to 4 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; even more preferably, it has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; and most preferably, it has 5 to 6 ring atoms (i.e., 5-6 membered heterocyclic alkyl groups), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocyclic alkyl groups include: azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, or azirropentyl. Non-limiting examples of the polycyclic heterocyclic alkyl groups include: spiroheterocyclic alkyl, fused heterocyclic alkyl, and bridged heterocyclic alkyl.

[0221] The term "spiroheteroalkyl" refers to a polycyclic heterocyclic alkyl group that shares a single atom (called a spiro atom) between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheteroalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, se, Si, and p(o). m and S(O) nThe heteroatoms (where m and n are integers from 0 to 2) excluding the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The spiroheteroalkyl group is preferably a spiroheteroalkyl group having 6 to 14 ring atoms (i.e., a 6-14 membered spiroheteroalkyl group), more preferably a spiroheteroalkyl group having 7 to 10 ring atoms (i.e., a 7-10 membered spiroheteroalkyl group). The spiroheterocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups based on the number of shared spiroatoms between the rings. Monospirocyclic alkyl groups or bispirocyclic alkyl groups are preferred, and more preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl groups. Non-limiting examples include: wait.

[0222] The term "fused heterocyclic alkyl" or "fenochycyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. This group has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, se, Si, and p(o). m and S(O) n The heteroatoms (where m and n are integers from 0 to 2) are excluding the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The fused heterocyclic alkyl group is preferably a fused heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 membered fused heterocyclic alkyl groups), more preferably a fused heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 membered fused heterocyclic alkyl groups). Based on the number of constituent rings, they are classified as bicyclic, tricyclic, tetracyclic, or polycyclic heterocyclic alkyl groups, preferably bicyclic or tricyclic fused heterocyclic alkyl groups, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic alkyl groups. Non-limiting examples include: wait.

[0223] The term "bridged heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group that shares two non-directly connected atoms with any two rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, se, Si, and p(o). m and S(O) n The bridged heterocyclic alkyl group (where m and n are integers from 0 to 2) consists of heteroatoms, excluding the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic alkyl group is preferably a bridged heterocyclic alkyl group having 6 to 14 ring atoms (i.e., 6-14 membered bridged heterocyclic alkyl), more preferably a bridged heterocyclic alkyl group having 7 to 10 ring atoms (i.e., 7-10 membered bridged heterocyclic alkyl). Depending on the number of constituent rings, it is classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl, with bicyclic or tricyclic bridged heterocyclic alkyl being preferred. Non-limiting examples include: wait.

[0224] The heterocyclic alkyl group includes polycyclic heterocyclic alkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group, such as 5-6 membered heterocyclic alkyl phenyl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, and 5-6 membered heterocyclic alkyl 5-6 membered C 5-6 Cycloalkyl groups, preferably 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, etc. The heterocycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the heterocycloalkyl group is substituted by a substituent, the substituent is no longer further substituted.

[0225] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12 Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C10). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthryl, etc.

[0226] The aryl group includes polycyclic systems that can be fused to heterocyclic alkyl or cycloalkyl rings, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 membered heterocyclic alkyl, preferably benzoC 4-6 Cycloalkyl, benzo4-6 membered heterocycloalkyl, further preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazahexyl, benzooxetyl, benzooxetyl, benzooxetyl, benzoazapentyl, benzooxetyl, benzooxetyl, benzoazahexetyl The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is no longer further substituted.

[0227] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, se, Si, and p(o). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C group. 6-10 Aryl or C 6-10 The compounds are aryl 5-10-membered heteroaryl groups, more preferably 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl, or phenyl 5-6-membered heteroaryl. Non-limiting examples include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene-phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene-pyridyl, pyridothiophene, pyridopyrrole, benzo-γ-pyranone, pyrido-γ-pyranone. wait.

[0228] The heteroaryl group includes a polycyclic system fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl rings with C positrons. 3-8 Cycloalkyl, 5-6-membered heteroaryl, 3-8-membered heterocycloalkyl, 5-6-membered heteroarylphenyl, preferably 5-6-membered heteroaryl-C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocycloalkyl, 5-6-membered heteroarylphenyl. The heteroaryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted. Non-limiting examples include: wait.

[0229] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.

[0230] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linking point. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0231] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0232] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0233] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0234] The term "alkyl subunit" refers to a divalent free alkyl structure formed by the loss of two hydrogen atoms, wherein the alkyl group is as defined above. Non-limiting examples include: methyl subunits. Ethyl subunit 1-Methylethylidene

[0235] The term "halogenated alkyl subunit" refers to an alkyl subunit substituted with one or more halogens, wherein the alkyl subunit is as defined above. Non-limiting examples include: fluoromethyl subunits. Difluoromethylidene

[0236] The term "mercapto" refers to -SH. The term "hydroxyl" refers to -OH. The term "nitro" refers to -NO2. The term "amino" refers to -NH2. The term "cyano" refers to -CN. The term "carboxyl" refers to -C(O)OH. The term "aldehyde" refers to -CHO. The term "oxo" or "oxo-group" refers to =O. The term "carbonyl" refers to C=O. The term "aminoacyl" refers to -C(O)NH2. The term "sulfonyl" refers to -S(O)2. The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above. The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. The term "alkylamine" refers to an alkyl group (-NH-), where the alkyl group is as defined above. The term "alkenyl" refers to a divalent straight-chain or branched alkenyl group. The term "alkynyl" refers to a divalent straight-chain or branched alkynyl group.

[0237] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0238] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0239] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0240] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0241] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0242] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0243] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0244] The terms "substitution" and "substituted" refer to the selective substitution of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with heteroatoms, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and a stable compound is formed. Exemplary substituents include, but are not limited to, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -CO-(C 3-8 cycloalkyl), -CO- (3-8 membered heterocycloalkyl), -CO- (C 5-12 aryl), -CO- (5-12 membered heteroaryl), hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-HC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -CH=N(C 1-6 Alkyl), -CH=NO(C) 1-6alkyl), -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0245] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0246] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0247] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0248] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of linking in the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes the cases of AMWB and AWMB, with AMWB being preferred.

[0249] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds of this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0250] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0251] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0252] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0253] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0254] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0255] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0256] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0257] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0258] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0259] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0260] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0261] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0262] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0263] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0264] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0265] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Attached Figure Description

[0266] Figure 1: Tumor growth curve. Detailed Implementation

[0267] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0268] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0269] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0270] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100×4.6mm, 3.5μM);

[0271] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0272] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0273] Example

[0274] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0275] Example 1

[0276] Step 1: Compound 1A (10 g, 40 mmol) was dissolved in anhydrous methanol (100 mL), and sodium borohydride (3.02 g, 80 mmol) was slowly added. The mixture was reacted at room temperature for 1 h, concentrated, and the residue was separated by silica gel column chromatography to obtain compound 1B (10 g, yield: 99%). LC-MS (ESI): m / z = 196.0 [M-55] + .

[0277] Step 2: Triphenylphosphine (12.5 g, 48 mmol) and diisopropyl azodicarbonate (9.7 g, 48 mmol) were dissolved in DCM (200 mL). After stirring for half an hour, a DCM solution (200 mL) of compound 1B (10 g, 40 mmol) and DPPA (13.2 g, 48 mmol) was added. The reaction was continued overnight. The mixture was concentrated, and the residue was separated by silica gel column chromatography to obtain compound 1C (9.7 g, yield: 73.2%).

[0278] Step 3: 1C (9.7 g, 35.1 mmol), ethyl acetoacetate (6.8 g, 52.7 mmol), and potassium carbonate (9.6 g, 70 mmol) were dissolved in dimethyl sulfoxide (100 mL) and reacted at 80 °C for 6 hours. After the reaction was complete, water (400 mL) was added to the reaction solution, followed by extraction with ethyl acetate (400 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1D (10.2 g, yield: 75.0%). LC-MS (ESI): m / z = 389.1 [M+H] + .

[0279] Step 4: Dissolve 1D (10.2 g, 26.2 mmol) in tetrahydrofuran (100 mL) and water (10 mL), then add potassium hydroxide (5.9 g, 105 mmol) and react at room temperature for 2 hours. After the reaction is complete, concentrate and dry to obtain compound 1E (16.2 g, crude product), proceed directly to the next step. LC-MS (ESI): m / z = 361.2 [M+H] + .

[0280] Step 5: Dissolve 1E (16.2 g, crude product) in water (100 mL), and add excess bromine until the starting material is completely eliminated. After the reaction is complete, add water (100 mL) to the reaction solution, and then extract with ethyl acetate (200 mL x 3). Dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography to obtain compound 1F (7.2 g, two-step yield: 69.5%). LC-MS (ESI): m / z = 395.2 [M+H] + .

[0281] Step 6: Compound 1G (7.3 g, 30 mmol) was dissolved in acetonitrile (100 mL), and anhydrous potassium carbonate (12.4 g, 90 mmol) and 3,3-difluorocyclobutyltrifluoromethanesulfonate (7.2 g, 30 mmol) were added. The mixture was reacted at 80 °C for 1 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain compound 1H (6.2 g, 62.1%). LC-MS (ESI): m / z = 333.2 [M+H]+ .

[0282] Step 7: Compound 1H (6.2 g, 18.6 mmol) was dissolved in N,N-dimethylacetamide (120 mL), followed by the addition of n-dodecyl mercaptan (11.2 g, 55.8 mmol) and 50% NaOH aqueous solution (2.9 g, 37.2 mmol). The reaction was carried out at 50 °C for 3 h. After the reaction was complete, water (500 mL) was added, and the pH was acidified to 4-5 with 1N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (300 mL × 3), and the organic phases were combined and washed with saturated brine (500 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 1I (5.4 g, yield: 91%). LC-MS (ESI): m / z = 319.2 [M+H]+.

[0283] Step 8: Compound 1I (5.4 g, 17 mmol) and intermediate 1 (8.5 g, 20 mmol, see reference WO2016 / 105485, 2016, A2 synthesis) were dissolved in acetonitrile (100 mL), and potassium carbonate (12.9 g, 34 mmol) was added. The reaction was carried out at 80 °C for 1 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1J (5.8 g, yield: 59.7%). LC-MS (ESI): m / z = 572.2 [M+H] + .

[0284] Step 9: Compound 1J (572 mg, 1 mmol), pinacol diborate (381 mg, 1.5 mmol), anhydrous potassium acetate (294 mg, 3 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol) were dispersed in anhydrous 1,4-dioxane (20 mL), purged with nitrogen, and reacted at 90 °C for 3 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue containing compound 1K was used directly in the next step.

[0285] Step 10: Add compound 1F (381 mg, 1 mmol), potassium carbonate (414 mg, 3 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol) to the crude product 1K obtained in the previous step, followed by 1,4-dioxane (20 mL) and water (2 mL). After purging with nitrogen, react at 90 °C for 3 h. After the reaction is complete, filter, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain compound 1L (278 mg, two-step yield: 40.1%).

[0286] Step 11: Dissolve 1 L (278 mg, 0.4 mmol) of compound in anhydrous methanol (10 mL), add excess dioxane hydrochloride solution, and react at room temperature for 2 h. After the reaction is complete, concentrate to obtain compound 1M (202 mg, crude product). LC-MS (ESI): m / z = 594.2 [M+H] + .

[0287] Step 12: Compound 1M (202 mg, crude product) was dispersed in DCM (10 mL), DIPEA (1 mL) was added, followed by cyanogen bromide (84.8 mg, 0.8 mmol). The reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, and the residue was separated by column chromatography to give compound 1 (56 mg, two-step yield: 22.6%). LC-MS (ESI): m / z = 619.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.28(s,1H),7.90(s,1H),7.80-7.72(m,1 H),7.68-7.61(m,1H),6.73(s,1H),6.50-6.19(m,1H),5.63-5.54(m,1H),5.15- 5.07(m,1H),4.91-4.69(m,2H),4.02-3.78(m,3H),3.73-3.65(m,1H),3.47-3.3 5(m,1H),3.18-2.98(m,2H),2.92-2.75(m,2H),2.38(s,3H),2.23-2.03(m,4H).

[0288] Example 2

[0289] Step 1: Dissolve 2A (5 g, 14.48 mmol) in dichloromethane (60 mL), then add trifluoroacetic acid (20 mL) and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution and proceed directly to step 2B. LC-MS (ESI): m / z = 245.0 [M+H] + .

[0290] Step 2: Dissolve 2B in water (60 mL) and acetic acid (20 mL), then add sodium nitrite (3.94 g, 57.12 mmol), and react at room temperature for 16 hours. After the reaction, extract the reaction solution with water (50 mL) (ethyl acetate 50 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 2C (2.4 g, 61%). LC-MS (ESI): m / z = 274.0 [M+H] + .

[0291] Step 3: Dissolve 2C (2.2 g, 8.03 mmol) in methanol (15 mL), then add acetic acid (5 mL), and add zinc powder (1.58 g, 24.09 mmol) at 0°C. React for 4 hours. After the reaction is complete, evaporate the reaction solution to dryness, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate to obtain the target compound 2D (1.3 g, crude product). LC-MS (ESI): m / z = 260.0 [M+H] + .

[0292] Step 4: Dissolve 2D (1.3 g, crude) in 1,4-dioxane (20 mL), then add triethylamine (1.52 g, 15 mmol) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (1.94 g, 7.5 mmol), and react at room temperature for 16 hours. After the reaction, extract the reaction solution with water (50 mL) (ethyl acetate 50 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 2E (950 mg, 47%). LC-MS (ESI): m / z = 404.0 [M+H] + .

[0293] Step 5: Dissolve 2E (650 mg, 1.61 mmol) in tetrahydrofuran (10 mL), add sodium hydroxide (190 mg, 4.83 mmol, 60%) at 0°C and react for 0.5 hours. Then add iodomethane (690 mg, 4.83 mmol) and react at room temperature for 3 hours. After the reaction is complete, quench the reaction solution with saturated ammonium chloride solution (10 mL), extract (ethyl acetate 10 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 2F (700 mg, crude product). LC-MS (ESI): m / z = 418.1 [M+H] + .

[0294] Step 6: Compound 1G (50.0 g, 205.7 mmol) and cyclopropyl trifluoromethanesulfonate (50.8 g, 267.4 mmol) were dissolved in N,N-dimethylformamide (800 mL), followed by the addition of cesium carbonate (100.5 g, 308.5 mmol). The reaction was carried out overnight at 100 °C. After the reaction was complete, water (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 2K (46 g, 78.9%). LC-MS (ESI): m / z = 283.0 [M+H] +

[0295] Step 7: Compound 2K (40.0 g, 141.3 mmol) was dissolved in N,N-dimethylacetamide (600 mL), followed by the addition of n-dodecyl mercaptan (143.0 g, 706.4 mmol) and 50% sodium hydroxide aqueous solution (67.8 g, 847.7 mmol). After the addition was complete, the mixture was heated to 90 °C and reacted for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and ethyl acetate and water were added. The mixture was stirred and separated, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then slurried (petroleum ether:ethyl acetate = 10:1 (v / v)) to obtain compound 2L (24 g, 63.1%). LC-MS (ESI): m / z = 269.0 [M+H] +

[0296] Step 8: Dissolve 2M (6.0 g, 43.1 mmol) and phenyltrimethylammonium tribromide (17.0 g, 45.3 mmol) in tetrahydrofuran (80 mL) and stir overnight at 35 °C. After the reaction is complete, add water (100 mL), extract with ethyl acetate (100 mL x 2), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to give the target compound 2N (4.0, 42.5%).

[0297] LC-MS (ESI): m / z = 217.9 [M+H] + .

[0298] Step 9: Compound 2N (4.5 g, 20.6 mmol) and compound 2L (4.4 g, 16.5 mmol) were dissolved in DMF (80 mL), and cesium carbonate (13.4 g, 41.3 mmol) was added. After the addition was complete, the mixture was stirred at 50 °C for 2 h. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 2O (810 mg, 9.7%). LC-MS (ESI): m / z = 406.0 [M+H] + .

[0299] Step 10: Compound 2O (0.81 g, 1.99 mmol) was dissolved in THF (20 mL) and stirred at 0 °C. Then, methyl magnesium bromide (3 M in THF) was added under nitrogen protection, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 3:1) to give compound 2P (610 mg, 72.5%).

[0300] LC-MS(ESI): m / z = 422.0 [M+H] + .

[0301] Step 11: Dissolve 2P (0.61 g, 1.44 mmol), pinacol diborate (0.55 g, 2.16 mmol), potassium acetate (0.42 g, 4.32 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (110 mg, 0.14 mmol) in 1,4-dioxane (15 mL), purge with nitrogen three times, and react at 95 °C for 16 hours. After the reaction is complete, proceed directly to the next step (2Q). LC-MS (ESI): m / z = 388.1 [M+H] + .

[0302] Step 12: Add 2F (660 mg, 1.58 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium(II) chloride (94 mg, 0.14 mmol), potassium carbonate (600 mg, 4.32 mmol), and water (1.5 mL) to the reaction solution of 2Q. After adding nitrogen, purge three times and react at 95°C for 3 hours. After the reaction, add water (20 mL), extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:10) to obtain the target compound 2R (0.58 mg, 58.9%). LC-MS (ESI): m / z = 681.3 [M+H] + .

[0303] Step 13: Dissolve 2R (0.45 g, 0.66 mmol) in dichloromethane (9 mL), then add trifluoroacetic acid (3 mL) and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution to obtain 2S, which can be directly used for the next step. LC-MS (ESI): m / z = 537.3 [M+H] + .

[0304] Step 14: Dissolve the crude product 2S from the previous step in dichloromethane (10 mL), then add N,N-diisopropylethylamine (2 mL) and cyanogen bromide (100 mg, 0.98 mmol) sequentially, and react at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure, and purify the residue by HPLC to obtain the target compound 2 (130 mg, 35.5%). LC-MS (ESI): m / z = 562.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.36(d,1H),8.08(s,1H),7.85-7.82(m,1H),7.77(s,1H) ,7.46-7.41(m,1H),6.74(s,1H),4.41(d,1H),4.19-4.11(m,2H),3.93-3.89(m, 1H),3.33-3.29(m,2H),3.04(s,3H),2.81-2.76(m,2H),2.60-2.50(m,2H),2.4 6(s,3H),2.17-2.13(m,2H),1.69(s,3H),0.90-0.83(m,2H),0.82-0.74(m,2H).

[0305] Step 1: 1 g (20 g, 82.28 mmol) was dissolved in tetrahydrofuran (300 mL). Sodium hydroxide (4.94 g, 123.42 mmol, 60%) was added under ice bath conditions, and the mixture was reacted for 0.5 hours. Then, bromomethyl methyl ether (12.34 g, 98.74 mmol) was added, and the reaction was continued at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (300 mL), then extracted (ethyl acetate 200 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give the target compound 3C (22 g, 93% yield). LC-MS (ESI): m / z = 287.0 [M+H] + .

[0306] Step 2: Dissolve 3C (22 g, 76.63 mmol) in N,N-dimethylacetamide (200 mL), then add n-dodecyl mercaptan (77.55 g, 383.17 mmol) and sodium hydroxide (36.78 g, 459.78 mmol, 50% aqueous solution), and react at 90°C for 2 hours. After the reaction, dilute the reaction solution with water (1000 mL), adjust the pH to 5, filter, and evaporate the filter cake to dryness to obtain the target compound 3D (17.2 g, yield 82%). LC-MS (ESI): m / z = 273.0 [M+H] + .

[0307] Step 3: 3D (3 g, 10.99 mmol), the R-configuration isomer of intermediate 1 (4.68 g, 10.99 mmol), and cesium carbonate (5.37 g, 16.48 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at 60°C for 1 hour. After the reaction, the reaction solution was extracted with water (100 mL) (50 mL x 3 ethyl acetate solutions), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give the target compound 3E (2.3 g, yield 42%). LC-MS (ESI): m / z = 526.0 [M+H] + .

[0308] Step 4: Dissolve 3E (2.3 g, 4.37 mmol) in dichloromethane (30 mL), then add trifluoroacetic acid (10 mL) and react at room temperature for 3 hours. After the reaction, evaporate the reaction solution to dryness, add water (30 mL) to adjust the pH to 8, then extract (30 mL x 3 of ethyl acetate), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compounds 3F (0.8 g, yield 37%) and 3G (0.47 g, yield 29%). 3F: LC-MS (ESI): m / z = 482.1 [M+H] + .3G:LC-MS(ESI):m / z=368.0[M+H] + .

[0309] Step 5: Dissolve 3H (0.5 g, 5.2 mmol) in tetrahydrofuran (4 mL) and methanol (2 mL), and add sodium borohydride (0.39 g, 10.4 mmol) under ice bath conditions. React at room temperature for 3 hours. After the reaction is complete, extract the reaction solution with water (20 mL) (ethyl acetate 10 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 3I (0.46 g, 90% yield).

[0310] Step 6: Dissolve 3I (0.46 g, 4.69 mmol) in dichloromethane (5 mL), then add triethylamine (1.42 g, 14.07 mmol), and add methanesulfonyl chloride (0.64 g, 5.63 mmol) at 0°C. React at room temperature for 1 hour. After the reaction is complete, extract the reaction solution with water (10 mL) (dichloromethane 10 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 3J (0.65 g, yield 78%).

[0311] Step 7: Dissolve 3F (0.8 g, 1.66 mmol), 3J (0.65 g, 3.69 mmol), and cesium carbonate (0.81 g, 2.49 mmol) in N,N-dimethylformamide (10 mL) and react at 100°C for 16 hours. After the reaction, extract the reaction solution with water (20 mL) (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 3K (0.1 g, yield 13%). LC-MS (ESI): m / z = 448.0 [M+H] +

[0312] Step 8: Using compound 3K (0.1 g, 0.22 mmol) as the starting material, compound 3 (0.1 g, 0.22 mmol) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 588.3 [M+H] +1 H NMR(400MHz, CDCl3)δ8.43(d,1H),8.13(s,1H),7.79(dd,1H),7.55(s,1H) ,7.51-7.44(m,1H),6.82(s,1H),5.24(t,1H),4.91(dd,1H),4.40(d,2H), 4.22-4.11(m,1H),3.31(d,2H),3.04(s,3H),2.79(t,2H),2.61-2.51(m,4 H),2.47(s,3H),2.45-2.39(m,2H),2.18-2.12(m,2H),0.56-0.49(m,4H).

[0313] Example 4

[0314] Step 1: 3g (470mg, 1.28mmol), bromocyclopentane (250mg, 1.66mmol), and cesium carbonate (630mg, 1.92mmol) were dissolved in N,N-dimethylformamide (5mL) and reacted at 90°C for 16 hours. After the reaction, the reaction solution was extracted with water (20mL) (10mL x 3 of ethyl acetate), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give the target compound 4A (330mg, yield 59%). LC-MS (ESI): m / z = 436.1 [M+H] + .

[0315] Step 2: Using compound 4A (0.33 g, 0.76 mmol) as the starting material, compound 4 (51.64 mg, yield 19%) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 576.3 [M+H] +1 H NMR(400MHz, CDCl3)δ8.39(d,1H),8.08(s,1H),7.72-7.66(m,1H),7.60(s,1H),7.45 -7.40(m,1H),6.78(s,1H),5.19(t,1H),4.75-4.66(m,1H),4.46-4.29(m,2H),4.21-4 .10(m,1H),3.34-3.25(m,2H),3.02(s,3H),2.81-2.72(m,2H),2.59-2.47(m,2H),2.4 5(s,3H),2.18-2.08(m,2H),2.01-1.93(m,2H),1.90-1.79(m,4H),1.70-1.58(m,2H).

[0316] Examples 5 and 6

[0317] Step 1: Triphenylphosphine (12.23 g, 46.63 mmol) and diethyl azodicarbonate (8.12 g, 46.63 mmol) were dissolved in tetrahydrofuran (200 mL). After stirring for half an hour, a tetrahydrofuran solution (50 mL) of compound 5A (10 g, 38.86 mmol) and diphenyl azide phosphate (12.83 g, 46.63 mmol) was added. The reaction was continued overnight. The mixture was concentrated, and the residue was separated by silica gel column chromatography to obtain compound 5B (13 g, crude product).

