Compound, pharmaceutical composition comprising same, and use thereof

Abstract

The present application provides a compound, a pharmaceutical composition comprising same, and a use thereof. The compound has a structure as represented by formula 0.

Description

A compound, a pharmaceutical composition containing the same and its use

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application No. 202410407014.9 filed on April 3, 2024 and Chinese patent application No. 202411285750.8 filed on September 12, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present application relates to the field of biomedicine, and specifically to a compound, a pharmaceutical composition containing the same, and uses thereof. Background Art

[0004] DNA chains are negatively charged, and nucleosomes are composed of charged histones. The two are usually bound together due to charge attraction. During DNA replication and transcription, this interaction needs to be untied, which requires the role of chromatin remodeling complexes. The SWI / SNF complex is a type of chromatin remodeling complex that uses the energy of ATP hydrolysis to achieve coordinated mobilization of nucleosomes and DNA.

[0005] The mammalian SWI / SNF complex is powered by two closely related paralogous ATPase subunits, SMARCA4 (BRG1) and SMARCA2 (BRM). These subunits assemble into a mutually exclusive complex, are co-expressed in most tissue types, and are localized in the nucleus. Studies have shown that SMARCA2 levels increase upon SMARCA4 inactivation. Furthermore, in SMARCA4 wild-type cells, knockdown of SMARCA2 leads to increased SMARCA4 expression and increased assembly of SMARCA4 into the SWI / SNF complex, suggesting that SMARCA2 and SMARCA4 compensate for each other's expression. Because SMARCA2 and SMARCA4 play complementary roles, and the activity of either SMARCA2 or SMARCA4 is required for chromatin remodeling, cancer cells lacking SMARCA4 become highly dependent on SMARCA2 for survival, and inhibition of SMARCA2 results in synthetic lethality between the two. As early as 2014, the synthetic lethal interaction between SMARCA4 and SMARCA2 was independently confirmed by two studies using unbiased (only random error but no systematic error) shRNA screens.

[0006] SMARCA4 is abnormally expressed in approximately 4% of human malignancies. Lung cancer, ovarian clear cell carcinoma, colorectal cancer, oral cancer, and melanoma all show abnormalities at varying frequencies. Therefore, SMARCA2 inhibitors have the potential to treat these cancers. Due to the shared homology between SMARCA4 and 2 proteins, selective SMARCA2 inhibitors are expected to further improve safety, and selective SMARCA2 inhibitors are currently needed to fill this gap in clinical research. Summary of the Invention

[0007] The present application provides a compound, a pharmaceutical composition containing the same, and uses thereof. The amide inversion strategy of the present invention significantly enhances the activity of the compound, such as enzyme activity and cell activity, and improves drugability and pharmacokinetic properties.

[0008] The first aspect of the present application provides a compound represented by formula 0, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] Ring A is selected from a 5-10 membered heteroaromatic ring, a C6-C10 aromatic ring, a C3-C10 alkyl ring or a 4-10 membered heterocyclic ring;

[0011] Each R a are each independently selected from deuterium, halogen, cyano, hydroxyl, -NR A1 R A2 , oxo, C1-C6 alkyl, C1-C6 alkoxy, -OC3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 membered aryl, -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, or two R atoms attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, wherein R A1 and R A2 Each is independently selected from H, deuterium, halogen, C1-C6 alkyl or -C(O)C1-C6 alkyl; T is selected from CR e R f , R e and Rf are each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl; as the R a The C1-C6 alkyl, C1-C6 alkoxy, -OC3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 membered aryl, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, amino, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or C3-C8 cycloalkyl;

[0012] t is 0, 1, 2, 3, 4, or 5;

[0013] L 1 Selected from-NR 4 -, -O- or -S-, R 4 is selected from H, deuterium, halogen or C1-C6 alkyl, wherein as R 4 The C1-C6 alkyl group is optionally substituted with deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0014] p is 0, 1, or 2;

[0015] Ring B is selected from a 5-10 membered heteroaromatic ring or a 6-10 membered aromatic ring;

[0016] Each R b Each is independently selected from deuterium, halogen, cyano, hydroxy, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl;

[0017] s is 0, 1, 2, 3, 4, or 5;

[0018] L 2 Selected from single bonds, The end is connected to the B ring, R 5 R is selected from H, deuterium, halogen, hydroxyl or C1-C6 alkyl 5 The C1-C6 alkyl group is optionally substituted with deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0019] n is 0 or 1;

[0020] R 1 and R 2 Each independently selected from hydrogen, C1-C6 alkyl or C1-C6 heteroalkyl, as R 1 and R 2 The C1-C6 alkyl and C1-C6 heteroalkyl groups are each independently optionally substituted by deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the heteroatom in the C1-C6 heteroalkyl group is O, S or N; preferably R 1 and R 2 Each independently selected from hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, preferably as R 1 and R 2 The C1-C3 alkyl and C1-C3 heteroalkyl groups are each independently optionally substituted by deuterium, halogen, C1-C3 alkyl or C1-C3 alkoxy; further preferably R 1 and R 2 Each independently selected from hydrogen, -CH3 or -CH2OCH3; more preferably R 1 and R 2 Each independently selected from hydrogen or -CH2OCH3;

[0021] m is 0, 1, 2, or 3; preferably m is 1;

[0022] R 6 is selected from H, deuterium, halogen, hydroxyl or C1-C6 alkyl, preferably R 6 Selected from H;

[0023] Ring C is selected from a 5-10 membered heteroaromatic ring or a 6-10 membered aromatic ring;

[0024] Each R c Each is independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0025] q is 0, 1, 2, 3, or 4;

[0026] X is selected from -S(O)2-, -S(O)-, -S(O)(=NR 7 )-、-C(O)-、-CR 8 R 9 -, R 7 R is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino or C1-C6 alkyl 7 The C1-C6 alkyl group is optionally substituted by deuterium, halogen, cyano, or hydroxyl; preferably R 7is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino or C1-C3 alkyl, and more preferably R 7 is selected from hydrogen, deuterium, halogen, cyano or methyl; R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino or C1-C6 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 8-membered ring; as R 8 and R 9 The C1-C6 alkyl group is optionally substituted by deuterium, halogen, cyano, or hydroxyl; preferably R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino or C1-C3 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring; more preferably R 8 and R 9 are each independently selected from halogen, cyano, methyl, CH2CN, -CH2OH, or R 8 and R 9 Together with the carbon atom to which they are attached, they form oxetanes;

[0027] R 3 Selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -NR g R h , or R 3 With R c and the atoms to which they are attached form a 5-8 membered ring, the 5-8 membered ring being optionally substituted with r R d Substituted, each of the R d Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocyclic group; R g and R h Each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl; as R 3 The heteroatom in the C1-C6 heteroalkyl group is O, S or N;

[0028] r is 0, 1, 2, 3, 4, 5 or 6.

[0029] In some embodiments of the first aspect of the present application, when n is 0, no

[0030] In some embodiments of the first aspect of the application, no

[0031] In some embodiments of the first aspect of the present application, R 3 Selected from C1-C3 alkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -NR g R h , or R 3 With R c and the atoms to which they are connected form a 5-membered carbocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, or an 8-membered heterocyclic ring, wherein the 5-membered carbocyclic ring, the 6-membered heterocyclic ring, the 7-membered heterocyclic ring, or the 8-membered heterocyclic ring is optionally replaced by r R d Substituted, each of the R d Each is independently selected from deuterium, halogen, cyano, hydroxy, amino, oxo, C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group; R g and R h Each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl; as R 3 The heteroatom in the C1-C3 heteroalkyl group is O, S or N.

[0032] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, or R attached to different ring atoms. d Together with the ring atoms to which they are connected, they constitute a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, and more preferably, R dEach is independently selected from deuterium, F, Cl, methyl or deuterated methyl;

[0033] In some embodiments of the first aspect of the present application, r is 0, 1, 2, 3, 4 or 5.

[0034] In some embodiments of the first aspect of the present application, the C ring is selected from a 5-6 membered heteroaromatic ring or a 6-10 membered aromatic ring; further preferably, the C ring is selected from a 5-6 membered heteroaromatic ring, a benzene ring, more preferably, the C ring is selected from a pyrrole ring, an imidazole ring, a pyrazole ring, a pyridine ring, a pyrimidine ring or a benzene ring, and further preferably, the C ring is selected from a pyrrole ring, an imidazole ring, a pyridine ring or a benzene ring; preferably, the C ring is

[0035] In some embodiments of the first aspect of the present application, ring C is The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected.

[0036] In some embodiments of the first aspect of the present application, preferably each R c Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl or C1-C6 haloalkoxy; preferably each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy; further preferably, each R c Each is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy; more preferably each R c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3; further preferably, each R c Each is independently selected from F, Cl, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0037] In some embodiments of the first aspect of the present application, preferably each R cEach is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3; further preferably, each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0038] In some embodiments of the first aspect of the present application, q is preferably 0, 1, 2, or 3, and more preferably q is 0 or 1.

[0039] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0040] In some embodiments of the first aspect of the present application, Selected from The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected.

[0041] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0042] In some embodiments of the first aspect of the present application, Selected from The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected.

[0043] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0044] In some embodiments of the first aspect of the present application, Selected from The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected.

[0045] In some embodiments of the first aspect of the present application, preferably X is -S(O)2-, -S(O)-, -S(O)(=NR 7 )-、-C(O)-、-CR 8 R 9 -, R 7 is selected from hydrogen, cyano, hydroxy, C1-C3 alkyl, R 8 and R 9 Each is independently selected from H, halogen, cyano, hydroxyl or C1-C3 alkyl, preferably R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring, as R 7 、R 8 and R 9 The C1-C3 alkyl group is optionally substituted by deuterium, halogen or hydroxyl, preferably substituted by hydroxyl; further preferably, X is -S(O)2-, -S(O)-, -S(O)(=NCH3)-, -S(O)(=NCN)-, -C(CH3)(CN)-, -C(CH3)F-, -C(CH3)(CH2OH)- or More preferably, X is -S(O)2- or -S(O)-; further more preferably, it is -S(O)2-.

[0046] In some embodiments of the first aspect of the present application, preferably R 3 With R c and the atoms they are connected to form a 5-8 membered ring, preferably for Preferred for

[0047] In some embodiments of the first aspect of the present application, Selected from

[0048] In some embodiments of the first aspect of the present application, it is preferred that for Preferred (More preferably ), (More preferably ), (More preferably ), (More preferably ), (More preferably ), or more preferably for or more preferably for,

[0049] In some embodiments of the first aspect of the present application, the compound of the general formula 0 is preferably selected from any one of the structures shown in the following general formula 0I:

[0050] Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 、n、R 1 、R 2 ,m,R 6 The definition of is the same as that in any of the above embodiments; q1 is 0, 1, 2 or 3.

[0051] In some embodiments of the first aspect of the present application, preferably, the D ring is selected from a 5- to 8-membered heterocyclic ring or a carbocyclic ring; preferably, the D ring is selected from represents a single bond or a double bond; wherein U is C or N, Z is a single bond, O, S, NH or CH2; W 1 and W 2 Each independently selected from C1-C2 alkylene, any -CH2- in the C1-2 alkylene may be substituted by O, S, or NH; preferably Selected from Preferred Selected from More preferred Selected from

[0052] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl or deuterated methyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group.

[0053] In some embodiments of the first aspect of the present application, preferably r is 0, 1, 2, 3, 4 or 5, and more preferably r is 0, 1, 2 or 5.

[0054] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from halogen, C1-C3 alkyl, or two R d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group or a 4-5 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are attached, they form a C4-C5 cycloalkyl or a 4-5 membered heterocyclic group.

[0055] In some embodiments of the first aspect of the present application, preferably each of the R d Each is independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl.

[0056] In some embodiments of the first aspect of the present application, it is preferred that Selected from Preferred Selected from

[0057] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0058] In some embodiments of the first aspect of the present application, it is further preferred that Selected from (More preferably ), (More preferably ),

[0059] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0060] In some embodiments of the first aspect of the present application, it is preferred that Selected from Preferred

[0061] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0062] In some embodiments of the first aspect of the present application, it is further preferred that Selected from (More preferably ), (More preferably ), (More preferably ), (More preferably ), (More preferably ),

[0063] In some embodiments of the first aspect of the present application, ring B is selected from a 5-10 membered heteroaromatic ring, preferably ring B is selected from a 5-6 membered monocyclic heteroaromatic ring and a 9-10 membered bicyclic fused heteroaromatic ring.

[0064] In some embodiments of the first aspect of the present application, ring B is selected from Preferably, ring B is selected from More preferably, Ring B is selected from China E 1 、E 2 、E 3 、E 4 、E 5 and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N;

[0065] China E 1 、E 2 、E 5 and E 6 Each independently selected from N or CH, and at least one is N, preferably E 1 N; E 3’ and E 4’ Each is independently selected from NH or CH2, and at least one is NH, preferably E 4’ For NH,

[0066] China E7 Independently selected from O, S, NH, CH2, E 8 and E 9 Each is independently selected from N, CH, and at least one is N or S, preferably E 7 For S, E 9 N, E 8 for CH;

[0067] In, E 6’ Independently selected from O, S, NH, CH2, preferably E 6’ For NH, E 1 、E 3 、E 4 、E 5 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N.

[0068] In some embodiments of the first aspect of the present application, ring B is selected from Preferably, ring B is selected from Preferably, ring B is selected from More preferably, ring B is The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected.

[0069] In some embodiments of the first aspect of the present application, preferably each R b Each is independently selected from halogen, oxo or C1-C6 alkyl, and further preferably each R b Each is independently selected from F, Cl, oxo, methyl or ethyl; more preferably each R b are each independently selected from halogen (eg, F).

[0070] In some embodiments of the first aspect of the present application, s is preferably 0, 1, 2, 3 or 4, preferably 0 or 1, and more preferably 0.

[0071] In some embodiments of the first aspect of the present application, preferably, ring B is selected from Preferably, the B ring is selected from

[0072] In some embodiments of the first aspect of the present application, ring B is selected from Preferably, the B ring is selected from The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected.

[0073] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0074] In some embodiments of the first aspect of the present application, Selected from Preferred Selected from More preferred The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected.

[0075] In some embodiments of the first aspect of the present application, L 1 Selected from-NR 4 -, R 4 is selected from H, deuterium, halogen, C1-C6 haloalkyl or C1-C6 deuterated alkyl, preferably R 4 Selected from H, deuterium or -CD3; preferably said L 1 It is -N(CD3)- or -NH-.

[0076] In some embodiments of the first aspect of the present application, p is preferably 0 or 1, and more preferably p is 0.

[0077] In some embodiments of the first aspect of the present application, ring A is selected from a 5-10 membered heteroaromatic ring and a C6-C10 aromatic ring.

[0078] In some embodiments of the first aspect of the present application, preferably ring A is selected from Among them, G 1 , G 1’ , G 13 , G 17 , G 18 , G 19 , G25 , G 26 , G 29 Each independently selected from O, NH, S or CH2, G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 9 , G 10 , G 11 , G 12 , G 14 , G 15 , G 16 , G 20 , G 21 , G 22 , G 23 , G 24 , G 27 , G 28 , G 30 , G 31 , G 32 , G 33 , G 34 Each independently selected from N or CH, preferably A ring is selected from More preferred

[0079] Preferred G 1 is selected from O, NH or -CH2-, more preferably G 1 Selected from O or -CH2-; preferably G 2 , G 3 , G 4 , G 5 Each independently selected from N or CH; preferably G 1’ Selected from O, NH or -CH2-; preferably G 6 , G 7 , G 8 , G 9 , G 10 Each independently selected from N or CH; preferably G 11 , G 12 Each independently selected from N or CH; preferably G 13 Selected from NH or S, more preferably G 13 Selected from S; preferably G 14 , G 15 , G 16 Each independently selected from N or CH; preferably G 17 , G 18 , G 19 Each independently selected from O, NH or CH2; preferably G20 , G 21 , G 22 Each independently selected from N or CH; preferably G 23 , G 24 Each independently selected from N or CH; preferably G 25 Selected from S; preferably G 26 Selected from CH2; preferably G 27 , G 28 , G 30 Each is independently selected from N or CH and at least one of them is N; preferably G 29 Each independently selected from NH or S; preferably G 31 , G 32 , G 33 , G 34 In, G 31 or G 34 is N, and the rest are CH.

[0080] In some embodiments of the first aspect of the present application, preferably, the A ring is

[0081] In some embodiments of the first aspect of the present application, it is more preferred that the A ring is

[0082] In some embodiments of the first aspect of the present application, it is further preferred that the A ring is

[0083] In some embodiments of the first aspect of the present application, preferably, the A ring is

[0084] In some embodiments of the first aspect of the present application, it is further preferred that the A ring is

[0085] In some embodiments of the first aspect of the present application, preferably each R a are each independently selected from halogen, cyano, -NR A1 R A2 , oxo, C1-C6 alkyl, C1-C6 alkoxy, -OC3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f, or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R A1 and R A2 are each independently selected from H, deuterium, halogen, C1-C6 alkyl or -C(O)C1-C6 alkyl, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, -OC3-C6 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from a saturated heterocyclic group, a partially unsaturated heterocyclic group, a monocyclic heterocyclic group, a condensed-ring heterocyclic group or a bridged heterocyclic group.

[0086] In some embodiments of the first aspect of the present application, it is further preferred that each R a are each independently selected from halogen, cyano, -NR A1 R A2 , oxo, C1-C3 alkyl, C1-C3 alkoxy, -OC3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, R A1 and R A2Each is independently selected from H, halogen, C1-C3 alkyl or -C(O)C1-C3 alkyl, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C1-C3 alkoxy, -OC3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, hydroxy, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, preferably the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, condensed ring heterocyclic group or bridged heterocyclic group.

[0087] In some embodiments of the first aspect of the present application, it is further preferred that each R a are each independently selected from halogen, cyano, -NR A1 R A2 , oxo, C1-C3 alkyl, C1-C3 alkoxy, -O(C3-C6 cycloalkyl), C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R A1 and R A2 Each is independently selected from H, C1-C3 alkyl or -C(O)C1-C3 alkyl, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R aThe C1-C3 alkyl, C1-C3 alkoxy, -O(C3-C6 cycloalkyl), C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, hydroxy, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl.

[0088] In some embodiments of the first aspect of the present application, it is more preferred that each R a Each is independently selected from F, Cl, cyano, oxo, -NH2, -C(O)CH3, -NHC(O)CH3, methyl, ethyl, methoxy, ethoxy, methoxyethyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoromethoxy, fluoroethoxy, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, fluorocyclopentane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0089] In some embodiments of the first aspect of the present application, t is preferably 0, 1, 2 or 3.

[0090] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0091] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0092] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0093] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0094] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0095] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0096] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the structures represented by formula I or formula II below:

[0097] Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 、m、n、R 1 、R 2 、R 6 The definition of is the same as that in any of the above embodiments; in the general formula I, Y is CH or N, preferably Y is CH.

[0098] In some embodiments of the first aspect of the present application, preferably each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy, and each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0099] In some embodiments of the first aspect of the present application, preferably each R cEach is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0100] In some embodiments of the first aspect of the present application, q1 is preferably 0 or 1.

[0101] In some embodiments of the first aspect of the present application, Z is preferably a single bond, O or CH2.

[0102] In some embodiments of the first aspect of the present application, W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O.

[0103] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group. d Each independently selected from deuterium, F, Cl, methyl or deuterated methyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group, or R attached to different ring atoms d Together with the ring atoms to which they are attached, they form a C3-C5 cycloalkyl group, and r is 0, 1, 2 or 5.

[0104] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0105] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0106] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0107] In some embodiments of the first aspect of the present application, it is preferred that Selected from Further optimization

[0108] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0109] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0110] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0111] In some embodiments of the first aspect of the present application, in Formula II, preferably each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy, and each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each independently selected from F, Cl, methyl, ethyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl or methyl.

[0112] In some embodiments of the first aspect of the present application, q1 is preferably 0 or 1.

[0113] In some embodiments of the first aspect of the present application, Z is preferably a single bond, O or CH2, and more preferably Z is O.

[0114] In some embodiments of the first aspect of the present application, W 1 and W 2Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O.

[0115] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group. d Each is independently selected from deuterium, F, Cl or methyl, and r is 0, 1 or 2.

[0116] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0117] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0118] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0119] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0120] In some embodiments of the first aspect of the present application, in Formula I, L 1 -NR 4 -, R 4 Selected from H or C1-C3 deuterated alkyl, preferably R 4 Selected from H or deuterated methane, more preferably R 4 Selected from H or -CD3; preferably p is 0 or 1.

[0121] In some embodiments of the first aspect of the present application, p in Formula II is 0.

[0122] In some embodiments of the first aspect of the present application, in Formula I or Formula II, L 2 Selected from The end is connected to the B ring, R5 is selected from H, deuterium, halogen, hydroxyl or C1-C3 alkyl, preferably R 5 is selected from H; preferably n is 0 or 1.

[0123] In some embodiments of the first aspect of the present application, in Formula I or Formula II, preferably R 6 Selected from H.

[0124] In some embodiments of the first aspect of the present application, in Formula I or Formula II, preferably R 1 and R 2 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, and R 1 and R 2 Each independently is hydrogen, methyl or -CH2OCH3, more preferably R 1 and R 2 One is hydrogen, and the other is H, methyl or -CH2OCH3.

[0125] In some embodiments of the first aspect of the present application, preferably, the compound of formula I is selected from any one of the structures represented by the following formula I0:

[0126] Preferably, the general formula I0 is selected from the structure shown in the following general formula I0-1:

[0127] More preferably, the general formula I0-1 is selected from the structure shown in the following general formula I0-1-1:

[0128] Preferably, the general formula I0-1-1 is selected from the structures shown in the following general formula I0-1-1-1:

[0129] Preferably, the compound of formula II is selected from any one of the structures shown in the following formula II0:

[0130] Preferably, the compound of the general formula II0 is selected from the structure shown in the following general formula II0-1:

[0131] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the structures represented by the following formula I1′ or formula III:

[0132] Preferably, the compound of the general formula I1' is selected from the structure shown in the following general formula I1:

[0133] Formula I1 wherein, Ring A, Ra ,t,R 1 、R 2 、R 6 、R c 、R d , r, R b The definitions of s are the same as those in any of the above embodiments; q1 is independently selected from 0 or 1.

[0134] In some embodiments of the first aspect of the present application, preferably E 1 、E 2 、E 3 、E 4 、E 5 and E 6 are independently selected from N and CH, and at least one of them is N, preferably both of them are N.

[0135] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0136] In some embodiments of the first aspect of the present application, it is more preferred Selected from

[0137] In some embodiments of the first aspect of the present application, it is more preferred Selected from

[0138] In some embodiments of the first aspect of the present application, Z is preferably a single bond, O or CH2; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, preferably any -CH2- in the C1-C2 alkylene may be substituted by O; further preferably W 1 Selected from CH2CH2, Z is O, W 2 selected from CH2; or W 1 is selected from CH2CH2, Z is CH2, W 2 Selected from CH2, wherein W 2 The CH2 is replaced by O.

[0139] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0140] In some embodiments of the first aspect of the present application, it is more preferred Selected from

[0141] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0142] More preferred

[0143] In some embodiments of the first aspect of the present application, it is preferred that Selected from More preferred

[0144] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0145] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0146] In some embodiments of the first aspect of the present application, it is more preferred Selected from

[0147] In some embodiments of the first aspect of the present application, preferably R 6 Selected from H.

[0148] In some embodiments of the first aspect of the present application, preferably, the general formula I1' or general formula III is selected from any one of the structures represented by the following general formula I01' or general formula III:

[0149] Preferably, the general formula I01' is selected from the structure shown in the general formula I1':

[0150] Preferably, the general formula I01' is selected from the structure represented by the following general formula I01":

[0151] Preferably, the general formula I01" is selected from the structure shown in the following general formula I1":

[0152] In some embodiments of the first aspect of the present application, the compound of the general formula I1' is selected from any one of the structures represented by the following general formulas I1-D1', I1-D2, and I1-D3:

[0153] Preferably, the general formula I1-D1' is selected from the structure shown in the general formula I1-D1:

[0154] The compound of the general formula II1 is selected from any one of the structures shown in the following general formula II1-D1:

[0155] Among them, A ring, R a ,t,R 1 、R 2 、R 6 、R b The definitions of s and E are the same as those in any of the above embodiments; 1 、E 2 、E 3 、E 4 、E 5 and E 6 The definition of is the same as that of any of the above embodiments,

[0156] In the general formula I1-D1' or the general formula III-D1, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl, deuterated methyl, or two R d The carbon atoms to which it is connected together form a C3-C5 cycloalkyl group;

[0157] Preferably r is 0, 1, 2 or 5, more preferably r is 0, 1 or 5;

[0158] Optimize each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each independently selected from F, Cl, cyano, methyl, ethynyl, -CHF2 or -OCHF2, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0159] Preferably, q1 is 0 or 1.

[0160] In some embodiments of the first aspect of the present application, it is preferred that Selected from More preferred

[0161] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0162] In some embodiments of the first aspect of the present application, it is more preferred that Selected from:

[0163] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0164] In some embodiments of the first aspect of the present application, it is more preferred that Selected from

[0165] In some embodiments of the first aspect of the present application, in the general formula I1-D2, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl, deuterated methyl; or two R connected to the same carbon atom d The carbon atoms to which it is connected together constitute a C3-C5 cycloalkyl group.

[0166] In some embodiments of the first aspect of the present application, r is preferably 0, 1 or 2, and more preferably r is 0 or 2.

[0167] In some embodiments of the first aspect of the present application, preferably each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably cEach is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each independently selected from F, Cl, cyano, methyl, ethynyl, -CHF2 or -OCHF2, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0168] In some embodiments of the first aspect of the present application, q1 is preferably 0 or 1.

[0169] In some embodiments of the first aspect of the present application, it is preferred that Selected from More preferred

[0170] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0171] In some embodiments of the first aspect of the present application, it is more preferred that Selected from

[0172] In some embodiments of the first aspect of the present application, in the general formula I1-D3, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from methyl, deuterated methyl, or two R d The carbon atoms to which it is connected together form a C3-C5 cycloalkyl group, or R d Together with the ring atoms to which they are attached, they form a C4-C5 cycloalkyl group.

[0173] In some embodiments of the first aspect of the present application, r is preferably 0, 1 or 2.

[0174] In some embodiments of the first aspect of the present application, preferably each Rc Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3.

[0175] In some embodiments of the first aspect of the present application, q1 is preferably 0 or 1, and preferably q1 is 0.

[0176] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0177] In some embodiments of the first aspect of the present application, the compound of general formula 0 is selected from any one of the structures represented by the following general formulas I1-A1, I1-A2, I1-A3, I1-A4, III-A1, III-A2, III-A3, and III-A4:

[0178] Among them, R 1 、R 2 、R 6 、R c 、R d , r, R b The definitions of s and E are the same as those in any of the above embodiments; 1 、E 2 、E 3 、E 4 、E 5 and E 6 The definition of is the same as that of any of the above embodiments; each q1 is independently selected from 0 or 1.

[0179] In some embodiments of the first aspect of the present application, in the general formula I1-A1 and general formula III-A1, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH.

[0180] In some embodiments of the first aspect of the present application, it is preferred that Selected from Preferably selected from More preferably

[0181] In some embodiments of the first aspect of the present application, preferably each R a Each is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 cycloalkyl or 4-8 membered heterocyclyl, -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R e and R fare each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R a Each is independently selected from F, Cl, cyano, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atoms to which they are attached, they form a cyclopropyl group; more preferably, each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0182] In some embodiments of the first aspect of the present application, t is preferably 0, 1 or 2.

[0183] In some embodiments of the first aspect of the present application, preferably, Each independently selected from Preferably, the general formula I1-A1 and the general formula III-A1 Each independently

[0184] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and the general formula III-A2, preferably R 1 and R 2Each independently is hydrogen, -CH3 or -CH2OCH3; more preferably R 1 and R 2 For hydrogen.

[0185] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and the general formula III-A2, preferably G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH; preferably Selected from Further optimization Selected from

[0186] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and the general formula III-A2, preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl or -C(O)C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or -C(O)C1-C3 alkyl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from a saturated heterocyclic group, a partially unsaturated heterocyclic group, a monocyclic heterocyclic group or a bridged heterocyclic group; more preferably, each R a Each is independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, fluoromethoxy, Preferably, t is 1, 2 or 3.

[0187] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and the general formula III-A2, preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from a saturated heterocyclic group, a partially unsaturated heterocyclic group, a monocyclic heterocyclic group, a condensed heterocyclic group or a bridged heterocyclic group.

[0188] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and general formula III-A2, preferably Each independently selected from Preferred More preferred

[0189] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and general formula III-A2, preferably Each independently selected from

[0190] In some embodiments of the first aspect of the present application, in the general formula I1-A2 and the general formula III-A2, it is further preferred that Each independently selected from

[0191] In some embodiments of the first aspect of the present application, in the general formulas I1-A2 and III-A2, more preferably Each independently selected from

[0192] In some embodiments of the first aspect of the present application, it is further preferred that the general formulas I1-A2 and III-A2 Independently

[0193] In some embodiments of the first aspect of the present application, in the general formulas I1-A3 and III-A3, G 11 , G 12 , G 14 , G 15 , G 16 Each independently selected from N or CH; preferably G 11 , G 12 Each independently selected from N or CH; preferably G 14 , G 15 , G 16 Selected from N or CH; G 13 Selected from NH or S, preferably G 13 For NH.