[0318] Step 2: 5B (13g, crude), ethyl acetoacetate (17.98g, 138.13mmol), and potassium carbonate (19.09g, 138.13mmol) were dissolved in dimethyl sulfoxide (200mL) and reacted at 100°C for 16 hours. After the reaction, the reaction solution was extracted with water (300mL) (ethyl acetate 200mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 5C (12.5g, yield 81%).

[0319] Step 3: Dissolve 5C (12.5 g, 31.69 mmol) in methanol (50 mL), tetrahydrofuran (50 mL), and water (50 mL), then add lithium hydroxide monohydrate (3.99 g, 95.06 mmol) and react at room temperature for 2 hours. After the reaction, adjust the pH of the reaction solution to 5-6, then extract (ethyl acetate 100 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain the target compound 5D (11.9 g, crude product). LC-MS (ESI): m / z = 311.1 [M+H-56]+.

[0320] Step 4: 5D (11.9 g, crude product) was dissolved in water (60 mL) and tetrahydrofuran (60 mL), followed by the addition of potassium hydroxide (5.47 g, 97.43 mmol) and liquid bromine (15.57 g, 97.43 mmol). The reaction mixture was reacted at room temperature for 16 hours. After the reaction, the reaction solution was extracted with water (100 mL) (100 mL x 3 ethyl acetate solutions), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 5E (8.5 g, yield 65%). LC-MS (ESI): m / z = 345.0 [M+H-56]+.

[0321] Step 5: Dissolve 5E (8.5 g, 21.18 mmol) in dioxane hydrochloride (100 mL, 4 M) and react at room temperature for 3 hours. After the reaction is complete, concentrate the reaction solution and proceed directly to the next step (5F crude product). LC-MS (ESI): m / z = 301.1 [M+H]+.

[0322] Step 6: Dissolve 5F (crude product) in tetrahydrofuran (100 mL), then add tert-butyl nitrite (6.16 g, 59.76 mmol), and react at 80°C for 16 hours. After the reaction, concentrate the reaction solution, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 5G (3.7 g, yield 56%). LC-MS (ESI): m / z = 330.0 [M+H] +

[0323] Step 7: Dissolve 5g (3.7g, crude product) in methanol (30mL), then add acetic acid (10mL), and add zinc powder (2.93g, 44.84mmol) at 0°C. React for 4 hours. After the reaction is complete, filter the reaction solution, concentrate the filtrate, and proceed directly to the next step (5H crude product). LC-MS (ESI): m / z = 316.1 [M+H] +

[0324] Step 8: Dissolve 5H (crude product) in 1,4-dioxane (30 mL), add triethylamine to adjust to alkalinity, then add N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (3.08 g, 11.87 mmol), and react at room temperature for 16 hours. After the reaction, extract the reaction solution with water (50 mL) (ethyl acetate 50 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 5I (1.5 g, yield 41%).

[0325] Step 9: Dissolve 5I (1.5 g, 3.26 mmol) in tetrahydrofuran (20 mL), add sodium hydrogen (200 mg, 4.89 mmol, 60%) at 0°C, react for 0.5 hours, then add iodomethane (1.39 g, 9.78 mmol), and react at room temperature for 3 hours. After the reaction is complete, quench the reaction solution with saturated ammonium chloride solution (10 mL), then extract (ethyl acetate 10 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 5J (1.1 g, yield 71%). LC-MS (ESI): m / z = 474.2 [M+H] +

[0326] Step 10: Dissolve 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane di(tetrafluoroborate) (17.49 g, 49.38 mmol) in dry N-methylpyrrolidone (150 mL), purge with nitrogen, and then add cuprous bromide (17.71 g, 123 mmol) in portions. After the addition is complete, stir at room temperature for 10 minutes. Keep at 25-30 °C and add difluorobromomethyltrimethylsilane (15.04 g, 74.07 mmol) dropwise to the reaction solution. After the addition is complete, continue stirring for 10 minutes. Add compound 5K (6.0 g, 24.69 mmol) to the reaction solution all at once, and let the reaction proceed overnight at room temperature. After the reaction was completed, the reaction solution was quenched in a saturated ammonium chloride solution, then extracted with methyl tert-butyl ether to separate the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give compound 5 L (2.8 g, yield 30.5%). LC-MS (ESI): m / z = 372.9 [M+H] +

[0327] Step 11: Compound 5L (2.6 g, 6.99 mmol) was dissolved in dry dichloromethane (20 mL), and silver tetrafluoroborate (2.72 g, 13.98 mmol) was added under nitrogen protection. The reaction was allowed to proceed at room temperature for 4 hours after the addition was complete. After the reaction was complete, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give compound 5M (1.66 g, yield 76.3%). LC-MS (ESI): m / z = 311.0 [M+H] +

[0328] Step 12: Dissolve 5M (1.66 g, 5.34 mmol) in N,N-dimethylacetamide (20 mL), then add n-dodecyl mercaptan (5.40 g, 26.68 mmol) and sodium hydroxide (1.26 g, 31.50 mmol, 50% aqueous solution), and react at 90°C for 2 hours. After the reaction, dilute the reaction solution with water (100 mL), adjust the pH to 5, filter, and evaporate the filter cake to dryness to obtain the target compound 5N (1.27 g, 80% yield). LC-MS (ESI): m / z = 296.9 [M+H] +

[0329] Step 13: Dissolve 5N (0.77 g, 2.59 mmol) and the R-configuration isomer of intermediate 1 (1.1 g, 2.59 mmol) in N,N-dimethylformamide (15 mL), and add cesium carbonate (1.69 g, 5.18 mmol). After the addition is complete, stir at 60 °C for 1 h. After the reaction is complete, add water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 5O (crude product). LC-MS (ESI): m / z = 550.0 [M+H]+.

[0330] Step 14: Dissolve 5O (crude product) in tetrahydrofuran (30 mL), then add tetrabutylammonium fluoride (1.66 g, 6.35 mmol), and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compounds 5P and 5P-1 (0.65 g, 58.6%). LC-MS (ESI): m / z = 436.0 [M+H]+.

[0331] Step 15: Using 5P and 5P-1 (0.3g, 0.69mmol) as raw materials, compound 5 (26.49mg, yield 10%) was synthesized according to the method in Example 2; LC-MS (ESI): m / z = 632.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.42(s,1H),8.22(s,1H),7.81-7.71(m ,1H),7.53(dd,1H),6.91(s,1H),5.61(t,1H),5.32-5.19(m,1H),5.11(t,1H ),4.23(dd,1H),4.04(dd,1H),3.92(dd,2H),2.94(s,3H),2.87-2.75(m,4H) ,2.43-2.35(m,5H),2.04-1.97(m,1H),1.94-1.83(m,2H),1.80-1.72(m,1H).

[0332] Compound 6 (104.6 mg, yield 40%); LC-MS (ESI): m / z = 632.2 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.43(s,1H),8.14(s,1H),7.80-7.70(m,1H) ,7.68(dd,1H),7.08(s,1H),5.92(d,1H),5.36-5.22(m,1H),5.15-4.99(m,1H),4 .58-4.42(m,2H),4.25(dd,1H),4.07(dd,1H),2.95(s,3H),2.83(t,4H),2.52(s, 3H),2.45-2.36(m,2H),2.05-1.97(m,1H),1.95-1.85(m,2H),1.83-1.70(m,1H).

[0333] Step 16: Compound 6 was chirally resolved to obtain compound 6-P1 (39 mg, yield 44%, retention time: 0.837 min) and compound 6-P2 (38 mg, yield 43%, retention time: 1.252 min).

[0334] Separation method: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A represents CO2, B represents ethanol (containing 0.1% ammonia); Isocratic elution, mobile phase B content 35%; Flow rate: 120 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Cycle time: 3 min; Sample preparation: Compound dissolved in acetonitrile and ethanol, sample concentration 3 mg / mL; Injection: 3 mL each time.

[0335] Compound 6-P1: LC-MS (ESI): m / z = 632.2 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ 8.51 (d, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.80–7.70 (m, 1H), 7.67 (dd, 1H), 7.07 (s, 1H), 5.90 (d, 1H), 5.36–5.24 (m, 1H), 5.10–5.01 (m, 1H), 4.5 9-4.44(m,2H),4.25(dd,1H),4.07(dd,1H),2.95(s,3H),2.87-2.77(m,4H),2.51( s,3H),2.45-2.37(m,2H),2.06-1.97(m,1H),1.93-1.83(m,2H),1.82-1.72(m,1H).

[0336] Compound 6-P2: LC-MS (ESI): m / z = 632.2 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ 8.51 (d, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.78–7.71 (m, 1H), 7.67 (dd, 1H), 7.07 (s, 1H), 5.90 (d, 1H), 5.34–5.25 (m, 1H), 5.09–5.01 (m, 1H), 4.6 1-4.41(m,2H),4.25(dd,1H),4.07(dd,1H),2.95(s,3H),2.86-2.75(m,4H),2.51( s,3H),2.44-2.37(m,2H),2.04-1.97(m,1H),1.93-1.84(m,2H),1.81-1.72(m,1H).

[0337] Example 7

[0338] Step 1: Compound 5N (0.77 g, 2.59 mmol) and the R-configuration isomer of intermediate 1 (1.1 g, 2.59 mmol) were dissolved in N,N-dimethylformamide (15 mL), and cesium carbonate (1.69 g, 5.18 mmol) was added. After the addition was complete, the mixture was stirred at 60 °C for 1 h. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 7A (crude product). LC-MS (ESI): m / z = 550.0 [M + H] + .

[0339] Step 2: Dissolve 7A (1.4 g, 2.54 mmol) in tetrahydrofuran (30 mL), then add tetrabutylammonium fluoride (1.66 g, 6.35 mmol), and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compounds 7B and 7B-1 (0.65 g, 58.6%). LC-MS (ESI): m / z = 436.0 [M+H] + .

[0340] Step 3: A mixture of 7B and 7B-1 (0.35 g, 0.8 mmol), pinacol diborate (0.3 g, 1.2 mmol), potassium acetate (0.24 g, 2.40 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (60 mg, 0.08 mmol) were dissolved in 1,4-dioxane (15 mL), purged with nitrogen three times, and reacted at 95 °C for 16 hours. After the reaction was complete, proceed directly to the next step (7C and 7C-1). LC-MS (ESI): m / z = 402.1 [M+H] + .

[0341] Step 4: 2F (370 mg, 0.89 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium(II) chloride (53 mg, 0.08 mmol), potassium carbonate (340 mg, 2.40 mmol), and water (1.5 mL) were added to the reaction solutions of 7C and 7C-1. Nitrogen gas was added three times to purge the solution, and the mixture was reacted at 95°C for 3 hours. After the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:10) to obtain the target compounds 7D and 7D-1 (360 mg, 64.2%). LC-MS (ESI): m / z = 695.3 [M+H] + .

[0342] Step 5: Dissolve a mixture of 7D and 7D-1 (0.36 g, 0.52 mmol) in dichloromethane (9 mL), then add trifluoroacetic acid (3 mL) and react at room temperature for 0.5 hours. After the reaction is complete, concentrate the reaction solution to obtain 7E and 7E-1, which can be directly used for the next step. LC-MS (ESI): m / z = 551.2 [M+H] + .

[0343] Step 6: Dissolve the crude products 7E and 7E-1 from the previous step in dichloromethane (10 mL), then add N,N-diisopropylethylamine (2 mL) and cyanogen bromide (84 mg, 0.80 mmol) sequentially, and react at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure, and purify the residue by HPLC to obtain the target compound 7 (60 mg, 20.1%). LC-MS (ESI): m / z = 576.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.43(s,1H),8.13(s,1H),7.77-7.72(m,1H),7.69-7.66(m,1H),7.08(s,1H),5.90(d,1 H),5.08-5.04(m,1H),4.58-4.47(m,3H),3.27-3.20(m,2H),3.00(s,3H),2.80-2.70(m,2H),2.53(s,3H),2.29-2.13(m,4H).

[0344] Example 8

[0345] Step 1: Compound 1G (3.0 g, 12.3 mmol) and trifluoroethyl trifluoromethanesulfonate (3.72 g, 16.0 mmol) were dissolved in acetonitrile (60 mL), followed by the addition of cesium carbonate (8.0 g, 24.7 mmol). The reaction was carried out overnight at 80 °C. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 8A (3 g, 74.8%). LC-MS (ESI): m / z = 324.9 [M+H] +

[0346] Step 2: Using 8A (2.0 g, 6.15 mmol) as the starting material, compound 8B (1.5 g, 78.4%) was synthesized following the synthesis method described in Step 7 of Example 1. LC-MS (ESI): m / z = 311.0 [M+H] + .

[0347] Step 3: Using 8B (0.8 g, 2.57 mmol) as the starting material, and referring to the synthesis method in step 8 of Example 1, crude compound 8C was synthesized and used directly in the next step. LC-MS (ESI): m / z = 564.1 [M+H] + .

[0348] Step 4: The crude compound 8C (1.3 g, 2.3 mmol) from the previous step was dissolved in dichloromethane (10 mL), followed by the addition of 4 M dioxane hydrochloride (10 mL). The reaction was allowed to proceed at room temperature for 1 hour after the addition was complete. After the reaction was complete, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to give compound 8D (0.6 g, 57.8%). LC-MS (ESI): m / z = 450.0 [M + H] +

[0349] Step 5: Using compound 8D (0.3 g, 0.67 mmol) as the starting material, compound 8 (85.0 mg, 33.9%) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 590.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.45(d,1H),8.17(s,1H),7.75(s,1H),7.59-7.56(m,1H),7.45-7.40(m,1H),6.73(s,1H),5.61-5.59(m,1H),4.59 -4.44(m,2H),4.17-4.08(m,3H),3.32-3.29(m,2H),3.04(s,3H),2.81-2.74(m,2H),2.58-2.48(m,2H),2.37(s,3H),2.16-2.12(m,2H).

[0350] Example 9

[0351] Step 1: 9A (1.4 g, 4.89 mmol) (compound 9A was synthesized according to Example 2) was dissolved in tetrahydrofuran (20 mL), followed by the addition of magnesium sulfate (2.94 g, 24.5 mmol) and 37% formaldehyde aqueous solution (0.60 g, 7.33 mmol), and finally acetic acid (88 mg, 1.47 mmol). The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was extracted with water (50 mL) (ethyl acetate 50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound 9B (1.15 g, 78.8%). LC-MS (ESI): m / z = 298.0 [M+H] + .

[0352] Step 2: Dissolve 9B (1.15 g, 3.86 mmol) in water (15 mL) and acetic acid (1.5 mL), then add sodium cyanoborohydride (0.61 g, 9.65 mmol) at 0 °C. Let the mixture react overnight at room temperature. After the reaction is complete, adjust the reaction solution to alkaline with a saturated sodium bicarbonate solution to obtain 9C, which is then used directly in the next step. LC-MS (ESI): m / z = 300.1 [M+H] + .

[0353] Step 3: The reaction solution of 9C from the previous step was stirred at 0°C, and then di-tert-butyl dicarbonate solution (1.60 g, 7.32 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to give compound 9D (0.47 g, 32.0%). LC-MS (ESI): m / z = 344.0 [M-55] + .

[0354] Step 4: Using 9E as raw material, 9F is obtained through three steps, referring to Example 8.

[0355] Step 5: Using 9F and 9D as raw materials, compound 9 was synthesized according to Example 8. LC-MS (ESI): m / z = 552.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.46(d,1H),8.24(s,1H),7.85(s,1H),7.59-7.55(m,1H),7.44-7.39(m,1H),6.75(s,1H),5.61-5.58(m,1H),4.47 -4.39(m,1H),4.18-4.07(m,2H),3.90-3.88(m,2H),3.07(s,3H),2.63-2.54(m,4H),2.34(s,3H),2.01-1.96(m,2H),1.86-1.80(m,2H).

[0356] Example 10

[0357] Step 1: Dissolve 10A (10 g, 44.05 mmol) in acetonitrile (200 mL), and add N-iodosuccinimide (10.9 g, 48.46 mmol). React at room temperature for 1 hour after the addition. Dilute with water, extract with ethyl acetate (100 mL x 3), wash the organic phase, dry, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (PE:EA (v / v) = 10:1) to obtain compound 10B (13 g, yield: 83.6%). LC-MS (ESI): m / z = 352.8 [M+H] + .

[0358] Step 2: 10B (10 g, 28.33 mmol) was dissolved in tetrahydrofuran (200 mL), and cyclopropylacetylene (9.36 g, 141.65 mmol), triethylamine (14.33 g, 141.65 mmol), cuprous iodide (0.54 g, 2.83 mmol), and palladium dichloride (1.99 g, 2.83 mmol) were added. The reaction was then carried out under nitrogen protection at 50 °C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate (100 mL x 3), washed with the organic phase, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA (v / v) = 10:1) to give compound 10C (5.0 g, yield: 60.6%). LC-MS (ESI): m / z = 291.0 [M+H] + .

[0359] Step 3: 10C (4 g, 13.74 mmol) was dissolved in ethanol (80 mL), and p-toluenesulfonic acid monohydrate (13.07 g, 68.7 mmol) was added. Then, under nitrogen protection, silver trifluoromethanesulfonate (0.18 g, 0.69 mmol) and triphenylphosphine chloride (0.34 g, 0.69 mmol) were added. After the addition was complete, the reaction was continued at room temperature for 2 hours. The mixture was diluted with water, extracted with ethyl acetate (50 mL x 3), washed with the organic phase, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA (v / v) = 5:1) to obtain compound 10D (3.6 g, yield: 84.7%). LC-MS (ESI): m / z = 309.0 [M+H] + .

[0360] Step 4: Dissolve 10D (1.5 g, 4.85 mmol) in methanol (20 mL), add sodium borohydride (0.55 g, 14.55 mmol) under ice bath conditions, and continue the reaction for 1 hour. Dilute with water (100 mL), extract with ethyl acetate (30 mL x 3), wash the organic phase, dry, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (PE:EA (v / v) = 5:1) to obtain compound 10E (1.4 g, yield: 92.7%). LC-MS (ESI): m / z = 311.0 [M+H] + .

[0361] Step 5: Dissolve 10E (1.4 g, 4.50 mmol) in dichloromethane (20 mL), add triethylsilane (1.57 g, 13.5 mmol) and trifluoroacetic acid (1.54 g, 13.5 mmol) at room temperature, and continue the reaction for 2 hours. Concentrate, add water, extract with ethyl acetate (30 mL x 3), wash the organic phase, dry, concentrate under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (PE:EA (v / v) = 10:1) to obtain compound 10F (1.1 g, yield: 82.8%). LC-MS (ESI): m / z = 295.0 [M+H] + .

[0362] Step 6: Using compound 10F (1.1 g, 3.56 mmol) as the starting material, compound 10 (90 mg, yield 20.1%) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 560.2 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.31(s,1H),7.80(s,1H),7.75-7.72(m,1H ),7.54-7.51(m,1H),6.61(s,1H),5.55(t,1H),5.12(t,1H),4.51-4.46(m,1H),3 .93(t,2H),3.21(d,2H),3.10-3.01(m,2H),2.99(s,3H),2.71(t,2H),2.35(s,3 H),2.23-2.09(m,4H),1.60(q,2H),0.81-0.76(m,1H),0.42(t,2H),0.09(t,2H).

[0363] Example 11

[0364] Step 1: Dissolve 11A (5 g, 49.94 mmol) in tetrahydrofuran (50 mL), and add deuterated lithium aluminum hydride (2.1 g, 49.94 mmol) in portions at -10°C. React at -10°C for 1 hour. After the reaction is complete, add water (2.1 mL) to the reaction solution and stir for 3 minutes. Then add sodium hydroxide solution (2.1 mL, 15%) and stir for 3 minutes. Add water (6.3 mL), heat to room temperature and stir for 15 minutes. Add anhydrous sodium sulfate and stir for 15 minutes. Filter the solution and concentrate the filtrate to obtain the target compound 11B (2.8 g, 75% yield).

[0365] Step 2: Dissolve 11B (2.8 g, 37.78 mmol) in dichloromethane (40 mL), then add triethylamine (11.47 g, 113.34 mmol), and slowly react with low-valent methanesulfonyl chloride (5.19 g, 45.34 mmol) at 0°C for 3 hours at room temperature. After the reaction is complete, extract the reaction solution with water (50 mL) (dichloromethane 40 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 11C (5.2 g, crude product).

[0366] Step 3: 11C (5.2 g, 34.16 mmol), 1G (8.3 g, 34.16 mmol), and cesium carbonate (16.7 g, 51.24 mmol) were dissolved in N,N-dimethylformamide (100 mL) and reacted at 100°C for 16 hours. After the reaction, the reaction solution was extracted with water (100 mL) (ethyl acetate 100 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give the target compound 11D (6.5 g, yield 63%). LC-MS (ESI): m / z = 299.0 [M+H]+.

[0367] Step 4: Dissolve 11D (6.5 g, 21.73 mmol) in N,N-dimethylacetamide (100 mL), then add n-dodecyl mercaptan (21.99 g, 108.65 mmol) and sodium hydroxide (5.22 g, 130.38 mmol, 50% aqueous solution), and react at 90°C for 2 hours. After the reaction, dilute the reaction solution with water (300 mL), adjust the pH to 5, filter, and evaporate the filter cake to dryness to obtain the target compound 11E (4.2 g, yield 67%). LC-MS (ESI): m / z = 287.0 [M+H-56]+.

[0368] Step 5: Dissolve 11E (2 g, 7.01 mmol), the R-configuration isomer of intermediate 1 (2.98 g, 7.01 mmol), and cesium carbonate (3.43 g, 10.52 mmol) in N,N-dimethylformamide (30 mL) and react at 60°C for 1 hour. After the reaction, extract the reaction solution with water (100 mL) (50 mL x 3 of ethyl acetate), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and proceed directly to the next step (11F crude product). LC-MS (ESI): m / z = 538.1 [M+H] +

[0369] Step 6: Add dioxane hydrochloride (30 mL, 4 M) to 11F (crude product) and react at room temperature for 1 hour. After the reaction, concentrate the reaction solution, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 11G (1.4 g, two-step yield 47%). LC-MS (ESI): m / z = 424.0 [M+H] +

[0370] Step 7: Using compound 11G (0.5 g, 1.18 mmol) as the starting material, compound 11 (92.46 g, 0.16 mmol) was synthesized according to the method in Example 2. LC-MS (ESI): m / z = 564.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.23(d,1H),7.83(s,1H),7.79-7.64( m,2H),6.70(s,1H),5.58(dd,1H),5.09(t,1H),4.58-4.42(m,1H),4.05-3. 86(m,2H),3.27-3.18(m,2H),2.99(s,3H),2.77-2.66(m,2H),2.39(s,3H), 2.25-2.04(m,4H),1.29-1.24(m,1H),0.61-0.53(m,2H),0.38-0.32(m,2H).

[0371] Example 12

[0372] Compound 12 (32 mg) was synthesized from compound 1G using the method described in Example 1. LC-MS (ESI): m / z = 611.2 [M+H] + .

[0373] 1H NMR (400MHz, DMSO) δ8.59(d,1H),8.31(s,1H),7.95(s,1H),7.79-7.69(m,1H),7.68-7.59(m,1H),6.73(s,1H),6.51-6.20(m,1H),5.67-5. 57(m,1H),5.19-5.14(m,1H),4.95-4.71(m,3H),4.00-3.79(m,3H),3 .76-3.61(m,1H),3.46-3.37(m,1H),2.38(s,3H),2.24-2.04(m,4H).

[0374] Example 13

[0375] Step 1: 3G (750 mg, 2.04 mmol), toluene-4-sulfonic acid oxetane-3-yl ester (698 mg, 3.06 mmol), and cesium carbonate (1.99 g, 6.12 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 80°C for 16 hours. After the reaction, the reaction solution was extracted with water (20 mL) (ethyl acetate 15 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 2:1) to obtain the target compound 13A (200 mg, yield: 23.14%).

[0376] LC-MS(ESI): m / z = 424.0 [M+H] + .

[0377] Step 2: Using compound 13A (0.2 g, 0.47 mmol) as the starting material, compound 13 (15 mg, yield: 5.39%) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 591.3 [M+H] +1H NMR(400MHz, CDCl3)δ8.47(d,1H),8.21(s,1H),7.62-7.59(m,1H),7.56(s,1H),7.45-7.41(m ,1H),6.66(s,1H),5.58-5.55(m,1H),5.25-5.20(m,1H),5.02-4.90(m,3H),4.88-4.85(m,2H ),4.30-4.26(m,1H),4.21-4.17(m,1H),4.16-4.05(m,2H),3.67(s,1H),3.45-3.38(m,2H),3 .29-3.26(m,2H),2.67-2.60(m,1H),2.38-2.34(m,4H),2.20-2.16(d,1H),1.97-1.82(m,3H).

[0378] Example 14

[0379] Step 1: Using compound 1G (2.41 g, 10.0 mmol) and bromomethylcyclopropane (1.62 g, 12.0 mmol) as starting materials, compound 14A (1.50 g, 28%) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 536.2 [M+H] + .

[0380] Step 2: Compound 14A (1.07 g, 2.0 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (4.0 mL, 2.0 mmol, 1 N tetrahydrofuran solution) was added. The mixture was stirred overnight at room temperature. After removing the solvent, the residue was separated by silica gel column chromatography to obtain compounds 14B (354 mg, 41%) and 14C (404 mg, 47%). Compound 14B: LC-MS (ESI): m / z = 422.1 [M+H] + Compound 14C: LC-MS (ESI): m / z = 422.1 [M+H] + .

[0381] Step 3: Using compound 14C (404 mg, 0.95 mmol) as the starting material, compound 14 was synthesized according to the method in Example 1. Compound 14 (200 mg) was chirally resolved to obtain P1 (25 mg, retention time: 1.982 min, designated as compound 14-P1), P2 (18 mg, retention time: 2.135 min, designated as compound 14-P2), P3 (11 mg, retention time: 0.849 min, designated as compound 14-P3), and P4 (10 mg, retention time: 1.513 min, designated as compound 14-P4). Preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: Chiralcel OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 130 mL / min; Column temperature: 38℃; Wavelength: 220 nm; Sample preparation: Sample concentration 3 mg / mL, methanol-acetonitrile solution.

[0382] Compound 14-P1: LC-MS (ESI): m / z = 601.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.41(s,1H),7.91-7.89(m,1H),7.69-7.66(m,2H),6.82(s,1H),5.85(t,J=4.8Hz,1H),4.58 -4.52(m,1H),4.22-4.15(m,3H),3.98(d,J=6.8Hz,2H),3.71-3.63(m,2H),2.79-2.70(m,1H), 2.58-2.53(m,2H),2.47-2.37(m,5H),1.37-1.32(m,1H),0.72-0.67(m,2H),0.44-0.40(m,2H).

[0383] Compound 14-P2: LC-MS (ESI): m / z = 601.4 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.49(s,1H),8.29(s,1H),7.81-7.78(m,1H),7.69(s,1H),7. 59-7.56(m,1H),6.72(s,1H),5.70(t,J=4.8Hz,1H),4.56-4.50(m,1H),4.23-4.08 (m,3H),3.98(d,J=6.8Hz,2H),3.67-3.61(m,2H),2.78-2.70(m,1H),2.61-2.53(m ,1H),2.42-2.36(m,5H),1.38-1.30(m,1H),0.71-0.66(m,2H),0.43-0.40(m,2H).

[0384] Compound 14-P3: LC-MS (ESI): m / z = 601.4 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.13(s,1H),7.80(s,1H),7.66(s,1H),7.51-7.47(m, 1H),6.80(s,1H),5.25(s,1H),4.59-4.53(m,1H),4.42(s,2H),4.22-4.18(m,1H),3.98-3 .88(m,2H),3.68-3.62(m,2H),2.81-2.73(m,1H),2.63-2.55(m,1H),2.48(s,3H),2.41- 2.38(m,1H),2.22-2.19(m,1H),1.37-1.31(m,1H),0.70-0.65(m,2H),0.42-0.38(m,2H).

[0385] Compound 14-P4: LC-MS (ESI): m / z = 601.4 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.47(s,1H),8.20(s,1H),7.88(s,1H),7.66(s,1H),7.56(s,1H),6.84(s,1H),5.35-5.20(m,1H),4.60-4.45 (m,3H),4.23-4.19(m,1H),3.92(d,J=6.0Hz,2H),3.72-3.63(m,2H),2.80-2.72(m,1H),2.62-2.39(m,6H),2.40-2.20(m,1H),1.35 -1.32(m,1H),0.71-0.65(m,2H),0.43-0.38(m,2H).

[0386] Example 15

[0387] Step 1: Using compound 5N (0.8 g, 2.69 mmol) as the starting material, compound 15 (365.67 mg, 0.60 mmol) was synthesized according to the method described in Example 7. LC-MS (ESI): m / z = 603.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.43(d,1H),8.13(s,1H),7.77-7.70(m ,1H),7.68(dd,1H),7.07(s,1H),5.91(d,1H),5.37-5.26(m,1H),5.10-5.02( m,1H),4.59-4.43(m,2H),4.32-4.21(m,1H),4.15-4.04(m,1H),3.30-3.18( m,4H),2.52(s,3H),2.49-2.38(m,2H),1.97-1.87(m,2H),1.82-1.73(m,2H).

[0388] Step 2: Compound 15 (351 mg) was separated by chirality to obtain compound 15-P1 (71 mg, yield 20%, retention time: 0.499 min) and compound 15-P4 (82 mg, yield 23%, retention time: 1.428 min). Separation method: Instrument: CAS-05-Prep-SFC-A; Column: AD column; Mobile phase: A represents CO2, B represents ethanol and acetonitrile (containing 0.1% ammonia); Isocratic elution, mobile phase B content 35%; Flow rate: 120 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Compounds were dissolved in acetonitrile and ethanol, sample concentration 15 mg / mL; Injection: 3 mL per injection. Compound 15-P2 (70 mg, yield 19%, retention time: 0.643 min) and compound 15-P3 (68 mg, yield 19%, retention time: 0.750 min) were obtained by a second chiral resolution. Resolution method: Instrument: CAS-05-Prep-SFC-C; Column: OD column; Mobile phase: A represents CO2, B represents ethanol (containing 0.1% ammonia); Isocratic elution, mobile phase B content 35%; Flow rate: 75 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Compounds were dissolved in acetonitrile and ethanol, sample concentration 15 mg / mL; Injection: 3 mL per injection.

[0389] Compound 15-P1: LC-MS (ESI): m / z = 603.3 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.42(d,1H),8.13(s,1H),7.79-7.71 (m,1H),7.67(dd,1H),7.07(s,1H),5.91(d,1H),5.38-5.26(m,1H),5.11-5 .00(m,1H),4.59-4.42(m,2H),4.25(dd,1H),4.08(dd,1H),3.29-3.18(m, 4H),2.51(s,3H),2.47-2.38(m,2H),1.98-1.87(m,2H),1.82-1.73(m,2H).

[0390] Compound 15-P2: LC-MS (ESI): m / z = 603.2 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.43(d,1H),8.13(s,1H),7.80-7.72 (m,1H),7.68(dd,1H),7.07(s,1H),5.91(d,1H),5.35-5.25(m,1H),5.13-5 .02(m,1H),4.63-4.43(m,2H),4.25(dd,1H),4.08(dd,1H),3.29-3.20(m, 4H),2.51(s,3H),2.48-2.37(m,2H),1.96-1.84(m,2H),1.83-1.70(m,2H).

[0391] Compound 15-P3: LC-MS (ESI): m / z = 603.2 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.43(s,1H),8.13(s,1H),7.79-7.71 (m,1H),7.68(dd,1H),7.07(s,1H),5.91(d,1H),5.36-5.27(m,1H),5.10-4 .99(m,1H),4.61-4.42(m,2H),4.26(dd,1H),4.08(dd,1H),3.29-3.19(m, 4H),2.52(s,3H),2.48-2.37(m,2H),1.96-1.86(m,2H),1.81-1.74(m,2H).

[0392] Compound 15-P4: LC-MS (ESI): m / z = 603.2 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.42(s,1H),8.13(s,1H),7.78-7.71 (m,1H),7.67(dd,1H),7.07(s,1H),5.91(d,1H),5.37-5.25(m,1H),5.12-5 .01(m,1H),4.57-4.44(m,2H),4.25(dd,1H),4.08(dd,1H),3.29-3.16(m, 4H),2.51(s,3H),2.47-2.39(m,2H),1.96-1.86(m,2H),1.83-1.74(m,2H).

[0393] Example 16

[0394] Step 1: Compound 10A (20 g, 88.08 mmol) was dissolved in N,N-dimethylacetamide (300 mL), followed by the addition of 50% sodium hydroxide aqueous solution (42 g, 528.48 mmol) and n-dodecyl mercaptan (89.14 g, 440.4 mmol). After the addition was complete, the mixture was heated to 95 °C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to approximately 3 with water (600 mL) and dilute hydrochloric acid. The mixture was filtered to obtain a solid crude product, which was then slurried and filtered with petroleum ether to obtain compound 16B (16.2 g, yield: 86.33%). LC-MS (ESI): m / z = 212.9 [M+H] + .

[0395] Step 2: Compound 16B (10 g, 46.94 mmol) was dissolved in tetrahydrofuran (200 mL). Sodium hydride (3.76 g, 93.88 mmol) was added under ice bath conditions. After reacting for half an hour, bromomethyl methyl ether (11.73 g, 93.88 mmol) was added, and the mixture was allowed to automatically rise to room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride, and water (200 mL) was added. Extraction was performed using EA (50 mL x 3), followed by washing, drying, and concentration under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA (v / v) = 10:1) to obtain the target compound 16C (11.9 g, yield: 98.6%). LC-MS (ESI): m / z = 257.0 [M+H] + .

[0396] Step 3: Compound 16C (12.0 g, 46.68 mmol) was dissolved in DMF (200 mL), then cooled to 0 °C, and phosphorus oxychloride (21.5 g, 140.04 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted overnight. After the reaction was complete, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution (500 mL). After the addition was complete, a saturated potassium carbonate solution was added to adjust the pH to 8-9. The mixture was filtered, the filter cake was washed with water, and then dried to obtain compound 16D (11.1 g, yield: 83.4%). LC-MS (ESI): m / z = 284.0 [M+H] + .

[0397] Step 4: Compound 16D (11.0 g, 38.58 mmol) was dissolved in dichloromethane (200 mL), followed by the addition of trifluoroacetic acid (0.66 g, 5.79 mmol). After the addition was complete, m-chloroperoxybenzoic acid (85%, 15.67 g, 77.16 mmol) was added in portions at room temperature. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, followed by washing with saturated sodium thiosulfate solution. The organic phase was separated, dried, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to obtain compound 16E (9.2 g, yield 75.6%). LC-MS (ESI): m / z = 301.1 [M+H] + .

[0398] Step 5: Compound 16E (9.0 g, 31.57 mmol) was dissolved in methanol (150 mL), followed by the addition of potassium carbonate (8.73 g, 63.14 mmol). The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to remove most of the methanol. Water was added to the residue, and the pH was adjusted to 5-6 with citric acid. Ethyl acetate was added for extraction, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to give compound 16F (6.5 g, yield: 65.3%). LC-MS (ESI): m / z = 272.9 [M+H] + .

[0399] Step 6: Compound 16F (4.6 g, 16.84 mmol) was dissolved in DMF (50 mL), followed by the addition of cesium carbonate (16.4 g, 50.52 mmol), and the reaction was heated to 50 °C and carried out for 0.5 hours. Then, deuterated iodomethane (7.3 g, 50.52 mmol) was added, and the reaction was continued for 2 hours. The mixture was then extracted with water and ethyl acetate, washed, dried, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give compound 16G (2.3 g, yield: 47.06%). LC-MS (ESI): m / z = 290.0 [M+H] + .

[0400] Step 7: Dissolve 16G (2.3g, 8.42mmol) in dichloromethane (30mL), then add trifluoroacetic acid (6mL) and react at room temperature for 2 hours. Concentrate under reduced pressure to obtain the crude product, which is then purified by column chromatography (PE:EA (v / v) = 3:1) to give compound 16H (1.5g, yield: 61.4%). LC-MS (ESI): m / z = 246.1 [M+H] + .

[0401] Step 8: Compound 16H (500 mg, 2.03 mmol) and the R-configuration isomer of intermediate 1 (860 mg, 2.03 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.32 g, 4.06 mmol) was added. After the addition was complete, the mixture was stirred at 60 °C for 2 h. After the reaction was complete, water (500 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16I (crude product). LC-MS (ESI): m / z = 501.2 [M+H] +

[0402] Step 9: Dissolve the product 16I from the previous step in tetrahydrofuran (10 mL), then add tetrabutylammonium fluoride (6 mL, 6.03 mmol, 1 M), and react at room temperature for one hour. After the reaction, extract the reaction solution with water (30 mL) (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 16J (300 mg, yield: 77.8%). LC-MS (ESI): m / z = 385.0 [M+H] +

[0403] Step 10: Dissolve 16J (135 mg, 0.35 mmol), pinacol diborate (133 mg, 0.52 mmol), potassium acetate (103 mg, 1.05 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (25.6 mg, 0.04 mmol) in 1,4-dioxane (10 mL), purge with nitrogen three times, and react at 95 °C for 16 hours. After the reaction, obtain 16K and proceed directly to the next step. LC-MS (ESI): m / z = 351.1 [M+H] + .

[0404] Step 11: Intermediate 2F (163 mg, 0.39 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium(II) chloride (25 mg, 0.04 mmol), potassium carbonate (162 mg, 1.17 mmol), and water (2 mL) were added to a reaction solution at 16 K. Nitrogen gas was added three times to purge the solution, and the mixture was reacted at 95 °C for 3 hours. After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate) to give compound 16L (106 mg, yield: 42.7%). LC-MS (ESI): m / z = 644.3 [M+H]+.

[0405] Step 12: Dissolve 16 L (106 mg, 0.16 mmol) in dichloromethane (6 mL), then add trifluoroacetic acid (1 mL) and react at room temperature for 0.5 hours. After the reaction is complete, concentrate the reaction solution to obtain 16 M and proceed directly to the next step. LC-MS (ESI): m / z = 500.3 [M+H] + .

[0406] Step 13: Dissolve the crude compound 16M from the previous step in dichloromethane (5 mL), then add N,N-diisopropylethylamine (0.1 mL) and cyanogen bromide (34 mg, 0.32 mmol), and react at room temperature for 2 hours. Add water (10 mL) to the reaction system, extract with DCM (5 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, and purify the crude product by HPLC to obtain compound 16 (6 mg, yield: 7.1%). LC-MS (ESI): m / z = 525.1 [M + H] +

[0407] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.22(s,1H),7.86(s,1H),7.75-7.73(m,1H),7.65-7.62(m,1H),6.65(s,1H),5.56(t,1H ),5.12(t,1H),4.52-4.47(m,1H),3.94-3.91(m,2H),3.22(d,2H),2.99(s,3H),2.72(t,2H),2.38(s,3H),2.21-2.09(m,4H).

[0408] Example 17

[0409] Step 1: Dissolve 7A (1.3 g, 2.36 mmol) in dichloromethane (10 mL), then add 4 M dioxane hydrochloride solution (10 mL). React at room temperature for 1 hour after the addition is complete. After the reaction is complete, concentrate the reaction solution, then add ethyl acetate (50 mL). Wash with saturated sodium bicarbonate solution and saturated brine, respectively. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the compound residue. Purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 17A (0.55 g, 53.4%). LC-MS (ESI): m / z = 436.0 [M+H] + .

[0410] Step 2: Using compound 17A (0.35 g, 0.80 mmol) as the starting material, compound 17 (70.0 mg, 26.8%) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 576.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.42(s,1H),8.21(s,1H),7.79-7.74(m,1H),7.55-7.51(m,1H),6.92(s,1H),5.61(t,1H),5.0 9(t,1H),4.54-4.49(m,1H),3.96-3.90(m,2H),3.24-3.20(m,2H),2.99(s,3H),2.75-2.69(m,2H),2.40(s,3H),2.24-2.10(m,4H).

[0411] Example 18

[0412] Step 1: Compound 18A (22.80 g, 88.6 mmol) was weighed into methanol (400 mL), and then sodium borohydride (10.30 g, 266 mmol) was slowly added. After the addition was complete, the mixture was heated under reflux for 3 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and then an appropriate amount of 1N HCl was added to disrupt the reaction. The mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound 18B (20.0 g, yield: 97.56%). LC-MS (ESI): m / z = 176.1 [M-55] + .

[0413] Step 2: Compound 18B (20.0 g, 86.47 mmol) was weighed into dichloromethane (400 mL), followed by the addition of imidazole (11.78 g, 173.03 mmol) and TBSCl (15.69 g, 104.10 mmol). After the addition was complete, the mixture was stirred at room temperature for 20 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was washed with saturated brine, followed by back-extraction with dichloromethane in aqueous phase. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 18C (12.6 g, yield: 42.17%). LC-MS (ESI): m / z = 190.3 [M-55] + . 1H NMR(400MHz, CDCl3)δ4.10(b,1H),3.81-3.77(m,1H),3.73-3.69(m,1H),3.63-3.58(m,2H), 3.24-3.16(m,2H),1.68-1.61(m,2H),1.56-1.50(m,1H),1.37(s,9H),0.82(s,9H),0(s,6H).

[0414] Step 3: Compound 18C (10.50 g, 30.42 mmol) was weighed into THF (90 mL), and DPPA (8.40 g, 30.42 mmol) was added under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 30 min. Triphenylphosphine (9.60 g, 36.60 mmol) and DIAD (6.95 g, 36.60 mmol) were separately weighed into THF (90 mL), and after the addition was complete, the mixture was stirred at room temperature for 30 min under nitrogen protection. Then, the mixed solution of triphenylphosphine and DIAD was added to the above reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 18 h. After the reaction was complete, the mixture was concentrated, and purified by column chromatography to obtain the target compound 18D (8.0 g, yield: 70.98%). LC-MS (ESI): m / z = 271.3 [M-99] + .

[0415] Step 4: Weigh compound 18D (8.0 g, 21.59 mmol) into tetrahydrofuran (80 mL), then add TBAF in tetrahydrofuran solution (40 mL). Stir at room temperature for 2 h. After the reaction is complete, concentrate and purify by column chromatography to obtain target compound 18E (4.60 g, 83.18%). LC-MS (ESI): m / z = 201.1 [M-55] + .

[0416] Step 5: Under nitrogen protection, compound 8A (11.38 g, 35.0 mmol) was weighed into THF (100.0 mL), followed by the sequential addition of tetrahydro-2-(2-propynoxy)-2H-pyran (14.72 g, 105.0 mmol), triethylamine (18.18 g, 180 mmol), cuprous iodide (570 mg, 0.3 mmol), and tetratetraphenylphosphine dichloride palladium (2.1 g, 0.3 mmol). After the addition was complete, the mixture was heated under reflux for 18 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The concentrated crude product was purified by column chromatography to obtain the target compound 18F (17.0 g) crude product, which was directly used in the next step of the reaction. LC-MS (ESI): m / z = 385.1 [M+H] + .

[0417] Step 6: Weigh compound 18F (17.0 g, crude product, 45.74 mmol) into methanol (150 mL), then add p-toluenesulfonic acid monohydrate (8.70 g, 45.74 mmol). After the addition is complete, stir the mixture overnight. Monitor the reaction by TLC until complete. After the reaction is complete, concentrate the crude product. Purify the crude product by column chromatography to obtain the target compound 18G (7.60 g, yield: 72.31%, two-step yield). LC-MS (ESI): m / z = 301.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.96(s,1H),6.44(s,1H),5.37-5.34(m,1H),4.72-4.65(m,2H),4.32-4.31(m,2H),3.91(s,3H).

[0418] Step 7: Weigh compound 18G (7.60 g, 25.30 mmol) into dichloromethane (200 mL), add triphenylphosphine (13.27 g, 50.60 mmol), and then slowly add carbon tetrabromide (16.78 g, 50.60 mmol) while stirring at room temperature. After stirring at room temperature for 30 min, the reaction was completed by TLC. The crude product was concentrated and purified by column chromatography to obtain the target compound 18H (7.50 g, yield: 81.69%). 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.00(s,1H),6.46(s,1H),4.73-4.66(m,2H),4.53(s,2H),3.93(s,3H).

[0419] Step 8: Weigh compound 18E (2.63 g, 10.25 mmol) into ultra-dry DMF (60 mL), cool to 0 °C under nitrogen protection, and then slowly add NaH (774 mg, 17.35 mmol, 60%) to the reaction solution. After the addition is complete, maintain this temperature and continue stirring for 30 min. Then weigh compound 18H (3.10 g, 8.54 mmol) and add it to the reaction solution. After the addition is complete, allow it to warm to room temperature and continue stirring for 1 h. Monitor the reaction by TLC. After the reaction is complete, add the reaction solution to water and extract twice with ethyl acetate. Combine the organic phases and wash them successively with saturated brine and water. Dry the mixture with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Purify the crude product by column chromatography to obtain the target compound 18I (3.15 g, yield: 68.48%). LC-MS (ESI): m / z = 539.2 [M+H] + ; 483.2 [M-55] + .

[0420] Step 9: 3.15 g of crude compound 18I was added to a mixture of DMF (40 mL) and water (5 mL), and the mixture was heated to 110 °C for 18 h. The reaction was monitored by TLC until completion. Heating was stopped, and the mixture was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and washed successively with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 18J (crude product) (1.52 g, yield: 48.25%). LC-MS (ESI): m / z = 539.3 [M+H] +

[0421] Step 10: Weigh compound 18J (1.52 g, 2.82 mmol) into DMAc (25 mL), then add dodecanethiol (2.88 g, 14.18 mmol) and 50% sodium hydroxide solution (1.90 g). After the addition is complete, heat to 90 °C and monitor the reaction by TLC. The reaction is complete after 1 h. Cool to room temperature, then add water to the reaction solution, adjust the pH to approximately 4 with 3N hydrochloric acid, extract twice with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. The crude product is purified by column chromatography to obtain the target compound 18K (0.71 g, yield: 47.97%). LC-MS (ESI): m / z = 525.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.13(s,1H),7.89(s,1H),6.65(s, 1H),5.07-5.04(m,1H),4.78-4.69(m,4H),4.19-4.16(m,1H),4.07-4.03( m,1H),3.94-3.91(m,1H),3.67-3.61(m,1H),2.87(b,1H),2.71-2.66(m,1 H),2.57-2.51(m,1H),2.22-2.11(m,1H),1.87-1.77(m,1H),1.42(s,9H).

[0422] Step 11: Weigh compound 18K (300 mg, 0.57 mmol) into acetonitrile (15 mL), then add cesium carbonate (371 mg, 1.14 mmol) and 2-bromo-1-(5-fluoropyridin-2-yl)ethane-1-one (according to patent WO2016205031 A1) (162 mg, 0.74 mmol) sequentially. After the addition is complete, heat at 55 °C for 1 h. Monitor the reaction by TLC. After the reaction is complete, filter, wash the filter cake with ethyl acetate, concentrate, and purify by column chromatography to obtain crude target compound 18L (380 mg, yield >100%). This crude product is directly used in the next reaction. LC-MS (ESI): m / z = 662.3 [M+H] + .

[0423] Step 12: Weigh compound 18L (380 mg, 0.58 mmol, crude product) into methanol (30 mL), then add sodium borohydride (67 mg, 1.74 mmol) to the reaction solution. Stir at room temperature for 10 min, and the reaction is complete after TLC spotting. After concentration, direct column chromatography purification yields the target compound 18M (295 mg, yield: 76.62%). LC-MS (ESI): m / z = 664.3 [M+H] + .

[0424] Step 13: Weigh compound 18M (295 mg, 0.45 mmol) into DCM (10 mL), then add trifluoroacetic acid (2 mL). After the addition is complete, stir at room temperature for 1 h. After the reaction is complete, concentrate to obtain crude trifluoroacetate of the target compound 18N (320 mg). This crude product is directly used in the next reaction. LC-MS (ESI): m / z = 564.1 [M+H] + .