[0194] In some embodiments of the first aspect of the present application, preferably each R a Each independently selected from halogen, C1-C3 alkyl, -NR A1 R A2 , the C1-C3 alkyl group is optionally replaced by R a 'Replace, R a ' is selected from C1-C3 alkoxy; R A1 and R A2 Each is independently selected from H, halogen, C1-C6 alkyl or -C(O)C1-C6 alkyl, preferably R A1 and R A2 Each is independently selected from H, C1-C6 alkyl or -C(O)C1-C6 alkyl, preferably R A1 and R A2 Each is independently selected from H, halogen, C1-C3 alkyl or -C(O)C1-C3 alkyl, preferably R A1 and R A2 Each is independently selected from H, C1-C3 alkyl or -C(O)C1-C3 alkyl; more preferably each R a Each is independently selected from methyl, F, ethyl, methoxyethyl, -NH2, -NHC(O)CH3; preferably t is 1 or 2.

[0195] In some embodiments of the first aspect of the present application, preferably, Each independently selected from

[0196] In some embodiments of the first aspect of the present application, preferably, Each independently selected from

[0197] In some embodiments of the first aspect of the present application, preferably R 1 and R 2 For hydrogen.

[0198] In some embodiments of the first aspect of the present application, in the general formulae I1-A4 and III-A4, G17, G18, and G19 are each independently selected from O, NH, or CH2; and G20, G21, and G22 are each independently selected from N or CH.

[0199] In some embodiments of the first aspect of the present application, preferably, Each independently selected from Preferably

[0200] In some embodiments of the first aspect of the present application, preferably each R a Each is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl or -C(O)C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl are optionally replaced by R a 'Replace, R a 'Selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; preferably each R a Each independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or -C(O)C1-C3 alkyl, preferably as R aThe C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, oxo, halogen, C1-C3 alkyl; further preferably each R a Each is independently selected from halogen, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; more preferably each R a Each is independently selected from F, Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, Further optimization of each R a Each independently selected from oxo or Preferably, t is 1 or 2.

[0201] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0202] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the structures represented by the following formulas I11 to I118 and II11 to II14:

[0203] R a ,t,R c 、R d The definitions of r are the same as those in any of the above embodiments; each q1 is independently 0, 1 or 2, preferably 0 or 1.

[0204] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the structures represented by formula I2 or formula II2:

[0205] Among them, A ring, R a ,t,L 2 、n、R 1 、R 2 、R 6 、Rc 、R d , r is defined as in any of the above embodiments; q1 is selected from 0 or 1.

[0206] In some embodiments of the first aspect of the present application, Y is preferably N or CH.

[0207] In some embodiments of the first aspect of the present application, Z is preferably O or CH2, and more preferably Z is O; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O.

[0208] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0209] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0210] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0211] In some embodiments of the first aspect of the present application, preferably R 6 Selected from H.

[0212] In some embodiments of the first aspect of the present application, the compound of general formula I2 or general formula II2 is preferably selected from any one of the structures represented by general formula I21, general formula I22, general formula II21 or general formula II22:

[0213] More preferably, the compound of formula I2 is selected from any one of the structures represented by the following formula I21' or I22':

[0214] More preferably, the compound of general formula I2 or general formula II2 is selected from any one of the structures represented by the following general formula I21″, general formula I22″, general formula II21″ or general formula II22″:

[0215] In some embodiments of the first aspect of the present application, the compound of formula O is selected from any one of the structures represented by the following formula I2-D, formula I2-D′ or formula II2-D:

[0216] Among them, A ring, R a ,t,R 1 、R 2 、R 6 The definition of is the same as that in any of the above embodiments.

[0217] In some embodiments of the first aspect of the present application, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl or deuterated methyl, or two R d The carbon atoms connected thereto together form a C3-C5 cycloalkyl group; preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each is independently selected from deuterium, F, Cl, methyl or deuterated methyl.

[0218] In some embodiments of the first aspect of the present application, r is preferably 0, 1 or 5.

[0219] In some embodiments of the first aspect of the present application, preferably each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each independently selected from F, Cl, cyano, methyl, propynyl, -CHF2 or -OCHF2, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2.

[0220] In some embodiments of the first aspect of the present application, each q1 is independently selected from 0 or 1.

[0221] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0222] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0223] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0224] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0225] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0226] In some embodiments of the first aspect of the present application, preferably L 2 for The end is connected to the B ring (such as thiazole ring), R 5 Selected from H, C1-C3 alkyl; preferably R 5 Selected from H.

[0227] In some embodiments of the first aspect of the present application, n is preferably 1.

[0228] In some embodiments of the first aspect of the present application, preferably R 1 and R 2 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, preferably R 1 and R 2 One is hydrogen, and the other is H, methyl or -CH2OCH3.

[0229] In some embodiments of the first aspect of the present application, preferably R 6 Selected from H.

[0230] In some embodiments of the first aspect of the present application, the compound of the general formula I2-D, I2-D', or II2-D is preferably selected from any one of the structures represented by the following general formula I2-D1, I2-D2, I2-D3, I2-D4, II2-D1, or II2-D2:

[0231] In some embodiments of the first aspect of the present application, the compound of formula I2 is selected from any one of the following formulas I2-A1, I2-A2, I2-A3, and I2-A4:

[0232] The compound of general formula II2 is selected from any one of the following general formula II2-A1 and general formula II2-A2:

[0233] Preferably, R in the general formula I2-A1, general formula I2-A2, general formula I2-A3, general formula I2-A4, general formula II2-A1, general formula II2-A2 a ,t,R 1 、R 2 、R 6 、R c 、R d , r is defined as in any of the above embodiments; each q1 is independently selected from 0 or 1.

[0234] In some embodiments of the first aspect of the present application, in the general formula I2-A1, the general formula I2-A3 and the general formula II2-A1, G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH.

[0235] In some embodiments of the first aspect of the present application, it is preferred that Selected from Further optimization Selected from

[0236] In some embodiments of the first aspect of the present application, preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl or -C(O)C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl are optionally replaced by R a 'Replace, R a 'Selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as Ra The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl or -C(O)C1-C3 alkyl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl; further preferably each R a Each is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, condensed ring heterocyclic group or bridged heterocyclic group; more preferably, each R a Each is independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, fluoromethoxy, More preferably, each R a Each independently selected from halogen, methyl, cyclopropane, Methoxy, ethoxy, fluoromethyl, fluoroethyl, fluoromethoxy, preferably t is 1 or 2.

[0237] In some embodiments of the first aspect of the present application, preferably, the general formula I2-A1, general formula I2-A3 and general formula II2-A1 Each independently selected from

[0238] In some embodiments of the first aspect of the present application, it is further preferred that the general formula I2-A1, general formula I2-A3 and general formula II2-A1 Each independently selected from

[0239] In some embodiments of the first aspect of the present application, in the general formula I2-A2, the general formula I2-A4 and the general formula II2-A2, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH.

[0240] In some embodiments of the first aspect of the present application, preferably, Each independently selected from Further preferred are those in the general formula I2-A2, I2-A4 and II2-A2 for

[0241] In some embodiments of the first aspect of the present application, preferably each R a Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl or -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R aEach independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group. e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are attached, a C3-C6 cycloalkyl group is optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R aEach is independently selected from F, Cl, cyano, -NH2, -NHC(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atoms to which they are attached, they form a cyclopropyl group; more preferably, each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; preferably t is 0, 1, 2 or 3, more preferably t is 0, 1 or 2.

[0242] In some embodiments of the first aspect of the present application, preferably, Each independently selected from Preferred are general formula I2-A2, general formula I2-A4 and general formula II2-A2 Each independently

[0243] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the structures represented by the following formulae III, IV', V, VI, and VII:

[0244] Preferably, the general formula IV' is selected from the structure shown in general formula IV:

[0245] Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 、n、R 1 、R 2 ,m,R 6 、R c 、R d , r is defined as in any of the above embodiments; each q1 is independently selected from 0 or 1.

[0246] In some embodiments of the first aspect of the present application, Y is selected from CH or N.

[0247] In some embodiments of the first aspect of the present application, preferably R 7 is selected from C1-C3 alkyl, cyano, and more preferably R 7 Selected from methyl or cyano.

[0248] In some embodiments of the first aspect of the present application, preferably R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino or substituted or unsubstituted C1-C6 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring; preferably R 8 and R 9 are each independently selected from H or substituted or unsubstituted C1-C3 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 4-membered ring; preferably R 8 and R 9 The substituents in are each independently selected from deuterium, halogen, cyano or hydroxyl.

[0249] In some embodiments of the first aspect of the present application, preferably R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, C1-C6 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl group, as R 8 and R 9 The C1-6 alkyl group is optionally substituted by deuterium, halogen, cyano or hydroxyl; preferably R 8 and R 9 are independently selected from halogen, cyano, C1-3 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 4-membered heterocycloalkyl group, as R 8 and R 9 The C1-3 alkyl group is optionally substituted by halogen, cyano or hydroxyl; further preferably R 8 and R 9 Each independently selected from methyl, F, cyano, -CH2OH or R 8 and R 9 Together with the carbon atoms to which they are attached,

[0250] In some embodiments of the first aspect of the present application, Z is preferably a single bond, O or CH2; preferably Z is CH2; more preferably Z is a single bond or O.

[0251] In some embodiments of the first aspect of the present application, W 1 and W 2 Each independently selected from C1-C2 alkylene, preferably W 1 and W 2 are each independently selected from methylene.

[0252] In some embodiments of the first aspect of the present application, the compound of formula III is preferably selected from any one of the structures represented by formula III01 to formula III03 below:

[0253] In some embodiments of the first aspect of the present application, the compound of formula III is preferably selected from any one of the structures shown in the following formulas III1 to III3:

[0254] In some embodiments of the first aspect of the present application, the compound of formula IV' is preferably selected from any one of the structures represented by formula IV01 or formula IV02:

[0255] Preferably, the compound of formula IV' is selected from any one of the structures shown in the following formula IV1 or formula IV2:

[0256] In some embodiments of the first aspect of the present application, the compound of formula V is preferably selected from any one of the structures represented by the following formula V01 or formula V2:

[0257] Preferably, the compound of the general formula V01 is selected from the structure shown in the following general formula V1:

[0258] In some embodiments of the first aspect of the present application, the compound of formula VI is preferably selected from any one of the structures represented by formula VI01, formula VI02 or formula VI03:

[0259] Preferably, the compound of formula VI is selected from any one of the structures shown in formula VI1, formula VI2 or formula VI3:

[0260] In some embodiments of the first aspect of the present application, the compound of formula VII is preferably selected from any one of the structures represented by formula VII01, formula VII02 or formula VII03:

[0261] Preferably, the compound of formula VII is selected from any one of the structures shown in formula VII1, formula VII2 or formula VII3:

[0262] In some embodiments of the first aspect of the present application, in Formula III01, Formula III1, Formula IV01, Formula IV1, Formula V01, Formula V1, Formula VI03 and Formula VI3, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH.

[0263] In some embodiments of the first aspect of the present application, preferably Each independently selected from Preferred for

[0264] In some embodiments of the first aspect of the present application, preferably each R a Each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, or -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group. e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R aEach is independently selected from F, Cl, cyano, -NH2, -NHC(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form C=CF2 or R a and the ring atoms to which they are connected together form a cyclopropyl group; more preferably each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; t is 0, 1, 2 or 3, preferably t is 0, 1 or 2.

[0265] In some embodiments of the first aspect of the present application, preferably Each independently selected from Preferred Each independently

[0266] In some embodiments of the first aspect of the present application, in general formula III02, general formula III2, general formula III03, general formula III3, general formula IV02, general formula IV2, general formula V2, general formula VI01, general formula VI1, general formula VI02, general formula VI2, general formula VII01, general formula VII1, general formula VII02, general formula VII2, general formula VII03 and general formula VII3, G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH.

[0267] In some embodiments of the first aspect of the present application, preferably Each independently selected from Further optimization Selected from

[0268] In some embodiments of the first aspect of the present application, each R aEach independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl or -C(O)C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl are optionally replaced by R a 'Replace, R a 'Selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or -C(O)C1-C3 alkyl, as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl; further preferably each R a Each independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, condensed ring heterocyclic group or bridged heterocyclic group; more preferably, each R a Each independently selected from F, Cl, -C(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, difluoromethoxy, More preferably, each R aEach independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, difluoromethoxy, Further optimization of each R a Each independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, difluoromethoxy, or Preferably, t is 1, 2 or 3, and more preferably t is 1 or 2.

[0269] In some embodiments of the first aspect of the present application, it is preferred that Selected from

[0270] In some embodiments of the first aspect of the present application, it is further preferred that Selected from

[0271] In some embodiments of the first aspect of the present application, preferably R 1 、R 2 For H.

[0272] In some embodiments of the first aspect of the present application, preferably L 2 Selected from The end is connected to the B ring.

[0273] In some embodiments of the first aspect of the present application, the compound of formula 0 is selected from any one of the following compounds:

[0274] In some embodiments, the compound of the invention is selected from compounds 1, 7-10, 13-15, 17, 20, 21, 23, 25, 26, 28-30, 32, 33, 35-44, 46-49, 67-77, 82-86, 98-121, 266-268, 271-274, 277-279, 282-285.

[0275] In some embodiments, the compound of the present invention is selected from compounds 78-81, 88, 122-132, 263-265, 269-270, 275-276, 280-281, and 286.

[0276] In some embodiments, the compound of the present invention is selected from compounds 2-6, 34, 161-165, 167-169, 175, 177-192, 194-202.

[0277] In some embodiments, the compounds of the invention are not

[0278] The second aspect of the present application provides a pharmaceutical composition comprising a compound provided by any embodiment of the first aspect, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The above-mentioned compound etc. are used as a pharmaceutical active ingredient (API) (or therapeutic agent).

[0279] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, and in some embodiments it further includes a pharmaceutically acceptable carrier, excipient, or vehicle. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered together with the therapeutic agent, and is suitable for contacting the tissues of humans and / or other animals without excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment. The above-mentioned pharmaceutical composition can act systemically and / or locally, and it can be achieved through suitable dosage forms. The dosage forms include but are not limited to tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, brews, and syrups. The above-mentioned pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one compound of the present invention, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt.

[0280] The third aspect of the present application provides a compound provided in any embodiment of the first aspect, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided in any embodiment of the second aspect, in the preparation of a medicament for preventing and / or treating cancer. The cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary cause, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0281] The fourth aspect of the present application provides a compound provided by any embodiment of the first aspect, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition provided by any embodiment of the second aspect, in the preparation of a medicament for preventing and / or treating diseases or conditions caused by loss-of-function mutations in BRG1 (SMARCA4).

[0282] The disease or condition caused by BRG1 (SMARCA4) loss-of-function mutation described in the fourth aspect of the present application is selected from cancer or tumor, and the cancer or tumor includes but is not limited to non-small cell lung cancer, colorectal cancer, bladder cancer, primary unexplained cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer or penile cancer.

[0283] The fifth aspect of the present application also provides a method for preventing and / or treating cancer, which comprises the following steps: administering a therapeutically effective amount of a compound of any embodiment of the first aspect above, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition provided in the second aspect to an individual in need thereof. The cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary cause, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0284] The term "effective amount" refers to a dose that can induce a biological or medical response in a cell, tissue, organ, or organism (e.g., individual), and is sufficient to achieve the desired preventive and / or therapeutic effect. The dosage regimen can be adjusted to provide the best desired response. For example, a single dose can be administered, divided doses can be administered over time, or the dosage can be reduced or increased in proportion to the actual situation. It is understood that for any particular individual, the specific dosage regimen should be adjusted as needed and the professional judgment of the person administering the composition or supervising the administration of the composition. The dosage of the compound of the present invention will depend on the individual situation, the severity of the disease or illness, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician. In general, the effective amount is about 0.001-10000 mg / kg subject body weight / day. In appropriate cases, the effective amount is about 0.01-1000 mg / kg subject body weight / day. About 0.01-1000 mg / kg subject body weight, typically about 0.1-500 mg / kg subject body weight, can be administered every day, every two days, or every three days. An exemplary dosing regimen is one or more times a day, or one or more times a week, or one or more times a month. When multiple doses are administered, the intervals between single doses can generally be daily, weekly, monthly, or annually. Alternatively, the drug can be administered in the form of a sustained-release formulation, in which case a lower frequency of administration is required. The dosage and frequency of administration may vary depending on the half-life of the drug in the subject, and may also vary depending on whether the application is prophylactic or therapeutic. In prophylactic applications, a relatively low dose is administered at relatively low frequency intervals for a long period of time; in therapeutic applications, it is sometimes necessary to administer a relatively high dose at shorter intervals until the progression of the disease is delayed or stopped, preferably until the individual shows partial or complete improvement in the symptoms of the disease, after which a prophylactic application may be adopted.

[0285] The term "treat" refers to the alleviation or elimination of the targeted disease or condition. If a subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, and at least one indicator or symptom of the subject shows observable and / or detectable relief and / or improvement, the subject has been successfully "treated." It is understood that treatment includes not only complete treatment, but also includes not achieving complete treatment but achieving some biologically or medically relevant results. The term "administrate / administrating / administration" (or "dosing") refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (such as a pharmaceutical composition of the present invention) to an individual or a cell, tissue, organ, biological fluid, etc., so that the pharmaceutically active ingredient or pharmaceutical composition comes into contact with the individual or a cell, tissue, organ, biological fluid, etc. Common modes of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0286] The term "having a need for it" refers to a doctor's or other caregiver's judgment that an individual needs or will benefit from a preventive and / or therapeutic process, and the conclusion of this judgment is based on various factors in the doctor's or other caregiver's area of ​​expertise. The term "individual" (or subject) refers to a human or non-human animal. The individuals of the present invention include individuals (patients) suffering from a disease and / or condition and normal individuals. The non-human animals of the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0287] The compounds and derivatives provided in this application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0288] Definitions of terms used in this application: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, the meanings that can be given to them by those skilled in the art should be given based on the disclosure and context.

[0289] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons on an atom in a molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form -S(O)- or -S(O)2-.

[0290] “May be replaced by…” means that “replacement” can but does not have to occur, and the description includes situations where it occurs or does not occur.

[0291] The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, for example, the prefix C1-C6 alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.

[0292] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. For example, "C1-C6 alkyl" includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0293] Furthermore, the "C1-C6 alkyl" includes straight-chain or branched groups whose carbon number is between 1 and 6 and whose endpoints are any two integers. For example, "C1-C6 alkyl" includes C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C2-C6 alkyl, C2-C5 alkyl, C2-C4 alkyl, C1-C3 alkyl, etc. The above list is for example only and does not limit the above range.

[0294] The term "heteroalkyl" refers to a group in which one or more carbon atoms (but not all carbon atoms or adjacent carbon atoms) in any of the above alkyl chains are independently replaced by one or more heteroatoms, such as N, O or S. For example, "C1-C6 heteroalkyl" includes -OCH2CH3, -CH2OCH3, -CH2CH2OH, etc.

[0295] The term "alkoxy" and its derivatives refer to any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C3 alkyl, etc.) that are connected to the rest of the molecule through an oxygen atom (-O-). The term "alkoxy" can be exemplified by the following structures: methoxy, ethoxy, etc.

[0296] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms. C-C alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: The C1-C6 alkylene group of the present application may be a C1 alkylene group (eg, -CH2-), a C2 alkylene group (eg, -CH2CH2-, etc.), a C3 alkylene group, a C4 alkylene group, a C5 alkylene group or a C6 alkylene group.

[0297] When two groups are used together, it means that one of the groups is connected to the rest of the molecule through the other group. For example, C1-C6 alkoxy C1-C6 alkyl means that the C1-C6 alkoxy group is connected to the molecule through the C1-C6 alkyl group, and the "C1-C6 alkyl" in the group "C1-C6 alkoxy C1-C6 alkyl" is actually "C1-C6 alkylene". In particular, for example, methoxyethyl means that the methoxy group is connected to the molecule through the ethylene group (i.e., CH3OCH2CH2-).

[0298] "Alkenyl" refers to an unsaturated hydrocarbon chain having a specified number of member atoms. Alkenyl groups can be straight or branched. Representative branched alkenyl groups have one, two, or three branches. For example, "C2-C6 alkenyl" includes ethenyl, propenyl, butenyl (1-butenyl, cis-2-butenyl, trans-2-butenyl, and isobutene), pentenyl (including its various isomers), and hexenyl (including its various isomers).

[0299] Furthermore, the "C2-C6 alkenyl" includes straight-chain or branched groups whose carbon number is between 2 and 6 and whose endpoints are any two integers. For example, the "C2-C6 alkenyl" includes C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C3-C6 alkenyl, C4-C5 alkenyl, C3-C5 alkenyl, C3-C4 alkenyl, etc. The above list is for example only and does not limit the above range.

[0300] "Alkynyl" refers to an unsaturated hydrocarbon chain having a specified number of member atoms. Alkynyl groups can be straight or branched. Representative branched alkynyl groups have one, two, or three branches. For example, "C2-C6 alkynyl" includes ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0301] Furthermore, the "C2-C6 alkynyl" includes straight-chain or branched groups whose carbon number is between 2 and 6 and whose endpoints are any two integers. For example, the "C2-C6 alkynyl" includes C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C3-C6 alkynyl, C4-C5 alkynyl, C3-C5 alkynyl, C3-C4 alkynyl, etc. The above list is for example only and does not limit the above range.

[0302] The 5-8 membered rings of the present application include saturated or unsaturated rings with 5, 6, 7 or 8 ring atoms, and may be carbocyclic or heterocyclic rings with heteroatoms, and include but are not limited to cyclic hydrocarbons with single or multiple rings (spiro, bridged, condensed), wherein heteroatoms refer to nitrogen atoms, oxygen atoms, sulfur atoms, etc. Examples of 5-8 membered rings include but are not limited to

[0303] The "cycloalkyl" or "alkyl ring" described in this application includes saturated or partially unsaturated cyclic alkanes with multiple carbon atoms and no ring heteroatoms, having a single ring or multiple rings (spiro ring, bridged ring, condensed ring). The term "C3-C8 cycloalkyl" refers to 3 to 8-membered all-carbon monocyclic and polycyclic rings. When the cycloalkyl is a monocyclic ring, the monocyclic ring is a saturated ring or a partially unsaturated ring. When the cycloalkyl is a polycyclic ring, all the rings are saturated rings or partially unsaturated rings, or some of the rings are saturated rings and some of the rings are partially unsaturated rings, but does not include the case where any one of the rings is an aromatic ring, for example Belongs to cycloalkyl, and Since one of the rings is aromatic (benzene), it does not belong to the cycloalkyl group, but rather to the aryl group defined below. Examples of C3-C8 cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Examples of monocyclic alkane systems include, for example, cyclopropane, cyclobutane, cyclohexane, cyclopentane, and cyclooctane. Examples of bridged cycloalkane systems include bicyclo[3,1,0]hexane, bicyclo[3,1,1]hexane, bicyclo[2,2,1]hexane, bicyclo[2,2,2]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[1.1.2]pentane.

[0304] The "heterocyclic group" or "heterocycle" described in this application refers to a monovalent or divalent saturated or partially unsaturated ring (a divalent saturated ring of a heterocyclic group is a heterocycloalkylene group) having a single ring or multiple rings (spirocyclic, bridged, condensed rings) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. In particular, when the heterocyclic group is a monocyclic ring, the monocyclic ring is a saturated ring or a partially unsaturated ring; when the heterocyclic group is a polycyclic ring, all of the rings are saturated rings or partially unsaturated rings, or some of the rings are saturated rings and some of the rings are partially unsaturated rings, but does not include the case where any one of the rings is an aromatic ring. For example, examples of monocyclic heterocyclic groups can be oxetane, azetidinyl, oxolane, oxhexane, piperazinyl, piperidinyl, morpholinyl, trioxane, etc. Examples of bridged rings of heterocyclic groups may be Examples of fused rings of heterocyclic groups may be The group Since one of the rings is an aromatic ring (thiazole ring), it does not belong to a heterocyclic group, but to a heteroaryl group as defined below. Taking a 4-10 membered heterocyclic group as an example, it includes a heterocyclic ring with any two integers between 4 and 10 ring atoms as endpoints.

[0305] As used herein, "aromatic ring" or "aryl" refers to a monovalent or divalent aromatic hydrocarbon group having multiple carbon atoms. An aromatic ring is typically a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic group having multiple carbon atoms. In addition, the term "aromatic ring" as used herein refers to a fused ring that can be a single aromatic ring, multiple aromatic rings fused together, or a single aromatic ring and a non-aromatic carbon ring fused together. Non-limiting examples include a benzene ring, a naphthalene ring, a tetrahydronaphthalene ring,

[0306] As used herein, "heteroaromatic ring" or "heteroaryl" refers to a monocyclic or fused bicyclic aromatic unsaturated ring containing at least one heteroatom, wherein the ring comprising the monocyclic group is an aromatic ring, and at least one ring in the fused polycyclic (e.g., bicyclic) ring is an aromatic ring. The heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, or the like. Specifically, the heteroaromatic ring generally contains multiple ring atoms, one or more of which are selected from O, N, and S. Preferably, there are one to three heteroatoms. Among them, for example, the heteroaromatic ring is represented by a pyridine ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a thiazole ring, a 1,2,4-triazole ring, a 1,2,3,4-tetrazole ring, an isoxazole ring, an oxazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan ring, an isothiazole ring, a pyridazine ring, a 1,2,4-triazine ring, a 1,3,5-triazine ring, a 1,2,4,5-tetrazine ring,

[0307] The unsaturated mentioned in this application refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the group or molecule.

[0308] The "halogen" described in the present application refers to fluorine, chlorine, bromine or iodine.

[0309] The "haloalkyl" mentioned in this application refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen. The alkyl group in the "haloalkyl" is as defined above. For example, a halogen-substituted C1-C6 alkyl group refers to an alkyl group containing 1-6 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or other chemically acceptable natural number of halogen atoms. Taking a fluoroalkyl group as an example, it can be a fluoromethyl group, a fluoroethyl group, or a fluoropropyl group. For example, as R a The haloalkyl group includes, but is not limited to, fluoromethyl (such as monofluoromethyl, difluoromethyl, trifluoromethyl), fluoroethyl (such as -CHFCH2F), and fluoropropyl.

[0310] "Haloalkoxy" means that one or more hydrogen atoms in an alkoxy group are replaced by halogen, wherein the alkoxy group is as defined above. The number of halogens in the haloalkoxy group is not particularly limited as long as it is a chemically acceptable number, for example, it can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or a natural number of halogens. Taking fluoroalkoxy as an example, it can be fluoromethoxy, fluoroethoxy, or fluoropropoxy. For example, as R a The haloalkoxy group includes, but is not limited to, fluoromethoxy (eg, monofluoromethoxy, difluoromethoxy, trifluoromethoxy), fluoroethoxy (eg, -OCHFCH2F), and fluoropropoxy.

[0311] The "oxo group" described in this application refers to an oxygen atom replacing two hydrogen atoms in a molecule through a double bond.

[0312] In this application The horizontal line extending in the middle of similar structures represents R a or R b The hydrogen atoms on any of the rings may be substituted.

[0313] In this application, "stereoisomer" refers to a compound with the same chemical structure, but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc. Unless otherwise indicated, all stereoisomers of the structural formula described in this application or mixtures of stereoisomers fall within the scope of this application. The term "enantiomer" used in this application refers to stereoisomers that are real objects and mirror images and cannot be superimposed on each other. "Diastereomer" refers to a stereoisomer whose molecule has two or more chiral centers and is a non-mirror image relationship between the molecules.

[0314] The term "geometric isomers" used in this application includes cis-trans isomers, isomeric polymers and syndiotactic polymers, rotational isomers caused by steric hindrance, etc.

[0315] The “*” marked in the compound structure in the preparation examples of this application indicates that the site is a chiral center, and the marked compound is a chiral compound.

[0316] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0317] As used herein, "tautomers" generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0318] In this application, "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) that is arranged in a specific crystal packing. All polymorphs have the same elemental composition. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to one polymorph being dominant.

[0319] In the present application, "solvate" refers to a mixture produced by dissolving a compound in a solvent.

[0320] In this application, "N-oxide" is also called amine oxide, which is a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0321] In this application, "isotope-labeled compound" refers to a molecule or group in which one or more atoms are replaced by their isotope atoms, such as hydrogen atoms replaced by deuterium atoms, where the proportion of deuterium atoms is greater than the abundance of deuterium in nature; for example, 12C is replaced by 13C.

[0322] In this application, "metabolites" refer to substances generated by chemical structural transformation of drug molecules under the action of the body after the drug molecules are absorbed by the body.