[0425] Step 14: Weigh 320 mg of trifluoroacetate (crude product) of compound 18N and add 10 mL of dichloromethane and 1 mL of DIPEA, then add 210 mg of cyanogen bromide (2.0 mmol). After the addition is complete, stir at room temperature for 1 h, concentrate to obtain the crude product, and purify the crude product by reverse-phase chromatography to obtain the target compound 18 (120 mg, yield: 45.28%). LC-MS (ESI): m / z = 589.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.52-8.51(m,1H),8.26-8.25(m,1H),7.89(s,1H),7.78-7.68(m ,2H),6.77(s,1H),5.97-5.95(m,1H),5.10-5.07(m,2H),4.78-4.69(m,2H),4.59-4.51(m ,3H),4.47-4.42(m,1H),4.03-3.99(m,1H),3.68-3.58(m,2H),3.47-3.37(m,1H),3.23- 3.17(m,1H),2.88-2.82(m,1H),2.75-2.71(m,1H),2.46-2.35(m,1H),2.09-2.00(m,1H).

[0426] Example 19

[0427] Step 1: Using compound 8B (3 g, 9.6 mmol) and compound 2N (2.18 g, 10 mmol) as starting materials, compound 19A (2.7 g, 62.7%) was synthesized according to the method described in step 9 of Example 2. LC-MS (ESI): m / z = 448.0 [M+H] + .

[0428] Step 2: Compound 19A (2.7 g, 6.0 mmol) was dissolved in anhydrous methanol (30 mL), and sodium borohydride (333 mg, 9 mmol) was slowly added. The mixture was stirred at room temperature for 1 h, then concentrated to remove the solvent. Water (50 mL) and ethyl acetate (50 mL) were added to the residue, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain compound 19B (2.2 g, 81.4%). LC-MS (ESI): m / z = 450.0 [M+H] + .

[0429] Step 3: Using compound 19B (2.2 g, 4.8 mmol) as the starting material, compound 19 (845 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 611.2 [M+H] + .

[0430] Step 4: SFC analysis method: Instrument: CAS-05-ANA-SFC-C, Column: IK column; Mobile phase: A: CO2, B: 0.05% DEA in MeOH and CH3CN; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0431] Compound 19 was first chirally resolved to yield compound 19-1 (SFC retention time: 0.984 min, 70.6 mg), compound 19-2 (SFC retention time: 2.073 min, 69.7 mg), compound 19-3 (SFC retention time: 2.690 min, 93.1 mg), and compound 19-4 (SFC retention time: 3.830 min, 92.6 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-E; Column: IG column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH and CH3CN; Flow rate: 100 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0432] Compound 19 was resolved by a second chiral reaction to obtain compound 19-5 (SFC analysis retention time: 1.014 min, 35.6 mg) and compound 19-6 (SFC analysis retention time: 1.501 min, 35.4 mg). SFC preparation method: instrument: CAS-05-Prep-SFC-E, column: OX column; mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH and CH3CN; flow rate: 120 mL / min; column temperature: 35℃; wavelength: 220 nm.

[0433] Compound 19 was resolved by a third chiral reaction to yield compound 19-7 (SFC retention time: 1.048 min, 29.8 mg) and compound 19-8 (SFC retention time: 1.537 min, 25.8 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-E; Column: OX column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH and CH3CN; Flow rate: 120 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0434] Compound 19-1: 1¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.81-7.65 (m, 2H), 6.90 (s, 1H), 6.52-6.20 (m, 1H), 5.98 (d, 1H), 5.14-5.06 (m, 1H), 4.89-4.69 (m, 1H), 4.61-4.50 (m, 3H), 4.49-4.41 (m, 1H), 3.94-3.79 (m, 1H), 3.75-3.65 (m, 1H), 3.49-3.37 (m, 1H), 2.52 (s, 3H), 2.25-2.05 (m, 4H).

[0435] LC-MS (ESI): m / z = 611.2 [M+H] + .

[0436] Compound 19-2: 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.81-7.65 (m, 2H), 6.90 (s, 1H), 6.52-6.20 (m, 1H), 5.98 (d, 1H), 5.14-5.06 (m, 1H), 4.89-4.69 (m, 1H), 4.61-4.50 (m, 3H), 4.49-4.41 (m, 1H), 3.94-3.79 (m, 1H), 3.75-3.65 (m, 1H), 3.49-3.37 (m, 1H), 2.52 (s, 3H), 2.25-2.05 (m, 4H).

[0437] LC-MS (ESI): m / z = 611.2 [M+H] + .

[0438] Compound 19-3: 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.81-7.65 (m, 2H), 6.90 (s, 1H), 6.52-6.20 (m, 1H), 5.98 (d, 1H), 5.14-5.06 (m, 1H), 4.89-4.69 (m, 1H), 4.61-4.50 (m, 3H), 4.49-4.41 (m, 1H), 3.94-3.79 (m, 1H), 3.75-3.65 (m, 1H), 3.49-3.37 (m, 1H), 2.52 (s, 3H), 2.25-2.05 (m, 4H).

[0439] LC-MS(ESI): m / z = 611.2 [M+H] + .

[0440] Compound 19-4: 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.32(s,1H),7.88(s,1H),7.81-7.6 5(m,2H),6.90(s,1H),6.52-6.20(m,1H),5.98(d,1H),5.14-5.06(m,1H), 4.89-4.69(m,1H),4.61-4.50(m,3H),4.49-4.41(m,1H),3.94-3.79(m,1 H),3.75-3.65(m,1H),3.49-3.37(m,1H),2.52(s,3H),2.25-2.05(m,4H).

[0441] LC-MS(ESI): m / z = 611.2 [M+H] + .

[0442] Compound 19-5: 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.31(s,1H),7.87(s,1H),7.79-7.6 7(m,2H),6.89(s,1H),6.75-6.44(m,1H),5.98(d,1H),5.14-5.06(m,1H), 4.83-4.72(m,1H),4.62-4.49(m,3H),4.48-4.40(m,1H),4.24-4.11(m,1 H),3.66-3.51(m,2H),2.51(s,3H),2.48-2.37(m,1H),2.28-2.08(m,3H).

[0443] LC-MS(ESI): m / z = 611.2 [M+H] + .

[0444] Compound 19-6: 1

[0445] Compound 19-6: 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.79-7.67 (m, 2H), 6.89 (s, 1H), 6.75-6.44 (m, 1H), 5.98 (d, 1H), 5.14-5.06 (m, 1H), 4.83-4.72 (m, 1H), 4.62-4.49 (m, 3H), 4.48-4.40 (m, 1H), 4.24-4.11 (m, 1H), 3.66-3.51 (m, 2H), 2.51 (s, 3H), 2.48-2.37 (m, 1H), 2.28-2.08 (m, 3H).

[0446] LC-MS (ESI): m / z = 611.2 [M+H] + .

[0447] Compound 19-7: 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.79-7.67 (m, 2H), 6.89 (s, 1H), 6.75-6.44 (m, 1H), 5.98 (d, 1H), 5.14-5.06 (m, 1H), 4.83-4.72 (m, 1H), 4.62-4.49 (m, 3H), 4.48-4.40 (m, 1H), 4.24-4.11 (m, 1H), 3.66-3.51 (m, 2H), 2.51 (s, 3H), 2.48-2.37 (m, 1H), 2.28-2.08 (m, 3H).

[0448] LC-MS (ESI): m / z = 611.2 [M+H] + .

[0449] Compound 19-8:LC-MS(ESI): m / z = 611.2 [M+H] + .

[0450] Example 20

[0451] Compound 20 (112 mg, 7% yield) was synthesized using 8A (845 mg, 2.6 mmol) and 5E (1.25 g, 3.1 mmol) as starting materials, following the method described in Example 1.

[0452] Compound 20 (112 mg) was separated into two fractions by chiral SFC, which were designated as compound 20-P1 (55 mg, retention time: 12.7 min) and compound 20-P2 (56 mg, retention time: 15.2 min).

[0453] Preparation method: Instrument: SFC Prep 150 AP; Column: Daicel IG (19mm × 250mm); The sample was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Isopropanol (0.05% ammonia); b. Isocratic elution, mobile phase B concentration 20ml / min; Total flow rate 32ml / min.

[0454] Compound 20-P1: 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.28(s,1H),7.94(s,1H),7.73(dt,1H),7.62(dd, 1H),6.71(s,1H),5.60(t,1H),5.28-5.21(m,1H),5.14(t,1H),4.90-4.76(m,2H),4.22 (dd,1H),4.04(dd,1H),3.93(d,2H),3.27-3.24(m,2H),3.23-3.19(m,2H),2.46-2.39( m,2H),2.37(s,3H),1.92-1.85(m,2H),1.79-1.73(m,2H).LC-MS(ESI):m / z=617.2[M+H] +

[0455] Compound 20-P2: 1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.28(s,1H),7.94(s,1H),7.73(dt,1H),7.62(dd, 1H),6.71(s,1H),5.60(t,1H),5.30-5.21(m,1H),5.15(t,1H),4.93-4.74(m,2H),4.21 (dd,1H),4.03(dd,1H),3.93(d,2H),3.29-3.25(m,2H),3.24-3.19(m,2H),2.46-2.38( m,2H),2.37(s,3H),1.94-1.82(m,2H),1.80-1.70(m,2H).LC-MS(ESI):m / z=617.2[M+H] + .

[0456] Example 21

[0457] Step 1: Compound 8B (0.45 g, 1.45 mmol) and cesium carbonate (0.71 g, 2.17 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 10 minutes. Finally, 2N (0.38 g, 1.74 mmol) was added, and the reaction was allowed to proceed for 1 hour at room temperature. After the reaction was complete, water (100 mL) was added, and a solid precipitated. The solid was filtered and dried to obtain compound 21A (0.445 g, 68.6%). LC-MS (ESI): m / z = 448.0 [M+H] +

[0458] Step 2: Compound 21A (0.445 g, 0.99 mmol) was dissolved in methanol (10 mL) and stirred at 0 °C. Sodium borohydride (0.11 g, 2.97 mmol) was then added, and the mixture was allowed to react at room temperature for 1 hour after the addition was complete. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to give compound 21B (0.45 g, 99.9%). LC-MS (ESI): m / z = 450.0 [M+H] + .

[0459] Step 3: Using compound 21B (0.45 g, 1.0 mmol) as the starting material, compound 21 (80.0 mg, 31.9%) was synthesized according to the method described in Example 7. LC-MS (ESI): m / z = 590.1 [M+H] + ;

[0460] Step 4: Compound 21 (80 mg) was chirally resolved to obtain P1 (retention time: 1.814 min, designated as compound 21-P1) and P2 (retention time: 2.063 min, designated as compound 21-P2). Preparation method: Instrument: CAS-05-Prep-SFC-C; Column: AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 70 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Sample concentration 10 mg / mL, acetonitrile-methanol solution. After separation and solvent removal, compounds 21-P1 (25 mg, 31.2%) and 21-P2 (25 mg, 31.2%) were obtained.

[0461] Compound 21-P1: LC-MS (ESI): m / z = 590.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.30(s,1H),7.86(s,1H),7.77-7.69(m,2H),6.89(s,1H),5.96(d,1H),5.12-5.08(m,1 H),4.59-4.51(m,4H),4.46-4.42(m,1H),3.26-3.23(m,2H),2.99(s,3H),2.76-2.71(m,2H),2.51(s,3H),2.27-2.12(m,4H).

[0462] Compound 21-P2: LC-MS (ESI): m / z = 590.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.30(s,1H),7.87(s,1H),7.77-7.69(m,2H),6.89(s,1H),5.97(d,1H),5.12-5.08(m,1 H),4.59-4.51(m,4H),4.46-4.42(m,1H),3.26-3.23(m,2H),2.99(s,3H),2.76-2.71(m,2H),2.51(s,3H),2.27-2.12(m,4H).

[0463] Example 22

[0464] Step 1: Using compound 22A (2.45 g, 9.56 mmol) (synthesized according to patent WO2004011457A1) and compound 18H (3.12 g, 8.60 mmol) as starting materials, compound 22B (2.5 g, yield: 55.05%) was obtained by referring to the synthesis method in step 8 of Example 18. LC-MS (ESI): m / z = 525.3 [M+H]+.

[0465] Step 2: Compound 22B (2.70 g, 9.56 mmol) was synthesized according to the method described in step 9 of Example 18 at 90 °C for 3 h to obtain compound 22C (0.92 g, yield: 34.07%). LC-MS (ESI): m / z = 525.1 [M+H]+.

[0466] Step 3: Using compound 22C (0.80 g, 1.53 mmol), compound 22D (0.58 g, yield: 74.49%) was synthesized according to the method described in step 10 of Example 18. LC-MS (ESI): m / z = 511.2 [M+H]+.

[0467] Step 4: Using compound 22D (0.20 g, 0.39 mmol) and 2-bromo-1-(5-fluoropyridin-2-yl)ethane-1-one (according to patent-WO2016205031A1) (100 mg, 0.47 mmol), crude compound 22E (0.26 g) was obtained by referring to step 11 of Example 18. LC-MS (ESI): m / z = 648.4 [M+H]+.

[0468] Step 5: Using compound 22E (0.26 g, 1.53 mmol), compound 22F (0.15 g, yield: 57.51%) was synthesized according to the method described in step 12 of Example 18. LC-MS (ESI): m / z = 650.4 [M+H]+.

[0469] Step 6: Using compound 22F (0.15 g, 1.53 mmol), the trifluoroacetate of compound 22G (0.15 g) was synthesized according to the method described in step 13 of Example 18. LC-MS (ESI): m / z = 550.1 [M+H]+.

[0470] Step 7: Using compound 22G (0.15 g, crude product), the synthesis method in step 14 of Example 18 was followed to obtain compound 22 (60 mg, yield, 38.26%). LC-MS (ESI): m / z = 575.0 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.53-8.52(m,1H),8.23(s,1H),7.89(s,1H),7.79-7.70(m,2H),6.9 3(s,1H),6.01-5.99(m,1H),5.52-5.46(m,1H),5.29-5.25(m,1H),5.13-5.10(m,1H),4.60- 4.53(m,3H),4.49-4.45(m,1H),4.36-4.30(m,1H),3.91-3.85(m,1H),3.79-3.76(m,1H),3. 61-3.58(m,1H),3.46-3.38(m,1H),3.30-3.25(m,1H),2.83-2.78(m,1H),2.03-1.92(m,1H).

[0471] Step 8: SFC analysis method: Instrument: CAS-05-ANA-SFC-D, Column: AD column; Mobile phase: A: CO2, B: 0.05% MNH3 in isopropanol and acetonitrile; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0472] Compound 22 (55 mg) was subjected to a first chiral resolution to obtain compounds 22-1 (SFC retention time: 0.553 min) and 22-2 (SFC retention time: 0.776 min). SFC preparation method: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol and acetonitrile; Flow rate: 130 mL / min; Column temperature: 35℃; Wavelength: 220 nm. Sample preparation: Compounds were prepared at a concentration of 3 mg / mL and dissolved in acetonitrile and methanol.

[0473] Compound 22-1 was resolved by a second chiral reaction to yield compounds 22-P1 (SFC retention time: 1.695 min, 13.7 mg) and 22-P2 (SFC retention time: 2.025 min, 13.9 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-G; Column: OJ column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Flow rate: 140 mL / min; Column temperature: room temperature; Wavelength: 220 nm. Sample preparation: Compound concentration was 2 mg / mL, dissolved in acetonitrile and methanol.

[0474] Compound 22-2 was resolved by a third chiral reaction to yield compounds 22-P3 (SFC retention time: 1.736 min, 13.5 mg) and 22-P4 (SFC retention time: 2.054 min, 13.5 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-G; Column: OJ column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Flow rate: 140 mL / min; Column temperature: room temperature; Wavelength: 220 nm. Sample preparation: Compound concentration was 2 mg / mL, dissolved in acetonitrile and methanol.

[0475] Compound 22-P1: LC-MS (ESI): m / z = 575.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.52-8.51(m,1H),8.23(s,1H),7.88(s,1H),7.79-7.69(m,2H),6.9 2(s,1H),5.98-5.97(m,1H),5.52-5.48(m,1H),5.28-5.24(m,1H),5.12-5.09(m,1H),4.59- 4.52(m,3H),4.48-4.44(m,1H),4.36-4.29(m,1H),3.91-3.87(m,1H),3.79-3.75(m,1H),3. 60-3.58(m,1H),3.45-3.38(m,1H),3.30-3.25(m,1H),2.82-2.77(m,1H),2.02-1.92(m,1H).

[0476] Compound 22-P2: LC-MS (ESI): m / z = 575.2 [M+H]+. 1¹H NMR (400 MHz, DMSO-d₆) δ 8.52-8.51 (m, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.78-7.70 (m, 2H), 6.92 (s, 1H), 5.99-5.98 (m, 1H), 5.52-5.48 (m, 1H), 5.28-5.24 (m, 1H), 5.13-5.09 (m, 1H), 4.59-4.53 (m, 3H), 4.49-4.45 (m, 1H), 4.36-4.29 (m, 1H), 3.91-3.85 (m, 1H), 3.79-3.75 (m, 1H), 3.60-3.58 (m, 1H), 3.45-3.38 (m, 1H), 3.30-3.25 (m, 1H), 2.82-2.78 (m, 1H), 2.02-1.92 (m, 1H).

[0477] Compound 22-P3: LC-MS (ESI): m / z = 575.1 [M+H]⁺. 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.52-8.51 (m, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.78-7.70 (m, 2H), 6.92 (s, 1H), 5.98-5.97 (m, 1H), 5.52-5.48 (m, 1H), 5.28-5.24 (m, 1H), 5.12-5.07 (m, 1H), 4.59-4.53 (m, 3H), 4.49-4.45 (m, 1H), 4.36-4.29 (m, 1H), 3.90-3.84 (m, 1H), 3.79-3.75 (m, 1H), 3.60-3.58 (m, 1H), 3.44-3.38 (m, 1H), 3.30-3.25 (m, 1H), 2.82-2.79 (m, 1H), 2.02-1.92 (m, 1H).

[0478] Compound 22-P4: LC-MS (ESI): m / z = 575.1 [M+H]⁺. 1H NMR(400MHz,DMSO-d6)δ8.53-8.52(m,1H),8.23(s,1H),7.88(s,1H),7.78-7.69(m,2H),6.9 2(s,1H),5.98-5.97(m,1H),5.52-5.48(m,1H),5.28-5.24(m,1H),5.13-5.08(m,1H),4.59- 4.53(m,3H),4.46-4.44(m,1H),4.36-4.29(m,1H),3.91-3.85(m,1H),3.79-3.75(m,1H),3. 60-3.58(m,1H),3.44-3.38(m,1H),3.30-3.25(m,1H),2.82-2.79(m,1H),2.02-1.92(m,1H).

[0479] Example 23

[0480] Step 1: Using compound 1F (7 g, 17.7 mmol) as the starting material, compound 23A (2.5 g, yield of 24.1% over five steps) was synthesized according to steps 1 to 5 of Example 2. LC-MS (ESI): m / z = 468.1 [M+H] + .

[0481] Step 2: Using compound 23A (468 mg, 1 mmol) and compound 19B (450 mg, 1 mmol) as starting materials, compound 23 (10.5 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 640.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.31(s,1H),7.86(s,1H),7.83-7.61(m,2H),7.00-6.78(m,1H),6.50-6.16(m,1H),6.03-5.91(m ,1H),5.15-5.06(m,1H),4.79-4.66(m,1H),4.66-4.36(m,5H),3.45-3.34(m,1H),3.07-2.98(m,4H),2.52(s,3H),2.26-2.08(m,4H).

[0482] Example 24

[0483] Step 1: Compound 24A (5.5 g, 40 mmol) was dissolved in THF (100 mL). CsF (12 g, 80 mmol) and TMSCF3 (8.5 g, 60 mmol) were added sequentially with stirring, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, water (10 mL) was added to quench the reaction, followed by the addition of 2 M hydrochloric acid (50 mL). Stirring was continued for 1 h, and then excess saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound 24B (7.2 g, 86.9%). LC-MS (ESI): m / z = 208.0 [M + H] + .

[0484] Step 2: Compound 24B (7.2 g, 34.7 mmol) was dissolved in DCM (100 mL), triethylamine (6 mL) was added, and MsCl (4.6 g, 40 mmol) was slowly added under ice-water bath conditions. The reaction was carried out at this temperature for 1 h. After the reaction was completed, the mixture was directly concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound 24C (7.8 g, 78.7%). LC-MS (ESI): m / z = 286.0 [M+H] + .

[0485] Step 3: Compound 24C (7.8 g, 27.3 mmol) was dissolved in anhydrous methanol (200 mL), and 5% palladium on carbon (2 g) was added. The reaction was carried out under a hydrogen atmosphere at 3 MPa for 24 h. After the reaction was complete, the mixture was filtered, the filter cake was washed with anhydrous methanol, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to obtain compound 24D (4.8 g, 92.3%). LC-MS (ESI): m / z = 192.1 [M+H] + .

[0486] Step 4: Compound 24D (4.8 g, 25 mmol) was dispersed in HBr (33% in AcOH) and refluxed for 24 h. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica gel column chromatography to obtain compound 24E (3.8 g, 85.4%). LC-MS (ESI): m / z = 178.1 [M+H] + .

[0487] Step 5: Compound 24E (3.8 g, 21.4 mmol) was dispersed in hexafluoroisopropanol (70 mL), and Rh / Al₂O₃ (1.3 g) was added. The reaction was carried out overnight under a hydrogen atmosphere at 3 MPa. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to obtain compound 24F (3.2 g, 82.0%). LC-MS (ESI): m / z = 184.1 [M+H] + .

[0488] Step 6: Compound 24F (3.8 g, 21.4 mmol) was dispersed in Boc2O (10 mL) and reacted at 50 °C for 4 h. The reaction solution was directly separated by silica gel column chromatography to obtain compound 24G (3.4 g, 56.6%); LC-MS (ESI): m / z = 228.1 [M-55] + .

[0489] Step 7: Using compound 24G (2.8 g, 10 mmol) as the starting material, compound 24H (2.8 g, crude product) was obtained by referring to the synthesis method in step 2 of Example 1.

[0490] Step 8: Using compound 24H (2.8 g, crude product) as the starting material, compound 24I (2.6 g, two-step yield: 63.3%) was synthesized according to the method described in step 3 of Example 1. LC-MS (ESI): m / z = 365.1 [M-55] + .

[0491] Step 9: Using compound 24I (2.6 g, 6.3 mmol) as the starting material, compound 24J (2.8 g, crude product) was synthesized according to the method described in step 4 of Example 1. LC-MS (ESI): m / z = 337.1 [M-55] + .

[0492] Step 10: Using compound 24J (2.8 g, crude product) as the starting material, compound 24K (2.2 g, two-step yield: 81.9%) was synthesized according to the method described in step 5 of Example 1. LC-MS (ESI): m / z = 427.1 [M+H] + .

[0493] Step 11: Using compound 1G as the starting material, compound 24M was synthesized according to the method described in Example 19. LC-MS (ESI): m / z = 385.0 [M+H] + .

[0494] Step 12: Using compound 24K (290 mg, 0.68 mmol) and compound 24M (270 mg, 0.7 mmol) as starting materials, compound 24 (105 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 578.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.26(s,1H),7.85-7.67(m,3H),6.79(s,1H),5.93(d,1H),5.15-5.04(m,1H),4.88(s,1H),4.53-4.43(m,1 H),4.42-4.32(m,1H),4.23-4.11(m,1H),3.55(s,2H),3.23-3.06(m,1H ),2.87-2.66(m,1H),2.52(s,3H),2.48-2.38(m,1H),2.18-2.00(m,3H).

[0495] Example 25

[0496] Compound 25 (204 mg) was synthesized from compound 24K (427 mg, 1 mmol) and compound 19B (450 mg, 1 mmol) according to the method described in Example 1. LC-MS (ESI): m / z = 643.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.33(s,1H),7.88(s,1H),7.80-7.64(m,2H),6.91(s,1H),5.99(d,1H),5.11(d,1H),4.94-4.83(m,1H),4. 65-4.40(m,4H),4.29-4.06(m,1H),3.64-3.40(m,2H),3.28-3.03(m,1H ),2.91-2.66(m,1H),2.52(s,3H),2.49-2.35(m,1H),2.20-1.98(m,3H).

[0497] Example 26

[0498] Compound 26 (204 mg) was synthesized from compound 1F (395 mg, 1 mmol) and compound 24M (385 mg, 1 mmol) according to the method described in Example 1. LC-MS (ESI): m / z = 546.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.25(s,1H),7.84-7.69(m,3H),6.78(s,1H),6.53-6.21(m,1H),5.93(d,1H),5.13- 5.05(m,1H),4.85-4.72(m,1H),4.55-4.32(m,2H),3.95-3.35(m,3H),2.52(s,3H),2.51-2.44(m,1H),2.29-2.06(m,3H).

[0499] Example 27

[0500] Step 1: Compound 1G (15.0 g, 61.7 mmol) and deuterated iodomethane (17.9 g, 123.4 mmol) were dissolved in N,N-dimethylformamide (200 mL), followed by the addition of cesium carbonate (50.3 g, 154.3 mmol). The reaction was carried out at 50 °C for 1 hour after the addition was complete. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 27A (14.0 g, 87.2%). LC-MS (ESI): m / z = 260.0 [M+H] +

[0501] Step 2: Using compound 27A as the starting material, compound 27 (0.48 g, 65.5%) was synthesized according to the method described in Example 21. LC-MS (ESI): m / z = 552.2 [M+H] + ;

[0502] Step 3: Compound 27 (480 mg) was chirally resolved to obtain P1 (retention time: 0.567 min, designated as compound 27-P1), P2 (retention time: 0.775 min, designated as compound 27-P2), P3 (retention time: 1.017 min, designated as compound 27-P3), and P4 (retention time: 4.167 min, designated as compound 27-P4). Preparation method: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol and acetonitrile; Flow rate: 110 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Sample concentration 10 mg / mL, acetonitrile-methanol solution. After separation and solvent removal, compounds 27-P1 (105 mg, 21.8%), 27-P2 (107 mg, 22.2%), 27-P3 (100 mg, 20.8%), and 27-P4 (115 mg, 23.9%) were obtained.

[0503] Compound 27-P1: LC-MS (ESI): m / z = 552.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.11(s,1H),7.71-7.68(m,1H),7.66(s,1H),7. 49-7.45(m,1H),6.81(s,1H),5.25-5.22(m,1H),5.03-4.96(m,1H),4.39(d,2H),4 .32-4.28(m,1H),4.24-4.20(m,1H),3.46-3.39(m,2H),3.29-3.26(m,2H),2.68-2 .63(m,1H),2.48(s,3H),2.40-2.34(m,1H),2.23-2.17(m,1H),1.98-1.79(m,3H).

[0504] Compound 27-P2: LC-MS (ESI): m / z = 552.2 [M+H] + ; 1¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.12 (s, 1H), 7.71-7.68 (m, 1H), 7.66 (s, 1H), 7.51-7.47 (m, 1H), 6.82 (s, 1H), 5.26-5.23 (m, 1H), 5.03-4.96 (m, 1H), 4.39 (d, 2H), 4.32-4.28 (m, 1H), 4.24-4.20 (m, 1H), 3.46-3.39 (m, 2H), 3.29-3.26 (m, 2H), 2.68-2.63 (m, 1H), 2.48 (s, 3H), 2.40-2.34 (m, 1H), 2.23-2.17 (m, 1H), 1.98-1.79 (m, 3H).

[0505] Compound 27-P3: LC-MS (ESI): m / z = 552.2 [M+H] + ; 1 ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.10 (s, 1H), 7.71-7.66 (m, 2H), 7.49-7.45 (m, 1H), 6.81 (s, 1H), 5.25-5.22 (m, 1H), 5.03-4.96 (m, 1H), 4.39 (d, 2H), 4.32-4.28 (m, 1H), 4.24-4.20 (m, 1H), 3.46-3.39 (m, 2H), 3.29-3.26 (m, 2H), 2.68-2.63 (m, 1H), 2.48 (s, 3H), 2.40-2.34 (m, 1H), 2.23-2.17 (m, 1H), 1.98-1.79 (m, 3H).

[0506] Compound 27-P4: LC-MS (ESI): m / z = 552.2 [M+H] + ; 1 ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.10 (s, 1H), 7.71-7.66 (m, 2H), 7.49-7.45 (m, 1H), 6.80 (s, 1H), 5.25-5.22 (m, 1H), 5.03-4.96 (m, 1H), 4.39 (d, 2H), 4.32-4.28 (m, 1H), 4.24-4.20 (m, 1H), 3.46-3.39 (m, 2H), 3.29-3.26 (m, 2H), 2.68-2.63 (m, 1H), 2.48 (s, 3H), 2.40-2.34 (m, 1H), 2.23-2.17 (m, 1H), 1.98-1.79 (m, 3H).

[0507] Example 28

[0508] Compound 28 (0.45 g, 53.7%) was obtained from compound 27A using the synthetic method described in Example 20. LC-MS (ESI): m / z = 552.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6))δ8.58(d,1H),8.22(s,1H),7.86(s,1H),7.78-7.72(m ,1H),7.65-7.61(m,1H),6.64(s,1H),5.56-5.54(m,1H),5.29-5.22(m,1H),5. 12(t,1H),4.24-4.20(m,1H),4.06-4.02(m,1H),3.97-3.88(m,2H),3.29-3.20 (m,4H),2.45-2.39(m,2H),2.37(s,3H),1.93-1.83(m,2H),1.80-1.72(m,2H).

[0509] Example 29

[0510] Step 1: Using compound 16H (1 g, 4.06 mmol) as the starting material, compound 29 (174.6 mg, 0.33 mmol) was synthesized according to the method in Example 7. LC-MS (ESI): m / z = 525.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.23(d,1H),7.84-7.68(m,3H),6.77(s,1H),5.91(d,1H),5.08(dd,1H),4.59- 4.44(m,2H),4.40-4.29(m,1H),3.28-3.17(m,2H),2.99(s,3H),2.79-2.67(m,2H),2.51(s,3H),2.27-2.09(m,4H).

[0511] Step 2: Compound 29 (169 mg) was separated by chirality to obtain compound 29-P1 (80 mg, yield 47%, retention time: 0.718 min) and compound 29-P2 (77 mg, yield 45%, retention time: 1.465 min). Separation method: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A represents CO2, B represents ethanol and acetonitrile (containing 0.1% ammonia); Isocratic elution, mobile phase B content 35%; Flow rate: 110 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Compounds were dissolved in acetonitrile and ethanol, sample concentration 2 mg / mL; Injection: 3 mL per injection.

[0512] Compound 15-P1: LC-MS (ESI): m / z = 525.2 [M+H]+; 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.23(s,1H),7.84-7.64(m,3H),6.77(s,1H),5.92(d,1H),5.08(dd,1H),4.61- 4.43(m,2H),4.41-4.28(m,1H),3.27-3.19(m,2H),2.99(s,3H),2.78-2.69(m,2H),2.51(s,3H),2.28-2.09(m,4H).

[0513] Compound 15-P2: LC-MS (ESI): m / z = 525.2 [M+H]+; 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.23(s,1H),7.83-7.68(m,3H),6.77(s,1H),5.92(d,1H),5.08(dd,1H),4.59- 4.43(m,2H),4.40-4.28(m,1H),3.27-3.20(m,2H),2.99(s,3H),2.80-2.69(m,2H),2.51(s,3H),2.27-2.09(m,4H).

[0514] Example 30

[0515] Step 1: Compound 30A (5 g, 19 mmol) was dissolved in dioxane (100 mL) and acetone (30 mL). XantPhos (1.27 g, 2.2 mmol) and cesium carbonate (13.74 g, 41.8 mmol) were added, and the mixture was purged with nitrogen three times. Palladium acetate (249 mg, 1.1 mmol) was added, and the mixture was purged with nitrogen three more times. The reaction was carried out overnight at 80 °C. After cooling to room temperature, the mixture was extracted with water (100 mL) and ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give compound 30B (3 g, 65% yield). LC-MS (ESI): m / z = 205.1 [M+H]+

[0516] Step 2: Dissolve 30C (5g, 22.10mmol) in tetrahydrofuran (50mL) under nitrogen protection, add diisobutylaluminum hydride (55.25mL, 55.25mmol, 1M) at -78°C, and react for 1 hour. After the reaction is complete, dilute the reaction solution with ethyl acetate (100mL), add water (2.21mL) under ice bath, stir, then add sodium hydroxide solution (2.21mL, 15%), then add water (5.53mL) and stir for 10 minutes. Add anhydrous sodium sulfate and stir for another 10 minutes. Filter the reaction solution, concentrate the filtrate to obtain the target compound 30D (4g, 98% yield).

[0517] Step 3: Dissolve 30D (4g, 21.71mmol) in dichloromethane (40mL), then add triethylamine (6.59g, 65.13mmol), and slowly add methanesulfonyl chloride (2.98g, 26.05mmol) dropwise at 0°C. React at room temperature for 3 hours. After the reaction is complete, extract the reaction solution with water (50mL) (dichloromethane 40mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target compound 30E (2.95g, crude product).

[0518] Step 4: 1.8 g (13.73 mmol) of tert-butyl methylcarbamate was dissolved in 30 mL of N,N-dimethylformamide. Sodium hydroxide (550 mg, 13.73 mmol, 60%) was added at 0°C and the mixture was reacted for 0.5 hours. Then, 30E (2.4 g, 9.15 mmol) was added, and the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with 30 mL of saturated ammonium chloride solution, then extracted (3 x 3 ethyl acetate solutions), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound 30F (2.2 g, 80% yield).

[0519] Step 5: Dissolve 30F (2.2 g, 7.40 mmol) in acetone (20 mL) and water (40 mL), then add pyridine 4-methylbenzenesulfonic acid (3.72 g, 14.80 mmol) and react at 50°C for 16 hours. After the reaction, extract the reaction solution with water (50 mL) (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain the target compound 30G (1.1 g, yield 58%).

[0520] Step 6: Dissolve 30g (1.1g, 4.34mmol) in tetrahydrofuran (20mL), under nitrogen protection, add diisobutylaluminum hydride (10.85mL, 10.85mmol, 1M) at -78°C, and react for 1 hour. After the reaction is complete, dilute the reaction solution with ethyl acetate (30mL), add water (0.5mL) under ice bath, stir, then add sodium hydroxide solution (0.5mL, 15%), then add water (1.1mL) and stir for 10 minutes. Add anhydrous sodium sulfate and stir for another 10 minutes. Filter the reaction solution, concentrate the filtrate to obtain the target compound 30H (1g, 90% yield).

[0521] Step 7: Dissolve 30H (0.9 g, 3.52 mmol) and triphenylphosphine (1.38 g, 5.28 mmol) in tetrahydrofuran (20 mL) under nitrogen protection. Add diphenyl azidophosphate (1.07 g, 5.28 mmol) under ice bath and react for 0.5 hours. Then add diisopropyl azodicarbonate (1.16 g, 4.22 mmol) and react at room temperature for 16 hours. After the reaction is complete, filter and concentrate the reaction solution. The residue is purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to give the target compound 30I (0.75 g, yield 75%).

[0522] Step 8: Dissolve 30I (0.75 g, 2.68 mmol) and 30B (0.83 g, 3.48 mmol) in dimethyl sulfoxide (10 mL), then add potassium tert-butoxide (0.45 g, 4.02 mmol), and react at room temperature for 2 hours. After the reaction, extract the reaction solution with water (20 mL) (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 30J (0.73 g, yield 54%). LC-MS (ESI): m / z = 501.3 [M+H]+

[0523] Step 9: Dissolve 30 J (0.73 g, 1.46 mmol) in N,N-dimethylacetamide (10 mL), then add n-dodecyl mercaptan (1.48 g, 7.3 mmol) and sodium hydroxide (0.7 g, 8.76 mmol, 50% aqueous solution), and react at 100°C for 1 hour. After the reaction, dilute the reaction solution with water (30 mL) and adjust the pH to 5. Extract (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 30K (0.45 g, yield 63%). LC-MS (ESI): m / z = 487.2 [M+H]+

[0524] Step 10: Dissolve 30K (0.45 g, 0.92 mmol), the R-configuration isomer of intermediate 1 (0.39 g, 0.92 mmol), and cesium carbonate (0.45 g, 1.38 mmol) in N,N-dimethylformamide (10 mL) and react at 60°C for 1 hour. After the reaction, extract the reaction solution with water (20 mL) (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the target compound 30L (0.27 g, yield 39%).

[0525] Step 11: Dissolve 30 L (0.27 g, 0.36 mmol) in dichloromethane (4 mL), then add trifluoroacetic acid (10 mL) and react at room temperature for 5 hours. After the reaction is complete, concentrate the reaction solution and proceed directly to the next step (30 M). LC-MS (ESI): m / z = 526.1 [M + H] +

[0526] Step 12: Dissolve 30M (the crude product from the previous step) in dichloromethane (4 mL), then add N,N-diisopropylethylamine (1 mL) and cyanogen bromide (61 mg, 0.58 mmol), and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC to obtain the target compound (34.65 mg, yield 22%). LC-MS(ESI): m / z=551.1[M+H]+; 1H NMR (400MHz, DMSO-d6) δ8.60(d,1H),8.42(s,1H),8.10(s,1H),7.82-7.70(m,1H),7.64(dd,1H),6.90(s,1H),5.62(t,1H),5.38(t,1H),5. 12(t,1H),4.69-4.52(m,1H),3.95(t,2H),3.71-3.53(m,2H),2.83-2 .75(m,4H),2.46-2.32(m,5H),2.15-2.04(m,3H),1.99-1.87(m,2H).

[0527] Example 31

[0528] Step 1: Compound 31A (7 g, 20.26 mmol) was dissolved in dichloromethane (120 mL), and Dysmart oxidant (11.17 g, 26.34 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 5 h. The reaction was confirmed to be complete by TLC. The mixture was diluted with dichloromethane (100 mL), and the organic phase was washed with saturated sodium bicarbonate and saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound 31B (4.0 g, yield 57.48%). LC-MS (ESI): m / z = 288.2 [M-56+H] + ;

[0529] Step 2: (Methoxymethyl)triphenylphosphine chloride (5.99 g, 17.46 mmol) was dissolved in ultra-dry THF (20 mL), purged with nitrogen three times, and cooled to 0 °C. LiHMDS (1 M, 17.46 mL, 17.46 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept at 0 °C for 30 min. Then, compound 31B (4 g, 11.64 mmol, dissolved in 20 mL THF) was added dropwise. After the addition was complete, the mixture was slowly raised to room temperature and stirred for 12 h. The reaction was confirmed to be complete by LC-MS. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give compound 31C (2.5 g, yield 57.78%). LC-MS (ESI): m / z = 316.3 [M-56+H] + ;

[0530] Step 3: Compound 31C (2.5 g, 6.73 mmol) was dissolved in tetrahydrofuran (20 mL), and then a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 13.46 mL, 13.46 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated, and the residue was purified by column chromatography (PE / EA = 2 / 1) to give compound 31D (1.5 g, yield 86.64%). LC-MS (ESI): m / z = 202.1 [M-56+H] + ;

[0531] Step 4: Compound 31D (1.5 g, 5.83 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.77 g, 17.5 mmol) and methanesulfonic anhydride (1.52 g, 8.74 mmol) were added sequentially in an ice-water bath. The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude compound 31E (2.5 g). LC-MS (ESI): m / z = 280.1 [M-56+H] + ;

[0532] Step 5: Crude compound 31E (2.5 g, 5.83 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of sodium azide (1.14 g, 17.49 mmol). The reaction mixture was heated to 80 °C and stirred overnight. After the reaction was complete, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (70 mL x 2). The crude product was concentrated and purified by column chromatography (PE / EA = 10 / 1) to obtain compound 31F (1.2 g, yield 73.12%). LC-MS (ESI): m / z = 227.1 [M-56+H] +;

[0533] Step 6: Compound 31F (1.2 g, 4.25 mmol) and ethyl acetoacetate (1.66 g, 12.76 mmol) were dissolved in dimethyl sulfoxide (20 mL), followed by the addition of potassium carbonate (1.76 g, 12.76 mmol). The reaction mixture was heated to 80 °C and stirred for 5 hours. After the reaction was complete, water (100 mL) was added for dilution, followed by extraction with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), and the crude product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to obtain compound 31G (1.2 g, yield 71.68%). LC-MS (ESI): m / z = 395.1 [M+H] + ;

[0534] Step 7: Compound 31G (1.2 g, 3.04 mmol) was dissolved in a mixed solvent of acetonitrile (20 mL) and water (5 mL). The mixture was cooled to 0 °C, and p-toluenesulfonic acid (1.05 g, 6.08 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 3 hours, and the reaction was confirmed to be complete by TLC. The mixture was then cooled to 0 °C, and ammonia (20 mL) and I2 (1.54 g, 6.08 mmol) were added. After the addition was complete, the mixture was stirred at room temperature overnight, and the reaction was confirmed to be complete by LCMS. The mixture was diluted with water (100 mL), extracted with EA (50 mL x 3), washed with saturated brine, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 31H (0.58 g, yield 50.51%). LC-MS (ESI): m / z = 378.1 [M+H] + ;

[0535] Step 8: Compound 31H (0.58 g, 1.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). KOH solution (2 M, 2.31 mL, 4.62 mmol) was added. After addition, the mixture was heated to 50 °C and reacted for 3 h. LC-MS confirmed the reaction was complete. The solution was depressurized and concentrated to obtain compound 31I (0.6 g, crude product), which was directly used in the next reaction. LC-MS (ESI): m / z = 350.2 [M+H] + ;

[0536] Step 9: The crude compound 31I (0.6 g, 1.54 mmol) was dissolved in water (10 mL), and bromine (0.74 g, 4.65 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated and purified by column chromatography (PE / EA = 2 / 1) to obtain compound 31J (400 mg, yield 67.16%). LC-MS (ESI): m / z = 384.1 [M+H] + ;

[0537] Step 10: Using compounds 31J and 31K (synthesized from compound 5N according to Example 7) as starting materials, compound 31 was obtained according to the synthesis method of Example 1. LC-MS (ESI): m / z = 586.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.51-8.50(m,1H),8.45-8.44(m,1H),8.14-8.13(m,1H ),7.77-7.66(m,2H),7.09(d,1H),5.93-5.91(m,1H),5.09-5.05(m,1H),4.93-4 .89(m,1H),4.56-4.47(m,2H),4.24-4.18(m,1H),3.59-3.51(m,2H),3.28-3.2 6(m,1H),3.14-3.08(m,1H),2.53(s,3H),2.43-2.35(m,1H),2.13-2.05(m,3H).

[0538] Example 32

[0539] Step 1: 32A (30 g, 123.43 mmol) was dissolved in dichloromethane (600 mL), followed by the addition of triethylamine (37.47 g, 370.29 mmol). Cyclopropylformyl chloride (25.80 g, 246.86 mmol) was then added dropwise at room temperature. After the addition was complete, the reaction was continued at room temperature for 2 hours. The solution was diluted with water, extracted with dichloromethane (200 mL x 3), washed with the organic phase, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA (v / v) = 3:1) to obtain compound 32B (38 g, yield: 98.9%). LC-MS (ESI): m / z = 312.1 [M+H] + .

[0540] Step 2: Dissolve 32B (38 g, 122.14 mmol) in mesitylene (800 mL), then add Lawson's reagent (98.80 g, 244.28 mmol), and heat at 170 °C for 6 hours. Cool, filter, wash the filter cake with toluene, and purify the filtrate directly by column chromatography (PE:EA (v / v) = 4:1) to obtain compound 32C (10 g, yield: 25.0%).

[0541] LC-MS (ESI): m / z = 328.1 [M+H] + .

[0542] Step 3: Dissolve 32C (10 g, 30.56 mmol) in dichloromethane (150 mL), add diethylaminosulfur trifluoride (12.11 mL, 91.68 mmol) at -78 °C, and then allow the mixture to automatically rise to room temperature for 2 hours. Dilute the reaction solution in ice water (200 mL), add saturated sodium bicarbonate solution under ice bath conditions, extract with dichloromethane (100 mL x 3), wash and dry the organic phase, concentrate under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (PE:EA (v / v) = 5:1) to obtain compound 32D (2.5 g, yield: 24.5%). LC-MS (ESI): m / z = 334.1 [M+H] + .

[0543] Step 4: Using 32D (2.5 g, 7.50 mmol) as the starting material, compound 32E (1.05 g, yield: 43.8%) was synthesized following the synthesis method described in Step 7 of Example 1. LC-MS (ESI): m / z = 320.1 [M+H] + .

[0544] Step 5: Using 32E (500 mg, 1.57 mmol) as the starting material, compound 32 (202 mg, 0.34 mmol) was synthesized according to the method described in Example 19. LC-MS (ESI): m / z = 598.2 [M+H] + .

[0545] Step 6: Compound 32 (202 mg) was chirally separated to obtain P1 (retention time: 0.750 min, designated as compound 32-P1) and P2 (retention time: 1.004 min, designated as compound 32-P2).

[0546] Separation method: Instrument: CAS-05-Prep-SFC-E; Column: IG column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol and acetonitrile; Flow rate: 130 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Sample concentration 15 mg / mL, acetonitrile and methanol mixed solution. After separation, compound 32-P1 (93 mg, 46.0%) and compound 32-P2 (91 mg, 45.0%) were obtained.

[0547] Compound 32-P1: LC-MS (ESI): m / z = 598.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.45(s,1H),8.16(s,1H),7.82(s,1H),7.69(s,1H),7.53-7 .49(m,1H),6.94(s,1H),5.29(t,1H),4.50-4.47(m,1H),4.39-4.35(m,1H),4.21 -4.15(m,1H),3.31(d,2H),3.04(s,3H),2.28-2.76(m,2H),2.60-2.53(m,2H),2. 51(s,3H),2.15(t,2H),1.64-1.61(m,1H),0.91-0.87(m,2H),0.75-0.70(m,2H).

[0548] Compound 32-P2: LC-MS (ESI): m / z = 598.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.15(s,1H),7.82(s,1H),7.66(s,1H),7.50-7 .46(m,1H),6.94(s,1H),5.25(t,1H),4.46-4.44(m,1H),4.36-4.32(m,1H),4.20 -4.14(m,1H),3.31(d,2H),3.04(s,3H),2.28-2.79(m,2H),2.60-2.53(m,2H),2. 51(s,3H),2.17(t,2H),1.65-1.62(m,1H),0.92-0.88(m,2H),0.75-0.72(m,2H).

[0549] Example 33

[0550] Step 1: Using 33A (5.0 g, 22.2 mmol) as the starting material, compound 33 (67 mg, 0.13 mmol) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 522.2 [M+H] + .

[0551] Step 2: Compound 33 (67 mg) was chirally separated to obtain P1 (retention time: 0.639 min, designated as compound 33-P1) and P2 (retention time: 1.372 min, designated as compound 33-P2).

[0552] Separation method: Instrument: CAS-05-Prep-SFC-G; Column: AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol and acetonitrile; Flow rate: 110 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Sample concentration 2 mg / mL, acetonitrile and methanol mixed solution. After separation, compound 33-P1 (23 mg, 34.3%) and compound 33-P2 (25 mg, 37.3%) were obtained.

[0553] Compound 33-P1: LC-MS (ESI): m / z = 522.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.22(s,1H),7.86(s,1H),7.77-7.72(m,1H) ,7.65-7.61(m,1H),6.65(s,1H),5.56(t,1H),5.10(t,1H),4.72-4.66(m,1H),3. 94-3.89(m,2H),3.62-3.58(m,1H),3.36-3.32(m,1H),2.61-2.51(m,1H),2.38(s ,3H),2.22-2.10(m,2H),1.63-1.59(m,1H),0.98-0.94(m,1H),0.91-0.78(m,3H).