[0323] In this application, "prodrug" refers to a compound that is obtained by chemically modifying a drug, is inactive or has low activity in vitro, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect.

[0324] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0325] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0326] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0327] The terms "treat," "treat," "treat," and "treating" mean to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0328] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0329] Obviously, based on the above content of this application, in accordance with common technical knowledge and customary means in this field, without departing from the above basic technical ideas of this application, various other forms of modifications, replacements or changes can be made.

[0330] The following is a detailed description of the above content of this application through specific implementation methods in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of this application to the following examples. All technologies implemented based on the above content of this application fall within the scope of this application. DETAILED DESCRIPTION

[0331] The present invention is further described in detail below through specific preparation examples and biological experiments. However, it should be understood that these examples and biological experiments are only used for specific illustration purposes and should not be understood as limiting the present invention in any form.

[0332] It is clear to those skilled in the art that, hereinafter, unless otherwise specified, the materials used are well known in the art and can be purchased from the market or obtained by those skilled in the art according to published literature or conventional methods. Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent, wherein: (i) the temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature, which generally refers to 15-35°C, preferably 20-30°C, and more preferably 20-25°C; (ii) the solvent is removed by evaporation under reduced pressure on a rotary evaporator, and the bath temperature is generally not higher than 60°C; (iii) the reaction process is tracked by thin layer chromatography (TLC); (iv) the final product has a satisfactory hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR) and / or mass spectrometry (MS) data.

[0333] Test equipment:

[0334] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and / or deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0335] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu 2030Plus-LCMS2020 mass spectrometer, an Agilent 1260-6125B single quadrupole mass spectrometer, or a Shimadzu LCMS-2020 mass spectrometer. HPLC was performed using a Shimadzu LCMS-2020 or Agilent 1260 high-performance liquid chromatograph.

[0336] Preparative high-performance liquid chromatography was performed using a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (column: Synergi Max-RP, 150×30 mm, 4 m) or a GILSON Trilution LC (column: SunFire Prep C18, 10 μm, 19×250 mm XBridge Prep C18, 10 μm, 19×250 mm)).

[0337] The model of the microwave synthesizer is Biotage Initiator+.

[0338] Synthesis of intermediates:

[0339] Intermediate synthesis: Int A

[0340] Step 1: To a suspension of sodium thiomethoxide (362.46 mg, 5.17 mmol) in N,N-dimethylformamide (25 mL) at -45°C, compound A-1 (0.60 mL, 4.93 mmol) was added portionwise. The reaction solution was stirred at -45°C for 3 hours, then returned to 25°C and stirred for 13 hours. The resulting reaction solution was poured into 30 mL of water and filtered. The filter cake was washed with 20 mL of water and dried to obtain compound A-2. 1 H NMR (400MHz, CDCl3) δ10.20 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.47-7.40 (m, 2H), 2.51 (s, 3H).

[0341] Step 2: To a solution of compound A-2 (350 mg, 1.51 mmol) in dichloromethane (4 mL) at 0°C was added (diethylamino)difluorosulfonium tetrafluoroborate (600 μL, 4.54 mmol). The reaction was stirred at 25°C for 3 hours. The reaction was quenched by the dropwise addition of saturated aqueous sodium bicarbonate (10 mL), extracted with 75 mL of ethyl acetate, and the combined organic layers dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to afford the crude product. Purification by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 95 / 5) afforded compound A-3. 1 H NMR (400MHz, CDCl3) δ7.51-7.45 (m, 2H), 7.44-7.39 (m, 1H), 6.93 (t, J = 55.2Hz, 1H), 2.52 (s, 3H). 19 F NMR (376MHz, CDCl3): δ-113.76 (s).

[0342] Step 3: At 0 ° C, m-chloroperbenzoic acid (176 mg, 0.87 mmol) was added to a solution of compound A-3 (100 mg, 0.40 mmol) in dichloromethane (2 mL). The reaction solution was stirred at 25 ° C for 1 hour. 5 mL of water was added to the reaction solution and diluted with 30 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound A-4 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 85 / 15) to obtain compound A-4. 1 H NMR (400MHz, CDCl3): δ8.27 (s, 1H), 7.91 (dd, J = 1.8, 8.3Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.58 (t, J = 55.2Hz, 1H), 3.16 (s, 3H). 19 F NMR (377MHz, CDCl3): δ-114.13 (s).

[0343] Step 4: To a solution of compound A-4 (170 mg, 0.60 mmol) and tert-butyl carbamate (0.09 mL, 0.89 mmol) in 1,4-dioxane (3.5 mL) were added tris(dibenzylideneacetone)dipalladium (54.60 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (51.75 mg, 0.09 mmol) and cesium carbonate (485.70 mg, 1.49 mmol), and heated and stirred at 100 ° C for 1 hour under a nitrogen atmosphere. The reaction solution was diluted with 10 mL of water and extracted with 75 mL of ethyl acetate. The combined organic phases were dried, filtered, and the filtrate was concentrated to obtain a crude product. Compound A-5 was obtained by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 75 / 25). 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.91-7.80 (m, 2H), 7.56 (t, J = 55.6Hz, 1H), 3.14 (s, 3H), 1.54 (s, 9H). 19 F NMR (376MHz, CDCl3): δ-112.75 (s).

[0344] Step 5: To a solution of compound A-5 (40 mg, 0.12 mmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.15 mL, 2.01 mmol), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by the dropwise addition of saturated aqueous sodium bicarbonate (20 mL) and extracted with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound Int A.

[0345] Intermediate synthesis: Int B

[0346] Step 1: At 0°C, B-1 (1.00 g, 8.92 mmol) was added to tetrahydrofuran (6.0 mL), followed by the slow addition of sodium hydride (0.46 g, 11.60 mmol). After stirring for 10 minutes, methylsulfonyl chloride (2.76 mL, 35.69 mmol) was added and stirred at 25°C for 2 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20.0 mL) for quenching, and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (80.0 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The mixture was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 4 / 1), and then slurried with petroleum ether / ethyl acetate (6 / 1, 8 mL) to obtain compound B-2. 1 HNMR (400MHz, DMSO-d6) δ8.37-8.33(m,1H),7.44(dd,J=3.6,2.4Hz,1H),6.98(dd,J=3.6,1.8Hz,1H),3.74(s,3H).

[0347] Step 2: Compound B-2 (630 mg, 3.31 mmol) and di-tert-butyl dicarbonate (1.77 mL, 8.28 mmol) were added to ethanol (18.0 mL), followed by palladium carbon (60 mg, 0.06 mmol, 10% mass fraction). The mixture was stirred at 25°C under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. Compound B-3 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 1 / 1) to obtain compound B-3. LCMS: m / z = 260.9 [M+H] + .

[0348] Step 3: Compound B-3 (80 mg, 0.31 mmol) was added to a dichloromethane (1.0 mL) solution, followed by trifluoroacetic acid (0.2 mL, 2.68 mmol), and stirred at 25°C for 3 hours. The reaction was monitored by TLC, and the reaction solution was concentrated to obtain compound Int B. LCMS: m / z = 161.0 [M+H] + .

[0349] Intermediate synthesis: Int C

[0350] Step 1: To a solution of compound C-2A (3.23 mL, 30.67 mmol) in dichloromethane (25 mL) was added dropwise a solution of 2,6-lutidine (3.93 mL, 33.74 mmol) in dichloromethane (25 mL) at 0°C. The reaction solution was stirred at 25°C for 0.5 hours, and then quenched with 1% aqueous sulfuric acid (32 mL, 0.06 mmol) at 0°C. 10 mL of water was added to the reaction solution, and the mixture was extracted with 60 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C-2B.

[0351] Step 2: To a solution of compound C-1 (2.00 g, 10.86 mmol) and triethylamine (1.66 mL, 11.95 mmol) in dichloromethane (30 mL) at -40°C, compound C-2B (1.57 mL, 17.38 mmol) was added. The reaction mixture was stirred at -40°C for 5 minutes. The reaction mixture was quenched with 30 mL of water and extracted with 120 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 75 / 25) to obtain compound C-2. 1 H NMR (400MHz, CDCl3) δ8.27(d,J=2.0Hz,1H),7.59(dd,J=9.9,16.6Hz,1H),7.51(d,J=2.0Hz,1H),6.7 4(dd,J=1.1,16.6Hz,1H), 6.38(dd,J=1.1,9.9Hz,1H), 4.38(q,J=7.1Hz,2H), 1.40(t,J=7.1Hz,3H).

[0352] Step 3: Diisobutylaluminum hydride (4.81 mL, 7.22 mmol) was added dropwise to a solution of compound C-2 (900 mg, 3.28 mmol) in dichloromethane (12 mL) at -78°C. The reaction mixture was stirred at -78°C for 0.5 hours. Aqueous hydrogen chloride solution (2N, 15 mL) was added to quench the mixture, followed by extraction with 75 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to yield compound C-3.

[0353] Step 4: Compound C-3 (320 mg, 1.38 mmol) was added to a solution of sodium hydride (82.7 mg, 2.07 mmol, 60% by mass) in tetrahydrofuran (6 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The mixture was quenched by adding water (30 mL) and extracted with ethyl acetate (90 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 75 / 25) to obtain compound C-4. 1 HNMR (400MHz, DMSO-d6) δ8.22 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 4.77 (br s, 2H), 4.21 (s, 4H).

[0354] Step 5: Dissolve compound C-4 (30 mg, 0.13 mmol) and di-tert-butyl dicarbonate (0.17 mL, 0.78 mmol) in methanol (2 mL), add palladium carbon (10 mg, 0.09 mmol, mass fraction 10%), and stir at 25 ° C for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, the filter cake was washed with 5 mL of methanol, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to obtain compound C-5. LCMS: m / z 303.0 [M+H] + .

[0355] Step 6: To a solution of compound C-5 (20 mg, 0.07 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.075 mL, 10.06 mmol), and the reaction mixture was stirred at 25°C for 5 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with 30 mL of ethyl acetate. The combined organic phases were dried, filtered, and concentrated to afford compound Int C.

[0356] Intermediate synthesis: Int D

[0357] Step 1: Dissolve compound D-1 (2.3 g, 10.13 mmol) and cerium chloride (1.25 g, 5.06 mmol) in tetrahydrofuran (46 mL). Slowly add a 1M solution of methylmagnesium bromide in tetrahydrofuran (30.39 mL) dropwise at -50°C. Warm the reaction mixture to 20°C and stir for 1 hour. Pour the reaction mixture into water (200 mL) and extract with ethyl acetate (200 mL x 2). The organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound D-2.

[0358] Step 2: Dissolve compound D-2 (2.40 g, 9.87 mmol) in dichloromethane (48 mL). Add trimethylsilyl cyanide (2.65 mL, 19.74 mmol) at 0°C, followed by indium bromide (0.70 g, 1.97 mmol). Stir the reaction mixture at 25°C for 1 hour. Pour the reaction solution into water (200 mL) and extract with dichloromethane (200 mL x 2). The organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product is purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound D-3. 1 H NMR(400MHz, DMSO-d6)δ7.82(d,J=1.6Hz,1H),7.59-7.50(m,1H),7.13(d,J=8.4Hz, 1H), 4.84-4.68 (m, 2H), 4.17 (d, J = 11.2Hz, 1H), 3.78 (d, J = 11.2Hz, 1H), 1.65 (s, 3H).

[0359] Step 3: Compound D-3 (50 mg, 0.20 mmol) and tert-butyl carbamate (46.86 mg, 0.40 mmol) were added to 1,4-dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (18.31 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.15 mg, 0.04 mmol), and cesium carbonate (162.91 mg, 0.50 mmol) were then added to the mixture. The reaction mixture was stirred at 110°C under nitrogen for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain compound D-4. 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 8. 4Hz,1H),6.55(s,1H),4.79(s,2H),4.11-3.89(m,2H),1.73(s,3H),1.46(s,9H).

[0360] Step 4: Dissolve compound D-4 (150 mg, 0.52 mmol) in 1,4-dioxane (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (2.17 mL, 4 M), and stir the reaction mixture at 25°C for 1 hour. Concentrate the reaction mixture under reduced pressure, add saturated aqueous sodium bicarbonate solution (20 mL), and then extract with dichloromethane (30 mL × 2). The organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound Int D. LCMS: m / z = 189.1 [M+H] + .

[0361] Intermediate synthesis: Int E

[0362] Step 1: At 25 ° C, sodium sulfide (3.35 g, 42.9 mmol) was added to a solution of compound E-1 (6.33 mL, 42.9 mmol) in N, N-dimethylformamide (100 mL). The reaction solution was stirred for 12 hours. 80 mL of water was added to the reaction solution to dilute it, and then the pH value was adjusted to about 3 with aqueous hydrochloric acid solution (1N). It was extracted with 240 mL of tert-butyl methyl ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 90 / 10) to obtain compound E-2.

[0363] Step 2: To a solution of compound E-2 (8.90 g, 36.0 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (1.50 g, 39.6 mmol) at 0°C, and the reaction mixture was stirred at this temperature for 1 hour. Aqueous hydrochloric acid (2N, 100 mL) was slowly added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound E-3.

[0364] Step 3: To a solution of compound E-3 (8.00 g, 36.5 mmol) and 1,2-dibromoethane (9.48 mL, 109.5 mmol) in N,N-dimethylformamide (150 mL) at 25°C, add potassium carbonate (15.1 g, 109.5 mmol). The reaction mixture was stirred at 70°C for 2 hours. 50 mL of water was added for dilution, followed by extraction with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20). Compound E-4 was obtained. 1H NMR (400MHz, CDCl3) δ7.55 (d, J = 1.9Hz, 1H), 7.46-7.43 (m, 1H), 7.37-7.31 (m, 2H), 6.4 6(dd,1H,J=9.5,16.5Hz), 5.45(d,1H,J=9.5Hz), 5.31(d,1H,J=16.5Hz), 4.73(s,2H).

[0365] Step 4: At 0 ° C, m-chloroperbenzoic acid (3.83 g, 18.8 mmol) was added to a solution of compound E-4 (2.20 g, 8.98 mmol) in dichloromethane (30 mL). The reaction solution was stirred at 25 ° C for 0.5 hours. The reaction solution was quenched with 10% aqueous sodium sulfite solution (50 mL), then extracted with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to obtain compound E-5. 1 H NMR(400MHz, DMSO-d6)δ8.00-7.96(m,2H),7.76(d,J=8.0Hz,1H),7.19(dd,J=9.9,16.4Hz,1H ), 6.41 (d, J = 16.5Hz, 1H), 6.32 (d, J = 9.9Hz, 1H), 5.60 (t, J = 5.6Hz, 1H), 4.74 (d, J = 5.5Hz, 2H).

[0366] Step 5: Compound E-5 (1.70 g, 6.13 mmol) was added to a suspension of sodium hydride (368 mg, 9.20 mmol, 60% mass fraction) in N,N-dimethylformamide (20 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (90 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to obtain compound E-6. 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 2.1, 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.20-4.17 (m, 2H), 3.70-3.66 (m, 2H).

[0367] Step 6: At 25°C, tris(dibenzylideneacetone)dipalladium (115.6 mg, 0.13 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (146.2 mg, 0.25 mmol) and cesium carbonate (823 mg, 2.53 mmol) were added to a solution of compound E-6 (350 mg, 1.26 mmol) and tert-butyl carbamate (221 mg, 1.89 mmol) in 1,4-dioxane (8 mL). The mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction solution was diluted with 15 mL of water and then extracted with 90 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 75 / 25) to obtain compound E-7. LCMS: m / z = 257.6 [M-55] + ; 1 H NMR (400MHz, CDCl3) δ7.91 (d, J = 2.3Hz, 1H), 7.83-7.74 (m, 1H), 7.30 (d, J = 8.3Hz, 1H), 6.66 (br s,1H),4.94(s,2H),4.41-4.30(m,2H),3.40-3.33(m,2H),1.54(s,9H).

[0368] Step 7: To a solution of compound E-7 (100 mg, 0.32 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL, 3.35 mmol), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL), then extracted with ethyl acetate (75 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int E. LCMS: m / z = 214.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.19(d,J=2.4Hz,1H),7.12(d,J=8.1Hz,1H),6.69(dd,J=2.4, 8.1Hz, 1H), 5.74 (s, 2H), 4.70 (s, 2H), 4.12 (dd, J = 4.0, 5.8Hz, 2H), 3.50-3.40 (m, 2H).

[0369] Intermediate synthesis: Int F

[0370] Step 1: At 25°C, add ethyl bromoacetate (5.05 mL, 45.66 mmol) and potassium carbonate (12.62 g, 91.33 mmol) to a solution of compound F-1 (10 g, 45.66 mmol) in acetonitrile (100 mL). The reaction solution was refluxed and stirred at 85°C for 8 hours. 80 mL of water was added to the reaction solution for dilution, and then extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound F-2. LCMS: m / z 305.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.12-7.98(m,2H),5.12(s,2H),4.38-4.21(m,2H),1.20(t,J=6.8Hz,3H).

[0371] Step 2: At 25°C, iron powder (5.28 g, 94.5 mmol) was added to a solution of compound F-2 (9.61 g, 31.5 mmol) in acetic acid (100 mL). The reaction solution was refluxed and stirred at 110°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound F-3. LCMS: m / z 229.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.49 (br s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 4.66 (s, 2H).

[0372] Step 3: Under nitrogen protection at 0°C, add borane tetrahydrofuran solution (66.26 mL, 1 M) to a solution of compound F-3 (6.07 g, 26.50 mmol) in tetrahydrofuran (60 mL). The reaction solution was refluxed and stirred at 75°C for 2 hours. The reaction solution was quenched with methanol (30 mL), and the quenched solution was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound F-4. LCMS: m / z 215.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ7.21 (br s, 1H), 6.87 (d, J = 7.9Hz, 1H), 6.57 (d, J = 7.9Hz, 1H), 4.08 (t, J = 4.8Hz, 2H), 3.38 (t, J = 3.8Hz, 2H).

[0373] Step 4: To a solution of compound F-4 (4.99 g, 23.2 mmol) and di-tert-butyl dicarbonate (12.4 mL, 58.0 mmol) in dichloromethane (50 mL) were added 4-dimethylaminopyridine (0.28 g, 2.32 mmol) and triethylamine (9.65 mL, 69.6 mmol), and the reaction solution was stirred at 25 ° C for 12 hours. 30 mL of water was added to the reaction solution, extracted with 150 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound Int F. LCMS: m / z 315.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.26-7.20 (m, 2H), 4.24 (t, J = 4.4Hz, 2H), 3.81 (t, J = 4.4Hz, 2H), 1.48 (s, 9H).

[0374] Intermediate synthesis: Int G, Int H

[0375] Step 1: At 25°C, compound H-1 (10.00 g, 39.30 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (8.88 g, 39.30 mmol) were added to dioxane-water (80.0 mL). Under a nitrogen atmosphere, sodium carbonate (8.32 g, 78.60 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (2.88 g, 3.93 mmol) were added and stirred at 90°C for 12 hours. The reaction mixture was filtered, and the filtrate was poured into water (100 mL), followed by extraction with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 60 / 40) to give H-2.

[0376] Step 2: At 25°C, H-2 (8.50 g, 37.50 mmol) was added to ethanol (60 mL), followed by sodium thiomethoxide (6.83 g, 97.50 mmol). The temperature was raised to 60°C and stirred for 2 hours. The reaction solution was quenched with aqueous sodium hypochlorite (50 mL, 5% by mass) and filtered to obtain compound H-3. LCMS: m / z = 181.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 12.14 (br s, 1H), 8.69 (s, 1H), 8.00 (d, J = 9.5Hz, 1H), 7.22 (s, 1H), 6.60 (d, J = 9.6Hz, 1H).

[0377] Step 3: At 25 ° C, H-3 (1.00 g, 5.54 mmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) isoxazole (1.30 g, 6.66 mmol) were added to dimethyl sulfoxide-water (20.0 mL). Under a nitrogen atmosphere, potassium fluoride (964 mg, 16.62 mmol) and dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (404 mg, 0.56 mmol) were added and stirred at 120 ° C for 12 hours. The above reaction solution was filtered and concentrated. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane = 1 / 99 ~ 15 / 85) and then purified by preparative high performance liquid chromatography column to obtain compound Int G. LCMS: m / z = 186.0 [M + H] + .

[0378] Step 4: At 25°C, compound Int G (350 mg, 1.89 mmol) was added to acetonitrile (10 mL), followed by phosphorus oxychloride (350 μL, 3.78 mmol). The temperature was raised to 80°C and stirred for 12 hours. The reaction solution was quenched by adding dropwise to a saturated solution of glacial sodium bicarbonate (20 mL). The mixture was then extracted with ethyl acetate (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound Int H. LCMS: m / z = 244.9 [M+42] + .

[0379] Intermediate synthesis: Int I

[0380] Step 1: Add compound Int G (200 mg, 1.08 mmol) to aqueous hydrochloric acid (3 mL, 8 M), raise the temperature to 100°C, and stir for 2 hours. The reaction mixture was concentrated to obtain compound I-1. LCMS: m / z 205.1 [M+H]+ .

[0381] Step 2: Add compound I-1 (190 mg, 0.93 mmol) to acetonitrile (2 mL), then add phosphorus oxychloride (1 mL), raise the temperature to 80°C, and stir for 5 hours. The reaction solution is added dropwise to an ice-saturated aqueous sodium bicarbonate solution (20 mL) to quench, filter, and purify the filtrate directly by preparative HPLC to obtain compound I-2. LCMS: m / z 223.0 [M+H] + .

[0382] Step 3: Compound I-2 (60 mg, 0.27 mmol) and compound Int E (57 mg, 0.27 mmol) were added to N, N-dimethylformamide (2 mL), and 1-propylphosphoric anhydride (342 mg, 0.81 mmol, mass fraction 50%) and N, N-diisopropylethylamine (134 μL, 0.81 mmol) were added and stirred at 25 ° C for 1 hour. The reaction solution was quenched by adding water (5 mL) and extracted with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol = 99 / 1 to 90 / 10) to obtain compound Int I. LCMS: m / z 418.0 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ: 10.73 (s, 1H), 9.40 (s, 1H), 8.64 (d, J = 8.4Hz, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.88-7.85 (m, 2H),7.75(d,J=8.6Hz,1H),7.49(d,J=8.0Hz,1H),4.84(s,2H),4.20-4.15(m,2H),4.11(s,2H),3.62-3.54(m,2H).

[0383] Intermediate synthesis: Int J

[0384] Step 1: To a solution of compound J-1 (1.00 g, 5.68 mmol) and cis-2,6-dimethylmorpholine (0.70 mL, 5.68 mmol) in dimethyl sulfoxide (15 mL) at 25°C, add N,N-diisopropylethylamine (1.88 mL, 11.4 mmol), then heat to 120°C and stir for 12 hours. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 10 / 90) to obtain compound J-2.

[0385] Step 2: At 25°C, compound J-2 (900 mg, 3.32 mmol), lithium chloride (703.48 mg, 16.60 mmol), tricyclohexylphosphine (93.08 mg, 0.33 mmol), and tris(dibenzylacetone)dipalladium (151.97 mg, 0.17 mmol) were added to dioxane (40 mL). Hexabutyltin dihydrate (2.01 mL, 3.98 mmol) was then added, and the reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was added to a saturated aqueous potassium fluoride solution (100 mL) and stirred for 2 hours. The mixture was extracted with ethyl acetate (50 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 90 / 10) to obtain compound J-3. LCMS: m / z = 483.0 [M+H]+.

[0386] Step 3: At 25°C, compound J-3 (756.67 mg, 1.57 mmol), cuprous iodide (56.12 mg, 0.29 mmol), tetrakistriphenylphosphine palladium (170.25 mg, 0.15 mmol), and compound Int H (300 mg, 1.47 mmol) were added to dioxane (20 mL). The reaction solution was stirred at 100°C for 3 hours. The reaction solution was added to a saturated aqueous potassium fluoride solution (100 mL) and stirred for 2 hours. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (dichloromethane / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound J-4. LCMS: m / z = 360.2 [M+H]+.

[0387] Step 4: Compound J-4 (266 mg, 0.74 mmol) and barium hydroxide (240 mg, 1.4 mmol) were added to isopropanol (15 mL) and water (10 mL) at 25°C, and the reaction mixture was stirred at 100°C for 4 hours. Aqueous hydrogen chloride solution (1 M) was added dropwise to the reaction mixture to adjust the pH to acidic. Methanol was then added and the mixture was purified by C18 reverse-phase silica gel column chromatography (water / acetonitrile = 99 / 1 to 60 / 40) to obtain compound Int J. LCMS: m / z = 379.2 [M+H]+.

[0388] Intermediate synthesis: Int K

[0389] Step 1: Dissolve compound K-1 (8 g, 44.69 mmol) in dichloromethane (20 mL), add di-tert-butyl dicarbonate (9.75 g, 44.69 mmol) and 4-dimethylaminopyridine (0.55 g, 4.47 mmol). The reaction mixture is stirred at 25°C for 2 hours. Pour the reaction solution into water (40 mL) and then extract with dichloromethane (30 mL x 2). The organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product is purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound K-2. LCMS: m / z = 301.0 [M+Na] + .

[0390] Step 2: Compound K-2 (870 mg, 3.12 mmol) and compound J-3 (1.8 g, 3.74 mmol) were added to 1,4-dioxane (40 mL). Tetrakistriphenylphosphine palladium (360.15 mg, 0.31 mmol) and cuprous iodide (118.71 mg, 0.62 mmol) were then added to the mixture. The reaction mixture was stirred at 100°C for 3 hours under nitrogen. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound K-3. LCMS: m / z = 391.2 [M+H] + .

[0391] Step 3: Dissolve compound K-3 (335 mg, 0.86 mmol) in 1,4-dioxane (1 mL), add a 1,4-dioxane solution of hydrochloric acid (10.7 mL, 4 M), and stir the reaction mixture at 25°C for 5 hours. Concentrate the reaction mixture under reduced pressure, add saturated aqueous sodium bicarbonate solution (100 mL), and then extract with ethyl acetate (100 mL × 2). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound Int K. LCMS: m / z = 291.2 [M+H] + .

[0392] Intermediate synthesis: Int L

[0393] Step 1: Compound Int K (120 mg, 0.41 mmol), triethylamine (114.57 μL, 0.83 mmol), and 4-dimethylaminopyridine (5.0 mg, 0.04 mmol) were added to dichloromethane (0.50 mL), followed by the addition of methyl 3-chloro-3-oxopropanoate (54 μL, 0.50 mmol) and stirred at 25°C for 1.5 hours. The reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Compound L-1 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound L-1. LCMS: m / z 391.1 [M+H] + .

[0394] Step 2: Compound L-1 (40 mg, 0.10 mmol) was added to a mixed solution of tetrahydrofuran (1.6 mL) and water (0.8 mL), followed by the addition of lithium hydroxide monohydrate (22 mg, 0.51 mmol), and stirred at 25°C for 3 hours. The reaction solution was adjusted to pH 2-3 with aqueous hydrochloric acid (2N) and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound Int L. LCMS: m / z 377.1 [M+H] + .

[0395] Intermediate synthesis: Int M

[0396] Step 1: A solution of compound J-3 (2 g, 4.16 mmol), compound M-1 (0.92 g, 4.16 mmol) and dichlorobis(triphenylphosphine)palladium (0.58 g, 0.83 mmol) in N,N-dimethylformamide (30 mL) was stirred at 100 ° C under a nitrogen atmosphere for 12 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound M-2. LCMS: m / z = 334.0 [M+H] + .

[0397] Step 2: To a mixed solution of compound M-2 (1 g, 3.00 mmol) in methanol (2.5 mL), tetrahydrofuran (5 mL), and water (2.5 mL) was added lithium hydroxide (0.14 g, 6.00 mmol). The reaction mixture was stirred at 10°C for 1 hour. The pH of the reaction mixture was adjusted to 4 with aqueous hydrochloric acid (1 M). The crude product was purified by C18 reverse phase column chromatography (acetonitrile / 0.1% aqueous formic acid) to obtain compound M-3. LCMS: m / z = 320.0 [M+H] + .

[0398] Step 3: To a solution of compound M-3 (300 mg, 0.94 mmol), glycine methyl ester hydrochloride (117.93 mg, 0.94 mmol) and N, N-diisopropylethylamine (364.22 mg, 2.82 mmol) in N, N-dimethylformamide (5 mL) was added a 50% ethyl acetate solution of propylphosphonic anhydride (1793.24 mg, 2.82 mmol). The final reaction solution was stirred at 10 ° C for 12 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 3), the organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound M-4. LCMS: m / z = 391.0 [M + H] + .

[0399] Step 4: To a mixed solution of compound M-4 (340 mg, 0.87 mmol) in methanol (1 mL), tetrahydrofuran (2 mL), and water (1 mL) was added lithium hydroxide (41.71 mg, 1.74 mmol), and the reaction mixture was stirred at 10°C for 1 hour. The reaction mixture was adjusted to pH 4 with aqueous hydrochloric acid (1 M). The crude product was purified by C18 reverse phase column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain compound Int M. LCMS: m / z = 377.0 [M+H] + .

[0400] Intermediate synthesis: Int N

[0401] Step 1: Add methyl 3-chloro-3-oxopropanoate (1.44 mL, 13.41 mmol) dropwise to a solution of compound N-1 (2 g, 11.17 mmol) in dichloromethane (25 mL) at 0°C and allow to react naturally at room temperature for 2 hours. Dilute with 10 mL of water and extract with ethyl acetate (30 mL). The crude product is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound N-2. LCMS: m / z 278.8 [M+H] + .

[0402] Step 2: Add lithium hydroxide (128.71 mg, 5.37 mmol) to a solution of compound N-2 (500 mg, 1.79 mmol) in methanol (10 mL) and water (1 mL). Stir at 25°C for 18 hours. Concentrate under reduced pressure to remove methanol, dilute with water (10 mL), adjust the pH to 7 with dilute aqueous hydrochloric acid (1 M), filter, collect the filter cake, and dry. Compound N-3 is obtained. LCMS: m / z 264.8 [M+H] + .

[0403] Step 3: Propylphosphonic anhydride (0.48 mL, 0.94 mmol) was added dropwise to a solution of compound N-3 (100 mg, 0.38 mmol), compound Int E (124.30 mg, 0.58 mmol), and triethylamine (0.20 mL, 1.41 mmol) in N,N-dimethylformamide (2 mL). The mixture was reacted at 25°C for 3 hours. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (30 mL). The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain compound Int N. LCMS: m / z 459.8 [M+H] + .

[0404] Intermediate synthesis: Int O

[0405] Step 1: To a solution of compound O-1 (1.78 g, 6.73 mmol), tricyclohexylphosphine (190 mg, 0.67 mmol), and lithium chloride (1.43 g, 33.6 mmol) in dioxane (90 mL) were added tris(dibenzylideneacetone)dipalladium (310 mg, 0.31 mmol) and hexabutylditin (3.98 g, 6.86 mmol), respectively. The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound O-2. LCMS: m / z = 450.2 [M+H] + .

[0406] Step 2: To a solution of compound O-2 (900 mg, 4.42 mmol), compound Int H (2.3 g, 5.30 mmol), and cuprous iodide (168 mg, 0.88 mmol) in dioxane (30 mL) was added palladium tetratriphenylphosphine (510 mg, 0.44 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound O-3. LCMS: m / z = 327.0 [M+H] + .

[0407] Step 3: To a mixed solution of compound O-3 (640 mg, 1.96 mmol) in isopropanol (10 mL) and water (10 mL) was added barium hydroxide (1.68 g, 9.18 mmol), and the reaction solution was stirred at 100°C for 16 hours. The reaction solution was diluted with dilute hydrochloric acid (10 mL), extracted with dichloromethane (5 mL × 3), and the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 5:1) to obtain compound Int O. LCMS: m / z = 346.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),9.38(s,1H),8.64(d,J=8.4Hz,1H),8.46(d,J=7.6Hz,1H),8.20( d,J=8.4Hz,1H),7.92(s,1H),7.52(d,J=7.6Hz,1H),7.00(t,J=54.8Hz,1H),4.03(s,3H),3.99(s,2H).

[0408] Intermediate synthesis: Int P

[0409] Step 1: A mixture of compound P-1 (5 g, 28.74 mmol), sodium 2-chloro-2,2-difluoroacetate (5.26 g, 34.48 mmol), and cesium carbonate (18.73 g, 57.4 mmol) in N,N-dimethylformamide (100 mL) and water (15 mL) was heated to 100°C under nitrogen and stirred for 16 hours. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound P-2. LCMS: m / z = 224.0, 226.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.89 (t, J = 8.0 Hz, 1H), 7.65 (t, J = 72.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H).

[0410] Step 2: To a solution of compound P-2 (2.2 g, 9.82 mmol), tricyclohexylphosphine (280 mg, 0.90 mmol), and lithium chloride (2.07 g, 48.83 mmol) in dioxane (90 mL) were added tris(dibenzylideneacetone)dipalladium (450 mg, 0.49 mmol) and hexabutylditin (5.80 g, 10.0 mmol), respectively. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound P-3. LCMS: m / z = 436.2 [M+H] + .

[0411] Step 3: To a solution of compound Int H (200 mg, 0.98 mmol), compound P-3 (554 mg, 1.28 mmol), and cuprous iodide (37 mg, 0.2 mmol) in dioxane (12 mL) was added palladium tetraphenylphosphine (113 mg, 0.1 mmol). The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound P-4. LCMS: m / z = 313.0 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ9.48(s,1H),8.80(d,J=8.8Hz,1H),8.71(d,J=8.8Hz,1H),8.49(d,J=7.6Hz ,1H),8.18(t,J=8.0Hz,1H),8.10(t,J=72.0Hz,1H),8.04(s,1H),7.30(d,J=8.0Hz,1H),4.44(s,2H).

[0412] Step 4: To a mixed solution of compound P-4 (260 mg, 0.83 mmol) in isopropanol (10 mL) and water (10 mL) was added barium hydroxide (713 mg, 4.16 mmol), and the reaction solution was stirred at 100°C for 16 hours. The reaction solution was diluted with dilute hydrochloric acid (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 5:1) to obtain compound Int P. LCMS: m / z = 332.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.74(d,J=8.8Hz,1H),8.65(d,J=8.8Hz,1H),8.47(d,J=7.6Hz, 1H),8.17(t,J=8.0Hz,1H),8.09(t,J=72.0Hz,1H),7.95(s,1H),7.29(d,J=8.0Hz,1H),3.95(s,2H).

[0413] Intermediate synthesis: Int R

[0414] Step 1: To a solution of ethanol (2.2 g, 47.75 mmol) in tetrahydrofuran (10 mL) at 0°C, sodium hydroxide (1.9 g, 47.50 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of compound R-1 (5 g, 18.90 mmol) at this temperature. The reaction mixture was stirred at 25°C under nitrogen for 16 hours. Dilute hydrochloric acid was added to the reaction mixture to adjust the pH to 3, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound R-2. LCMS: m / z = 246.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.18 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0415] Step 2: To a solution of compound R-2 (3.7 g, 15.04 mmol) in N,N-dimethylformamide (50 mL) were added dimethylhydroxylamine hydrochloride (2.20 g, 22.56 mmol), HATU (8.58 g, 22.56 mmol) and N,N-diisopropylethylamine (5.83 g, 45.11 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound R-3. LCMS: m / z = 289.0

[0416] [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=7.6Hz,1H),7.13(d,J=8.0Hz,1H),4.39(q,J=7.2Hz,2H),3.69(s,3H),3.28(s,3H),1.35(t,J=7.2Hz,3H).

[0417] Step 3: Dissolve compound R-3 (4.0 g, 12.45 mmol) in tetrahydrofuran (50 mL), cool to 0°C, and slowly add methylmagnesium bromide (12.45 mL, 37.35 mmol, 3 M tetrahydrofuran solution). The reaction mixture is stirred at 25°C for 2 hours. Saturated ammonium chloride (100 mL) is added to quench the mixture, and the mixture is extracted with ethyl acetate (100 mL x 2). The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound R-4. LCMS: m / z = 244.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

[0418] Step 4: To a solution of compound R-4 (2.7 g, 9.96 mmol) in dichloromethane (50 mL) were added tert-butyldimethylsilyl trifluoromethanesulfonate (3.95 g, 14.93 mmol) and triethylamine (3.02 g, 29.87 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in acetonitrile (50 mL), and then a selective fluorine reagent (4.23 g, 11.95 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. Saturated ammonium chloride (80 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound R-5. LCMS: m / z = 262.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.27 (d, J = 7.8 Hz, 1H), 7.49 ( d, J = 7.8 Hz, 1H), 5.91 ( d, J = 47.2 Hz, 2H), 4.45 ( q, J = 7.2 Hz, 2H), 1.39 ( t, J = 7.2 Hz, 3H).

[0419] Step 5: A solution of (R)-2-methyl-CBS-oxazaborolidine (2.2 g, 7.97 mmol) in tetrahydrofuran (40 mL) was cooled to 0°C. Borane in tetrahydrofuran (12 mL, 11.96 mmol, 1 M solution in tetrahydrofuran) was added. The reaction mixture was stirred at 0°C for 30 minutes. Compound R-5 (2.2 g, 7.97 mmol) was then added and stirred at 0°C for 6 hours. The reaction mixture was quenched with methanol (10 mL) and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound R-6. LCMS: m / z = 264.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=8.0Hz,1H),7.07(dd,J=8.0,0.8Hz,1H),5.94(d,J=5.2Hz,1H),4.77-4.6 8(m,1H),4.66-4.57(m,1H),4.46(dd,J=9.2,6.4Hz,1H),4.37(qd,J=7.2,4.8Hz,2H),1.33(t,J=7.2Hz,3H).

[0420] Step 6: Dissolve compound R-6 (2.2 g, 7.91 mmol) in dichloromethane (50 mL), cool to 0°C, and add diethylaminosulfur trifluoride (1.91 g, 11.87 mmol). Stir the reaction mixture at 0°C for 2 hours. Slowly add saturated sodium bicarbonate (50 mL) to quench the mixture, extract with dichloromethane (100 mL x 2), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound R-7. LCMS: m / z = 266.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H),5.95-5.61(m,1H),5.02-4.74(m,2H),4.41-4.36(m,2H),1.34(t,J=7.2Hz,3H).

[0421] Step 7: Dissolve compound R-7 (1.0 g, 3.57 mmol) in hexabutyltin (10 mL), add lithium chloride (756 mg, 17.83 mmol), tris(dibenzylideneacetone)dipalladium (163 mg, 0.18 mmol), and tricyclohexylphosphine (100 mg, 0.36 mmol). Stir the reaction mixture at 100°C for 4 hours. Quench the reaction mixture with aqueous potassium fluoride (80 mL) and extract with ethyl acetate (50 mL x 2). The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 49:1) to obtain compound R-8. LCMS: m / z = 478.2 [M+H] + .

[0422] Step 8: To a solution of compound R-8 (1.0 g, 1.99 mmol), compound Int H (0.5 g, 2.46 mmol), and cuprous iodide (120 mg, 0.63 mmol) in dioxane (12 mL) was added palladium tetraphenylphosphine (290 mg, 0.25 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound R-9. LCMS: m / z = 355.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.66(d,J=8.8Hz,1H),8.44(d,J=7.6Hz,1H),8.28(d,J=8.8Hz,1H),7.98 (s,1H),7.35(d,J=7.6Hz,1H),6.17-5.54(m,1H),5.29-4.83(m,2H),4.66-4.34(m,4H),1.37(t,J=7.2Hz,3H).

[0423] Step 9: To a mixed solution of compound R-9 (260 mg, 0.66 mmol) in isopropanol (4 mL) and water (4 mL) was added barium hydroxide (678.86 mg, 3.96 mmol). The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was adjusted to pH 6 by adding 1M dilute hydrochloric acid and then directly purified by C18 (water (trifluoroacetic acid, 0.1%):acetonitrile = 1 / 1) to obtain compound R-10. LCMS: m / z = 354.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),9.36(s,1H),8.62(d,J=8.8Hz,1H),8.45(d,J=7.6Hz,1H),8.26(d,J=8.4Hz,1H),7.91(s ,1H),7.42-7.40(m,1H),5.85-5.72(m,1H),5.22(dd,J=16.8Hz,1H),4.53(q,J=6.8Hz,2H),3.98(s,2H),1.40(t,J=7.2Hz,3H).

[0424] Step 10: To a solution of compound R-10 (60 mg, 0.17 mmol) in tetrahydrofuran (4 mL) was added wet palladium on carbon (20 mg). The reaction mixture was stirred at 25°C for 4 hours under a hydrogen balloon. The reaction mixture was filtered and dried. Compound Int R was obtained directly by purification via C18 (water (trifluoroacetic acid, 0.1%):acetonitrile = 1 / 1). LCMS: m / z = 356.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.55(s,1H),9.37(s,1H),8.61(d,J=8.8Hz,1H),8.40(d,J=7.6Hz,1H),8.24(d,J=8.8Hz,1H),7.92(s,1 H),7.29(d,J=7.6Hz,1H),5.79-5.65(m,1H),4.58-4.39(m,2H),3.98(s,2H),1.67(dd,J=24.4,6.4Hz,3H),1.37(t,J=7.2Hz,3H).

[0425] Intermediate synthesis: Int S

[0426] Step 1: Chlorosulfonic acid (200 mL) was slowly added to compound S-1 (40 g, 256.23 mmol). The reaction mixture was heated to 80°C under nitrogen and stirred for 16 hours. The reaction mixture was cooled to 0°C and ice water (500 mL) was slowly added. Solids precipitated and were filtered. The filter cake was rinsed with water (200 mL) and the solids were collected to obtain crude compound S-2. This crude product was used directly in the next reaction. 1 HNMR (400MHz, DMSO-d6) δ7.91-7.90(m,1H),7.66-7.62(m,1H).

[0427] Step 2: To a solution of compound S-2 (37 g, 145.32 mmol) in toluene (500 mL) was added triphenylphosphine (114.3 g, 435.96 mmol) and stirred at 90°C for 16 hours. A solid precipitated and was filtered. The filter cake was rinsed with toluene (200 mL) and the solid was collected to obtain crude compound S-3. This crude product was used directly in the next reaction. LCMS: m / z = 186.9 [MH] - .

[0428] Step 3: Slowly add sulfuric acid (20 mL) to a solution of compound S-3 (50 g, 188.17 mmol, 50% purity) in methanol (200 mL). The reaction mixture is stirred at 80°C for 16 hours. Methanol is removed under reduced pressure, and the mixture is diluted with water (500 mL). The mixture is extracted with ethyl acetate (500 mL x 2). The organic phases are combined, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound S-4. LCMS: m / z = 201.0 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ7.78–7.77(m,1H),7.46–7.43(m,1H),3.81(s,3H).

[0429] Step 4: To a solution of compound S-4 (25 g, 123.64 mmol) in N,N-dimethylformamide (300 mL) were added cesium carbonate (201.42 g, 618.20 mmol) and 1,3-dibromopropane (229.95 g, 148.37 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound S-5. LCMS: m / z = 243.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.71(t,J=1.7Hz,1H),7.62(dd,J=10.4,2.1Hz,1H),4.38–4.31(m,2H),3.83(s,3H),3.08–3.00(m,2H),2.25–2.20(m,2H).

[0430] Step 5: To a solution of compound S-5 (5.94 g, 22.07 mmol) in acetonitrile (60 mL) were added a selective fluorine reagent (9.77 g, 27.58 mmol) and diethylaminosulfur trifluoride (0.71 g, 4.41 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound S-6. LCMS: m / z = 261.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.89–7.68(m,2H),6.47–6.19(m,1H),4.67–4.57(m,1H),4.12–3.98(m,1H),3.85(s,3H),2.62–2.51(m,2H).

[0431] Step 6: Dissolve compound S-6 (3.5 g, 12.10 mmol) in tetrahydrofuran (20 mL), methanol (10 mL), and water (5 mL). Add lithium hydroxide (0.58 g, 24.21 mmol). Stir the reaction mixture at 25°C for 2 hours. Add dilute hydrochloric acid to adjust the pH to 3. Then, extract with ethyl acetate (100 mL x 2). Combine the organic phases, dry them over anhydrous sodium sulfate, and filter them. Concentrate the filtrate to obtain crude compound S-7. LCMS: m / z = 247.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.32(s,1H),7.79–7.69(m,2H),6.37–6.15(m,1H),4.62–4.56(m,1H),4.12–3.97(m,1H),2.61–2.51(m,2H).

[0432] Step 7: Compound S-7 (2.7 g, 10.97 mmol) was dissolved in methanol (50 mL) and water (50 mL), and potassium peroxymonosulfate (26.96 g, 43.86 mmol) was added. The reaction solution was stirred at 25°C for 6 hours. The insoluble material was removed by filtration, and the filtrate was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound S-8. LCMS: m / z = 279.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.29–8.10(m,2H),6.35–6.22(m,1H), 4.64–4.59(m,1H),4.20–4.13(m,1H),2.92–2.71(m,1H),2.66–2.54(m,1H).

[0433] Step 8: Dissolve compound S-8 (400 mg, 1.37 mmol) in tert-butyl alcohol (6 mL) and add diphenylphosphoryl azide (594 mg, 2.16 mmol) and triethylamine (291 mg, 2.88 mmol). Stir the reaction mixture at 60°C for 6 hours. Concentrate the reaction mixture. The crude product is directly purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound S-9.

[0434] Step 9: Compound S-9 (400 mg, 10.97 mmol) was dissolved in tert-butanol (8 mL). The reaction solution was stirred at 100 ° C for 16 hours. The reaction solution was cooled to 25 ° C, 1-4 dioxane hydrochloride (4 mL, 4 M) was added, and the reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL × 2) were added for extraction, the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound Int S. LCMS: m / z = 250.0 [M + H] + . 1 H NMR(400MHz, DMSO-d6)δ6.90(dd,J=2.7,1.2Hz,1H),6.73(dd,J=12.3,2.8Hz,1H),6.12–5.99(m, 1H), 5.78 (s, 2H), 4.37–4.32 (m, 1H), 3.85 (t, J = 12Hz, 1H), 2.76–2.56 (m, 1H), 2.47–2.38 (m, 1H).

[0435] Intermediate synthesis: Int SA

[0436] Step 1: Compound S-7 (2.5 g, 8.99 mmol) was separated by SFC (separation column: WATERS 150 preparative SFC (AD-H), mobile phase: A: carbon dioxide, B: methanol (0.1% NH3 (7N in MeOH)), gradient: B%: 5%-25% over 4.0 minutes, flow rate: 100 mL / min, column temperature: 35°C, ABPR: 100 psi) to obtain compound SA-1 (retention time: 2.118 minutes, any single configuration and opposite to that of SB-1). Compound SB-1 (retention time: 3.838 minutes, any single configuration and opposite to that of SA-1). The crude compound SA-1 was spin-dried, diluted with dilute hydrochloric acid (20 mL, 1 M), and extracted with dichloromethane (50 mL x 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound SA-1. LCMS: m / z = 279.0 [M+H] +The crude compound SB-1 was dried, diluted with dilute hydrochloric acid (20 mL, 1 M), and extracted with dichloromethane (50 mL x 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound SB-1. LCMS: m / z = 279.0 [M+H] + .

[0437] Step 2: Dissolve compound SA-1 (620 mg, 2.12 mmol) in tert-butyl alcohol (6 mL), add diphenylphosphoryl azide (920 mg, 3.34 mmol) and triethylamine (451 mg, 4.46 mmol), and stir the reaction at 60°C for 6 hours. Concentrate the reaction mixture. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound SA-2.

[0438] Step 3: Dissolve compound SA-2 (600 mg, 1.88 mmol) in tert-butanol (8 mL). Stir the reaction solution at 100°C for 16 hours. Cool the reaction solution to 25°C, add 1-4-dioxane hydrochloride (4 mL, 4 M), and continue stirring the reaction solution at 25°C for 2 hours. Concentrate the reaction solution under reduced pressure, add saturated sodium bicarbonate (50 mL), and extract with ethyl acetate (50 mL × 2). Combine the organic phases and wash with brine (50 mL), dry over anhydrous sodium sulfate, and filter. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound SA. LCMS: m / z = 250.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ6.90(dd,J=2.8,1.2Hz,1H),6.73(dd,J=12.4,2.8Hz,1H),6.12–5.99(m,1 H), 5.81 (s, 2H), 4.38–4.32 (m, 1H), 3.85 (t, J = 12.0Hz, 1H), 2.78–2.57 (m, 1H), 2.49–2.42 (m, 1H).

[0439] Intermediate synthesis: Int SB

[0440] Step 1: Dissolve compound SB-1 (400 mg, 1.44 mmol) in tert-butyl alcohol (6 mL). Add diphenylphosphoryl azide (600 mg, 2.18 mmol) and triethylamine (300 mg, 2.96 mmol). Stir the reaction mixture at 60°C for 6 hours. Concentrate the reaction mixture. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound SB-2.

[0441] Step 2: Dissolve compound SB-2 (400 mg, 1.25 mmol) in tert-butanol (8 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and 1-4-dioxane hydrochloride (4 mL, 4 M) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL × 2) were added for extraction. The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound SB. LCMS: m / z = 250.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ6.90(dd,J=2.8,1.2Hz,1H),6.73(dd,J=12.4,2.8Hz,1H),6.12–5.99(m,1 H), 5.81 (s, 2H), 4.42–4.29 (m, 1H), 3.85 (t, J = 12.0Hz, 1H), 2.82–2.60 (m, 1H), 2.49–2.42 (m, 1H).

[0442] Intermediate synthesis: Int T

[0443] Step 1: Slowly add chlorosulfonic acid (150 mL) to compound T-1 (30 g, 173.85 mmol). Heat the reaction mixture to 80°C under nitrogen and stir for 16 hours. Cool the reaction mixture to 0°C and slowly add ice water (500 mL). Solids precipitate and filter. Rinse the filter cake with water (200 mL) and collect the solids to obtain crude compound T-2. This crude product is used directly in the next reaction. 1 HNMR (400MHz, DMSO-d6) δ8.02 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H).

[0444] Step 2: To a solution of compound T-2 (30 g, 110.68 mmol) in toluene (500 mL) was added triphenylphosphine (87 g, 331.69 mmol). The mixture was stirred at 90°C for 16 hours. A solid precipitated and was filtered. The filter cake was rinsed with toluene (200 mL) and the solid was collected to obtain crude compound T-3. This crude product was used directly in the next reaction. LCMS: m / z = 202.9 [MH] - .

[0445] Step 3: To a solution of compound T-3 (40 g, 97.74 mmol, 50% purity) in methanol (200 mL) was slowly added concentrated sulfuric acid (20 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, added with water (500 mL), and extracted with ethyl acetate (500 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound T-4. LCMS: m / z = 219.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 2.0Hz, 1H), 7.63 (s, 1H), 3.80 (s, 3H).

[0446] Step 4: To a solution of compound T-4 (15 g, 68.60 mmol) in N,N-dimethylformamide (200 mL) were added cesium carbonate (111.76 g, 343.01 mmol) and 1,3-dibromopropane (16.62 g, 82.32 mmol). The reaction mixture was stirred at 25°C for 16 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined and washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound T-5. LCMS: m / z = 259.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.91-7.78(m,2H),4.38-4.29(m,2H),3.84(s,3H),3.10-2.96(m,2H),2.25-2.19(m,2H).

[0447] Step 5: A solution of compound T-5 (5.3 g, 20.49 mmol) in acetonitrile (60 mL) was cooled to 0°C, and a selective fluorine reagent (9.07 g, 25.61 mmol) and diethylaminosulfur trifluoride (0.66 g, 4.10 mmol) were added. The reaction mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound T-6. LCMS: m / z = 277.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),6.41-6.16(m,1H),4.60(dt,J =12.4,4.6Hz,1H),4.03(tt,J=8.7,3.6Hz,1H),3.85(s,3H),2.57-2.52(m,1H),2.49-2.46(m,1H).

[0448] Step 6: Dissolve compound T-6 (1.60 g, 5.78 mmol) in tetrahydrofuran (8 mL), methanol (4 mL), and water (2 mL). Add lithium hydroxide (0.28 g, 11.56 mmol). Stir the reaction mixture at 25°C for 2 hours. Add dilute hydrochloric acid to adjust the pH to 3. Extract with ethyl acetate (100 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain crude compound T-7. LCMS: m / z = 263.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=2.0Hz,1H),7.88(d,J=2.0Hz,1H),6.36-6.15(m,1H),4.62-4.56(m 1H),4.05-3.99(m,1H),2.54-2.48(m,1H),2.49-2.43(m,1H).

[0449] Step 7: Compound T-7 (1.2 g, 4.57 mmol) was dissolved in methanol (10 mL) and water (10 mL), and potassium peroxymonosulfate (5.62 g, 9.14 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The insoluble material was removed by filtration, and the filtrate was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound T-8. LCMS: m / z = 295.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),6.32-6.19(m,1 H), 4.64-4.06 (m, 1H), 4.09 (t, J = 12.0Hz, 1H), 2.93-2.73 (m, 1H), 2.68-2.56 (m, 1H).

[0450] Step 8: Dissolve compound T-8 (760 mg, 2.45 mmol) in tert-butyl alcohol (10 mL), add diphenylphosphoryl azide (1065 mg, 3.87 mmol) and triethylamine (522 mg, 2.11 mmol), and stir the reaction at 60°C for 6 hours. The reaction mixture is concentrated. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound T-9.

[0451] Step 9: Dissolve compound T-9 (400 mg, 1.19 mmol) in tert-butanol (8 mL). The reaction solution was stirred at 100 ° C for 16 hours. The reaction solution was cooled to 25 ° C, and 1-4 dioxane hydrochloride (4 mL, 4 M) was added and the reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL × 2) were added for extraction. The organic phases were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound Int T. LCMS: m / z = 266.0 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ7.04(d,J=2.8Hz,1H),6.96(d,J=2.8Hz,1H),6.11-5.98(m,1H),5. 79(s,2H),4.38-4.33(m,1H),3.81(t,J=11.9Hz,1H),2.77-2.60(m,1H),2.46-2.42(m,1H).

[0452] Intermediate synthesis: Int U

[0453] Step 1: To a solution of compound U-1 (20.00 g, 79.67 mmol) in N,N-dimethylformamide (200 mL) was added sodium sulfide (0.86 g, 4.27 mmol). The reaction mixture was heated to 30°C and stirred under nitrogen for 18 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield crude compound U-2, which was used directly in the next reaction.

[0454] Step 2: To a solution of compound U-2 (200.00 mg, 1.31 mmol) in tetrahydrofuran (50 mL) at 0°C was added lithium aluminum tetrahydride (3.18 g, 83.75 mmol). The reaction mixture was stirred at 0°C under nitrogen for 1 hour. The reaction mixture was quenched with 1M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate (5 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude compound U-3. This crude product was used directly in the next reaction.

[0455] Step 3: To a solution of compound U-3 (16.40 g, 59.49 mmol) and potassium carbonate (28.68 g, 207.52 mmol) in N,N-dimethylformamide (160 mL) was added 1,2-dibromoethane (64.97 g, 345.86 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound U-4. 1 H NMR (400MHz, CDCl3) δ: 7.35 (t, J=1.5Hz, 1H), 7.19 (dd, J=8.8, 1.9Hz, 1H), 6.47 (dd, J= 16.5, 9.4Hz, 1H), 5.53 (d, J = 9.4Hz, 1H), 5.44 (d, J = 16.5Hz, 1H), 4.79 (d, J = 2.0Hz, 2H).

[0456] Step 4: To a solution of compound U-4 (12.80 g, 48.65 mmol) in dichloromethane (52 mL) at 0°C was added m-chloroperbenzoic acid (12.5 g, 57.95 mmol). The reaction was stirred at 25°C for 16 hours. Insoluble matter was removed by filtration, and the filtrate was diluted with water (350 mL) and extracted with ethyl acetate (350 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound U-5. 1H NMR (400MHz, DMSO-d6) δ7.73(td,J=7.6,6.2,2.0Hz,1H),7.65–7.60(m,1H),7.10(dd,J=16.4,9.5Hz,1H),6.04(d,J=16.3H z, 1H), 5.94 (d, J = 9.4Hz, 1H), 5.84 (dd, J = 6.1, 4.4Hz, 1H), 4.74 (dd, J = 13.3, 4.4Hz, 1H), 4.61 (ddd, J = 13.3, 6.1, 2.2Hz, 1H).

[0457] Step 5: To a solution of compound U-5 (9.30 g, 33.32 mmol) in N,N-dimethylformamide (186 mL) was added sodium hydride (2.67 g, 66.64 mmol) at 0°C. The reaction was stirred at 0°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution (350 mL) and extracted with ethyl acetate (350 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound U-6. 1 H NMR (400MHz, CDCl3) δ7.83-7.79(m,1H),7.38(dd,J=8.6,2.0Hz,1H),5.15(d,J=14.6Hz,1H) ,4.53–4.35(m,3H),3.46(ddd,J=13.3,9.7,3.7Hz,1H),3.26(ddd,J=13.3,5.0,2.7Hz,1H).

[0458] Step 6: To a solution of compound U-6 (2.3 g, 8.24 mmol) in antimony trichloride (0.41 g, 1.79 mmol) in chloroform (25 mL) was added diethylaminosulfur trifluoride (25 mL) at 0°C. The reaction mixture was stirred at 50°C under nitrogen for 16 hours. The reaction mixture was quenched with sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound U-7. LCMS: m / z = 279.2 [MH] - . 1H NMR(400MHz, CDCl3) δ7.56(t,J=1.6Hz,1H),7.28–7.25(m,1H),5.58(ddd,J=43.1,3.4,1.6Hz,1H),5.26(d,J=13 .4Hz, 1H), 4.69 (dd, J=13.4, 2.7Hz, 1H), 4.45 (ddd, J=13.3, 7.4, 3.3Hz, 1H), 4.09 (ddd, J=31.1, 13.4, 1.6Hz, 1H).