[0554] Compound 33-P2: LC-MS (ESI): m / z = 522.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.22(s,1H),7.86(s,1H),7.75-7.72(m,1H) ,7.65-7.61(m,1H),6.64(s,1H),5.56(t,1H),5.11(t,1H),4.72-4.66(m,1H),3. 94-3.90(m,2H),3.62-3.58(m,1H),3.36-3.32(m,1H),2.61-2.50(m,1H),2.38(s ,3H),2.22-2.13(m,2H),1.63-1.59(m,1H),0.98-0.94(m,1H),0.90-0.79(m,3H).

[0555] Example 34

[0556] Step 1: Compound 34A (15.0 g, 43.41 mmol) was dissolved in tetrahydrofuran (150 mL). Sodium hydride (2.08 g, 52.09 mmol) was slowly added under ice-water bath conditions. After stirring for 30 min, iodomethane (9.24 g, 65.11 mmol) was added. The reaction mixture was brought to room temperature and stirred for another 4 h. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to quench the reaction, followed by dilution with water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 34B (7.5 g, yield: 48.0%).

[0557] Step 2: Compound 34B (7.5 g, 20.85 mmol) was dissolved in tetrahydrofuran (100 mL), and then tetrabutylammonium fluoride (10.90 g, 41.70 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated, and the residue was purified by column chromatography to obtain compound 34C (4.6 g, yield: 89.0%).

[0558] Step 3: Diisopropyl azodicarbonate (4.55 g, 22.50 mmol) was added dropwise to a tetrahydrofuran solution of triphenylphosphine (5.9 g, 22.50 mmol) in 100 mL under an ice-water bath. After stirring for half an hour, a tetrahydrofuran solution of compound 34C (4.6 g, 18.75 mmol) and diphenyl azide phosphate (6.19 g, 22.50 mmol) in 100 mL was added. The reaction was continued for 2 hours, and the mixture was concentrated. The residue was purified by column chromatography to give compound 34D (4.0 g, yield: 79.0%). LC-MS (ESI): m / z = 171.10 [M-100+H] + .

[0559] Step 4: Compound 34D (4.0 g, 14.80 mmol) and ethyl acetoacetate (5.78 g, 44.40 mmol) were dissolved in dimethyl sulfoxide (100 mL), and potassium carbonate (6.13 g, 44.40 mmol) was added. The reaction mixture was heated to 100 °C and stirred overnight. After the reaction was complete, water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 34E (4.8 g, yield: 84.8%).

[0560] Step 5: Compound 34E (4.8 g, 12.55 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL), methanol (30 mL), and water (30 mL). Lithium hydroxide (1.05 g, 25.10 mmol) was then added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the methanol and tetrahydrofuran were removed by concentration. The pH was adjusted to 3-4 with 1N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 34F (4.5 g, crude product).

[0561] Step 6: Compound 34F (4.5 g, 12.69 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and water (30 mL). Potassium hydroxide (3.56 g, 63.45 mmol) and liquid bromine (10.14 g, 63.45 mmol) were added sequentially under ice-water bath conditions. The reaction mixture was gradually brought to room temperature and stirred overnight. After the reaction was complete, water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 34G (3.8 g, yield: 76.9%).

[0562] Step 7: Using compound 34G (300 mg, 0.67 mmol) as the starting material, compound 34 (25 mg) was obtained by following the synthesis method in Example 12. LC-MS (ESI): m / z = 605.0 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.31(s,1H),7.87(s,1H),7.78-7.68( m,2H),6.89(s,1H),5.97(d,1H),5.13-5.06(m,1H),4.78-4.64(m,1H),4.6 0-4.50(m,3H),4.48-4.41(m,1H),3.67-3.60(m,1H),3.54(d,2H),3.51-3. 44(m,1H),3.37-3.33(m,1H),3.30(s,3H),2.53(s,3H),2.20-1.90(m,4H).

[0563] Example 35

[0564] Compound 35 (18 mg) was obtained from compound 24M (300 mg, 0.78 mmol) using the synthetic method described in Example 24. LC-MS (ESI): m / z = 540.20 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.24(s,1H),7.81-7.70(m,3H),6.77(s,1H),5.91(d,1H),5.12-5.05(m,1H),4.76-4.65(m,1H),4.51-4.4 5(m,1H),4.39-4.33(m,1H),3.67-3.60(m,1H),3.55(d,2H),3.52-3.44 (m,1H),3.37-3.33(m,1H),3.30(s,3H),2.53(s,3H),2.15-2.05(m,4H).

[0565] Example 36

[0566] Compound 12 (40 mg) was obtained from compound 27A (3.0 g, 11.53 mmol) using the synthetic method described in Example 20. LC-MS (ESI): m / z = 540.40 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.23(s,1H),7.86(s,1H),7.78-7.72(m,1H) ,7.66-7.61(m,1H),6.66(s,1H),5.60-5.53(m,1H),5.16-5.10(m,1H),4.71-4.6 1(m,1H),3.97-3.88(m,2H),3.66-3.58(m,1H),3.54(d,2H),3.50-3.44(m,1H),3 .37-3.33(m,1H),3.30(s,3H),2.37(s,3H),2.15-2.00(m,3H),1.99-1.88(m,1H).

[0567] Example 37

[0568] Step 1: 8A (1.63 g, 5.0 mmol) was dissolved in dioxane (80 mL), followed by the addition of cinnarizine diboronate (1.65 g, 6.5 mmol), Pd2(dba)3 (458 mg, 0.5 mmol), tricyclohexylphosphine (281 mg, 1.0 mmol), and potassium acetate (1.47 g, 15 mmol). The reaction was carried out at 90 °C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, water (20 mL), 37A (1.72 g, 4.17 mmol), Pd(dppf)Cl2 (305 mg, 0.417 mmol), and potassium carbonate (1.73 g, 12.5 mmol) were added sequentially. The reaction was carried out at 100 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain compound 37B (1.69 g, 70% yield). LC-MS(ESI):m / z==523.2[M+H- t Bu] +

[0569] Step 2: Using 37B (1.69 g, 2.92 mmol) as the starting material, compound 37C (1.08 g, 65% yield) was synthesized following step 7 of Exercise 1. LC-MS (ESI): m / z = 509.2 [M+H- t Bu] +

[0570] Step 3: Dissolve 37C (564 mg, 1.0 mmol) in acetonitrile (34 mL), then add 37D (262 mg, 1.2 mmol) and cesium carbonate (978 mg, 3.0 mmol) sequentially. React at 50 °C for 10 minutes. Remove the solvent by vacuum concentration, and purify the residue by silica gel column chromatography to obtain compound 37E (589 mg, yield 84%). LC-MS (ESI): m / z = 646.2 [M+H- t Bu] +

[0571] Step 4: Dissolve 37E (589 mg, 0.84 mmol) in methanol (30 mL), add sodium borohydride (96 mg, 2.52 mmol), and react for 10 minutes. Concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography to obtain compound 37F (479 mg, yield 81%).

[0572] LC-MS(ESI):m / z==648.2[M+H- t Bu] +

[0573] Step 5: Dissolve 37F (479 mg, 0.68 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and react for 1 h. After the reaction, concentrate under reduced pressure to remove the solvent. Dissolve the residue in acetonitrile (40 mL), then add potassium carbonate (2.82 g, 20.4 mmol) and cyanogen bromide (2.88 g, 27.2 mmol) sequentially, and react for 1 h. After the reaction, concentrate under reduced pressure to remove the solvent. Purify the residue by silica gel column chromatography to obtain compound 37 (248 mg, yield 58%). LC-MS (ESI): m / z = 629.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.52(d,1H),8.30(s,1H),7.88(s,1H),7.78-7.72(m,1H),7.71-7. 67(m,1H),6.88(s,1H),5.97(d,1H),5.13-5.06(m,1H),4.93-4.81(m,1H),4.71-4.61(m,1 H),4.56(q,2H),4.53-4.49(m,1H),4.48-4.40(m,1H),3.74-3.65(m,1H),3.61-3.50(m,1H ),2.59-2.51(m,1H),2.50(s,3H),2.38-2.30(m,1H),2.29-2.21(m,1H),2.20-2.13(m,1H).

[0574] Example 38

[0575] Step 1: Using compound 38A (10 g, 92.17 mmol) as the starting material, compound 38B (13.6 g, 41%) was synthesized according to the method described in Example 1; LC-MS (ESI): m / z = 361.2 [M+H] + .

[0576] Step 2: Using compound 38B (400 mg, 1.11 mmol) and compound 31K (540 mg, 1.11 mmol) as starting materials, compound 38 (110 mg, yield 17.6%) was synthesized according to the method in Example 2; LC-MS (ESI): m / z = 563.2 [M+H] + .

[0577] 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.32(s,1H),7.93(s,1H),7.78-7.73(m,1H),7.69-7.59(m,1H),7.04(s,1H) ),5.25-5.05(m,2H),4.61-4.48(m,2H),4.29-4.19(m,2H),4.05-3.89(m,4H),3.65-3.57(m,2H),2.55(s,3H).

[0578] Example 39

[0579] Step 1: Using 8A (845 mg, 2.6 mmol) and 5E (870 mg, 2.17 mmol) as starting materials, compound 39A (861 mg, 70% yield) was synthesized following the procedure in Step 1 of Example 37. LC-MS (ESI): m / z = 511.6 [M+H- t Bu] +

[0580] Step 2: Using 39A (861 mg, 1.52 mmol) as the starting material, compound 39B (697 mg, yield 83%) was synthesized following the procedure in Step 2 of Example 37. LC-MS (ESI): m / z = 497.2 [M+H- t Bu] +

[0581] Step 3: Using 39B (697 mg, 1.26 mmol) as the starting material, compound 39C (478 mg, yield 55%) was synthesized following the procedure in Step 3 of Example 37. LC-MS (ESI): m / z = 634.3 [M+H- t Bu]+

[0582] Step 4: Using 39C (478 mg, 0.69 mmol) as the starting material, compound 39D (245 mg, yield 51%) was synthesized following step 3 of Example 37. LC-MS (ESI): m / z = 636.3 [M+H- t Bu] +

[0583] Step 5: Using 39D (245 mg, 0.35 mmol) as a starting material, compound 39 (163 mg, 75% yield) was synthesized following steps 11 and 12 of Example 1. LC-MS (ESI): m / z = 617.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.51(d,1H),8.30(s,1H),7.87(s,1H),7.78-7.72(m,1H),7.71-7. 68(m,1H),6.88(s,1H),5.96(d,1H),5.33-5.27(m,1H),5.12-5.06(m,1H),4.55(q,2H),4. 53-4.49(m,1H),4.46-4.41(m,1H),4.27-4.22(m,1H),4.09-4.04(m,1H),3.28-3.20(m,4H ),2.50(s,3H),2.43-2.40(m,1H),2.02-1.96(m,1H),1.94-1.86(m,2H),1.81-1.74(m,2H).

[0584] Example 40

[0585] Step 1: Using compound 27A (20 g, 77.2 mmol) as the starting material, 40A (5 g) was synthesized according to the method described in Example 18. LC-MS (ESI): m / z = 298.1 [M+H] + .

[0586] Step 2: Using compound 40A (2.5 g, 8.39 mmol) and compound 22A (2.58 g, 10.07 mmol) as starting materials, compound 40B (1 g) was synthesized according to the method described in Example 22. LC-MS (ESI): m / z = 446.2 [M+H] + .

[0587] Step 3: Using compound 40B (500 mg, 1.12 mmol) as the starting material, compound 40 (80 mg) was synthesized according to the method described in Example 22. LC-MS (ESI): m / z = 510.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.52-8.51(m,1H),8.16(s,1H),7.81-7.71(m,3H),6.80(s, 1H),5.93-5.92(m,1H),5.50-5.47(m,1H),5.27-5.23(m,1H),5.11-5.07(m,1H),4.5 2-4.47(m,1H),4.40-4.28(m,2H),3.90-3.84(m,1H),3.79-3.74(m,1H),3.61-3.56 (m,1H),3.44-3.37(m,1H),3.26-3.23(m,1H),2.81-2.77(m,1H),1.98-1.90(m,1H).

[0588] Example 41

[0589] Step 1: Compound 40B (500 mg, 1.12 mmol), intermediate 1 (500 mg, 1.17 mmol), and cesium carbonate (547 mg, 1.68 mmol) were dissolved in DMF (30 mL). After the addition was complete, the mixture was heated to 70 °C and stirred for 1 hour. After the reaction was complete, the reaction solution was poured into water and extracted with EA. The organic phase was washed successively with saturated ammonium chloride and saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 41A (280 mg, yield: 35.7%). LC-MS (ESI): m / z = 699.5 [M+H] + .

[0590] Step 2: Compound 41A (300 mg, 0.43 mmol) was dissolved in methanol (5 mL), and 1,4-dioxane hydrochloride (4 M, 5 mL) was added. After the addition was complete, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 41B (250 mg, crude product), which was directly used in the next step of the reaction. LC-MS (ESI): m / z = 485.3 [M+H] + .

[0591] Step 3: Crude compound 41B (250 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL), followed by the sequential addition of N,N-diisopropylethylamine (265 mg, 2.05 mmol) and cyanogen bromide (130 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the crude product was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 41 (85 mg, yield: 40.4%). LC-MS (ESI): m / z = 510.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.58-8.55(m,1H),8.20-8.15(m,1H),7.86-7.56(m,3H),6.71-6.65(m,1H),5.59-5.52(m,1H),5.41-5 .23(m,1H),5.12-5.04(m,2H),4.34-4.21(m,1H),4.05-3.75(m,4H),3.66-3.38(m,2H),2.84-2.65(m,1H),1.94-1.88(m,1H).

[0592] Compound 41 (80 mg) was chirally resolved to obtain 41-1 (retention time: 1.106 min) and 41-2 (retention time: 1.517 min). SFC analysis method: Instrument: CAS-05-ANA-SFC-D; Column: OX column; Mobile phase: A for CO2; B for 0.05% MNH3 in ethanol and acetonitrile; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm. SFC purification method: Instrument: CAS-05-Prep-SFC-F; Column: OX column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol and acetonitrile; Flow rate: 120 mL / min; Column temperature: room temperature; Wavelength: 220 nm. After sample separation, the sample was concentrated by rotary evaporator at a bath temperature of 35°C, and then the solvent was dried by freeze dryer at -80°C to obtain compound 41-1 (43 mg, 53.7%) and compound 41-2 (21 mg, 26.2%).

[0593] Compound 41-1: LC-MS (ESI): m / z = 510.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.58-8.57(m,1H),8.20-8.15(m,1H),7.87-7.56(m,3H),6.71-6.65(m,1H),5.59-5.52(m,1H),5.41-5 .23(m,1H),5.12-5.04(m,2H),4.34-4.22(m,1H),4.05-3.75(m,4H),3.66-3.38(m,2H),2.84-2.65(m,1H),1.95-1.89(m,1H).

[0594] Compound 41-2: LC-MS (ESI): m / z = 510.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.58-8.57(m,1H),8.20-8.15(m,1H),7.87-7.55(m,3H),6.71-6.65(m,1H),5.59-5.52(m,1H),5.41-5 .23(m,1H),5.12-5.04(m,2H),4.34-4.22(m,1H),4.05-3.75(m,4H),3.66-3.38(m,2H),2.84-2.65(m,1H),1.95-1.89(m,1H).

[0595] Example 42

[0596] Step 1: Using compound 1G (2.43 g, 10 mmol) as the starting material, compound 42A (2.6 g, yield: 94.2%) was obtained by referring to the synthesis method in step 6 of Example 1.

[0597] Step 2: Using compound 42A (2.6 g, 9.4 mmol) as the starting material, compound 42B (2.2 g, yield: 89.3%) was obtained by referring to the synthesis method in step 7 of Example 1.

[0598] Step 3: Using compound 42B (1.1 g, 4.2 mmol) as the starting material, compound 42C (654 mg, yield: 39.1%) was obtained by referring to the synthesis method in step 1 of Example 19.

[0599] Step 4: Using compound 42C (654 mg, 1.6 mmol) as the starting material, compound 42D (650 mg, yield: 99.2%) was obtained by referring to the synthesis method in step 2 of Example 19.

[0600] Step 5: Using compound 1F (401 mg, 1 mmol) as the starting material, compound 42 (156 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 562.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m, 1H),4.90-4.68(m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).

[0601] Step 6: Compound 42 (156 mg) was chirally resolved to obtain compounds 42-P1 (SFC retention time: 0.630 min, 16.2 mg), 42-P2 (SFC retention time: 0.644 min, 16.5 mg), 42-P3 (SFC retention time: 1.352 min, 18.3 mg), 42-P4 (SFC retention time: 1.473 min, 16.9 mg), 42-P5 (SFC retention time: 1.946 min, 14.8 mg), 42-P6 (SFC retention time: 2.183 min, 14.3 mg), 42-P7 (SFC retention time: 2.554 min, 12.7 mg), and 42-P8 (SFC retention time: 2.848 min, 13.2 mg). SFC analysis method: Instrument: CAS-05-ANA-SFC-C, Column: IM column; Mobile phase: A: CO2, B: 0.05% DEA in methanol and acetonitrile; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0602] Compound 42 was resolved by first chiral separation to obtain compounds 42-P5 (SFC retention time: 1.946 min, 14.8 mg), 42-P6 (SFC retention time: 2.183 min, 14.8 mg), 42-P7 (SFC retention time: 2.554 min, 12.7 mg), and 42-P8 (SFC retention time: 2.848 min, 13.2 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-E; Column: IM column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in MeOH and CH3CN; Flow rate: 130 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0603] Compound 42 was subjected to a second chiral resolution to obtain compound 42-P1 (SFC analysis retention time: 0.630 min, 16.2 mg) and compound 42-P2 (SFC analysis retention time: 0.644 min, 16.5 mg). SFC preparation method: instrument: CAS-05-Prep-SFC-A, column: AD column; mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH; flow rate: 120 mL / min; column temperature: room temperature; wavelength: 220 nm.

[0604] Compound 42 was separated by a third chiral reaction to yield compound 42-P3 (SFC retention time: 1.352 min, 18.3 mg) and compound 42-P4 (SFC retention time: 1.473 min, 16.9 mg). SFC preparation method: Instrument: CAS-05-Prep-SFC-A; Column: AD column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH; Flow rate: 100 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0605] Compound 42-P1: 1H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0606] Compound 42-P2: 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0607] Compound 42-P3: 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0608] Compound 42-P4: 1H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0609] Compound 42-P5: 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0610] Compound 42-P6: 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0611] Compound 42-P7: 1H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0612] Compound 42-P8: 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.25(s,1H),7.93-7.59(m,3H),6.79(s ,1H),6.76-6.11(m,1H),5.97-5.86(m,1H),5.15-5.03(m,1H),4.90-4.68 (m,1H),4.65-4.33(m,2H),4.26-3.79(m,1H),3.78-3.50(m,2H),2.52(s ,3H),2.50-2.27(m,1H),2.28-2.04(m,3H).LC-MS(ESI):m / z=562.2[M+H] + .

[0613] Example 43

[0614] Compound 43 (9 mg) was synthesized from compounds 31J (383 mg, 1 mmol) and 24M (384 mg, 1 mmol) according to the method described in Example 1. LC-MS (ESI): m / z = 535.2 [M+H] + ;

[0615] 1H NMR(400MHz,DMSO-d6)δ8.52-8.51(m,1H),8.25(d,1H),7.81-7.71(m,3H) ,6.78(s,1H),5.93-5.92(m,1H),5.11-5.07(m,1H),4.91-4.87(m,1H),4.5 0-4.46(m,1H),4.38-4.34(m,1H),4.21-4.18(m,1H),3.56-3.50(m,2H),3 .13-3.07(m,2H),2.51-2.50(m,3H),2.41-2.34(m,1H),2.12-2.04(m,3H).

[0616] Example 44

[0617] Compound 44 (0.5 g) was synthesized from compound 8A (2.0 g, 6.17 mmol) according to the method described in Example 38. LC-MS (ESI): m / z = 577.2 [M+H]+. 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.21(s,1H),7.77-7.74(m,2H),7.65-7.60(m,1H),6.87(s,1H),5.23-5.20(m,1H),5 .11-5.08(m,1H),4.80(s,7H),4.58-4.42(m,4H),4.29-4.20(m,2H),4.04-3.90(m,4H),3.21-3.30(m,4H),2.53(s,3H).

[0618] Example 45

[0619] Step 1: Using compound 42D (2.0 g, 5 mmol) and compound 38B (1.8 g, 5 mmol) as starting materials, compound 45 (0.84 g, 32%) was synthesized according to the method described in Example 21. LC-MS (ESI): m / z = 528.2 [M+H] +Compound 45 (840 mg) was chirally resolved to obtain P1 (165 mg, retention time: 2.062 min, designated as compound 45-P1), P2 (180 mg, retention time: 2.045 min, designated as compound 45-P2), P3 (145 mg, retention time: 2.231 min, designated as compound 45-P3), and P4 (155 mg, retention time: 2.214 min, designated as compound 45-P4). Preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: Chiralcel OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 130 mL / min; Column temperature: 38℃; Wavelength: 220 nm; Sample preparation: Sample concentration 3 mg / mL, methanol-acetonitrile solution.

[0620] Compound 45-P1: LC-MS (ESI): m / z = 528.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.82-7.78(m,1H),7.71(s,1H),7.68-7.61(m,1H),6.78(s,1H),5.26-5.16(m,1H ),5.15-5.02(m,1H),4.58-4.51(m,1H),4.49-4.41(m,1H),4.30-4.20(m,2H),4.06-3.91(m,4H),3.67-3.54(m,2H),2.53(s,3H).

[0621] Compound 45-P2: LC-MS (ESI): m / z = 528.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.79-7.75(m,1H),7.71(s,1H),7.68-7.61(m,1H),6.78(s,1H),5.26-5.16(m,1H ),5.15-5.02(m,1H),4.58-4.51(m,1H),4.43-4.40(m,1H),4.30-4.20(m,2H),4.06-3.91(m,4H),3.67-3.54(m,2H),2.53(s,3H).

[0622] Compound 45-P3: LC-MS (ESI): m / z = 528.2 [M+H]+ . 1 H NMR (400MHz, CD3OD) δ8.42(d,J=2.6Hz,1H),8.17(s,1H),7.88-7.56(m,3H),6.76-6.73(m,1H),5.28-5.14(m,1 H),5.13-4.98(m,1H),4.61-4.35(m,2H),4.31-4.14(m,2H),4.09-3.85(m,4H),3.70-3.48(m,2H),2.53(s,3H).

[0623] Compound 45-P4: LC-MS (ESI): m / z = 528.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.85-7.76(m,1H),7.71(s,1H),7.69-7.60(m,1H),6.78(s,1H),5.27-5.15(m,1H ),5.17-5.01(m,1H),4.58-4.51(m,1H),4.48-4.40(m,1H),4.33-4.20(m,2H),4.08-3.91(m,4H),3.69-3.54(m,2H),2.53(s,3H).

[0624] Example 46

[0625] Step 1: Using compound 24M (0.5 g, 1.30 mmol) and compound 38B (0.47 g, 1.30 mmol) as starting materials, compound 46 (0.23 g, 35%) was synthesized according to the method in Example 21. Compound 46 (230 mg) was chirally resolved to obtain P1 (35 mg, retention time: 2.072 min, designated as compound 46-P1), P2 (38 mg, retention time: 2.055 min, designated as compound 46-P2), P3 (36 mg, retention time: 2.241 min, designated as compound 46-P3), and P4 (34 mg, retention time: 2.264 min, designated as compound 46-P4). Preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: Chiralcel OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 130 mL / min; Column temperature: 38℃; Wavelength: 220 nm; Sample preparation: Sample concentration 3 mg / mL, methanol-acetonitrile solution.

[0626] Compound 46-P1: LC-MS (ESI): m / z = 512.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.16(s,1H),7.79-7.75(m,1H),7.73(s,1H),7.65-7.61(m,1H),6.76(s,1H),5.27-5.15(m,1H ),5.14-5.00(m,1H),4.52-4.50(m,1H),4.41-4.38(m,1H),4.29-4.18(m,2H),4.04-3.88(m,4H),3.69-3.50(m,2H),2.53(s,3H).