[0459] Step 7: To a mixed solution of compound U-7 (1.18 g, 4.20 mmol) in methanol (94 mL) and water (11 mL) was added potassium peroxymonosulfate (15.48 g, 25.19 mmol) at 0°C. The reaction mixture was stirred at 50°C for 16 hours. The insoluble matter was removed by filtration, and the filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound U-8. LCMS: m / z = 313.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.15 (dd, J=9.0, 2.0Hz, 1H), 7.98 (t, J=1.5Hz, 1H), 6.31-6. 14(m,1H),5.16(d,J=14.6Hz,1H),4.80(dd,J=14.6,2.5Hz,1H),4.47-4.31(m,2H).

[0460] Step 8: Palladium acetate (14 mg, 0.06 mmol) was added to a solution of compound U-8 (200 mg, 0.64 mmol), tert-butyl carbamate (82 mg, 0.70 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (74 mg, 0.13 mmol), and potassium carbonate (177 mg, 1.28 mmol) in dioxane (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound U-9. 1HNMR (400MHz, DMSO-d6) δ10.12(s,1H),8.12(d,J=2.1Hz,1H),7.65(dd,J=11.8,2.2Hz,1H),6.10(dd,J= 42.2, 2.7Hz, 1H), 5.09 (d, J = 14.4Hz, 1H), 4.73 (dd, J = 14.3, 2.2Hz, 1H), 4.45-4.33 (m, 2H), 1.49 (s, 9H).

[0461] Step 9: To a solution of compound U-9 (486 mg, 1.39 mmol) in dichloromethane (4.9 mL) was added trifluoroacetic acid (2.5 mL), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield Int U. LCMS: m / z = 250.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.12–7.09(m,1H),6.53(dd,J=12.0,2.4Hz,1H),5.41(ddd,J=43.3, 2.9, 1.3Hz, 1H), 5.00 (d, J = 14.1Hz, 1H), 4.64 (dd, J = 14.1, 2.2Hz, 1H), 4.30-4.21 (m, 2H).

[0462] Intermediate synthesis: Int V

[0463] Step 1: Sodium sulfide (7.29 g, 93.4 mmol) was added to a solution of compound V-1 (25.00 g, 93.4 mmol) in N,N-dimethylformamide (200 mL). The reaction mixture was heated to 25°C and stirred for 18 hours under nitrogen. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude compound V-2. This crude product was used directly in the next reaction. LCMS: m / z = 278.9 [MH] - .

[0464] Step 2: To a solution of compound V-2 (19.5 g, 48.8 mmol) in tetrahydrofuran (500 mL) was added lithium aluminum tetrahydride (58 mL, 1 mol / L) at 0°C. The reaction mixture was stirred under nitrogen at 0°C for 2 hours. The reaction mixture was quenched with 1M aqueous hydrochloric acid solution, and the aqueous phase was extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude compound V-3. This crude product was used directly in the next reaction. LCMS: m / z = 250.9 [MH] - .

[0465] Step 3: To a solution of compound V-3 (16.9 g, 39.9 mmol) and potassium carbonate (16.58 g, 119.98 mmol) in N,N-dimethylformamide (300 mL) was added 1,2-dibromoethane (37.57 g, 199.9 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound V-4. LCMS: m / z = 261.0 [M+H-18] + . 1 H NMR (400MHz, DMSO-d6) δ7.64(d,J=2.0Hz,1H),7.43(d,J=1.9Hz,1H),6.75(dd,J= 16.5, 9.4Hz, 1H), 5.63-5.51 (m, 2H), 5.22 (t, J = 5.2Hz, 1H), 4.62 (d, J = 5.2Hz, 2H).

[0466] Step 4: To a solution of compound V-4 (4.8 g, 17.1 mmol) in dichloromethane (100 mL) at 0°C was added m-chloroperbenzoic acid (3.7 g, 17.1 mmol). The reaction mixture was stirred at 0°C for 4 hours. A saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound V-5. LCMS: m / z = 296.8 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.91(d,J=2.0Hz,1H),7.74(d,J=2.0Hz,1H),7.13(dd,J=16.3,9.5Hz,1H),6.03(d,J=16.4Hz ,1H),5.99(dd,J=5.9,4.5Hz,1H),5.92(d,J=9.4Hz,1H),4.84(dd,J=13.8,4.4Hz,1H),4.72(dd,J=13.7,5.8Hz,1H).

[0467] Step 5: To a solution of compound V-5 (4.50 g, 15.2 mmol) in tetrahydrofuran (100 mL) at 0°C, sodium hydride (1.22 g, 34.4 mmol) was added. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound V-6. LCMS: m / z = 296.8 [M+H] + .

[0468] Step 6: To a solution of compound V-6 (3.1 g, 10.49 mmol) in antimony trichloride (2.39 g, 10.49 mmol) in chloroform (25 mL) was added diethylaminosulfur trifluoride (25 mL) at 0°C. The reaction was stirred at 50°C under nitrogen for 16 hours. The reaction was quenched with sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound V-7. 1 H NMR(400MHz, CDCl3)δ7.65(d,J=1.9Hz,1H),7.55(d,J=2.0Hz,1H),5.63-5.52(m,1H), 5.39(d,J=13.4Hz,1H), 4.85(d,J=13.4Hz,1H), 4.41-4.34(m,1H), 4.13-4.02(m,1H).

[0469] Step 7: To a mixed solution of compound V-7 (1.25 g, 4.20 mmol) in methanol (35 mL), tetrahydrofuran (35 mL), and water (35 mL) at 0°C was added potassium peroxymonosulfate (20.0 g, 32.7 mmol). The reaction mixture was stirred at 50°C for 48 hours. The insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound V-8. 1 H NMR(400MHz, CDCl3)δ8.25(d,J=2.0Hz,1H),7.89(d,J=2.0Hz,1H),5.51-5.40(m,1H),5 .29(t,J=2.1Hz,1H),5.08(d,J=14.4Hz,1H),4.53-4.49(m,1H),4.45(d,J=1.9Hz,1H).

[0470] Step 8: Palladium acetate (68 mg, 0.31 mmol) was added to a solution of compound V-8 (1.2 g, 3.06 mmol), tert-butyl carbamate (394 mg, 3.36 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (353 mg, 0.61 mmol), and potassium carbonate (854 mg, 6.12 mmol) in dioxane (60 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound V-9. LCMS: m / z = 310.0 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.28(d,J=2.3Hz,1H),7.88(d,J=2.2Hz,1H),6.19–6 .06(m,1H),5.26(d,J=14.5Hz,1H),4.93(d,J=14.5Hz,1H),4.44-4.31(m,2H),1.50(s,9H).

[0471] Step 9: Trifluoroacetic acid (3 mL) was added to a solution of compound V-9 (600 mg, 1.64 mmol) in dichloromethane (10 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (5 mL × 3), and the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by reverse phase column C18 (NH4HCO3, H2O / MeCN) system to obtain Int V. LCMS: m / z = 266.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ7.28(d,J=2.4Hz,1H),6.90(d,J=2.4Hz,1H),6.20(s,2H),6.04-5.94(m ,1H),5.14(d,J=14.4Hz,1H),4.80(d,J=14.4Hz,1H),4.34(t,J=1.5Hz,1H),4.32-4.21(m,1H).

[0472] Intermediate synthesis: Int W

[0473] Step 1: Palladium acetate (68 mg, 0.31 mmol) was added to a solution of compound V-9 (700 mg, 1.91 mmol), (tributyltin)methanol (734 mg, 2.29 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.19 mmol) in dioxane (50 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound W-1. LCMS: m / z = 306.0 [M+H-56]. + . 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.80 (d, J = 2.4Hz, 1H), 6.09-5.90 (m, 1H), 5.44 (t, J = 5.5Hz, 1H) ,5.09(d,J=14.5Hz,1H),4.81(d,J=14.5Hz,1H),4.58-4.55(m,2H),4.37(t,J=2.0Hz,1H),4.32-4.29(m,1H),1.49(s,9H).

[0474] Step 2: To a solution of compound W-1 (649 mg, 1.80 mmol) in dichloromethane (20 mL) at 0°C was added manganese dioxide (2.3 g, 27.0 mmol). The reaction mixture was stirred under nitrogen at 25°C for 16 hours. The mixture was filtered through celite. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound W-2. LCMS: m / z = 304.0 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.15(s,1H),8.55(d,J=2.4Hz,1H),8.23(d,J=2.5Hz,1H),6.17-6.0 4(m,1H),5.83(d,J=14.8Hz,1H),4.93(d,J=14.8Hz,1H),4.44-4.42(m,1H),4.38-4.36(m,1H),1.51(s,9H).

[0475] Step 3: To a solution of compound W-2 (520 mg, 1.45 mmol) in dichloromethane (10 mL) at -78°C, diethylaminosulfur trifluoride (932 mg, 5.79 mmol) was added. The reaction mixture was heated to 25°C and stirred for 1 hour. The reaction mixture was quenched with sodium bicarbonate solution (25 mL) and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound W-3. LCMS: m / z = 382.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.46(d,J=2.3Hz,1H),8.04(d,J=2.4Hz,1H),7.40(t,J=54.0Hz,1H),6.16 -6.05(m,1H),5.12(d,J=14.8Hz,1H),4.93(d,J=14.8Hz,1H),4.42-4.41(m,1H),4.37-4.35(m,1H),1.50(s,9H).

[0476] Step 4: Trifluoroacetic acid (3 mL) was added to a solution of compound W-3 ​​(410 mg, 1.08 mmol) in dichloromethane (10 mL), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (5 mL × 2). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by reverse phase column C18 (NH4HCO3, H2O / MeCN) system to obtain compound Int W. LCMS: m / z = 282.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.43(d,J=2.4Hz,1H),7.24(s,1H),7.04(d,J=2.5Hz,1H),6.20(s,2H),6.03- 5.92(m,1H),5.01(d,J=14.7Hz,1H),4.81(d,J=14.6Hz,1H),4.35(t,J=1.5Hz,1H),4.32-4.22(m,1H).

[0477] Specific embodiment synthesis:

[0478] Example 1: Preparation of Compound 1

[0479] Step 1: The photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (6.4 mg, 0.04 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl]nickel dichloride (2.3 mg, 0.01 mmol), tris(trimethylsilyl)silane (0.59 mL, 1.90 mmol), and sodium carbonate (269.04 mg, 2.54 mmol) were added to a solution of compound Int F (400 mg, 1.27 mmol) and cyclobutyl bromide (0.48 mL, 5.08 mmol) in ethylene glycol dimethyl ether. The reaction mixture was placed in a 40W blue light reactor under nitrogen and stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound 1-1. LCMS: m / z 291.3 [M+H] +; 1H NMR (400MHz, CDCl3) δ7.08(d,J=8.1Hz,1H),6.83(d,J=8.1Hz,1H),4.27-4.20(m,2H),3.94-3.85(m,2 H), 3.58 (t, J = 8.8Hz, 1H), 2.37-2.25 (m, 4H), 2.01 (d, J = 10.0Hz, 1H), 1.90-1.78 (m, 1H), 1.57 (s, 9H).

[0480] Step 2: To a solution of compound 1-1 (5.19 g, 17.9 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (10 mL, 134.2 mmol), and the reaction mixture was stirred at 25°C for 12 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to approximately 8, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound 1-2. LCMS: m / z 191.0 [M+H] + .

[0481] Step 3: At 25 ° C, compound Int H (130 mg, 0.64 mmol) and compound 1-2 (122 mg, 0.64 mmol) were added to dioxane (3.0 mL). Under a nitrogen atmosphere, cesium carbonate (416 mg, 1.28 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (54 mg, 0.06 mmol) were added and stirred at 100 ° C for 1 hour. The above reaction solution was filtered and concentrated, and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound 1-3. LCMS: m / z = 358.1 [M+H] + .

[0482] Step 4: Compound 1-3 (50 mg, 0.14 mmol) was added to an aqueous hydrochloric acid solution (8 M, 3 mL) at 25°C, the temperature was raised to 100°C, and the mixture was stirred for 2 hours. The reaction mixture was purified by preparative HPLC (0.1% formic acid, acetonitrile-water = 5 / 95 to 75 / 25) to obtain compound 1-4. LCMS: m / z = 377.1 [M+H] + .

[0483] Step 5: At 25°C, compound 1-4 (50 mg, 0.13 mmol) and compound Int E (28 mg, 0.13 mmol) were added to N,N-dimethylformamide (4.0 mL), and 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (76 mg, 0.20 mmol) and N,N-diisopropylethylamine (66 μL, 0.40 mmol) were added and stirred for 1 hour. The above reaction solution was purified by preparative high performance liquid chromatography column (0.1% ammonium bicarbonate, acetonitrile-water = 5 / 95 to 85 / 15) to obtain compound 1. LCMS: m / z = 572.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ12.56(s,1H),8.87(s,1H),8.75(d,J=9.6Hz,2H),8. 17(d,J=7.9Hz,1H),8.03(d,J=9.5Hz,1H),7.89(s,1H),7.29(d,J=8.1Hz,1H) ,7.16-7.13(m,1H),6.84(d,J=8.1Hz,1H),4.88(s,2H),4.68-4.22(m,8H),3. 52(t,J=8.6Hz,1H),3.33-3.25(m,2H),2.28-2.18(m,4H),2.00-1.83(m,2H).

[0484] Example 2: Synthesis of Compound 2

[0485] To a solution of compound Int C (10 mg, 0.05 mmol) and compound 1-4 (11.29 mg, 0.03 mmol) in N,N-dimethylformamide (0.4 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.4 mg, 0.06 mmol) and N,N-diisopropylethylamine (20 μL, 0.10 mmol), and the reaction solution was stirred at 25 ° C for 0.5 hours. The reaction solution was quenched by adding 5 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water 15 / 85 to 85 / 15) to obtain compound 2. LCMS: m / z 561.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ10.37(s,1H),9.06(s,1H),8.46(d,J=9.1Hz,1H),8.31(d,J=9 .0Hz,1H),7.66-7.52(m,2H),7.25(d,J=8.0Hz,1H),6.89(d,J=8.1Hz,1H),6.34(d, J=1.8Hz,1H),4.70(s,2H),4.36(s,4H),4.19-4.12(m,2H),3.91(s,2H),3.89-3.82 (m,2H),3.57-3.52(m,1H),2.26-2.20(m,4H),1.98-1.91(m,1H),1.85-1.80(m,1H).

[0486] Example 3: Synthesis of Compound 3

[0487] Step 1: Int F (320 mg, 0.95 mmol), cyclopropylboronic acid pinacol ester (240 mg, 1.43 mmol), and cesium carbonate (1.08 g, 3.33 mmol) were dissolved in a mixture of dioxane (10 mL) and water (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg, 0.1 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 110°C for 5 hours. The reaction mixture was filtered, and the filtrate was poured into water (30 mL), followed by extraction with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 3-1. LCMS: m / z 277.1 [M+H]+.

[0488] Step 2: Dissolve compound 3-1 (210 mg, 0.76 mmol) in dichloromethane (2.5 mL) and add trifluoroacetic acid (0.5 mL). Stir the reaction solution at 25 ° C for 12 hours. Slowly add solid sodium bicarbonate to adjust the pH to about 9. Extract with ethyl acetate (100 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 70 / 300) to obtain compound 3-2. LCMS: m / z 177.0 [M+H] +;

[0489] Step 3: 3-2 (11.54 mg, 0.06 mmol) and Int H (20 mg, 0.10 mmol) were dissolved in dioxane (0.6 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2', 4', 6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (4.18 mg, 5 μmol) and cesium carbonate (64.00 mg, 0.20 mmol) were added. The reaction solution was heated to 100 ° C under a nitrogen atmosphere and stirred for 2 hours. After filtering the above reaction solution, the filtrate was poured into water (10 mL) and then extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 3-3. LCMS: m / z=344.1[M+H]+;

[0490] Step 4: Compound 3-3 (30 mg, 0.09 mmol) and aqueous hydrochloric acid (6 N, 1 mL) were heated to 100°C and stirred for 1 hour. The reaction mixture was adjusted to pH 6 with aqueous sodium hydroxide (1 M). The solution was then filtered and purified by preparative HPLC (0.1% formic acid, acetonitrile-water = 70 / 30 to 99 / 1) to provide compound 3-4. LCMS: m / z = 363.1 [M+H]+.

[0491] Step 4: Compound 3-4 (13 mg, 0.04 mmol) and compound Int C (8.90 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and N,N-diisopropylethylamine (14 μL, 0.08 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.2 mg, 0.04 mmol) were added respectively. The reaction solution was stirred at 25 ° C for 2 hours. The above reaction solution was poured into water (10 mL) and then extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (0.1% formic acid, acetonitrile-water = 20 / 70 to 95 / 5) to obtain compound 3. LCMS: m / z = 547.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:10.50(s,1H),9.32(s,1H),8.44-8.38(m,1H),8.36-8.30(m, 1H),7.83(s,1H),7.55(d,J=1.9Hz,1H),7.28(d,J=8.1Hz,1H),7.07(d,J=8.3Hz,1H), 6.35(d,J=1.6Hz,1H),4.71(s,2H),4.40-4.35(m,4H),4.18-4.13(m,2H),4.08(s,2H) ,3.87(d,J=3.1,1.8Hz,2H),2.09-2.01(m,1H),0.93-0.87(m,2H),0.83-0.78(m,2H).

[0492] Example 4: Synthesis of Compound 4

[0493] Step 1: Under a nitrogen atmosphere, cesium carbonate (4.16 g, 12.69 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (700 mg, 0.95 mmol) were added to a mixed solution of compound Int F (2 g, 6.35 mmol) and potassium ethylene trifluoroborate (1.02 g, 7.61 mmol) in dioxane (20 mL) and water (5 mL) and stirred at 90 ° C for 2 hours. After filtering the above reaction solution, the filtrate was poured into water (30 mL) and then extracted with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 4-1. LCMS: m / z 263.1 [M+H] + .

[0494] Step 2: Compound 4-1 (325 mg, 1.24 mmol) was added to methanol (10 mL), followed by palladium on carbon (130 mg, 0.12 mmol, 10% mass fraction). The mixture was stirred at 25°C under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered under reduced pressure through celite, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated to obtain compound 4-2. LCMS: m / z 265.1 [M+H] + .

[0495] Step 3: Compound 4-2 (300 mg, 1.13 mmol) was added to dichloromethane (5 mL) and trifluoroacetic acid (1 mL) and stirred at 25°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), then extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-3.

[0496] Step 4: Compound 4-3 (25 mg, 0.15 mmol) and compound Int H (30 mg, 0.15 mmol) were added to dioxane (3.0 mL). Under a nitrogen atmosphere, cesium carbonate (97 mg, 0.30 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (13 mg, 0.01 mmol) were added and stirred at 100 ° C for 1 hour. After filtering the above reaction solution, the filtrate was poured into water (8 mL) and then extracted with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound 4-4.

[0497] Step 5: Compound 4-4 (35 mg, 0.11 mmol) was added to aqueous hydrochloric acid (2 mL, 8 M), the temperature was raised to 100°C, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and the solution was purified by preparative HPLC (0.1% formic acid, acetonitrile-water = 30 / 70 to 50 / 50) to obtain compound 4-5. LCMS: m / z 351.1 [M+H] + .

[0498] Step 6: Compound 4-5 (10 mg, 0.03 mmol) and compound Int C (6 mg, 0.03 mmol) were added to N,N-dimethylformamide (2 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.04 mmol) and N,N-diisopropylethylamine (11 μL, 0.09 mmol), and stirred at 25°C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography (0.1% ammonium bicarbonate / acetonitrile-water = 40 / 60 to 60 / 40) to give compound 4. LCMS: m / z 535.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ: 10.39 (s, 1H), 9.10 (s, 1H), 8.43 (d, J = 9.3Hz, 1H), 8.30 ( d,J=9.3Hz,1H),7.64(s,1H),7.57(d,J=1.9Hz,1H),7.27(d,J=8.1Hz,1H),6.94(d ,J=8.1Hz,1H),6.34(d,J=1.9Hz,1H),4.71(s,2H),4.41-4.32(m,4H),4.18-4.12 (m,2H),3.94(s,2H),3.89-3.83(m,2H),2.70-2.62(m,2H),1.22(t,J=7.6Hz,3H).

[0499] Example 5: Synthesis of Compound 5

[0500] Step 1: To a mixed solution of compound Int F (200 mg, 0.63 mmol) and 1-cyclopentenylboronic acid pinacol ester (147.8 mg, 0.76 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (51.82 mg, 0.06 mmol) and cesium carbonate (413.5 mg, 1.47 mmol) were added. The reaction solution was stirred at 100°C for 2 hours under a nitrogen atmosphere. 15 mL of water was added to dilute the reaction solution and extracted with 75 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 5-1 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 5-1. LCMS: m / z = 303.1 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ7.15-7.09(m,1H),7.08-7.03(m,1H),6.47(s,1H),4.30-4.23(m,2H) ),3.95-3.90(m,2H),2.79-2.72(m,2H),2.57-2.53(m,2H),2.07-2.00(m,2H),1.57(s,9H).

[0501] Step 2: Add palladium on carbon (30 mg, 0.03 mmol, 10% by mass) to a solution of compound 5-1 (200 mg, 0.66 mmol) in methanol (4 mL). Stir at 25°C for 0.5 h under a hydrogen atmosphere. Filter the reaction mixture, rinse the filter cake with 10 mL of methanol, and concentrate the filtrate to obtain compound 5-2. LCMS: m / z = 305.1 [M+H] + ;1 H NMR (400MHz, CDCl3): δ7.08(d,J=8.3Hz,1H),6.86(d,J=8.3Hz,1H),4.27-4.21(m,2H),3 .95-3.87(m,2H),3.17-3.03(m,1H),2.08-1.97(m,2H),1.83-1.64(m,6H),1.55(s,9H).

[0502] Step 3: To a solution of compound 5-2 (200 mg, 0.66 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL, 13.42 mmol), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with 60 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 5-3 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50). LCMS: m / z = 205.1 [M+H] + .

[0503] Step 4: At 25°C, compound 5-3 (22.07 mg, 0.11 mmol) and compound Int H (20 mg, 0.10 mmol) were dissolved in 1,4-dioxane (1 mL). Methanesulfonic acid (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (4.18 mg, 0.01 mmol) and cesium carbonate (80.00 mg, 0.25 mmol) were added. The reaction solution was stirred at 100°C under a nitrogen atmosphere for 1 hour. 5 mL of water was added to dilute the reaction solution and extracted with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 5-4 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 60 / 40) to obtain compound 5-4. LCMS: m / z = 372.2 [M+H] + .

[0504] Step 5: At 25°C, a solution of compound 5-4 (30 mg, 0.08 mmol) in aqueous hydrochloric acid (1 mL, 6 M) was stirred at 100°C for 1 hour. The reaction solution was purified by preparative HPLC (0.1% formic acid, acetonitrile-water = 20 / 80 to 90 / 10) to give compound 5-5. LCMS: m / z = 391.1 [M+H] + .

[0505] Step 6: To a solution of compound 5-5 (15 mg, 0.04 mmol) and compound Int C (9.3 mg, 0.05 mmol) in N,N-dimethylformamide (0.3 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.5 mg, 0.05 mmol) and N,N-diisopropylethylamine (13.3 μL, 0.08 mmol), and the reaction solution was stirred at 25 ° C for 1 hour. The reaction solution was diluted with 5 mL of water and extracted with 15 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (0.01% formic acid, acetonitrile-water = 15 / 85 to 90 / 10) to obtain compound 5. LCMS: m / z = 575.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),9.16(s,1H),8.49-8.40(m,1H),8.37-8.30(m ,1H),7.70(s,1H),7.56(d,J=1.8Hz,1H),7.27(d,J=8.1Hz,1H),6.97(d,J=8.1Hz,1H) ,6.35(d,J=1.6Hz,1H),4.71(s,2H),4.38(d,J=3.5Hz,4H),4.19-4.13(m,2H),3.98(s ,2H),3.90-3.84(m,2H),3.09(t,J=7.9Hz,1H),2.02-1.94(m,2H),1.75-1.59(m,6H).

[0506] Example 6: Synthesis of Compound 6

[0507] Step 1: At 25°C, to a solution of compound Int F (600 mg, 1.90 mmol) and potassium vinyl fluoroborate (306.01 mg, 2.28 mmol) in 1,4-dioxane (10 mL) and water (2 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (139.3 mg, 0.19 mmol) and cesium carbonate (1.24 g, 3.81 mmol) were added. The reaction solution was stirred at 90°C for 2 hours under a nitrogen atmosphere. 30 mL of water was added to dilute the reaction solution and extracted with 90 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 6-1 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20). LCMS: m / z = 263.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.12(d,J=8.4Hz,1H),7.00(d,J=8.4Hz,1H),6.71(dd,J=10.7,17.3Hz,1H),6 .11(dd,J=1.5,17.3Hz,1H),5.37-5.29(m,1H),4.30-4.23(m,2H),3.95-3.90(m,2H),1.57(s,9H).

[0508] Step 2: A solution of compound 6-1 (140 mg, 0.53 mmol) and (triphenylphosphonium) difluoroacetic acid inner salt (850 mg, 2.39 mmol) in n-hexane (3 mL) was stirred at 110°C for 12 hours. The reaction solution was diluted with 10 mL of water and extracted with 45 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 6-2 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 6-2. LCMS: m / z = 313.0 [M+H] + .

[0509] Step 3: To a solution of compound 6-2 (100 mg, 0.32 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL, 6.71 mmol), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with 45 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 6-3 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 75 / 25) to obtain compound 6-3. 1 H NMR (400MHz, CDCl3) δ6.92(d,J=8.0Hz,1H),6.50(d,J=8.0Hz,1H),4.86(br s,1H),4.26-4.18(m,2H),3.60-3.50(m,2H),2.74-2.66(m,1H),1.99-1.94(m,1H),1.75-1.66(m,1H).

[0510] Step 4: At 25°C, to a reaction solution of compound 6-3 (32.8 mg, 0.15 mmol) and compound Int H (30 mg, 0.15 mmol) in 1,4-dioxane (0.8 mL), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium (12.53 mg, 0.01 mmol) and cesium carbonate (96.0 mg, 0.29 mmol) were added. The reaction solution was heated to 100°C under a nitrogen atmosphere and stirred for 1 hour. The reaction solution was diluted with 10 mL of water and extracted with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 6-4 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 75 / 25) to obtain compound 6-4. LCMS: m / z = 380.1 [M+H] + .

[0511] Step 5: Compound 6-4 (35 mg, 0.09 mmol) in aqueous hydrochloric acid (0.4 mL, 8 M) was stirred at 100°C for 1 hour. The reaction solution was purified by preparative HPLC (0.01% formic acid, acetonitrile-water = 5 / 95 to 85 / 15) to obtain compound 6-5. LCMS: m / z = 399.0 [M+H] + .

[0512] Step 6: To a solution of compound 6-5 (20 mg, 0.05 mmol) and compound Int C (13.20 mg, 0.07 mmol) in N,N-dimethylformamide (0.5 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.6 mg, 0.08 mmol) and N,N-diisopropylethylamine (21 μL, 0.13 mmol), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was diluted with 10 mL of water and extracted with 45 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 6 was purified by preparative high-performance liquid chromatography (0.01% formic acid, acetonitrile-water = 10 / 90 to 85 / 15) to obtain compound 6. LCMS: m / z = 549.7 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.07(s,1H),8.35-8.25(m,1H),8.19(d,J=9. 0Hz,1H),7.64-7.55(m,2H),7.33(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),6.34(d,J =1.0Hz,1H),4.70(s,2H),4.59-4.49(m,1H),4.44-4.31(m,2H),4.21-4.11(m,3H), 3.91(s,2H),3.87(s,2H),3.14-3.06(m,1H),2.07-2.02(m,1H),1.97-1.89(m,1H).

[0513] Example 7: Synthesis of Compound 7

[0514] Compound 4-5 (10 mg, 0.03 mmol) and compound Int E (6 mg, 0.03 mmol) were added to N,N-dimethylformamide (2 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.04 mmol) and N,N-diisopropylethylamine (11 μL, 0.09 mmol), and the mixture was stirred at 25°C for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 50 / 50 to 60 / 40) to obtain compound 7. LCMS: m / z 546.1 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ:10.71(s,1H),9.06(s,1H),8.42-8.37(m,1H),8.33(d,J=2.1H z,1H),8.28(d,J=9.3Hz,1H),7.86(dd,J=8.2,2.2Hz,1H),7.64(s,1H),7.49(d,J=8.3Hz ,1H),7.26(d,J=8.1Hz,1H),6.92(d,J=8.1Hz,1H),4.84(s,2H),4.38-4.32(m,4H),4.21 -4.14(m,2H),4.00(s,2H),3.59-3.55(m,2H),2.68-2.62(m,2H),1.21(t,J=7.5Hz,3H).

[0515] Example 8: Synthesis of Compound 8

[0516] Compound 6-4 (16 mg, 0.04 mmol) and compound Int E (8 mg, 0.04 mmol) were added to N,N-dimethylformamide (0.6 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μL, 0.08 mmol). The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water) to obtain compound 8. LCMS: m / z = 594.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),9.04(s,1H),8.29-8.19(m,2H),8.14(d,J=9Hz,1H),7.81(m ,1H),7.60(s,1H),7.43(d,J=8Hz,1H),7.27(d,J=8Hz,1H),7.07(d,J=8Hz,1H),4.78(s,2H),4.57 -4.19(m,4H),4.13-4.09(m,2H),3.96(s,2H),3.56-3.48(m,2H),3.04(m,1H),2.02-1.97(m,2H).

[0517] Example 9: Synthesis of Compound 9

[0518] Step 1: To a solution of compound Int F (1.0 g, 3.17 mmol) and cuprous iodide (1.21 g, 6.34 mmol) in 1,4-dioxane (2 mL) were added bis(triphenylphosphine)palladium chloride (0.22 g, 0.32 mmol) and tributyl(1-ethoxyethylene)tin (1.60 mL, 4.76 mmol). The reaction solution was heated to 100°C under a nitrogen atmosphere and stirred for 2 hours. 15 mL of saturated potassium fluoride aqueous solution was added to the reaction solution and stirred to quench the mixture. The mixture was extracted with ethyl acetate (60 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 80 / 20) to obtain compound 9-1. LCMS: m / z = 307.1 [M+H] + .

[0519] Step 2: To a solution of compound 9-1 (580 mg, 1.89 mmol) in tetrahydrofuran (10 mL) was added concentrated hydrochloric acid (2 mL), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-2. LCMS: m / z = 179.1 [M+H] + .

[0520] Step 3: Add compound 9-2 (100 mg, 0.55 mmol) to diethylaminosulfur trifluoride (2 mL) and stir at 40 ° C for 2 hours. The above reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution (50 mL) to quench and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 60 / 40) to obtain compound 9-3. LCMS: m / z 201.1 [M+H] + .

[0521] Step 4: Compound 9-3 (5 mg, 0.02 mmol) and Int I (10 mg, 0.02 mmol) were added to dioxane (2.0 mL). Under a nitrogen atmosphere, cesium carbonate (16 mg, 0.05 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (2 mg, 0.01 mmol) were added. The reaction solution was stirred at 100 ° C for 1 hour. The reaction solution was poured into 10 mL of water, extracted with 20 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 10 / 90 to 70 / 30) to obtain compound 9. LCMS: m / z 582.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 10.42 (s, 1H), 9.12 (s, 1H), 8.47 (d, J = 9.4Hz, 1H), 8.21-8.18 (m, 1H), 8.13 (d, J = 9.4Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7 .66(s,1H),7.36-7.29(m,3H),4.94(s,2H),4.54-4.42(m,4H),4.37-4.32(m,2H),4.03(s,2H),3.40-3.34(m,2H),1.97(t,J=18.4Hz,3H).

[0522] Example 10: Synthesis of Compound 10

[0523] Step 1: At -78 ° C, compound Int F (500 mg, 1.59 mmol) was added to tetrahydrofuran (10 mL). Under a nitrogen atmosphere, n-butyl lithium (5 mL, 2.5 M) was added dropwise, and the reaction solution was stirred for 1 hour, and then cyclobutanone (0.60 mL, 7.93 mmol) was added dropwise. The reaction solution was kept stirring at -78 ° C for 1 hour. The above reaction solution was slowly poured into an aqueous ammonium chloride solution (15 mL) to quench. It was then extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 60 / 40) to obtain compound 10-1. LCMS: m / z 207.1 [M+H] + .

[0524] Step 2: Add compound 10-1 (120 g, 0.58 mmol) to dichloromethane (3 mL), cool the reaction solution to 0 ° C, and then add diethylaminosulfur trifluoride (115 μL, 0.87 mmol). The reaction solution is kept at 0 ° C and stirred for 1 hour. The above reaction solution is added dropwise to a saturated aqueous sodium bicarbonate solution (10 mL) to quench. Then extract with ethyl acetate (30 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain a crude product. The crude product is purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 70 / 30) to obtain compound 10-2. LCMS: m / z 209.1 [M+H] + .

[0525] Step 3: Compound 10-2 (3 mg, 0.01 mmol) and compound Int I (5 mg, 0.01 mmol) were added to dioxane (1 mL). Under a nitrogen atmosphere, cesium carbonate (8 mg, 0.02 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (1 mg, 0.01 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 1 hour. After the reaction solution was cooled, the reaction solution was poured into 10 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 5 / 99 to 80 / 20) to obtain compound 10. LCMS: m / z 590.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ: 10.53 (s, 1H), 9.08 (s, 1H), 8.56 (d, J = 9.3Hz, 1H), 8.17-8.08 (m, 2H), 8.05 (s,1H),7.70(s,1H),7.33-7.29(m,1H),7.21-7.18(m,1H),5.37-5.35(m,1H),4.94(s,2H),4.56 -4.48(m,2H),4.47-4.41(m,2H),4.37-4.31(m,2H),4.08(s,2H),3.40 -3.34(m,2H),2.70-2.55(m,4H),2.23-2.20(m,1H),1.83-1.80(m,1H); 19 F NMR (CDCl3, 376MHz) δ: -134.44 (s).

[0526] Example 11: Synthesis of Compound 11

[0527] To a solution of compound Int A (7.05 mg, 0.03 mmol) and compound 1-4 (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.4 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.12 mg, 0.03 mmol) and N,N-diisopropylethylamine (11.01 μL, 0.07 mmol), and the reaction solution was stirred at 25°C for 1 hour. 5 mL of water was added for dilution, and the mixture was extracted with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 10 / 90 to 80 / 20) to obtain compound 11. LCMS: m / z = 580.0 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ10.92(s,1H),9.08(s,1H),8.47(d,J=9.4Hz,1H),8.40( s,1H),8.31(d,J=9.4Hz,1H),8.12(dd,J=1.8,8.4Hz,1H),7.90(d,J=8.4Hz,1H ),7.70-7.40(m,2H),7.25(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),4.37(s,4H) ,4.04(s,2H),3.54(s,1H),3.29(s,3H),2.30-2.20(m,4H),2.00-1.80(m,2H); 19F NMR (376MHz, CDCl3): δ-109.50 (s).

[0528] Example 12: Synthesis of Compound 12

[0529] Step 1: To a solution of compound 12-1 (500.0 mg, 2.84 mmol) and cesium carbonate (2.78 g, 8.52 mmol) in N,N-dimethylformamide (5.0 mL), trideuteromethylamine hydrochloride (241 mg, 3.41 mmol) was added. The reaction solution was stirred at 100 ° C for 6 hours. The above reaction solution was poured into water (20 mL) and then extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 12-2. LCMS: m / z = 190.0 [M+H] + .

[0530] Step 2: Compound 12-2 (120.0 mg, 0.63 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (46.20 mg, 0.063 mmol) were added to dioxane (1.2 mL). Under a nitrogen atmosphere, the temperature was lowered to 0°C, and cyclobutylzinc bromide (1.05 mL, 0.32 mmol) was slowly added dropwise. The reaction mixture was then heated to 75°C and stirred for 2 hours. The above reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 12-3. LCMS: m / z = 166.2 [M+H] + .

[0531] Step 3: Under a nitrogen atmosphere, compound Int I (15 mg, 0.04 mmol) and compound 12-3 (7.0 mg, 0.04 mol) were added to dioxane (0.1 mL), and methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (3.05 mg, 0.0036 mmol) and cesium carbonate (23.39 mg, 0.07 mmol) were added to the reaction solution. The reaction solution was stirred at 100 ° C for 1 hour. The above reaction solution was poured into water (5 mL) and then extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 10 / 90 to 75 / 25) to obtain compound 12. LCMS: m / z = 547.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.98(s,1H),8.32(d,J=2.0Hz,1H),8.13(d,J=9.2 Hz,1H),7.88(dd,J=2.0,8.0Hz,1H),7.78(t,J=7.8Hz,1H),7.58(s,1H),7.49(d,J=8.0Hz ,1H),7.28(dd,J=8.6,12.8Hz,2H),7.08(d,J=7.6Hz,1H),4.84(s,2H),4.19-4.15(m,2H ), 3.98 (s, 2H), 3.63 (s, 2H), 2.25 (d, J = 6.0Hz, 4H), 2.04-1.91 (m, 2H), 1.86-1.80 (m, 1H).

[0532] Example 13: Synthesis of Compound 13

[0533] Step 1: Compound 13-1 (800 mg, 3.52 mmol), di-tert-butyl dicarbonate (0.83 mL, 3.88 mmol), 4-dimethylaminopyridine, and N,N-diisopropylethylamine (0.64 mL, 3.88 mmol) were added sequentially to a tetrahydrofuran (20.0 mL) solution. The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 10 / 90) to obtain compound 13-2. LCMS: m / z = 270.8 [M-55] + . 1H NMR (400MHz, DMSO-d6) δ 8.02 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 1.51 (s, 9H).

[0534] Step 2: To a solution of ethylene glycol dimethyl ether (20.0 mL) were added 13-2 (900 mg, 2.75 mmol), cyclobutyl bromide (0.52 mL, 5.50 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (80 mg, 0.55 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (110 mg, 0.28 mmol), tris(trimethylsilyl)silane (0.86 mL, 2.75 mmol) and sodium carbonate (583 mg, 5.50 mmol) in sequence, and stirred at 25 ° C for 5 hours under nitrogen atmosphere and blue light irradiation. The reaction mixture was washed with water (20 mL × 2) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 30 / 70) to obtain compound 13-3. LCMS: m / z = 303.2 [M+H] + .

[0535] Step 3: Compound 13-3 (260 mg, 0.86 mmol) and 2-(difluoromethanesulfonyl)pyridine (332 mg, 1.72 mmol) were added to a solution of N,N-dimethylformamide (10.0 mL). The mixture was cooled to -30°C under a nitrogen atmosphere and reacted for 10 minutes. Then, a solution of potassium tert-butoxide in tetrahydrofuran (2.58 mL, 1 M) was slowly added dropwise. Stirring was continued at -30°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 30 / 70) to obtain compound 13-4. LCMS: m / z = 337.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.79(dd,J=1.6,8.0Hz,1H),7.03(d,J=8.0Hz,1H),3.72-3.65(m,2H),3.59(quin ,J=8.6Hz,1H),2.63-2.60(m,2H),2.35-2.19(m,4H),2.03-1.95(m,1H),1.87-1.76(m,1H),1.45(s,9H).19 F NMR (377MHz, DMSO-d6) δ -83.37 (d, J = 36.1Hz), -85.86 (d, J = 36.1Hz).

[0536] Step 4: Compound 13-4 (60 mg, 0.18 mmol) and a solution of hydrochloric acid in dioxane (1.0 mL, 4 M) were added to an anhydrous dichloromethane solution (2.5 mL) and stirred at 25°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and ethyl acetate (10 mL) was added. The pH was then adjusted to approximately 7 with a saturated aqueous sodium carbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (methanol:dichloromethane = 0.1 / 99.9 to 5 / 95) to obtain compound 13-5. LCMS: m / z = 237.0 [M+H] + .

[0537] Step 5: Compound Int I (6 mg, 0.01 mmol), compound 13-5 (3.39 mg, 0.01 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (1.22 mg, 0.01 mmol) and cesium carbonate (14.0 mg, 0.04 mmol) were added to an anhydrous dioxane (1.0 mL) solution in sequence, and the mixture was heated to 100 ° C. and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was washed with water (5 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative high performance liquid chromatography (0.01% ammonium bicarbonate, water-acetonitrile = 95 / 5 to 95 / 5) to give compound 13. LCMS: m / z=618.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.71 (s, 1H), 9.08 (s, 1H), 8.33 (d, J = 2.0Hz, 1H), 8.24 (d, J = 9.2Hz, 1H),7.93(d,J=9.2Hz,1H),7.89-7.87(m,2H),7.66(s,1H),7.50(d,J=8.4Hz,1H),7.01(d,J= 8.0Hz,1H),4.84(s,2H),4.28(t,J=5.6Hz,2H),4.19-4.17(m,2H),4.01(s,2H),3.59(d,J=4. 4Hz,2H),3.55(s,1H),2.73(s,2H),2.23-2.16(m,4H),1.99-1.92(m,1H),1.80-1.75(m,1H).19 F NMR (376MHz, DMSO-d6) δ -85.09 (d, J = 40.0Hz), -86.48 (d, J = 39.6Hz).

[0538] Example 14: Synthesis of Compound 14

[0539] Step 1: Dissolve compound Int F (50 mg, 0.16 mmol), zinc cyanide (2.1 mg, 0.02 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (13.07 mg, 0.02 mmol) in N,N-dimethylacetamide (2 mL). Under a nitrogen atmosphere, the reaction solution was heated to 100 ° C and stirred for 12 hours. The above reaction solution was poured into water (10 mL), then extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 85 / 15) to obtain compound 14-1. LCMS: m / z = 262.0 [M+H] + .

[0540] Step 2: Dissolve compound 14-1 (40 mg, 0.15 mmol) in dichloromethane (3 ml), then slowly add trifluoroacetic acid (1 ml) dropwise to the reaction mixture. Stir the reaction mixture at 25°C for 30 minutes. Concentrate the reaction mixture to obtain a crude product, which is then purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 65 / 35) to obtain compound 14-2.

[0541] Step 3: Compound 14-2 (3.24 mg, 0.02 mmol), compound Int I (7 mg, 0.02 mmol) and cesium carbonate (16.4 mg, 0.05 mmol) were added to dioxane (0.5 mL), and methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (0.5 mg, 0.6 μmol) was added under a nitrogen atmosphere. The reaction solution was warmed to 100 ° C and stirred for 12 hours. The above reaction solution was poured into water (3 mL), extracted with ethyl acetate (3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 5 / 95~85 / 15) to obtain compound 14. LCMS: m / z=543.1[M+H]+; 1H NMR (400MHz, DMSO-d6) δ10.73(s,1H),9.15(s,1H),8.41(d,J=9.0Hz,1H),8.33(d,J=2.0Hz,1H),8.22(d,J=9.0Hz,1H),7.87(dd,J=2.0,8.0Hz,1H ),7.71-7.66(m,2H),7.49(d,J=8.0Hz,2H),4.84(s,2H),4.51-4.48(m,2 H),4.41-4.38(m,2H),4.19-4.16(m,2H),4.03(s,2H),3.60-3.56(m,2H).

[0542] Example 15: Synthesis of Compound 15

[0543] Step 1: Compound 9-2 (100 mg, 0.56 mmol) and compound Int H (104 mg, 0.51 mmol) were added to dioxane (1.0 mL). Under nitrogen protection, cesium carbonate (249 mg, 0.77 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium (44 mg, 0.05 mmol) were added and stirred at 100°C for 2 hours. The reaction solution was poured into water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL) and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 5 / 1) to obtain 15-1. LCMS: m / z = 346.0 [M+H] + .

[0544] Step 2: Add compound 15-1 (45 mg, 0.09 mmol) to aqueous hydrochloric acid (0.5 mL, 8 N). The reaction mixture was heated to 80°C and stirred for 2 hours. The pH of the reaction mixture was adjusted to 5-6 with aqueous sodium hydroxide (1 N), filtered, and the filtrate was purified by preparative HPLC (0.3% trifluoroacetic acid, acetonitrile-water = 1 / 99 to 20 / 80) to obtain compound 15-2. LCMS: m / z = 365.2 [M+H] + .

[0545] Step 3: Compound 15-2 (25 mg, 0.07 mmol) and compound Int E (15 mg, 0.08 mmol) were added to N,N-dimethylformamide (2 mL), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) and N,N-diisopropylethylamine (34 μL, 0.21 mmol), and stirred at 25°C for 2 hours. The reaction mixture was poured into water (15 mL), then extracted with ethyl acetate (60 mL × 2), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to obtain compound 15. LCMS: m / z = 560.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:10.73(s,1H),9.15(s,1H),8.44-8.41(m,1H),8. 39-8.36(m,1H),8.33(d,J=2.0Hz,1H),7.88(dd,J=8.0,2.3Hz,1H),7.72-7 .66(m,2H),7.49(t,J=8.4Hz,2H),4.84(s,2H),4.53-4.48(m,2H),4.44-4. 40(m,2H),4.21-4.14(m,2H),4.04(s,2H),3.61-3.56(m,2H),2.53(s,3H).

[0546] Example 16: Synthesis of Compound 16

[0547] Step 1: Potassium peroxymonosulfate (3.76 g, 6.12 mmol) was added to a mixed solution of compound E-4 (3 g, 12.24 mmol) in tetrahydrofuran (20 mL) and water (20 mL). The final reaction solution was stirred at 30°C for 30 minutes. The reaction solution was extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated brine (20 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound 16-1. LCMS: m / z = 258.9 [MH] - .

[0548] Step 2: Sodium hydride (0.34 g, 8.62 mmol) was added to a solution of compound 16-1 (1.5 g, 5.74 mmol) in N,N-dimethylformamide (15 mL). The final reaction solution was stirred at 30°C for 30 minutes. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain compound 16-2. LCMS: m / z = 261.0 [M+H] + .

[0549] Step 3: A solution of compound 16-2 (300 mg, 1.15 mmol), triethylamine (0.32 mL, 2.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (93.82 mg, 0.11 mmol) in methanol (15 mL) was stirred at 70°C under a carbon monoxide atmosphere for 12 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 16-3. LCMS: m / z = 241.0 [M+H] + .

[0550] Step 4: To a mixed solution of compound 16-3 (180 mg, 0.75 mmol) in methanol (2 mL) and water (2 mL) was added lithium hydroxide (35.88 mg, 1.5 mmol). The final reaction solution was stirred at 30°C for 3 hours. The reaction solution was adjusted to pH 5-6 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate (5 mL x 2). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16-4. LCMS: m / z = 227.0 [M+H] + .

[0551] Step 5: To a solution of compound 16-4 (70 mg, 0.31 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (176.46 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.62 mmol) in N,N-dimethylformamide (2 mL) was added compound Int H (59.91 mg, 0.31 mmol), and the final reaction solution was stirred at 30 ° C for 12 hours. The reaction solution was diluted with water (3 mL), extracted with ethyl acetate (5 mL × 3), the organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 16-5. LCMS: m / z = 402.0 [M + H] + .

[0552] Step 6: Compound 16-5 (50 mg, 0.12 mmol), compound 1-2 (23.67 mg, 0.12 mmol), cesium carbonate (81.08 mg, 0.25 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (21.16 mg, 0.02 mmol) in dioxane (1 mL) were stirred at 110 ° C. under a nitrogen atmosphere for 2 hours. The crude product was purified by preparative high performance liquid chromatography (0.01 M ammonium bicarbonate, acetonitrile / water = 35 / 65 to 65 / 35) to give compound 16. LCMS: m / z = 556.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 9.48 (t, J = 6.0Hz, 1H), 9.12 (s, 1H), 8.47 (d, J = 9.2Hz, 1H), 8.34-8.30 (m, 2 H),8.07(dd,J=7.6,2.0Hz,1H),7.57(d,J=7.6Hz,1H),7.51(s,1H),7.24(d,J=8.0Hz,1H),6.89(d, J=8.0Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=5.6Hz,2H),4.63(d,J=14.0Hz,1H),4.39-4.29(m, 6H),3.56-3.52(m,1H),3.36-3.35(m,2H),2.25-2.16(m,4H),1.98-1.91(m,1H),1.86-1.79(m,1H).

[0553] Example 17: Synthesis of Compound 17

[0554] Step 1: At 25 ° C, compound 17-1 (13.00 g, 81.76 mmol) was added to dichloromethane (130 mL), and then boron tribromide (33.8 g, 135.2 mmol) was added. The reaction solution was stirred at 25 ° C for 16 hours. The above reaction solution was slowly added dropwise to a mixed solution of dichloromethane (300 mL) and methanol (30 mL) to quench. The reaction solution was concentrated to obtain a mixture, and 80 mL of ethyl acetate (80 mL × 2) was added for slurry. Filter and dry to obtain compound 17-2. LCMS: m / z = 146.00 [M + H] + .

[0555] Step 2: At 25°C, compound 17-2 (4.00 g, 27.58 mmol) and compound 1-bromo-2-chloroethane (4.73 g, 32.98 mmol) were added to N,N-dimethylformamide (30 mL). Potassium carbonate (11.39 g, 82.45 mmol) was then added. Stir at 25°C for 16 hours. The reaction solution was poured into 200 mL of water, extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Compound 17-3 was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 30 / 70). LCMS: m / z = 208.0 [M+H]+.

[0556] Step 3: Compound 17-3 (2.5 g, 12.08 mmol) was added to N,N-dimethylformamide (25 mL) at 25°C. Potassium carbonate (5.00 g, 36.23 mmol) was added and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17-4. LCMS: m / z = 171.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.32 (s, 1H), 7.66 (s, 1H), 4.12 (t, J = 4.6Hz, 2H), 3.45 (t, J = 4.5Hz, 2H).

[0557] Step 4: At 25°C, compound 17-4 (1.60 g, 9.36 mmol) was added to a mixture of dichloromethane (25 mL) and 4-dimethylaminopyridine (171.52 mg, 1.40 mmol). Triethylamine (2.84 g, 28.08 mmol) was added, and di-tert-butyl carbonate (3.06 g, 14 mmol) was added dropwise in a 25°C water bath, with the temperature not exceeding 35°C. The reaction was allowed to react for 2 hours. The reaction solution was directly purified by flash silica gel column chromatography (petroleum ether / DCM = 99 / 1 to 30 / 70) to obtain compound 17-5. LCMS: m / z = 272.0 [M+H] + ; 1 H NMR (400MHz, DMSO) δ8.21 (s, 1H), 4.30 (t, J = 4.6Hz, 2H), 3.87 (t, J = 4.6Hz, 2H), 1.51 (s, 9H).

[0558] Step 5: At 25 ° C, compound 17-5 (800 mg, 3.69 mmol) and ferric acetylacetonate (651 mg, 1.84 mmol) were added to N-methylpyrrolidone (16 mL). After replacing the nitrogen, cyclobutylmagnesium bromide (22 mL, 0.5 M) was added dropwise. The reaction solution was stirred at 45 ° C for 4 hours. The reaction solution was poured into water (100 mL) to quench, and then extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / dichloromethane = 99 / 1 to 30 / 70) to obtain compound 17-6. LCMS: m / z = 292.1 [M+H] + .

[0559] Step 6: Compound 17-6 (420 mg, 1.44 mmol) was added to a mixture of dichloromethane (6 mL) and trifluoroacetic acid (2 mL) at 25°C. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 30 / 70) to obtain compound 17-7. LCMS: m / z = 192.0 [M+H] + .

[0560] Step 7: At 25°C, compound 17-7 (106 mg, 0.55 mmol) and compound Int H (135.45 mg, 0.67 mmol) were added to dioxane (15 mL), followed by cesium carbonate (361.21 mg, 1.11 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (94.28 mg, 0.11 mmol). The reaction solution was stirred at 90°C for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (dichloromethane / ethyl acetate = 99 / 1 to 30 / 70) to obtain compound 17-8. LCMS: m / z = 359.1 [M+H] + .

[0561] Step 8: Compound 17-8 (88 mg, 0.25 mmol) and barium hydroxide (168 mg, 0.98 mmol) were added to isopropanol and water (8 mL, 2:1) at 25°C. The reaction mixture was stirred at 100°C for 4 hours. Aqueous hydrogen chloride solution (1 M) was added dropwise to the reaction mixture to adjust the pH to acidic. Methanol was added and the mixture was purified by C18 reverse-phase silica gel column chromatography (water / acetonitrile = 99 / 1 to 60 / 40) to obtain compound 17-9. LCMS: m / z = 378.1 [M+H]+.

[0562] Step 9: Compound 17-9 (55 mg, 0.15 mmol) and Int E (37.29 mg, 0.17 mmol) were added to N,N-dimethylformamide (4.0 mL) at 25°C. 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (72.04 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) were then added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water) to give compound 17. LCMS: m / z = 573.2 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),9.19(s,1H),8.58(d,J=9.1Hz,1H),8.46(d,J=9.2 Hz,1H),8.33(d,J=2.3Hz,1H),8.21(s,1H),7.89(dd,J=8.2,2.3Hz,1H),7.75(s,1H),7.5 0(d,J=8.2Hz,1H),4.85(s,2H),4.44-4.42(m,2H),4.38-4.36(m,2H),4.22–4.15(m,2H), 4.05(s,2H),3.64–3.55(m,3H),2.33–2.22(m,4H),2.02–1.94(m,1H),1.88-1.84(m,1H).

[0563] Example 18: Synthesis of Compound 18

[0564] Step 1: A solution of compound 16-2 (700 mg, 2.68 mmol), trifluoroacetamide (909.06 mg, 8.04 mmol), magnesium oxide (648.18 mg, 16.08 mmol), and iodophenyl diacetic acid (1.03 mL, 5.36 mmol) in dichloromethane (40 mL) was stirred at 30°C for 5 minutes, followed by the addition of dimerized rhodium acetate (118.48 mg, 0.27 mmol). The reaction mixture was stirred at 30°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated, and the crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 18-1. LCMS: m / z = 372.0 [M+H] + .

[0565] Step 2: Potassium carbonate (2547.43 mg, 18.43 mmol) was added to a methanol solution (10 mL) of compound 18-1 (980 mg, 2.63 mmol). The reaction mixture was stirred at 30°C for 4 hours. The reaction mixture was concentrated, and the crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 18-2. LCMS: m / z = 276.0 [M+H] + .

[0566] Step 3: At 25°C, compound 18-2 (150 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (43.45 mg, 1.09 mmol, 60%) and iodomethane (0.03 mL, 0.55 mmol) were added. The reaction mixture was stirred for 1 hour. The reaction mixture was poured into ice water (5 mL) and then extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain compound 18-3. LCMS: m / z = 290.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.24 (d, J = 2Hz, 1H), 7.66 (dd, J = 2, 7.9Hz, 1H), 7.24-7.19 (m, 1H), 5.11-5.03 (m,1H),4.73-4.65(m,1H),4.46-4.35(m,1H),4.26-4.17(m,1H),3.46-3.32(m,2H),2.59(s,3H).

[0567] Step 4: Dissolve compound 18-3 (120 mg, 0.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (16.89 mg, 0.02 mmol), and triethylamine (0.11 mL, 0.83 mmol) in methanol (10 mL). Stir at 80°C under a carbon monoxide atmosphere for 15 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 18-4. LCMS: m / z = 270.0 [M+H] + .

[0568] Step 5: To a solution of compound 18-4 (110 mg, 0.41 mmol) in methanol (5 mL) and water (5 mL) was added lithium hydroxide (34.24 mg, 0.82 mmol). The mixture was then stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by C18 reverse phase column chromatography (acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to obtain compound 18-5. LCMS: m / z = 256.0 [M+H] + .

[0569] Step 6: At 25°C, N,N-diisopropylethylamine (0.12 mL, 0.71 mmol) was added to a solution of compound 18-5 (60 mg, 0.24 mmol) and compound Int H (59.16 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (107.24 mg, 0.28 mmol) was then added and stirred for 1 hour. The reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 18-6. LCMS: m / z = 430.9 [M+H] + .

[0570] Step 7: Compound 1-2 (10.60 mg, 0.06 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (1.97 mg, 0.01 mmol) and cesium carbonate (30.24 mg, 0.09 mmol) were added to a solution of compound 18-6 (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL). The reaction mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water) to obtain compound 18. LCMS: m / z = 585.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ9.51-9.44(m,1H),9.06-9.02(m,1H),8.45(d,J=1.2Hz,1H),8.40(d,J=9.2Hz ,1H),8.26(d,J=9.2Hz,1H),8.12(dd,J=1.6,7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.47-7.43(m,1H),7. 17(d,J=8.0Hz,1H),6.82(d,J=8.4Hz,1H),4.95-4.88(m,1H),4.83-4.75(m,1H),4.71-4.63(m,2H),4 .26(s,4H),4.18-4.06(m,2H),3.53-3.49(m,3H),2.38(s,3H),2.19-2.13(m,4H),1.95-1.81(m,2H).

[0571] Example 19: Synthesis of Compound 19

[0572] Step 1: At 25°C, compound 18-2 (290 mg, 1.05 mmol) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (153.96 mg, 1.26 mmol) and cyanogen bromide (222.46 mg, 2.10 mmol) were added. The reaction mixture was stirred for 12 hours. The reaction mixture was poured into ice water (5 mL), and then extracted with dichloromethane (5 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 19-1. LCMS: m / z = 301.0 [M+H] + .

[0573] Step 2: Dissolve compound 19-1 (200 mg, 0.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (27.12 mg, 0.03 mmol), and triethylamine (0.18 mL, 1.33 mmol) in methanol (10 mL). Stir at 80°C for 15 hours under a carbon monoxide atmosphere. Concentrate the reaction mixture under reduced pressure to obtain a crude product. The crude product is purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 19-2. LCMS: m / z = 281.0 [M+H] + .