[0627] Compound 46-P2: LC-MS (ESI): m / z = 512.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.16(s,1H),7.79-7.76(m,1H),7.76-7.60(m,2H),6.76(s,1H),5.27-5.15(m,1H),5.14 -5.00(m,1H),4.52-4.48(m,1H),4.41-4.38(m,1H),4.29-4.18(m,2H),4.04-3.88(m,4H),3.69-3.50(m,2H),2.53(s,3H).

[0628] Compound 46-P3: LC-MS (ESI): m / z = 512.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.42(d,J=2.6Hz,1H),8.17(s,1H),7.88-7.56(m,3H),6.76-6.73(m,1H),5.28-5.14(m,1 H),5.13-4.98(m,1H),4.61-4.35(m,2H),4.31-4.14(m,2H),4.09-3.85(m,4H),3.70-3.48(m,2H),2.53(s,3H).

[0629] Compound 46-P4: LC-MS (ESI): m / z = 512.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.42(d,1H),8.16(s,1H),7.79-7.76(m,1H),7.73(s,1H),7.65(m,1H),6.76(s,1H),5.27-5.15(m,1H),5 .14-5.00(m,1H),4.56-4.49(m,1H),4.41-4.38(m,1H),4.29-4.18(m,2H),4.04-3.88(m,4H),3.69-3.50(m,2H),2.53(s,3H).

[0630] Example 47

[0631] Step 1: Using compound 1G (2.43 g, 10 mmol) as the starting material, compound 47A (620 mg) was synthesized according to the method in Example 1.

[0632] Step 2: Using compound 47A (620 mg, 1.1 mmol) as the starting material, compound 47 (116 mg) was synthesized according to the method in Example 1.

[0633] 1 H NMR(400MHz,DMSO)δ8.61-8.59(m,1H),8.31(s,1H),7.95(s,1H),7.82-7.55( m,2H),6.74(s,1H),5.68-5.56(m,1H),5.22-5.10(m,1H),4.96-4.73(m,3H),4 .22-4.10(m,1H),4.01-3.88(m,2H),3.51(s,2H),3.25-2.98(m,1H),2.88-2. 61(m,1H),2.47-2.32(m,4H),2.17-1.98(m,3H).LC-MS(ESI):m / z=643.3[M+H] + .

[0634] Example 48

[0635] Compound 48 (0.28 g, 52.6%) was synthesized from compound 8A using the same method as compound 33. LC-MS (ESI): m / z = 587.2 [M+H] +Compound 48 (280 mg) was chirally resolved to obtain P1 (retention time: 1.753 min, designated as compound 48-P1) and P2 (retention time: 1.869 min, designated as compound 48-P2). Preparation method: Instrument: CAS-05-Prep-SFC-F; Column: OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Flow rate: 140 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Sample preparation: Sample concentration 8 mg / mL, acetonitrile-methanol solution. After separation and solvent removal, compounds 48-P1 (110 mg, 39.2%) and 48-P2 (100 mg, 35.7%) were obtained.

[0636] Compound 48-P1: LC-MS (ESI): m / z = 587.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.29(s,1H),7.95(s,1H),7.76-7.71(m ,1H),7.65-7.61(m,1H),6.72(s,1H),5.61(t,1H),5.15(t,1H),4.93-4.66( m,3H),3.95-3.92(m,2H),3.63-3.57(m,1H),3.36-3.32(m,1H),2.61-2.55( m,1H),2.38(s,3H),2.25-2.10(m,2H),1.63-1.59(m,1H),0.99-0.77(m,4H).

[0637] Compound 48-P2: LC-MS (ESI): m / z = 587.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.29(s,1H),7.95(s,1H),7.76-7.71(m ,1H),7.65-7.61(m,1H),6.71(s,1H),5.61(t,1H),5.15(t,1H),4.93-4.66( m,3H),3.95-3.92(m,2H),3.63-3.57(m,1H),3.36-3.32(m,1H),2.61-2.55( m,1H),2.38(s,3H),2.25-2.10(m,2H),1.63-1.59(m,1H),0.99-0.77(m,4H).

[0638] Example 49

[0639] Step 1: Using compound 48C as the starting material, compound 49 (0.35g) was synthesized according to the method in Example 21.

[0640] Compound 49: LC-MS (ESI): m / z = 587.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.31(s,1H),7.87(s,1H),7.78-7.69(m, 2H),6.90(s,1H),5.98(d,1H),5.12-5.08(m,1H),4.78-4.70(m,1H),4.59-4.5 2(m,3H),4.47-4.43(m,1H),3.64-3.58(m,1H),3.38-3.32(m,1H),2.64-2.58 (m,1H),2.52(s,3H),2.28-2.13(m,2H),1.66-1.62(m,1H),1.00-0.79(m,4H).

[0641] Example 50

[0642] Step 1: Using 50A (3.0 g, 14.2 mmol) as the starting material, compound 50B (370 mg, 0.75 mmol) was synthesized according to the method described in Example 19. LC-MS (ESI): m / z = 492.2 [M+H] + .

[0643] Step 2: 50B (370 mg, 0.75 mmol) was dissolved in dimethylformamide (6 mL), and then N-iodosuccinimide (185 mg, 0.83 mmol) was added. The mixture was reacted at room temperature for 3 hours. The solution was diluted with water, extracted with ethyl acetate, washed, concentrated, and then purified by column chromatography (PE:EA (v / v) = 1:4) to obtain compound 50C (320 mg, yield: 68.8%). LC-MS (ESI): m / z = 618.2 [M+H] + .

[0644] Step 3: Compound 50C (320 mg, 0.52 mmol) was weighed into toluene (10 mL), followed by the sequential addition of trimethylsilylpropyne (180 mg, 1.56 mmol), triethylamine (260 mg, 2.6 mmol), cuprous iodide (9.9 mg, 0.05 mmol), tetra(triphenylphosphine)palladium (65 mg, 0.05 mmol), and a tetrahydrofuran solution of tetrabutylammonium fluoride (2.6 mL, 2.6 mmol). The reaction was carried out at room temperature for 12 hours under nitrogen protection. The mixture was then diluted with water, extracted with ethyl acetate, washed, dried, and concentrated to obtain a crude product. The crude product was purified by HPLC to obtain the target compound 50 (21 mg, yield: 7.6%). LC-MS (ESI): m / z = 530.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.42(s,1H),8.23(s,1H),7.95(s,1H),7.75(q,1H),7.48-7.44(m,1H),7.00(t,1H),5.26(t,1H),4.53-4.49(m, 1H),4.37-4.354(m,1H),4.33-4.17(m,1H),3.31(d,2H),3.04(s,3H),2.82-2.76(m,2H),2.57-2.50(m,2H),2.48(s,3H),2.15(d,5H).

[0645] Example 51

[0646] Compound 51 (6.36 mg, 0.01 mmol) was synthesized from compound 51A according to the method described in Example 2. LC-MS (ESI): m / z = 602.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.52(d,1H),8.30(s,1H),7.87(s,1H),7.80-7.66(m,2H),6.88(s,1H),5.97(d,1H),5.19-5.02(m,2H), 4.63-4.49(m,3H),4.48-4.40(m,1H),3.77(s,2H),3.11(s,2H),2.94-2.83(m,2H),2.83-2.75(m,2H),2.53(s,3H),2.46(s,3H).

[0647] Example 52

[0648] Compound 52 (5.89 mg, 0.01 mmol) was synthesized from compound 8D using the method described in Example 2. LC-MS (ESI): m / z = 602.3 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.28(s,1H),7.94(s,1H),7.79-7.69(m,1H),7.62(dd,1H),6.71(s,1H),5.61(t,1H),5.14(t,1H),5 .08(dd,1H),4.92-4.76(m,2H),3.93(dd,2H),3.75(s,2H),3.10(s,2H),2.90-2.80(m,2H),2.80-2.72(m,2H),2.53(s,3H),2.32(s,3H).

[0649] Example 53

[0650] Compound 53 (302 mg, 49.0% yield) was synthesized from compound 42B (1.0 g, 3.8 mmol) according to the method described in Example 1. LC-MS (ESI): m / z = 541.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.23(s,1H),7.83(s,1H),7.79-7.74(m,1H),7.69-7.66(m,1H),6.69(s,1H),5.56(t,1H ),5.09(t,1H),4.53-4.47(m,1H),3.98-3.89(m,2H),3.22(d,2H),2.99(s,3H),2.73(t,2H),2.39(s,3H),2.24-2.07(m,4H).

[0651] Example 54

[0652] Compound 54 (750 mg) was obtained from compound 8D (800 mg, 1.61 mmol) using the synthetic method described in Example 2. LC-MS (ESI): m / z = 605.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.29(s,1H),7.94(s,1H),7.77-7.70(m,1H), 7.65-7.60(m,1H),6.72(s,1H),5.65-5.57(m,1H),5.18-5.12(m,1H),4.90-4.76(m ,2H),4.72-4.62(m,1H),3.98-3.89(m,2H),3.66-3.58(m,1H),3.54(d,2H),3.50- 3.41(m,1H),3.37(s,3H),2.15-1.87(m,6H),1.52-1.34(m,1H),0.90-0.81(m,1H).

[0653] Example 55

[0654] Step 1: Compound 55A (1.0 g, 9.80 mmol), triethylamine (2.97 g, 29.40 mmol), and 4-dimethylaminopyridine (0.12 g, 0.98 mmol) were dissolved in dichloromethane (20 mL) and stirred at 0 °C. Finally, p-toluenesulfonyl chloride (2.43 g, 12.74 mmol) was added, and the mixture was allowed to react overnight at room temperature. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to give compound 55B (2.1 g, 83.6%).

[0655] Step 2: Compound 55B (1.65 g, 6.42 mmol) and 1 G (1.3 g, 5.35 mmol) were dissolved in N,N-dimethylformamide (20 mL), followed by the addition of cesium carbonate (2.61 g, 8.02 mmol). The reaction was carried out overnight at 100 °C. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 55C (1.2 g, 68.6%). LC-MS (ESI): m / z = 327.0 [M+H] +

[0656] Compound 55 (25.0 mg, 21.8%) was synthesized from compound 55C (1.2 g, 3.67 mmol) according to the method described in Example 8. LC-MS (ESI): m / z = 592.3 [M+H]+ ; 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.28(s,1H),7.94(s,1H),7.76-7.71(m,1H),7.65-7.61(m,1H),6.71(s,1H),5.61(t,1H),5.1 5(t,1H),4.54-4.46(m,1H),3.96-3.90(m,2H),3.24-3.21(m,2H),2.99(s,3H),2.74-2.69(m,2H),2.38(s,3H),2.23-2.09(m,4H).

[0657] Example 56

[0658] Compound 56 (14 mg) was synthesized from compound 42D (770 mg, 1.92 mmol) and compound 37A (1.19 g, 2.88 mmol) according to the method described in Example 14. LC-MS (ESI): m / z = 580.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.42(s,1H),8.11(s,1H),7.80-7.60(m,2H),7.50-7.40(m,1H),6.79(s,1H),5.30-5.10(m,1H),4.60-4.50(m,1H),4.45 -4.32(m,2H),4.28-4.06(m,2H),3.75-3.58(m,2H),2.85-2.71(m,1H) ,2.63-2.54(m,1H),2.48(s,3H),2.43-2.35(m,1H),2.25-2.15(m,1H).

[0659] Example 57

[0660] Step 1: 57A (1.7 g, 17.50 mmol) was dissolved in toluene (60 mL), followed by the addition of 1-Boc-4-aminopiperidine (3.5 g, 17.50 mmol) and Zn(OTf)₂ (6.4 g, 17.50 mmol), and the mixture was refluxed overnight. The system was cooled to room temperature, and 10% potassium carbonate aqueous solution (40 mL) was added, followed by extraction with ethyl acetate (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane:methanol (v / v) = 12:1) to give compound 57B (3.2 g, 65%). LC-MS (ESI): m / z = 280.2 [M+H]+ .

[0661] Step 2: Dissolve 57B (3g, 10.71mmol) in DMF (40mL), then add NBS (1.9g, 10.71mmol), and react at room temperature for 30 minutes. After the reaction, add water (50mL), extract with ethyl acetate (50mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane:methanol (v / v) = 12:1) to give compound 57C (1.5g, 39%). LC-MS (ESI): m / z = 358.1 [M+H] + .

[0662] Step 3: Using compound 57C as the starting material, 57D (0.2 g) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 430.1 [M+H] + .

[0663] Step 4: Using compounds 27A and 57D as starting materials, compound 57 (10 mg) was synthesized according to the method described in Example 8. LC-MS (ESI): m / z = 538.4 [M+H] + .

[0664] 1 H NMR (400MHz, DMSO) δ8.59(d,1H),8.01(d,1H),7.82-7.70(m,2H),7.66-7.58(m,1H),6.54(s,1H),5.55-5.49(m,1H),5.11(t,1H),4.16-4.04( m,1H),3.98-3.87(m,2H),3.25-3.16(m,2H),2.98(s,3H),2.72-2.64( m,2H),2.39(s,3H),2.26(s,3H),2.25-2.15(m,2H),1.95-1.88(m,2H).

[0665] Example 58

[0666] Step 1: Using compound 42D (2.5 g, 6.25 mmol) and compound 5E (2.5 g, 6.25 mmol) as starting materials, compound 58 (1.10 g, 31%) was synthesized according to the method described in Example 21. LC-MS (ESI): m / z = 568.2 [M+H] +Compound 58 (1.10 g) was chirally resolved to obtain P1 (251 mg, retention time: 4.127 min, designated as compound 58-P1), P2 (241 mg, retention time: 4.122 min, designated as compound 58-P2), P3 (245 mg, retention time: 4.124 min, designated as compound 58-P3), and P4 (255 mg, retention time: 4.122 min, designated as compound 58-P4). Preparation method: Instrument: Waters 150 preparative SFC (SFC-26); Column: Chiralcel OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Flow rate: 130 mL / min; Column temperature: 38℃; Wavelength: 220 nm; Sample preparation: Sample concentration 3 mg / mL, methanol-acetonitrile solution.

[0667] Compound 58-P1: LC-MS (ESI): m / z = 568.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.85-7.73(m,1H),7.71(s,1H),7.68-7.59(m,1H),6.78(s,1H),5.35-5.17(m,2H),4.56-4.50 (m,1H),4.48-4.39(m,1H),4.37-4.30(m,1H),4.26-4.21(m,1H),3.50 -3.37(m,2H),3.32-3.24(m,2H),2.58-2.45(m,5H),2.15-1.78(m,4H).

[0668] Compound 58-P2: LC-MS (ESI): m / z = 568.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.85-7.75(m,1H),7.71(s,1H),7.68-7.61(m,1H),6.78(s,1H),5.34-5.16(m,2H),4.57-4.51 (m,1H),4.48-4.41(m,1H),4.36-4.30(m,1H),4.28-4.20(m,1H),3.50 -3.36(m,2H),3.33-3.25(m,2H),2.56-2.44(m,5H),2.15-1.76(m,4H).

[0669] Compound 58-P3: LC-MS (ESI): m / z = 568.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.83-7.75(m,1H),7.71(s,1H),7.68-7.60(m,1H),6.78(s,1H),5.33-5.17(m,2H),4.56-4.51 (m,1H),4.47-4.40(m,1H),4.36-4.30(m,1H),4.26-4.20(m,1H),3.49 -3.37(m,2H),3.32-3.26(m,2H),2.56-2.48(m,5H),2.14-1.78(m,4H).

[0670] Compound 58-P4: LC-MS (ESI): m / z = 568.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.17(d,1H),7.83-7.76(m,1H),7.71(s,1H),7.68-7.61(m,1H),6.78(s,1H),5.33-5.18(m,2H),4.57-4.49 (m,1H),4.47-4.39(m,1H),4.35-4.28(m,1H),4.25-4.18(m,1H),3.49 -3.37(m,2H),3.35-3.25(m,2H),2.58-2.46(m,5H),2.14-1.78(m,4H).

[0671] Example 59

[0672] Step 1: Compound 24A (12 g, 87 mmol) was dissolved in DMF (150 mL). CsF (30 g, 80 mmol) and (difluoromethyl)trimethylsilane (16.1 g, 130 mmol) were added sequentially with stirring, and the reaction was carried out overnight at 50 °C. After the reaction was complete, water (20 mL) was added to quench the reaction, followed by the addition of 2 M hydrochloric acid (100 mL). Stirring was continued for 1 h, and then excess saturated sodium bicarbonate solution was added. Extraction was performed with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (400 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound 59B (7.6 g, 46.2%). LC-MS (ESI): m / z = 190.1 [M + H] + .

[0673] Step 2: Using compound 59B (7.6 g, 40 mmol) as the starting material, compound 59C (460 mg) was synthesized according to the method described in Example 24. LC-MS (ESI): m / z = 409.1 [M+H] + .

[0674] Step 3: Using compound 59C (230 mg, 0.56 mmol) and compound 19B (225 mg, 0.5 mmol) as starting materials, compound 59 (38 mg) was synthesized according to the method in Example 1. LC-MS (ESI): m / z = 625.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.56-8.49(m,1H),8.34-8.29(m,1H),7.88(s,1H),7.80-7.66(m,2H),6.90(s,1H),6.46-6.08(m,1H),5.99(d,1H),5.16 -5.04(m,1H),4.96-4.78(m,1H),4.66-4.39(m,4H),4.07-3.95(m,1H) ,3.60-3.43(m,2H),2.70-2.54(m,1H),2.52(s,3H),2.43-1.95(m,5H).

[0675] Example 60

[0676] Step 1: Using compound 2E (2.0 g, 4.95 mmol) as the starting material, compound 60A (560 mg, yield: 27.2%) was synthesized according to the method described in Example 2. LC-MS (ESI): m / z = 432.2 [M+H] + .

[0677] Compound 60 (152 mg, yield: 31.3%) was synthesized from compound 60A (530 mg, 1.38 mmol) according to the method described in Example 16. LC-MS (ESI): m / z = 539.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),8.23(s,1H),7.86(s,1H),7.78-7.73(m,1H),7.65-7.61(m,1H),6.65(s,1H),5.56(t,1H),5.12(t,1 H),4.53-4.46(m,1H),3.96-3.87(m,2H),3.26-3.17(m,4H),2.78-2.73(m,2H),2.38(s,3H),2.25-2.16(m,2H),2.08(d,2H),1.17(t,3H).

[0678] Example 61

[0679] Step 1: Compound 16 (1.8 g, 3.43 mmol) was dissolved in tetrahydrofuran (20 mL), and under nitrogen protection, sodium bis(trimethylsilyl)amino (4.46 mL, 4.46 mmol, 1 M) was added at -78 degrees Celsius and reacted for 30 minutes. Then, methyl terpentinate (1.55 g, 10.29 mmol) was added and reacted at -78 degrees Celsius for 2 hours. After the reaction, the reaction solution was quenched with saturated ammonium chloride solution, then extracted with water (20 mL) (ethyl acetate 20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain the crude target compound. The crude compound was then purified by SFC (Preparation method: 1. Instrument: SFC Prep 150AP; Column: Daicel IK (19 mm × 250 mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Methanol (0.05% ammonia) b. Isocratic elution, mobile phase B flow rate 12 mL / min c. Total flow rate 40 mL / min. p1 14.3 min, P2 (compound 61) 16.2 min, preparation and purification yielded target compound 61 (0.7 g, yield 31%). LC-MS (ESI): m / z = 639.3 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.24(s,1H),7.87(s,1H),7.83-7.72(m,1H),7.64(dd, 1H),6.58(s,1H),5.76(t,1H),5.45-5.17(m,2H),4.56-4.43(m,1H),4.22-4.03(m,2H),3.25 -3.16(m,2H),2.99(s,3H),2.74-2.65(m,2H),2.36(s,3H),2.24-2.07(m,4H),1.10(s,9H).

[0680] Example 62

[0681] Compound 62 (2.1 g, 3.98 mmol) was obtained from compound 27A using the synthesis method described in Example 16.

[0682] LC-MS(ESI): m / z=528.3[M+H]+; 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.23(s,1H),

[0683] 7.86(s,1H),7.79-7.69(m,1H),7.63(dd,1H),6.65(s,1H),5.56(t,1H),5.11(t,1H),4.58-4.34 (m,1H),4.01-3.79(m,2H),3.26-3.14(m,2H),2.79-2.61(m,2H),2.38(s,3H),2.27-2.07(m,4H).

[0684] Example 63

[0685] Step 1: Compound 63A (10 g, 41.7 mmol) was dissolved in anhydrous acetonitrile (200 mL). 2-Azide-1,3-dimethylimidazolium hexafluorophosphate (14.3 g, 50.0 mmol) and triethylamine (21.1 g, 208 mmol) were added sequentially with stirring, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound 63B (9.8 g, 88.2%). LC-MS (ESI): m / z = 211.1 [M-55] +

[0686] Step 2: Using compound 63B (9.8 g, 36.8 mmol) as the starting material, compound 63C (3.2 g) was synthesized according to the methods described in Examples 1 and 2. LC-MS (ESI): m / z = 399.1 [M+H] + .

[0687] Step 3: Using compound 63C (366 mg, 1 mmol) and compound 8D (450 mg, 1 mmol) as starting materials, compound 63 (41 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 615.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.60-8.57(m,1H),8.23(s,1H),7.94(s,1H),7.78-7.69(m,1H),7.65-7.60(m,1H),6.65(s,1H),5.62-5.58( m,1H),5.16-5.12(m,1H),4.96-4.70(m,2H),3.96-3.88(m,2H),2.77(s,3H),2.47(s,3H),2.43-2.27(m,6H),2.00-1.86(m,6H).

[0688] Example 64

[0689] Step 1: Using compound 63C (337 mg, 0.84 mmol) and compound 19B (450 mg, 1 mmol) as starting materials, compound 64 (204 mg) was synthesized according to the method described in Example 1. LC-MS (ESI): m / z = 615.2 [M+H] + .

[0690] Step 2: Compound 64 was resolved by SFC to obtain compounds 64-P1 (SFC retention time: 0.523 min, 95.6 mg) and 64-P2 (SFC retention time: 0.784 min, 90.8 mg). SFC analysis method: Instrument: CAS-05-ANA-SFC-D; Column: AD column; Mobile phase: A: CO2, B: 0.05% MNH3 in ethanol and acetonitrile; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0691] Compound 64-P1: 1H NMR (400MHz, DMSO) δ8.53-8.49(m,1H),8.25(s,1H),7.87(s,1H),7.80-7.66(m,2H),6.80(s,1H),5.99-5.92(m,1H),5.13-5 .04(m,1H),4.61-4.38(m,4H),2.77(s,3H),2.60(s,3H),2.41-2.33(m,6H),1.99-1.90(m,6H).LC-MS(ESI):m / z=615.2[M+H] + .

[0692] Compound 64-P2: 1 H NMR (400MHz, DMSO) δ8.53-8.49(m,1H),8.25(s,1H),7.87(s,1H),7.80-7.66(m,2H),6.80(s,1H),5.99-5.92(m,1H),5.13-5 .04(m,1H),4.61-4.38(m,4H),2.77(s,3H),2.60(s,3H),2.41-2.33(m,6H),1.99-1.90(m,6H).LC-MS(ESI):m / z=615.2[M+H] + .

[0693] Example 65

[0694] Step 1: Dissolve 2E (3.5 g, 8.66 mmol) in N,N-dimethylformamide (30 mL), add sodium hydride (1.04 g, 25.98 mmol, 60%) at 0°C, stir for 30 minutes, then add iodocyclobutane (4.73 g, 25.98 mmol), and react at 80°C for 16 hours. After the reaction, quench the reaction solution with saturated ammonium chloride solution, extract (ethyl acetate 50 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the target compound (550 mg, yield 13%). LC-MS (ESI): m / z = 458.2 [M+H] + .

[0695] Step 2: Using compound 27A as the starting material, compound 65 (33.84 mg, 0.06 mmol) was synthesized according to the method described in Example 16. LC-MS (ESI): m / z = 565.4 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.23(d,1H),7.86(s,1H),7.79-7.6 9(m,1H),7.66-7.55(m,1H),6.65(s,1H),5.61-5.47(m,1H),5.12(t,1H), 4.56-4.42(m,1H),3.97-3.81(m,3H),3.15-3.04(m,2H),2.82-2.69(m,2 H),2.37(s,3H),2.27-2.14(m,4H),2.12-2.01(m,4H),1.76-1.59(m,2H).