[0574] Step 3: To a solution of compound 19-2 (180 mg, 0.64 mmol) in methanol (5 mL) and water (5 mL) was added lithium hydroxide (40.42 mg, 0.96 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by C18 reverse phase silica gel column chromatography (acetonitrile / 0.1% trifluoroacetic acid aqueous solution) to obtain compound 19-3. LCMS: m / z = 2670 [M+H] + .

[0575] Step 4: To a solution of compound 19-3 (75 mg, 0.28 mmol) and compound Int H (81.81 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) at 25°C was added N,N-diisopropylethylamine (0.14 mL, 0.85 mmol). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128.52 mg, 0.34 mmol) was then added and stirred for 1 hour. The reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 19-4. LCMS: m / z = 441.8 [M+H] + .

[0576] Step 5: Compound 1-2 (25.83 mg, 0.14 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19.2 mg, 0.02 mmol) and cesium carbonate (73.73 mg, 0.23 mmol) were added to a solution of compound 19-4 (50 mg, 0.11 mmol) in 1,4-dioxane (1 mL). The reaction solution was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (0.01 mM ammonium bicarbonate, acetonitrile-water) to obtain compound 19. LCMS: m / z = 596.5 [M+H] + .

[0577] Example 20: Synthesis of Compound 20

[0578] Step 1: Compound 1-2 (400 mg, 2.10 mmol) and N-chlorosuccinimide (280.75 mg, 2.10 mmol) were added to acetonitrile (10 mL) at 25°C and stirred for 4 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) to obtain compound 20-1. LCMS: m / z = 225.0 [M+H]+.

[0579] Step 2: At 25°C, compound 20-1 (88 mg, 0.39 mmol) and compound Int H (80 mg, 0.39 mmol) were added to dioxane (10 mL), followed by cesium carbonate (256 mg, 0.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (92.4 mg, 0.16 mmol) and palladium acetate (17 mg, 0.08 mmol). The reaction solution was stirred at 100°C for 16 hours. The above reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). Drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure gave a crude product. The crude product was purified by flash silica gel column chromatography (dichloromethane / ethyl acetate = 99 / 1 to 70 / 30) to give compound 20-2. LCMS: m / z = 392.2 [M+H] + .

[0580] Step 3: Compound 20-2 (110 mg, 0.28 mmol) and barium hydroxide (239 mg, 1.4 mmol) were added to isopropanol (6 mL) and water (3 mL) at 25°C, and the reaction mixture was stirred at 100°C for 4 hours. Aqueous hydrogen chloride solution (1 M) was added dropwise to the reaction mixture to adjust the pH to acidic. Methanol was added, and the mixture was purified by C18 reverse phase column chromatography (water / acetonitrile = 99 / 1 to 60 / 40) to obtain compound 20-3. LCMS: m / z = 411.2 [M+H] + .

[0581] Step 4: Compound 20-3 (30 mg, 0.07 mmol) and Int E (17.13 mg, 0.08 mmol) were added to N,N-dimethylformamide (3.0 mL) at 25°C. 2-(7-Azabenzotriazole)-tetramethyluronium hexafluorophosphate (41.65 mg, 0.11 mmol) and N,N-diisopropylethylamine (18.88 mg, 0.15 mmol) were then added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water) to give compound 20. LCMS: m / z = 606.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.11(s,1H),8.41–8.30(m,3H),7.88(dd,J= 8.2,2.3Hz,1H),7.68(s,1H),7.50(d,J=8.2Hz,1H),7.46(s,1H),4.84(s,2H),4.44 –4.33(m,4H),4.21–4.14(m,2H),4.02(s,2H),3.84(t,J=8.4Hz,1H),3.62–3.54(m ,2H),2.26(td,J=8.7,6.1Hz,4H),2.02–1.93(m,1H),1.81(dd,J=11.2,5.9Hz,1H).

[0582] Example 21: Synthesis of Compound 21

[0583] Step 1: Sodium sulfide (8.37 g, 107.28 mmol) was added to a solution of compound 21-1 (25 g, 107.28 mmol) in N,N-dimethylformamide (250 mL). The reaction mixture was stirred at 30°C for 12 hours. The pH of the reaction mixture was adjusted to 5-6 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate (250 mL x 3). The organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100) to obtain compound 21-2.

[0584] Step 2: To a solution of compound 21-2 (11 g, 44.51 mmol) in tetrahydrofuran (110 mL) at 0°C, lithium aluminum hydride (1.87 g, 44.51 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. The pH of the reaction mixture was adjusted to 4-5 with aqueous hydrochloric acid (1 M), extracted with ethyl acetate (150 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 21-3. LCMS: m / z = 218.9 [MH] - .

[0585] Step 3: Potassium carbonate (5.62 g, 40.65 mmol) was added to a solution of compound 21-3 (3 g, 13.55 mmol) and 1,2-dibromotetradeuterated ethane (1.17 mL, 13.55 mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 70 ° C for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 21-4. LCMS: m / z = 247.9 [MH] - .

[0586] Step 4: To a mixed solution of compound 21-4 (1.8 g, 7.2 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added potassium peroxymonosulfate (8.85 g, 14.39 mmol). The reaction mixture was stirred at 30°C for 12 hours. The reaction mixture was extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 21-5. LCMS: m / z = 279.9 [MH] - .

[0587] Step 5: Sodium hydride (0.33 g, 8.24 mmol, 60% mass fraction) was added to N,N-dimethylformamide (15 mL) of compound 21-5 (1.55 g, 5.49 mmol), and the final reaction solution was stirred at 30 ° C for 10 minutes. The reaction solution was quenched with saturated ammonium chloride (10 mL) aqueous solution, extracted with ethyl acetate (15 mL × 3), and the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 21-6. LCMS: m / z = 281.0 [M+H] + .

[0588] Step 6: Sodium hydride (49.79 g, 1.24 mmol, 60% mass fraction) was added to a solution of compound 21-6 (350 mg, 1.24 mmol) in N,N-dimethylformamide (3 mL), and then deuterated iodomethane (180.45 mg, 1.24 mmol) was added to the reaction solution. The reaction solution was stirred at 25 ° C for 30 minutes. The reaction solution was quenched with saturated ammonium chloride (2 mL) aqueous solution, extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 21-7. LCMS: m / z = 298.0 [M+H] + .

[0589] Step 7: A mixture of compound 21-7 (210 mg, 0.7 mmol), tert-butyl carbamate (82.5 mg, 0.7 mmol), cesium carbonate (458.9 mg, 1.41 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40.75 mg, 0.07 mmol), and tris(dibenzylacetone)dipalladium (64.49 mg, 0.07 mmol) in dioxane (5 mL) was stirred at 110°C under a nitrogen atmosphere for 12 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 21-8. LCMS: m / z = 279.2 [M-55] + .

[0590] Step 8: Add trifluoroacetic acid (1 mL, 0.03 mmol) to a solution of compound 21-8 (200 mg, 0.6 mmol) in dichloromethane (5 mL). Stir the reaction mixture at 25°C for 1 hour. Adjust the pH of the reaction mixture to 7-8 with aqueous ammonia. Concentrate the reaction mixture, and purify the crude product by flash silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 21-9. LCMS: m / z = 235.2 [M+H] + .

[0591] Step nine: To compound 21-9 (50 mg, 0.21 mmol), compound I-2 (7.51 mg, 0.21 mmol) and N, N-diisopropylethylamine (55.16 mg, 0.43 mmol) in N, N-dimethylformamide (2 mL) was added 1-propylphosphoric anhydride (407.37 mg, 0.64 mmol, 50% mass fraction). The final reaction solution was stirred at 20 ° C for 12 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 21-10. LCMS: m / z = 439.1 [M + H] + .

[0592] Step 10: Compound 21-10 (22 mg, 0.05 mmol), compound 14-2 (8.08 mg, 0.05 mmol), cesium carbonate (32.66 mg, 0.1 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (8.52 mg, 0.01 mmol) in dioxane (3 mL) were stirred at 110 ° C. under a nitrogen atmosphere for 1 hour. The crude product was purified by preparative high performance liquid chromatography (0.225% formic acid, acetonitrile-water = 50 / 50 to 80 / 20) to obtain compound 21 (formate salt). LCMS: m / z = 564.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.73 (s, 1H), 9.15 (s, 1H), 8.42 (d, J = 9.2Hz, 1H), 8.32 (d, J = 2.0Hz, 1H), 8.23-8.21 (m, 2H), 7.90 (dd, J = 8.0, 2. 4Hz,1H),7.71(s,1H),7.68(d,J=8.0Hz,1H),7.51(s,1H),7.49(s,1H),4.51-4.49(m,2H),4.41-4.39(m,2H),4.04(s,2H),3.52(s,1H).

[0593] Example 22: Synthesis of Compound 22

[0594] Step 1: Dissolve compound 22-1 (130 mg, 0.76 mmol), cyclopropylboronic acid (327.29 mg, 3.81 mmol), silver oxide (47.20 mg, 0.38 mmol), and potassium phosphate (526.43 mg, 2.29 mmol) in 1,4-dioxane (2 mL). After replacing the nitrogen atmosphere, add 1,1-bis(tert-butylphosphine)palladium dichloride (49.20 mg, 0.08 mmol). The reaction mixture was heated to 100°C and stirred for 18 hours under a nitrogen atmosphere. The mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-35%) to afford compound 22-2. LCMS: m / z = 177.1 [M+H]+.

[0595] Step 2: Compound Int H (50 mg, 0.25 mmol) and compound 22-2 (43.27 mg, 0.25 mmol) were added to 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (7.12 mg, 0.01 mmol) and cesium carbonate (240.01 mg, 0.74 mmol) were added to the mixture. The reaction mixture was stirred at 110°C under nitrogen for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (25 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-45%) to give compound 22-3. LCMS: m / z = 344.2 [M+H] + .

[0596] Step 3: Dissolve compound 22-3 (26 mg, 0.08 mmol) in concentrated hydrochloric acid (315 μL, 3.79 mmol). Heat the reaction mixture to 90°C and stir for 2 hours. Concentrate the reaction mixture under reduced pressure to dryness to obtain a crude product. The crude product is purified by C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain compound 22-4. LCMS: m / z = 363.2 [M+H] + .

[0597] Step 4: Compound 22-4 (32 mg, 0.09 mmol) and compound Int E (20.71 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (2 mL). A 50% ethyl acetate solution of propylphosphonic anhydride (280.96 mg, 0.44 mmol) and diisopropylethylamine (73 μL, 0.44 mmol) were added to the mixture. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (10 mM ammonium bicarbonate, acetonitrile-water) to obtain compound 22. LCMS: m / z = 557.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),10.70(s,1H),9.12(s,1H),8.68(d,J=9.2 Hz,1H),8.49(d,J=9.2Hz,1H),8.38-8.29(m,2H),7.93-7.85(m,1H),7.65(s,1H) ,7.49(d,J=8.4Hz,1H),7.11(d,J=8.0Hz,1H),4.84(s,2H),4.22-4.13(m,2H),4. 01(s,2H),3.63-3.53(m,2H),2.65(s,3H),2.28-2.20(m,1H),1.18-1.09(m,4H).

[0598] Example 23: Synthesis of Compound 23

[0599] Step 1: To a mixed solution of compound 6-1 (250 mg, 0.95 mmol) in dioxane (5 mL) and water (5 mL) was added potassium osmate dihydrate (35.0 mg, 0.1 mmol) and stirred for 30 minutes, followed by sodium periodate (407.7 mg, 1.91 mmol). The final reaction solution was stirred at 20°C for 1 hour. The reaction solution was extracted with ethyl acetate (5 mL × 3), the organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 23-1. LCMS: m / z = 208.9 [M-55] + .

[0600] Step 2: Add diethylaminosulfur trifluoride (579.43 mg, 3.59 mmol) to a solution of compound 23-1 (190 mg, 0.72 mmol) in dichloromethane (5 mL). The final reaction solution was stirred at 20°C for 1 hour. The reaction solution was poured into water (5 mL) and extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 23-2. LCMS: m / z = 231.0 [M-55] + .

[0601] Step 3: Add trifluoroacetic acid (0.5 mL, 0.03 mmol) to a solution of compound 23-2 (150 mg, 0.52 mmol) in dichloromethane (5 mL) and stir at 20°C for 1 hour. Adjust the pH of the reaction mixture to 7-8 with aqueous ammonia. Concentrate the reaction mixture and purify the crude product by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 23-3. LCMS: m / z = 187.0 [M+H] + .

[0602] Step 4: A solution of compound Int H (196.89 mg, 0.97 mmol), compound 23-3 (90 mg, 0.48 mmol), cesium carbonate (315.04 mg, 0.97 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (82.23 mg, 0.10 mmol) in dioxane (5 mL) was stirred at 110° C. under a nitrogen atmosphere for 1 hour. The reaction solution was concentrated, and the crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 23-4. LCMS: m / z = 354.2 [M+H] + .

[0603] Step 5: A solution of compound 23-4 (60 mg, 0.17 mmol) in concentrated hydrochloric acid (0.71 mL, 8.49 mmol) was stirred at 100°C for 2 hours. The reaction solution was concentrated, and the crude product was purified by C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain compound 23-5. LCMS: m / z = 373.2 [M+H] + .

[0604] Step 6: To a solution of compound 23-5 (10 mg, 0.03 mmol), compound Int E (5.73 mg, 0.03 mmol) and N,N-diisopropylethylamine (6.94 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (51.27 mg, 0.08 mmol). The final reaction solution was stirred at 20 ° C for 12 hours. The reaction solution was purified by preparative high performance liquid chromatography (0.1% formic acid, acetonitrile-water = 40 / 60 to 70 / 30) to obtain compound 23. LCMS: m / z 568.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.12(s,1H),8.35(d,J=2.4Hz,2H),8.33(d,J=2.4Hz,1H),7.88(dd,J=8.0,2.4Hz,1H),7.69(s,1H),7.49(dd, J=8.0,3.6Hz,2H),7.34(d,J=8.0Hz,1H),6.86(t,J=56.0Hz,1H),4.84(s, 2H),4.46-4.40(m,4H),4.19-4.16(m,2H),4.02(s,2H),3.60-3.57(m,2H).

[0605] Example 24: Synthesis of Compound 24

[0606] Step 1: Compound Int H (250 mg, 1.23 mmol) and 2-amino-3-acetylpyridine (200 mg, 1.47 mmol) were added to 1,4-dioxane (3 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (209 mg, 0.25 mmol) and cesium carbonate (1000 mg, 3.07 mmol) were then added to the mixture. Stir at 110°C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (25 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 24-1. LCMS: m / z = 304.2 [M+H] + .

[0607] Step 2: Dissolve compound 24-1 (150 mg, 0.49 mmol) in concentrated hydrochloric acid (2 mL, 24 mmol). Heat the reaction mixture to 90°C and stir for 2 hours. Concentrate the reaction mixture under reduced pressure to dryness to obtain a crude product. The crude product is purified by C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain compound 24-2. LCMS: m / z = 323.2 [M+H] + .

[0608] Step 3: Compound 24-2 (45 mg, 0.14 mmol) and Int E (35.73 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL), and a 50% ethyl acetate solution of propylphosphonic anhydride (178.18 mg, 0.28 mmol) and diisopropylethylamine (58 μL, 0.35 mmol) were added to the mixture. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction solution was quenched by adding 5 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (0.1% ammonium bicarbonate, acetonitrile-water = 20 / 80 to 95 / 5) to obtain compound 24. LCMS: m / z = 518.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.70(s,1H),9.13(s,1H),8.76(d,J =9.2Hz,1H),8.64-8.43(m,3H),8.31(d,J=2.4Hz,1H),7.89(dd,J=2.4,8.0 Hz,1H),7.65(s,1H),7.49(d,J=8.4Hz,1H),7.20(dd,J=4.8,7.6Hz,1H),4. 84(s,2H),4.25-4.08(m,2H),4.01(s,2H),3.67-3.51(m,2H),2.70(s,3H).

[0609] Example 25: Synthesis of Compound 25

[0610] Step 1: To a mixed solution of compound 25-1 (2 g, 8.44 mmol) and cyclopropylboronic acid (0.87 g, 10.13 mmol) in dioxane (30 mL) were added potassium phosphate (4.86 g, 21.10 mmol), silver oxide (0.21 g, 1.69 mmol), and bistriphenylphosphine palladium dichloride (0.63 g, 0.84 mmol). The reaction was heated to 90°C and stirred for 18 hours under nitrogen protection. The reaction solution was filtered, extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1) to obtain compound 25-2. LCMS: m / z 198.0 [M+H] + .

[0611] Step 2: Dissolve compound 25-2 (400 mg, 2.02 mmol), hexabutylditin (1406 mg, 2.42 mmol), lithium chloride (428 mg, 10.10 mmol), tris(dibenzylideneacetone)dipalladium (185 mg, 0.20 mmol), and tricyclohexylphosphine (57 mg, 0.20 mmol) in a dioxane (10 mL) solution and heat to 100 ° C under a nitrogen atmosphere for 18 hours. Dilute with water (10 mL), extract with ethyl acetate (50 mL), dry with anhydrous sodium sulfate, filter, and collect the filtrate and concentrate. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 97 / 3) to obtain compound 25-3. LCMS: m / z 410.2 [M+H] + .

[0612] Step 3: Dissolve compound 25-3 (601.41 mg, 1.47 mmol), Int H (300 mg, 1.47 mmol), and cuprous iodide (93.51 mg, 0.29 mmol) in dioxane (10 mL), and add bistriphenylphosphine palladium dichloride (103.41 mg, 0.15 mmol). Under a nitrogen atmosphere, heat to 100 ° C and react for 18 hours. Filter the reaction solution, collect the filtrate, and concentrate. The crude product is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 25-4. LCMS: m / z 287.1 [M+H] + .

[0613] Step 4: Dissolve compound 25-4 (180 mg, 0.63 mmol) in concentrated hydrochloric acid (2 mL, 24 mmol) and heat to 70°C for 3 hours. Concentrate under reduced pressure and dilute with 10 mL of water. The crude product is purified by C18 reverse-phase silica gel column chromatography to obtain compound 25-5. LCMS: m / z 306.2 [M+H] + .

[0614] Step 5: Propylphosphonic anhydride (168.0 μL, 0.66 mmol) was added dropwise to a solution of compound 25-5 (40 mg, 0.13 mmol), Int E (33.52 mg, 0.16 mmol), and N,N-diisopropylethylamine (108.26 μL, 0.66 mmol) in N,N-dimethylformamide (1 mL), and the mixture was reacted at 25°C for 8 hours. Diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The crude product was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water = 15 / 85 to 85 / 15) to obtain compound 25. LCMS: m / z 501.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.44-9.34(m,1H),8.77-8.58(m,2H),8.44-8.27(m,2H),7.98(s,1H),7.94-7.79(m,2 H),7.57-7.44(m,2H),4.84(s,2H),4.27-4.15(m,2H),4.11(s,2H),3.63-3.53(m,2H),2.29-2.21(m,1H),1.18-0.98(m,4H).

[0615] Example 26: Synthesis of Compound 26

[0616] Compounds Int J (60 mg, 0.16 mmol) and Int E (37.19 mg, 0.17 mmol) were added to N,N-dimethylformamide (4.0 mL) at 25°C, followed by 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (72.34 mg, 0.19 mmol) and N,N-diisopropylethylamine (40.99 mg, 0.32 mmol). The mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water) to provide compound 26. LCMS: m / z = 574.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.37(s,1H),8.68–8.62(m,2H),8.33(d,J=2.3Hz, 1H),7.98–7.93(m,2H),7.89(dd,J=8.2,2.3Hz,1H),7.79(dd,J=8.5,7.4Hz,1H),7.50(d ,J=8.2Hz,1H),7.05(d,J=8.5Hz,1H),4.84(s,2H),4.35-4.31(m,2H),4.20–4.16(m,2H) ,4.11(s,2H),3.71-3.66(m,2H),3.61–3.57(m,2H),2.54(s,2H),1.22(d,J=6.2Hz,6H).

[0617] Example 27: Synthesis of Compound 27

[0618] Compound Int J (40 mg, 0.11 mmol) and compound Int A (23.38 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). To the mixture was added a 50% ethyl acetate solution of propylphosphonic anhydride (336.32 mg, 0.53 mmol) and diisopropylethylamine (88 μL, 0.53 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (10 mM ammonium bicarbonate, acetonitrile-water) to obtain compound 27. LCMS: m / z = 582.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ10.96(s,1H),9.37(s,1H),8.72-8.60(m,2H),8.40(s,1H),8. 17-8.10(m,1H),7.98(s,1H),7.94(d,J=7.5Hz,1H),7.90(d,J=8.5Hz,1H),7.79(t,J= 8.0Hz,1H),7.70-7.43(m,1H),7.05(d,J=8.5Hz,1H),4.32(d,J=12.5Hz,2H),4.14(s, 2H), 3.73-3.64 (m, 2H), 3.29 (s, 3H), 2.53 (s, 1H), 2.48 (s, 1H), 1.22 (d, J = 6.0Hz, 6H).

[0619] Example 28: Synthesis of Compound 28

[0620] Step 1: At 25°C, compound Int H (300 mg, 1.47 mmol) and compound 28-1 (251.34 mg, 1.47 mmol) were added to dioxane (20 mL). Cesium carbonate (960.04 mg, 2.95 mmol), 1-propylphosphonic anhydride (340.99 mg, 0.59 mmol), and palladium acetate (66.15 mg, 0.29 mmol) were then added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (dichloromethane / ethyl acetate = 99 / 1 to 80 / 20) to obtain compound 28-2. LCMS: m / z = 338.0 [M+H]+.

[0621] Step 2: Compound 28-2 (250 mg, 0.74 mmol) and barium hydroxide (634.09 mg, 3.70 mmol) were added to isopropanol (12 mL) and water (8 mL) at 25°C. The reaction mixture was stirred at 100°C for 4 hours. Aqueous hydrogen chloride solution (1 M) was added dropwise to adjust the pH to acidic. Methanol was then added and the mixture was purified by C18 reverse-phase column chromatography (water / acetonitrile = 99 / 1 to 60 / 40) to afford compound 28-3. LCMS: m / z = 357.0 [M+H]+.

[0622] Step 3: Compound 28-3 (60 mg, 0.17 mmol) and compound Int E (39.45 mg, 0.18 mmol) were added to N,N-dimethylformamide (4.0 mL) at 25°C. 2-(7-Azabenzotriazole)-tetramethyluronium hexafluorophosphate (76.74 mg, 0.20 mmol) and N,N-diisopropylethylamine (43.47 mg, 0.34 mmol) were then added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by preparative HPLC (0.1% ammonium bicarbonate, acetonitrile-water) to obtain compound 28. LCMS: m / z = 551.9 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.10(d,J=0.8Hz,1H),8.34–8.30(m,2H),8.23(d,J=9.1Hz,1H),7.96(d,J=2.3Hz,1H),7.88(dd,J=8.1,2.3Hz ,1H),7.67(s,1H),7.56(d,J=2.3Hz,1H),7.49(d,J=8.2Hz,1H),4.84(s,2 H),4.43–4.36(m,4H),4.20–4.15(m,2H),4.02(s,2H),3.61–3.55(m,2H).

[0623] Example 29: Synthesis of Compound 29

[0624] Step 1: Dissolve compound 29-1 (2.4 g, 15.99 mmol) in acetonitrile (50 mL), add N-bromosuccinimide (3.56 g, 19.98 mmol), and heat the reaction solution to 85°C and stir for 16 hours. After the reaction solution is concentrated under reduced pressure, pour it into water (100 mL), and then extract it with dichloromethane (100 mL×2). The organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is added to a mixed solvent of petroleum ether / ethyl acetate (50 mL, v / v=5 / 1) and slurried to purify compound 29-2. LCMS: m / z=229.0[M+H] + .

[0625] Step 2: Compound 29-2 (3.0 g, 13.10 mmol) and trimethylboroxane (1.9 mL, 65.49 mmol) were added to 1,4-dioxane (100 mL) and water (20 mL). Tetrakistriphenylphosphine palladium (760 mg, 0.65 mmol) and cesium carbonate (12.80 g, 39.30 mmol) were then added to the mixture. The reaction mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane = 0-5%) and C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% formic acid in water) to obtain compound 29-3. LCMS: m / z = 165.0 [M+H] + .

[0626] Step 3: Dissolve compound 29-3 (470 mg, 2.86 mmol) in tetrahydrofuran (15 mL) and slowly add borane tetrahydrofuran solution (7.16 mL, 1 M) dropwise. Heat the reaction mixture to 80°C and stir for 2 hours. Cool the reaction mixture to room temperature, pour into water (50 mL), and then extract with ethyl acetate (50 mL × 2). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0-35%) to obtain compound 29-4. LCMS: m / z = 151.0 [M+H] + .

[0627] Step 4: Compound Int H (150 mg, 0.74 mmol) and compound 29-4 (110.63 mg, 0.74 mmol) were added to 1,4-dioxane (9 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (62.64 mg, 0.07 mmol) and cesium carbonate (720.03 mg, 2.21 mmol) were added to the mixture. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 reverse phase silica gel column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to give compound 29-5. LCMS: m / z = 318.2 [M+H] + .

[0628] Step 5: Dissolve compound 29-5 (220 mg, 0.69 mmol) in concentrated hydrochloric acid (2.90 mL, 34.66 mmol). Heat the reaction mixture to 90°C and stir for 2 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain compound 29-6. LCMS: m / z = 337.2 [M+H] + .

[0629] Step 6: Compound 29-6 (40 mg, 0.12 mmol) and compound Int E (27.90 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (2 mL). To the mixture was added a 50% ethyl acetate solution of propylphosphonic anhydride (378.39 mg, 0.59 mmol) and diisopropylethylamine (99 μL, 0.59 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (10 mM ammonium bicarbonate, acetonitrile-water) to obtain compound 29. LCMS: m / z = 532.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ10.71(s,1H),9.05(s,1H),8.32(d,J=2.0Hz,1H),8.31-8.23(m,2H),7.90-7.85(m,1H),7.78(d,J=1.0Hz,1H),7.62(s,1 H),7.49(d,J=8.0Hz,1H),7.21(d,J=1.5Hz,1H),4.84(s,2H),4.41-4.32 (m,4H),4.20-4.14(m,2H),4.00(s,2H),3.63-3.54(m,2H),2.26(s,3H).

[0630] Example 30: Synthesis of Compound 30

[0631] Step 1: Slowly add lithium diisopropylamide (26.25 mL, 198.47 mmol) and hexamethylphosphoric triamide (66 mL, 379.35 mmol) dropwise to a solution of compound 30-1 (25 g, 165.39 mmol) in tetrahydrofuran (200 mL) at -70°C. Maintain the temperature for 50 minutes. Rapidly add 1,2-dibromoethane (36 mL, 413.47 mmol) dropwise to the mixture. Slowly warm to room temperature and continue stirring for 18 hours. Quench with saturated aqueous ammonium chloride (50 mL), extract with ethyl acetate (250 mL x 2), wash with saturated brine (250 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain compound 30-2.

[0632] Step 2: Add a solution of lithium aluminum hydride in tetrahydrofuran (39.73 mL, 2.5 M) to a solution of compound 30-2 (16 g, 90.29 mmol) in tetrahydrofuran (200 mL) at -70°C. Maintain the reaction temperature for 2 hours. Cool the reaction mixture to 0°C, slowly add pure water (3.77 mL) and stir for 10 minutes, followed by addition of aqueous sodium hydroxide solution (3.77 mL). Stir at 25°C for 10 minutes, then add pure water (7.6 mL). Stir for 15 minutes, then dry over anhydrous sodium sulfate, and filter the mixture through celite. Concentrate the filtrate under reduced pressure to obtain compound 30-3.

[0633] Step 3: Add diisopropyl azodicarboxylate (15.84 mL, 80.43 mmol) dropwise to a solution of triphenylphosphine (21.10 g, 80.43 mmol) in tetrahydrofuran (30 mL) at -20°C. Maintain stirring for 30 minutes. Add a solution of compound 30-3 (8 g, 53.62 mmol) in tetrahydrofuran (30 mL) dropwise to the above solution. Continue reacting at -20°C for 30 minutes, then add a solution of acetone cyanohydrin (14.72 mL, 160.87 mmol) in tetrahydrofuran (30 mL) dropwise. Naturally warm to 25°C and react for 18 hours. Quench with 50 mL of water, extract with ethyl acetate (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The filtrate is then dissolved in ethanol (100 mL), and zinc chloride (13 g) is added as a solid. Stir for 1 hour, filter, and collect the filtrate and concentrate. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol=95 / 5) to give compound 30-4.

[0634] Step 4: Add a tetrahydrofuran solution of borane dimethyl sulfide complex (47.41 mL, 2.0 M) dropwise to a tetrahydrofuran solution of compound 30-4 (3 g, 18.96 mmol) (50 mL) at 0°C, slowly warm to 25°C and stir for 18 hours. Slowly add methanol (10 mL) dropwise to the reaction solution to quench it, add aqueous hydrochloric acid (3 mL, 6 M) dropwise, stir for 30 minutes, adjust the pH to 11 with aqueous sodium hydroxide (6 M), dilute with water (30 mL), extract with dichloromethane (150 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product was purified by flash silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain compound 30-5. LCMS: m / z 163.0 [M+H] + .