[0696] Example 66

[0697] Step 1: Compound 66A (6.0 g, 36.37 mmol) was dissolved in N,N-dimethylformamide (80 mL) and stirred at 0 °C. Sodium hydride (1.75 g, 72.74 mmol) was slowly added under nitrogen protection. After the addition was complete, the mixture was stirred at this temperature for 0.5 hours. Then, 1-(tert-butoxycarbonyl)-4-(methanesulfonyloxy)piperidine (15.2 g, 54.55 mmol) was added, and the reaction was carried out overnight at 100 °C. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 66B (6.0 g, 47.3%). LC-MS (ESI): m / z = 294.0 [M-55] +

[0698] Step 2: Compound 66B (3.4 g, 9.76 mmol) was dissolved in tetrahydrofuran (50 mL) and stirred at 0 °C. Under nitrogen protection, a 2 M solution of diisopropylaminolithium tetrahydrofuran (15 mL, 29.28 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 0.5 hours. Finally, iodomethane (3.14 g, 29.28 mmol) was added, and the mixture was allowed to return to room temperature overnight. After the reaction was complete, saturated ammonium chloride aqueous solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to give compound 66C (1.0 g, 28.2%). LC-MS (ESI): m / z = 308.0 [M-55] +

[0699] Step 3: Compound 66C (1.0 g, 2.76 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 4 M dioxane hydrochloride solution (10 mL). The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, the solvent was evaporated to dryness, and the residue was dissolved in methanol (20 mL). Potassium carbonate was then added to adjust the reaction system to alkaline conditions. Finally, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 66D, which was used directly in the next step. LC-MS (ESI): m / z = 264.1 [M+H] +

[0700] Step 4: Dissolve the product 66D from the previous step in water (10 mL), adjust the reaction solution to weakly acidic with acetic acid, then add sodium nitrite (0.28 g, 4.13 mmol). After the addition is complete, react overnight at room temperature. After the reaction is complete, extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine, dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 66E (0.6 g, 75.0%). LC-MS (ESI): m / z = 293.1 [M+H] +

[0701] Step 5: Compound 66E (0.42 g, 1.44 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL), followed by the sequential addition of zinc powder (0.75 g, 11.52 mmol) and ammonium chloride (1.39 g, 25.92 mmol). The reaction was allowed to proceed at room temperature for 3 hours after the addition was complete. After the reaction was complete, the mixture was filtered, and the filtrate was used directly in the next step. LC-MS (ESI): m / z = 277.0 [M+H] +

[0702] Step 6: Add sodium bicarbonate (2.42 g, 28.80 mmol) to the filtrate from the previous step, followed by di-tert-butyl dicarbonate (0.79 g, 3.60 mmol). React overnight at room temperature. After the reaction is complete, extract with ethyl acetate (50 mL × 2). Combine the organic phases and wash with saturated brine. Dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to give compound 66G (0.15 g, 27.5%). LC-MS (ESI): m / z = 321.0 [M-55] +

[0703] Step 7: Compound 66G (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 0 °C. Sodium hydride (5.3 mg, 0.22 mmol) was slowly added under nitrogen protection. After the addition was complete, the mixture was stirred at this temperature for 0.5 hours. Finally, iodomethane (31 mg, 0.22 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to give compound 66H (40 mg, 96.4%). LC-MS (ESI): m / z = 391.1 [M+H] +

[0704] Step 8: Using 66H as the raw material, compound 66 (10 mg, 25.8%) was synthesized according to the synthesis method in Example 16.

[0705] LC-MS (ESI): m / z = 542.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),7.99(s,1H),7.82

[0706] (s,1H),7.77-7.72(m,1H),7.65-7.61(m,1H),6.26(s,1H),5.51(t,1H),5.09(s,1H),4.33-4.26(m,1H) ,3.93-3.91(m,2H),3.18-3.15(m,2H),2.97(s,3H),2.68-2.63(m,2H),2.20(s,3H),2.07-1.90(m,4H).

[0707] Example 67

[0708] Compound 67 (290.98 mg, 0.50 mmol) was synthesized from compound 1G according to the method described in Example 16. LC-MS (ESI): m / z = 575.3 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.27(d,1H),7.92(s,1H),7.78-7.69(m,1H),7.68-7.59(m,1H),6.71(s,1H),6.61-6.23(m,1H), 5.60(t,1H),5.14(t,1H),4.60-4.31(m,3H),4.02-3.85(m,2H),3.26-3.17(m,2H),2.80-2.64(m,2H),2.39(s,3H),2.26-2.08(m,4H).

[0709] Example 68

[0710] Compound 68 (73.82 mg, 0.13 mmol) was synthesized from compound 27A according to the method described in Example 16. LC-MS (ESI): m / z = 553.4 [M+H]+; 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.23(s,1H),7.86(s,1H),7.79-7.71 (m,1H),7.63(dd,1H),6.65(s,1H),5.56(t,1H),5.11(t,1H),4.55-4.39( m,1H),4.01-3.86(m,2H),3.55-3.39(m,1H),3.16-3.07(m,2H),2.86-2.6 9(m,2H),2.37(d,3H),2.30-2.17(m,2H),2.13-2.05(m,2H),1.19(d,6H).

[0711] Biological testing evaluation

[0712] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0713] The structure of Comparative Example 1 of the present invention is shown below, and it was prepared according to the method of Example 46 of Patent WO2022187443.

[0714] 1. FGFR1-3 kinase activity test

[0715] The compound was diluted with DMSO to a concentration of 2.5×. 4 μL of the compound was transferred to a 384 reaction plate (784075, Greiner) using a power pipette. FGFR1 (working concentration: 1 nM) and protein 3 (working concentration: 0.3 nM) were diluted with kinase reaction buffer (5x Buffer, 5 mM MgCl2, 1 mM DTT, 1% Tween 20), and 2 μL of the kinase solution was transferred to the 384 reaction plate. The plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 60 minutes. A mixture of substrate (working concentration: 1 μM) and ATP (working concentration: 40–50 μM) was diluted with kinase reaction buffer, and 4 μL of the substrate and ATP mixture was added to the reaction plate. The plate was centrifuged at 1000 rpm for 1 minute. The 384 reaction plate was sealed with sealing film, and the reaction was started by incubation at 25°C for 60 minutes. Prepare XL665 and antibody detection reagents using detection buffer. Add 5 μL of kinase detection reagent to each well of a 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 60 min. Read the fluorescence signal ratios at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader. Calculate the inhibition rate of the compound using the formula: Inhibition rate % = (Ratio of compound - Ratio of solvent) / (Ratio of positive control - Ratio of solvent) * 100%. Perform fitting analysis using the log(inhibitor) vs. response -- Variable slope (four parameters) equation in Graphpad software to calculate the IC50 of the sample. 50 Numerical value.

[0716] Experimental results: The compounds of this invention inhibit the activities of FGFR1, FGFR2, and FGFR3 enzymes in vitro, especially showing a significant inhibitory effect on FGFR3 enzyme activity. The IC50 values ​​of the compounds in the examples for FGFR3 enzyme activity are shown in the figures. 50 Value less than 100 nM. IC 50 Values ​​are represented by grades A, B, C, and D, with A representing 0. <IC 50 ≤10nM, B represents 10nM <IC 50 ≤30nM, where C represents 30nM <IC 50 ≤100nM, D represents IC 50 >100nM.

[0717] Table 1

[0718] "-" Not detected

[0719] Conclusion: The compounds of this invention, such as those in the examples, exhibit inhibitory effects on the activities of FGFR1 and FGFR3 enzymes in vitro, particularly showing a significant inhibitory effect on FGFR3 enzyme activity. Some compounds showed IC50 values ​​below 1 nM for FGFR3. 50 For example, the IC50 of compound 15-P2 50 The IC50 of compound 15-P4 is 0.017 nM. 50 The IC50 of compound 16 is 0.02 nM. 50 The IC50 of compound 21-P2 is 0.17 nM. 50 The IC50 of compound 53 was 0.019 nM. 50 The IC50 of compound 67 is 0.031 nM. 50 The selectivity was 0.14 nM; and the FGFR3 / FGFR1 selectivity of compounds 15-P4, 16, 53, 55, and 57 was greater than 300-fold, while the FGFR3 / FGFR2 selectivity of compounds 15-P2, 15-P4, 16, 53, 55, and 57 was greater than 100-fold.

[0720] 2. Inhibition of RT112 cell (FGFR3-TACC3 fusion) proliferation

[0721] RT112 cells (Mingzhou Biotechnology, MZ-336126) were cultured in DMEM complete medium (+10% FBS) at 37°C for 48 h in a CO2 incubator. Cells were digested with trypsin and counted, then the density was adjusted to 1.67 × 10⁻⁶ cells / year. 4 Cells / mL. 90 μL (3000 cells) of cells were seeded into each well of a 96-well clear plate and transferred to a CO2 incubator at 37°C for overnight incubation. After overnight incubation, 10 μL of the diluted compound (starting at 10 μM, 3-fold dilution, 10 concentrations) was added to each well using a pipette. A positive control was serum-free medium containing DMSO. The mixture was thoroughly mixed and incubated at 37°C for 96 hours. After incubation, the cells were removed... 2.0 The assay solution (Vazyme, DD1101-03) was brought to room temperature. 100 μL of CellCounting-Lite 2.0 assay solution was added to each well. The plate was sealed with the sealing film and shaken on a shaker for 15 min (the entire process should be performed in the dark). The fluorescence signal value (LUM) of each well was detected using the Luminescence module of a microplate reader (BMG LRBTECH). The inhibition rate of the compound was calculated using a formula. The IC50 of the sample was calculated using the log(inhibitor) vs. response-variable slope (four parameters) equation fitted by Graphpad software. 50 Numerical values. The vertical axis represents the percentage of inhibition rate, and the horizontal axis represents the logarithm of the sample concentration (Log10).

[0722] Experimental results: The compounds of this invention exhibit inhibitory activity against RT112 cells in vitro. The IC50 of the compounds in the examples against RT112 cells was [not specified in the original text]. 50 Value less than 100 nM. IC 50 Values ​​are represented by grades A, B, C, and D, with A representing 0. <IC 50 ≤30nM, B represents 30nM <IC 50 ≤100nM, where C represents 100nM <IC 50 ≤300nM, D represents IC 50 >300nM.

[0723] Table 2

[0724] Conclusion: The compounds of this invention, such as those in the examples, significantly inhibited the activity of RT112 cells, suggesting that these compounds possess certain inhibitory activity against tumor cells with abnormal FGFR3. Some of these compounds exhibited IC50 values ​​below 10 nM against RT112 cells (FGFR3). 50 For example, the IC50 of compound 15-P2 50 The IC50 of compound 15-P4 is 0.58 nM. 50 The IC50 of compound 16 is 0.61 nM. 50 The IC50 of compound 21-P2 is 2.95 nM. 50 The IC50 of compound 53 is 0.82 nM. 50 The IC50 of compound 67 is 0.86 nM. 50 The IC value is 0.93 nM, compared to that of Comparative Example 1. 50 It is 18.73 nM.

[0725] 3. Inhibition of DMS114 cell proliferation (FGFR1 amplification)

[0726] DMS114 cells (Mingzhou Biotechnology, MZ-0632) were cultured in RPMI complete medium (+10% FBS+1% PS) at 37°C for 48 h in a CO2 incubator. Cells were digested with trypsin and counted, then the density was adjusted to 1.67 x 10⁻⁶ cells / year. 4 Cells / mL. Seed 180 μL (1000 cells) per well into a clear 96-well plate and incubate overnight at 37°C in a CO2 incubator. After overnight incubation, add 20 μL of the diluted compound (starting at 10 μM, 3-fold dilution, 10 concentrations) to each well using a pipette. The positive control is serum-free medium containing DMSO. Mix thoroughly and incubate at 37°C in a CO2 incubator for 96 hours. After incubation, remove... 2.0 The assay solution (Vazyme, DD1101-03) was brought to room temperature. 100 μL of CellCounting-Lite 2.0 assay solution was added to each well. The plate was sealed with the sealing film and shaken on a shaker for 15 min (the entire process should be performed in the dark). The fluorescence signal value (LUM) of each well was detected using the Luminescence module of a microplate reader (BMG LRBTECH). The inhibition rate of the compound was calculated using a formula. The IC50 of the sample was calculated using the log(inhibitor) vs. response-variable slope (four parameters) equation fitted by Graphpad software. 50 Numerical values. The vertical axis represents the percentage of inhibition rate, and the horizontal axis represents the logarithm of the sample concentration (Log10).

[0727] Experimental results: The compounds of this invention exhibit weak or no inhibitory effect on DMS114 cells in vitro. IC50 50 Values ​​are represented by grades A, B, C, and D, with A representing 0. <IC 50 ≤30nM, B represents 30nM <IC 50 ≤100nM, where C represents 100nM <IC 50 ≤300nM, D represents IC 50 >300nM.

[0728] Table 3

[0729] Conclusion: The compounds of the present invention, such as those in the examples, have no or weak inhibitory effect on DMS114 cell activity, suggesting that the compounds in the examples have selective inhibitory effects on tumor cells with abnormal FGFR3. For example, compounds 15-P2, 15-P4, 16, 21-P2, 53, 55, and 67 showed at least 500-fold higher selectivity for RT112 (FGFR3) / DMS114 (FGFR1) cells, which is superior to Comparative Example 1 (264-fold).

[0730] 4. Pharmacokinetic assays in mice

[0731] 4.1 Experimental animals: BABL / c male mice, 22–35 g, 6 mice / compound. Purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0732] 4.2 Experimental Design: On the day of the experiment, mice were randomly divided into groups according to their body weight. They were fasted for 12–14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0733] Table 4.1 Dosage Information

[0734] Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS; Gavage administration solvent: 5% DMSO + 5% HS-15 + 90% (20% SBE-B-CD)

[0735] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0736] Table 4.2 Pharmacokinetic parameters of the tested compounds in mouse plasma

[0737] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in mice.

[0738] 5. Rat pharmacokinetic test

[0739] 5.1 Experimental animals: SD rats, 170-200g, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0740] 5.2 Experimental Design: On the day of the experiment, rats were randomly divided into groups according to their body weight. They were fasted for 12–14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0741] Table 5. Drug Administration Information

[0742] Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS; Gavage administration solvent: 5% DMSO + 5% HS-15 + 90% (20% SBE-B-CD)

[0743] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0744] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in rats.

[0745] 6. hERG potassium ion channel function test

[0746] Implementation platform: Electrophysiological manual patch-clamp system

[0747] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0748] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ig). hERG The step voltage was applied from -80 mV to +20 mV for 2 seconds, then repolarized to -50 mV for 1 second before returning to -80 mV. This voltage stimulation was applied every 10 seconds, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0749] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1 - (I / Io)] × 100%

[0750] Where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0751] Compound IC 50 The following equation was used to fit and calculate the result using GraphPad Prism 5 software: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope))

[0752] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0753] Table 6

[0754] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit hERG.

[0755] 7: Evaluation of the in vivo antitumor efficacy of the compound in the M-NSG mouse UM-UC-14 human bladder cancer subcutaneous xenograft (CDX) model

[0756] This embodiment aims to construct a UM-UC-14 human bladder cancer subcutaneous xenograft model using severely immunodeficient M-NSG mice, and to systematically evaluate the in vivo antitumor activity and preliminary safety of the tested compounds:

[0757] 7.1 Cell Culture: UM-UC-14 bladder cancer cells (derived from the Kanglong Cell Bank) were seeded into EMEM complete medium containing 10% fetal bovine serum, 2 ml glutamine, and 1× non-essential amino acids, and cultured routinely in a 37°C, 5% CO2 incubator. When cell confluence reached 90%, cells were passaged using trypsin-EDTA digestion (≤5 passages), and cells in the logarithmic growth phase were collected, adjusted to a suitable concentration, and used for in vivo seeding.

[0758] 7.2 Experimental Animals and Model Construction: Six- to eight-week-old female M-NSG mice (purchased from Shanghai Nanmo Biotechnology Co., Ltd.) were selected. After acclimatization, UM-UC-14 cell suspension (1×10⁻⁶ cells / mL) was subcutaneously injected into the right back of the mice.7 One cell / 0.1 mL (containing matrix gel), a total of 96 animals were inoculated.

[0759] 7.3 Grouping and Administration: Subcutaneous xenografts were administered when their average volume reached 150–200 mm. 3 At that time, based on tumor volume and mouse weight, mice were randomly stratified to select 48 mice with uniform tumor volume. These mice were randomly divided into a solvent control group and a group with different doses of the test compound, and were administered the drug according to the preset protocol.

[0760] 7.4 Monitoring of drug efficacy and safety: During the experiment, the weight changes of mice were monitored tw...

Claims

1. A compound of general formula (I), (Ia), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ring A is Ring A1 is a 4-10-membered nitrogen-containing heterocyclic alkyl group or an 11-12-membered nitrogen-containing heterocyclic alkyl group, optionally further surrounded by 1-4 R groups. A replace; Ring A2 is C 3-8 cycloalkyl, optionally further surrounded by 1-4 R A replace; Z is Or it may not exist, in which Connected to Y; Alternatively, R3 and the adjacent pyridopyrazol group together with the attached atom form a 5-8 membered heterocycle or a 5-8 membered carbon ring; Ring B can be phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridazinyl. Optional further by 1-4 R B replace; Y represents a bond, -O-, or C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -OC 1-6 alkylene-, -C 1-6 Alkylene-O-, -OC 3-6 Cycloalkylene- or -C 3-6 Cycloalkylene-O-, wherein the alkylene, alkenylene, ynylene, or cycloalkylene group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl, C 2-4 alkenyl or C 2-4 Group substitution of the alkynyl group; R1 is a halogen, hydroxyl, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, -OC 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-11 membered heterocycloalkyl), -O- (5-6 membered heteroaryl), -C 1-6 Alkyl-C 3-8 cycloalkyl, -C 2-6 alkenyl-C 3-8 cycloalkyl, -OC 1-6 Alkyl-C 3-8 cycloalkyl or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl, or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; R2 is C 1-6 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy group substitution; R3 can be deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylamine group, C 1-6 alkylthio or C 1-6 Hydroxyalkyl; R A and R B Each of these can be independently represented as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine or C 1-6 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution; Or, any R A R3 and its linked ring atoms form a 5-7 membered heterocyclic alkyl group, optionally further bonded by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution; -L = -C 1-3 Alkyl-CH=, -C 3-6 Cycloalkyl-CH=, wherein the alkyl group or cycloalkyl group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; L b C 1-6 Alkyl, C 1-6 Alkyl group - (4-6 membered heterocyclic alkyl group), -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, wherein the alkyl group is optionally further composed of 1-4 elements selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OC(O)NH2, C 3-6 The cycloalkyl group is substituted, wherein the cycloalkyl group is optionally further replaced by 1-2 groups selected from deuterium, halogen, hydroxyl, amino, SF5, SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Substitution of alkyl groups; R a1 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), -N(CN)(C 3-6 (cycloalkyl), wherein the alkyl group, or cycloalkyl group, is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl group substitution; R a2 -CN, -N(CN)(C 1-6 alkyl), -CO-(C 1-6 alkyl)-N(CN)(C 1-6 alkyl), -(C 1-6 alkyl)-N(CN)(C 1-6 Alkyl), amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-3 Alkyl groups are substituted.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown as general formula (I-1A), general formula (I-1B), general formula (I-2A), general formula (I-2B), general formula (I-3A), general formula (I-3B), general formula (I-4A), general formula (I-4B), general formula (I-5A), general formula (I-5B), general formula (I-6A), general formula (I-6B), general formula (Ia-1), general formula (Ia-6), or general formula (Ia-7): in: Y is -O-, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -OC 1-3 alkylene-, -C 1-3 Alkylene-O-, -OC 3-4 Cycloalkylene- or -C 3-4 Cycloalkylene-O-; R1 is a halogen, hydroxyl, amino, or C. 1-3 Alkyl, C 2-4 alkenyl, -OC 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-3 Alkyl, C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-6 membered monocyclic heterocyclic alkyl), -O- (7-11 membered polycyclic heterocyclic alkyl), -O- (5-6 membered heteroaryl), -C 1-3 Alkyl-C 3-8 cycloalkyl, -C 2-4 alkenyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-C 3-8 cycloalkyl, -OC 1-3 Alkyl-(4-6 membered monocyclic heterocyclic alkyl) or -CH=C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl, or cycloalkyl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; L b -CH2-C(CF3)(OH)-, -CH2-C(CH3)(OH)-, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-, -CH2-CH(OC(O)NH2)-, -CH2-(4-6 membered heterocyclic alkyl)-, -CH2-CH(OP(O)(OH)2)-, -CH2-CH(OCH2P(O)(OH)2)-, -CH(C 3-6 cycloalkyl-OH)-.

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Ring A1 is * indicates that it is related to R a1 Linkage sites; Ring A2 is * indicates the link site with L; Y represents the following: -O-, -CH2-, -CH=CH-, -OCH2-, -CH2O-, -O-cyclobutyl, -cyclobutyl-O-; R2 is C 1-3 Alkyl groups, further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, -OC(O)NH2, C 1-3 Alkyl, -OC(O)-C 1-3 Alkyl group, -OC(O)CH2-C 1-3 Alkyl group, -OC(O)CH(NH2)-C 1-3 Alkyl group, -OCH2OC(O)-C 1-4 Alkyl group, -OCH2P(O)(OCH2OC(O)C 1-4 Alkyl)2、-OP(CH2OCH3)(O)(NHC(CH3)COOC 1-4 Alkyl), -OP(O)(OH)2, -OCH2OP(O)(OH)2, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy group substitution; R A and R B Each of these can be independently represented as deuterium, halogen, hydroxyl, amino, oxo group, SF5, SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine or C 1-3 Alkyl subunits, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, or alkyl subunits are optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy group substitution; -L = -C 1-3 Alkyl-CH=, -C 3-4 cycloalkyl-CH=; R a1 R a2 Each is independently -CN, -N(CN)(C 1-3 alkyl), -CO-(C 1-3 alkyl)-N(CN)(C 1-3 alkyl), -(C 1-3 alkyl)-N(CN)(C 1-3 Alkyl), -N(CN)(C 1-3 (deuterated alkyl), -N(CN)(C) 1-3 Halogenated alkyl), -N(CN)(C 3-6 Cycloalkyl groups, preferably -CN, -N(CN)(CH3), -CO-(CH3)-N(CN)(CH3), -(CH3)-N(CN)(CH3), -N(CN)(CD3), -N(CN)(CH2CF3), -N(CN)(CH2CHF2), -N(CN)(CH(CH3)2), -N(CN)(cyclopropyl), -N(CN)(cyclobutyl), -N(CN)(cyclopropyl-CH3), -N(CN)(C(CH3)3).

4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R1 is F, Cl, -CH=CH2, -OCF3, -OCH2CF3, -OCD3, -OCD2CD3, -OCD2CF3, -C≡C-CH3, -OCH2CHF2, -OCHF2, -OCH2F, -OCF2CF3, -OCH2CH2F, -OCHFCH2F, -OCF2CH2F, -OCH2CD3, -OCHFCHF2, -OCF2CHF2, -OCH2CHF2, -OCF2CH3, 5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R2 is -CH2OH, -CH2OC(O)NH2, -CH2OC(O)CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)CH(NH2)CH(CH3)2, -OCH2OC(O)-C(CH3)3, -OCH2P(O)( and / or, Ring B is And / or, for And / or, for And / or, for 6. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formulas (I-1B-1), (I-1B-2), (I-1B-3), (Ia-3), (Ia-4), and (Ia-5):

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, characterized in that, Selected from one of the structures in Table 1 and Table 2.

8. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. The pharmaceutical composition according to claim 8, comprising 1-1500 mg of the compound of any one of claims 1-7, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

10. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, or the pharmaceutical composition of claim 10 or 11, in the preparation of a medicament, preferably the medicament being a medicament for the prevention and / or treatment of FGFR-mediated diseases.

11. The use according to claim 10, wherein the FGFR-mediated disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-7, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8 or 9, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer Selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

Images