[0635] Step 5: Sodium hydride (1.11 g, 27.74 mmol, 60% mass fraction) was added to a toluene (20 mL) solution of compound 30-5 (900 mg, 5.55 mmol), and the temperature was raised to 120°C for 18 hours. Ethanol (10 mL) was added dropwise to quench the mixture, and the mixture was diluted with water (30 mL). The mixture was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 30-6. LCMS: m / z 161.0 [M+H] + .

[0636] Step 6: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl) (0.14 g, 0.16 mmol) was added to a mixed solution of compound 30-6 (0.33 g, 1.62 mmol), compound Int H (0.26 g, 1.62 mmol), and cesium carbonate (1.32 g, 4.05 mmol) in dioxane (5 mL), and stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give compound 30-7. LCMS: m / z 328.1 [M+H] + .

[0637] Step 7: Dissolve compound 30-7 (280 mg, 0.86 mmol) in 5 mL of concentrated hydrochloric acid and heat to 70°C for 3 hours. Concentrate under reduced pressure and dilute with water (5 mL). Purify the crude product using C18 reverse-phase silica gel column chromatography (0.1% tr...

Claims

1. A compound represented by formula (0), or a stereoisomer, or a tautomer, or a polymorph, or a solvate, or a hydrate, or an N-oxide, or an isotope-labeled compound, or a metabolite, or an ester, or a prodrug, or a pharmaceutically acceptable salt thereof: in, Ring A is selected from a 5-10 membered heteroaromatic ring, a C6-C10 aromatic ring, a C3-C10 alkyl ring or a 4-10 membered heterocyclic ring; Each R a are each independently selected from deuterium, halogen, cyano, hydroxyl, -NR A1 R A2 , oxo, C1-C6 alkyl, C1-C6 alkoxy, -O(C3-C6 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 membered aryl, -C(O)C1-C6 alkyl, or two R groups attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, or two R atoms attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, wherein R A1 and R A2 Each is independently selected from H, deuterium, halogen, C1-C6 alkyl or -C(O)C1-C6 alkyl; T is selected from CR e R f , R e and R f are each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl; as the R a The C1-C6 alkyl, C1-C6 alkoxy, -O (C3-C6 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 membered aryl, -C (O) C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, amino, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or C3-C8 cycloalkyl; t is 0, 1, 2, 3, 4, or 5; L 1 Selected from-NR 4 -, -O- or -S-, R 4 is selected from H, deuterium, halogen or C1-C6 alkyl, wherein as R 4 The C1-C6 alkyl group is optionally substituted with deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy; p is 0, 1, or 2; Ring B is selected from a 5-10 membered heteroaromatic ring or a 6-10 membered aromatic ring; Each R b Each is independently selected from deuterium, halogen, cyano, hydroxy, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl; s is 0, 1, 2, 3, 4, or 5; L 2 Selected from single bonds, The end is connected to the B ring, R 5 R is selected from H, deuterium, halogen, hydroxyl or C1-C6 alkyl 5 The C1-C6 alkyl group is optionally substituted with deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy; n is 0 or 1; R 1 and R 2 Each independently selected from hydrogen, C1-C6 alkyl or C1-C6 heteroalkyl, as R 1 and R 2 The C1-C6 alkyl and C1-C6 heteroalkyl groups are each independently optionally substituted by deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the heteroatom in the C1-C6 heteroalkyl group is O, S or N; preferably R 1 and R 2 Each independently selected from hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, preferably as R 1 and R 2 The C1-C3 alkyl and C1-C3 heteroalkyl groups are each independently optionally substituted by deuterium, halogen, C1-C3 alkyl or C1-C3 alkoxy; further preferably R 1 and R 2 Each independently selected from hydrogen, -CH3 or -CH2OCH3; more preferably R 1 and R 2 Each independently selected from hydrogen or -CH2OCH3; m is 0, 1, 2, or 3; preferably m is 1; R 6 Selected from H, deuterium, halogen, hydroxyl or C1-C6 alkyl, preferably R 6 Selected from H; Ring C is selected from a 5-10 membered heteroaromatic ring or a 6-10 membered aromatic ring; Each R c Each is independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl or C1-C6 haloalkoxy; q is 0, 1, 2, 3, or 4; X is selected from -S(O)2-, -S(O)-, -S(O)(=NR 7 )-、-C(O)-、-CR 8 R 9 -, R 7 R is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino or C1-C6 alkyl 7 The C1-C6 alkyl group is optionally substituted by deuterium, halogen, cyano, or hydroxyl; preferably R 7 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino or C1-C3 alkyl, and more preferably R 7 is selected from hydrogen, deuterium, halogen, cyano or methyl; R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino or C1-C6 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 8-membered ring; as R 8 and R 9 The C1-C6 alkyl group is optionally substituted by deuterium, halogen, cyano, or hydroxyl; preferably R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, amino or C1-C3 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring; more preferably R 8 and R 9 are each independently selected from halogen, cyano, methyl, -CH2CN, -CH2OH, or R 8 and R 9 Together with the carbon atom to which they are attached, they form oxetanes; R 3 Selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -NR g R h , or R 3 With R c and the atoms to which they are attached form a 5-8 membered ring, the 5-8 membered ring being optionally substituted with r R d Substituted, each of the R d Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocyclic group; R g and R h Each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl; as R 3 The heteroatom in the C1-C6 heteroalkyl group is O, S or N; r is 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: R 3 Selected from C1-C3 alkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -NR g R h , or R 3 With R c and the atoms to which they are connected form a 5-membered carbocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, or an 8-membered heterocyclic ring, wherein the 5-membered carbocyclic ring, the 6-membered heterocyclic ring, the 7-membered heterocyclic ring, or the 8-membered heterocyclic ring is optionally replaced by r R d Substituted, each of the R d Each is independently selected from deuterium, halogen, cyano, hydroxy, amino, oxo, C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group; R g and R h Each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl; as R 3 The heteroatom in the C1-C3 heteroalkyl group is O, S or N; Preferably, each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, or R attached to different ring atoms. d Together with the ring atoms to which they are connected, they constitute a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, and more preferably, R d Each is independently selected from deuterium, F, Cl, methyl or deuterated methyl; Preferably, r is 0, 1, 2, 3, 4 or 5.

3. The compound according to claim 1 or 2, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The C ring is selected from a 5-6 membered heteroaromatic ring or a 6-10 membered aromatic ring; more preferably, the C ring is selected from a 5-6 membered heteroaromatic ring or a benzene ring, more preferably, the C ring is selected from a pyrrole ring, an imidazole ring, a pyrazole ring, a pyridine ring, a pyrimidine ring or a benzene ring, and even more preferably, the C ring is selected from a pyrrole ring, an imidazole ring, a pyridine ring or a benzene ring; Preferably, the C ring is The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected; Optimize each R c Each is independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl or C1-C6 haloalkoxy; Optimize each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy; Further preferably, each R c Each is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy; More preferably, each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3; Further optimization of each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2; Preferably, q is 0, 1, 2, or 3, and more preferably, q is 0 or 1; Preferred Selected from The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected; Further optimization Selected from The left side Indicates -XR 3 Connected, right Indicates -NR 6 - connected; Preferably, X is -S(O)2-, -S(O)-, -S(O)(=NR 7 )-、-C(O)-、-CR 8 R 9 -, R 7 is selected from hydrogen, cyano, hydroxy, C1-C3 alkyl, R 8 and R 9 Each is independently selected from H, halogen, cyano, hydroxyl or C1-C3 alkyl, preferably R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring, as R 7 、R 8 and R 9 The C1-C3 alkyl group is optionally substituted by deuterium, halogen or hydroxy, preferably substituted by hydroxy; More preferably, X is -S(O)2-, -S(O)-, -S(O)(=NCH3)-, -S(O)(=NCN)-, -C(CH3)(CN)-, -C(CH3)F-, -C(CH3)(CH2OH)- or More preferably, X is -S(O)2- or -S(O)-; further more preferably -S(O)2-; preferably R 3 With R c and the atoms they are connected to form a 5-8 membered ring, preferably for or Selected from Preferred for Preferred (More preferably )、 (More preferably )、 (More preferably )、 (More preferably )、 (More preferably )、 or more preferably for or more preferably for Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formula 0I: Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 ,n,R 1 、R 2 ,m,R 6 The meaning is the same as that in claim 1 or 2; q1 is 0, 1, 2, or 3; Preferably, the D ring is selected from a 5- to 8-membered heterocyclic or carbocyclic ring; preferably, the D ring is selected from in, Indicates a single bond or a double bond; U is C or N, Z is a single bond, O, S, NH or CH2; W 1 and W 2 Each is independently selected from C1-C2 alkylene, wherein any -CH2- in the C1-2 alkylene may be substituted by O, S or NH; Preferred Selected from Preferred Selected from Preferably, each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl or deuterated methyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-7 membered heterocyclic group; Preferably, r is 0, 1, 2, 3, 4 or 5, and more preferably, r is 0, 1, 2 or 5; Preferably, each of the R d Each is independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl; Preferred Selected from Further optimization Selected from Preferred (More preferably )、 (More preferably )、 Preferred Selected from Preferred Selected from Further optimization Selected from Preferred (More preferably )、 (More preferably )、 (More preferably )、 (More preferably )、 (More preferably )、 4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Ring B is selected from 5-10 membered heteroaromatic rings, preferably ring B is selected from 5-6 membered monocyclic heteroaromatic rings and 9-10 membered bicyclic fused heteroaromatic rings, preferably, ring B is selected from Preferably, ring B is selected from Preferably, ring B is selected from More preferably, ring B is The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected; China E 1 、E 2 、E 3 、E 4 、E 5 and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N; China E 1 、E 2 、E 5 and E 6 Each independently selected from N or CH, and at least one is N, preferably E 1 N; E 3’ and E 4’ Each is independently selected from NH or CH2, and at least one is NH, preferably E 4’ For NH, China E 7 Independently selected from O, S, NH, CH2, E 8 and E 9 Each is independently selected from N, CH, and at least one is N or S, preferably E 7 For S, E 9 N, E 8 for CH; In, E 6’ Independently selected from O, S, NH, CH2, preferably E 6’ For NH, E 1 、E 3 、E 4 、E 5 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N; Optimize each R b Each is independently selected from halogen, oxo or C1-C6 alkyl, and further preferably each R b Each is independently selected from F, Cl, oxo, methyl or ethyl; more preferably each R b are each independently selected from halogen (e.g., F); Preferably, s is 0, 1, 2, 3 or 4, preferably 0 or 1, more preferably 0; Preferably, the B ring is selected from Preferably, the B ring is selected from The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected; Preferred Selected from Preferred Selected from More preferred for The left side Indicates -(L 2 ) n - Connected, right side Indicates -(L 1 ) p - connected.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: L 1 Selected from-NR 4 -, R 4 is selected from H, deuterium, halogen, C1-C6 haloalkyl or C1-C6 deuterated alkyl, preferably R 4 Selected from H, deuterium or -CD3; preferably said L 1 is -N(CD3)- or -NH-; Preferably, p is 0 or 1, and more preferably p is 0.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from a 5-10 membered heteroaromatic ring, a C6-C10 aromatic ring; Preferably, the A ring is selected from Among them, G 1 , G 1’ , G 13 , G 17 , G 18 , G 19 , G 25 , G 26 , G 29 Each independently selected from O, NH, S or CH2, G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 9 , G 10 , G 11 , G 12 , G 14 , G 15 , G 16 , G 20 , G 21 , G 22 , G 23 , G 24 , G 27 , G 28 , G 30 , G 31 , G 32 , G 33 , G 34 Each independently selected from N or CH, preferably ring A is selected from More preferred Preferred G 1 is selected from O, NH or -CH2-, more preferably G 1 Selected from O or -CH2-; Preferred G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH; Preferred G 1’ Selected from O, NH or -CH2-; Preferred G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH; Preferred G 11 , G 12 are each independently selected from N or CH; Preferred G 13 Selected from NH or S, more preferably G 13 Selected from S; Preferred G 14 , G 15 , G 16 are each independently selected from N or CH; Preferred G 17 , G 18 , G 19 are each independently selected from O, NH or CH2; Preferred G 20 , G 21 , G 22 are each independently selected from N or CH; Preferred G 23 , G 24 are each independently selected from N or CH; Preferred G 25 Selected from S; Preferred G 26 selected from CH2; Preferred G 27 , G 28 , G 30 are each independently selected from N or CH and at least one of them is N; Preferred G 29 are each independently selected from NH or S; Preferred G 31 , G 32 , G 33 , G 34 In, G 31 or G 34 is N, the rest are CH; Preferably, the A ring is More preferably, the A ring is It is further preferred that the A ring is It is further preferred that the A ring is Optimize each R a are each independently selected from halogen, cyano, -NR A1 R A2 , oxo, C1-C6 alkyl, C1-C6 alkoxy, -O(C3-C6 cycloalkyl), C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)C1-C6 alkyl, or two R groups attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R A1 and R A2 are each independently selected from H, deuterium, halogen, C1-C6 alkyl or -C(O)C1-C6 alkyl, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, -O (C3-C6 cycloalkyl), C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered heteroaryl, -C (O) C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from a saturated heterocyclic group, a partially unsaturated heterocyclic group, a monocyclic heterocyclic group, a condensed ring heterocyclic group or a bridged heterocyclic group; Further preferably, each R a are each independently selected from halogen, cyano, -NR A1 R A2 , oxo, C1-C3 alkyl, C1-C3 alkoxy, -O(C3-C6 cycloalkyl), C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R A1 and R A2 Each is independently selected from H, C1-C3 alkyl or -C(O)C1-C3 alkyl, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C1-C3 alkoxy, -O(C3-C6 cycloalkyl), C2-C4 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)C1-C3 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a 'Selected from deuterium, halogen, cyano, hydroxy, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl; More preferably, each R a Each is independently selected from F, Cl, cyano, oxo, -NH2, -C(O)CH3, -NHC(O)CH3, methyl, ethyl, methoxy, ethoxy, methoxyethyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoromethoxy, fluoroethoxy, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, fluorocyclopentane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; Preferably, t is 0, 1, 2 or 3; Preferably Selected from Preferably Selected from It is further preferred that Selected from More preferred 7. The compound according to any one of claims 1 to 6, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of formula 0 is selected from any one of the structures shown in the following formula I or formula II: Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 ,m,n,R 1 、R 2 、R 6 The meaning is the same as that in any one of claims 1 to 6; In the general formula I, Y is CH or N, preferably Y is CH; Optimize each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy, and each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2; Preferably, q1 is 0 or 1; Preferably, Z is a single bond, O or CH2; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O; Preferably, each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group. d Each independently selected from deuterium, F, Cl, methyl or deuterated methyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group, or R attached to different ring atoms d Together with the ring atoms to which they are attached, they form a C3-C5 cycloalkyl group, and r is 0, 1, 2 or 5; Preferred Selected from Further optimization Selected from Preferred Selected from Further optimization Selected from Further optimization Selected from In the general formula II, preferably each R c Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy, and each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each independently selected from F, Cl, methyl, ethyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each independently selected from F, Cl or methyl; Preferably, q1 is 0 or 1; Preferably, Z is a single bond, O or CH2, and more preferably, Z is O; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O; Preferably, each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, or two R attached to the same carbon atom d Together with the carbon atoms to which they are attached, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group, or R attached to different ring atoms d Together with the ring atoms to which they are connected, they form a C3-C5 cycloalkyl group or a 3-5 membered heterocyclic group. d Each is independently selected from deuterium, F, Cl or methyl, and r is 0, 1 or 2; Preferred Selected from Preferred Selected from Further optimization Selected from 8. The compound according to claim 7, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: In the general formula I, L 1 -NR 4 -, R 4 Selected from H or C1-C3 deuterated alkyl, preferably R 4 Selected from H or deuterated methane, more preferably R 4 Selected from H or -CD3; preferably p is 0 or 1; In the general formula II, p is 0; In general formula I or general formula II, L 2 Selected from The end is connected to the B ring, R 5 is selected from H, deuterium, halogen, hydroxyl or C1-C3 alkyl, preferably R 5 Selected from H; preferably n is 0 or 1; In general formula I or general formula II, preferably R 6 Selected from H; In general formula I or general formula II, preferably R 1 and R 2 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, and R 1 and R 2 Each independently is hydrogen, methyl or -CH2OCH3, more preferably R 1 and R 2 One is hydrogen, and the other is H, methyl or -CH2OCH3; Preferably, the compound of general formula I is selected from any one of the structures shown in the following general formula I0: Preferably, the general formula I0 is selected from the structure shown in the following general formula I0-1: More preferably, the general formula I0-1 is selected from the structure shown in the following general formula I0-1-1: Preferably, the general formula I0-1-1 is selected from the structures shown in the following general formula I0-1-1-1: Preferably, the compound of formula II is selected from any one of the structures shown in the following formula II0: Preferably, the compound of the general formula II0 is selected from the structure shown in the following general formula II0-1:

9. The compound according to any one of claims 1 to 8, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formula I1' or general formula II1: Among them, A ring, R a ,t,R 1 、R 2 、R 6 、R c 、R d , r, R b , s is as defined in any one of claims 1 to 8; q1 is each independently selected from 0 or 1; Preferred E 1 、E 2 、E 3 、E 4 、E 5 and E 6 are each independently selected from N, CH, and at least one is N, preferably both are N; Preferred Selected from More preferred Selected from Preferably, Z is a single bond, O or CH2; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, preferably any -CH2- in the C1-C2 alkylene may be substituted by O; further preferably W 1 Selected from CH2CH2, Z is O, W 2 selected from CH2; or W 1 is selected from CH2CH2, Z is CH2, W 2 Selected from CH2, wherein W 2 The CH2 is replaced by O; Preferred Selected from More preferred Preferred Selected from More preferred Preferred Selected from More preferred Preferred Selected from More preferred Preferred R 6 Selected from H; Preferably, the general formula I1' or the general formula III is selected from any one of the structures represented by the following general formula I01' or the general formula III: Preferably, the general formula I01' is selected from the structure represented by the following general formula I01":

10. The compound according to claim 9, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula I1' is selected from any one of the structures represented by the following general formulas I1-D1', I1-D2, and I1-D3: The compound of the general formula II1 is selected from any one of the structures shown in the following general formula II1-D1: Among them, A ring, R a ,t,R 1 、R 2 、R 6 、R b , s are as defined in any one of claims 1 to 8; E 1 、E 2 、E 3 、E 4 、E 5 and E 6 The same as defined in claim 4 or 9; In the general formula I1-D1' or the general formula III-D1, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl, deuterated methyl, or two R d The carbon atoms to which it is connected together form a C3-C5 cycloalkyl group; Preferably r is 0, 1, 2 or 5, more preferably r is 0, 1 or 5; Optimize each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2; Preferably, q1 is 0 or 1; Preferred Selected from More preferred Selected from: Preferred Selected from More preferred Selected from In the general formula I1-D2, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from deuterium, F, Cl, methyl, deuterated methyl; or two R connected to the same carbon atom d The carbon atoms to which it is connected together form a C3-C5 cycloalkyl group; Preferably r is 0, 1 or 2, more preferably 0 or 1; Optimize each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2; Preferably, q1 is 0 or 1; Preferred Selected from More preferred Selected from In the general formula I1-D3, preferably each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each independently selected from methyl, deuterated methyl, or two R d The carbon atoms to which it is connected together form a C3-C5 cycloalkyl group, or R d Together with the ring atoms to which they are attached, they form a C4-C5 cycloalkyl group; Preferably r is 0, 1 or 2; Optimize each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3; Preferably q1 is 0 or 1, preferably q1 is 0; Preferred Selected from 11. The compound according to any one of claims 1 to 9, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures represented by the following general formulas I1-A1, I1-A2, I1-A3, I1-A4, III-A1, III-A2, III-A3, and III-A4: Among them, R 1 、R 2 、R 6 、R c 、R d , r, R b , s are as defined in any one of claims 1 to 8; E 1 、E 2 、E 3 、E 4 、E 5 and E 6 The same as defined in claim 4 or 9; Each q1 is independently selected from 0 or 1; In the general formula I1-A1 and general formula III-A1, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH; Preferred Selected from Preferred for Optimize each R a Each is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 cycloalkyl or 4-8 membered heterocyclyl, -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, R e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; Preferably, t is 0, 1 or 2; Preferably, the general formula I1-A1 and the general formula III-A1 Each independently selected from Preferably, the general formula I1-A1 and the general formula III-A1 Each independently In the general formula I1-A2 and the general formula III-A2, preferably R 1 and R 2 Each independently is hydrogen, -CH3 or -CH2OCH3; more preferably R 1 and R 2 is hydrogen; In the general formula I1-A2 and the general formula III-A2, preferably G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH; preferably Selected from Further optimization Selected from In the general formula I1-A2 and the general formula III-A2, preferably each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, fused heterocyclic group or bridged heterocyclic group; more preferably, each R a Each is independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, fluoromethoxy, Preferably, t is 1, 2 or 3; In the general formula I1-A2 and general formula III-A2, preferably Each independently selected from In the general formula I1-A2 and general formula III-A2, it is further preferred Each independently selected from In the general formula I1-A2 and III-A2, more preferably Each independently selected from In the general formulas I1-A3 and III-A3, G 11 , G 12 , G 14 , G 15 , G 16 Each independently selected from N or CH; preferably G 11 , G 12 Each independently selected from N or CH; preferably G 14 , G 15 , G 16 Selected from N or CH; G 13 Selected from NH or S, preferably G 13 for NH; Optimize each R a Each independently selected from halogen, C1-C3 alkyl, -NR A1 R A2 , the C1-C3 alkyl group is optionally replaced by R a 'Replace, R a ' is selected from C1-C3 alkoxy; R A1 and R A2 Each is independently selected from H, C1-C6 alkyl or -C(O)C1-C6 alkyl, preferably R A1 and R A2 Each is independently selected from H, C1-C3 alkyl or -C(O)C1-C3 alkyl; more preferably each R a Each independently selected from methyl, F, ethyl, methoxyethyl, -NH2, -NHC(O)CH3; preferably t is 1 or 2; Preferably, the general formula I1-A3 and III-A3 Each independently selected from Preferably, the general formula I1-A3 and III-A3 Each independently selected from Preferred R 1 and R 2 is hydrogen; In the general formulae I1-A4 and III-A4, G17, G18, and G19 are each independently selected from O, NH, or CH2; G20, G21, and G22 are each independently selected from N or CH; Preferred general formulas I1-A4 and III-A4 Each independently selected from Preferably Optimize each R a Each independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, oxo, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; more preferably each R a Each is independently selected from F, Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, Further optimization of each R a Each independently selected from oxo or Preferably, t is 1 or 2; Preferred Selected from 12. The compound according to any one of claims 1 to 11, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formulas I11 to I118 and II11 to II14: R a ,t,R c 、R d , r is as defined in any one of claims 1 to 11; Each q1 is independently 0, 1 or 2, preferably 0 or 1.

13. The compound according to any one of claims 1 to 8, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formula I2 or general formula II2: Among them, A ring, R a ,t,L 2 ,n,R 1 、R 2 、R 6 、R c 、R d , r is as defined in any one of claims 1 to 8; q1 is selected from 0 or 1; Preferably Y is N or CH; Preferably, Z is O or CH2, more preferably, Z is O; W 1 and W 2 Each is independently selected from C1-C2 alkylene; any -CH2- in the C1-C2 alkylene may be substituted by O, S, or NH, and preferably any -CH2- in the C1-C2 alkylene may be substituted by O; Preferred Selected from Preferred Selected from Preferred Selected from Preferred Preferred R 6 Selected from H; Preferably, the compound of the general formula I2 or II2 is selected from any one of the structures represented by the following general formula I21, I22, II21 or II22: More preferably, the compound of formula I2 is selected from any one of the structures represented by the following formula I21' or I22': More preferably, the compound of the general formula I2 or II2 is selected from any one of the structures represented by the following general formula I21″, general formula I22″, general formula II21″ or general formula II22″:

14. The compound according to any one of claims 1 to 13, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formula I2-D, general formula I2-D' or general formula II2-D: Among them, A ring, R a ,t,R 1 、R 2 、R 6 has the same meaning as defined in any one of claims 1 to 13; Preferably, each of the R d Each independently selected from deuterium, halogen, C1-C3 alkyl or deuterated C1-C3 alkyl, further preferably said R d Each is independently selected from deuterium, F, Cl, methyl or deuterated methyl; Preferably r is 0, 1 or 5; Optimize each R c Each R is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy, more preferably c Each is independently selected from F, Cl, Br, cyano, methyl, ethyl, ethynyl, propynyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3, preferably each R c Each is independently selected from F, Cl, Br, cyano, methyl, ethynyl, -CHF2 or -OCHF2; Preferably, each q1 is independently selected from 0 or 1; Preferred Selected from Preferred Selected from Preferred Selected from Preferred Selected from Preferred Selected from Preferred L 2 for The end is connected to the B ring (such as thiazole ring), R 5 Selected from H, C1-C3 alkyl; preferably R 5 Selected from H; Preferably n is 1; Preferred R 1 and R 2 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 heteroalkyl, preferably R 1 and R 2 One is hydrogen, and the other is H, methyl or -CH2OCH3; Preferred R 6 Selected from H; Preferably, the compound of the general formula I2-D, I2-D', II2-D is selected from any one of the structures represented by the following general formula I2-D1, general formula I2-D2, general formula I2-D3, general formula I2-D4, general formula II2-D1 or general formula II2-D2:

15. The compound according to claim 13 or 14, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of general formula I2 is selected from any one of the following general formulas I2-A1, I2-A2, I2-A3, and I2-A4: The compound of general formula II2 is selected from any one of the following general formula II2-A1 and general formula II2-A2: Preferably, R in the general formula I2-A1, general formula I2-A2, general formula I2-A3, general formula I2-A4, general formula II2-A1, general formula II2-A2 a ,t,R 1 、R 2 、R 6 、R c 、R d , r is as defined in claim 13 or 14; Each q1 is independently selected from 0 or 1; In the general formula I2-A1, general formula I2-A3 and general formula II2-A1, G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH; Preferred Selected from Further optimization Selected from Optimize each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl, preferably as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably, the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, condensed ring heterocyclic group or bridged heterocyclic group; more preferably, each R a Each is independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, fluoromethoxy, More preferably, each R a Each independently selected from halogen, methyl, cyclopropane, Methoxy, ethoxy, fluoromethyl, fluoroethyl, fluoromethoxy, preferably t is 1 or 2; Preferably, the general formula I2-A1, general formula I2-A3 and general formula II2-A1 Each independently selected from Further preferred are the general formulas I2-A1, I2-A3 and II2-A1 Each independently selected from In the general formula I2-A2, general formula I2-A4 and general formula II2-A2, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH; Preferably, the general formula I2-A2, general formula I2-A4 and general formula II2-A2 Each independently selected from Further preferred are the general formulas I2-A2, I2-A4 and II2-A2 for Optimize each R a Each is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl or -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group. e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are attached, a C3-C6 cycloalkyl group is optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; preferably t is 0, 1, 2 or 3, more preferably t is 0, 1 or 2; Preferred are general formula I2-A2, general formula I2-A4 and general formula II2-A2 Each independently selected from Preferred are general formula I2-A2, general formula I2-A4 and general formula II2-A2 Each independently 16. The compound according to any one of claims 1 to 6, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formulas III, IV', V, VI, and VII: Among them, A ring, R a ,t,L 1 , p, B ring, R b ,s,L 2 ,n,R 1 、R 2 ,m,R 6 、R c 、R d , r is as defined in any one of claims 1 to 6; Y is selected from CH or N; Each q1 is independently selected from 0 or 1; Preferred R 7 is selected from C1-C3 alkyl, cyano, and more preferably R 7 is selected from methyl or cyano; Preferred R 8 and R 9 are each independently selected from H, deuterium, halogen, cyano, C1-C6 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl group, as R 8 and R 9 The C1-6 alkyl group is optionally substituted by deuterium, halogen, cyano or hydroxyl; preferably R 8 and R 9 are independently selected from halogen, cyano, C1-3 alkyl, or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 3- to 4-membered heterocycloalkyl group, as R 8 and R 9 The C1-3 alkyl group is optionally substituted by halogen, cyano or hydroxyl; further preferably R 8 and R 9 Each independently selected from methyl, F, cyano, -CH2OH or R 8 and R 9 Together with the carbon atoms to which they are attached, Preferably, Z is a single bond, O or CH2; preferably, Z is a single bond or O; W 1 and W 2 Each independently selected from C1-C2 alkylene, preferably W 1 and W 2 are each independently selected from methylene; Preferably, the compound of formula III is selected from any one of the structures shown in formula III01 to formula III03 below: Preferably, the compound of formula IV' is selected from any one of the structures shown in the following formula IV01 or formula IV02: Preferably, the compound of formula V is selected from any one of the structures shown in the following formula V01 or formula V2: Preferably, the compound of formula VI is selected from any one of the structures represented by formula VI01, formula VI02 or formula VI03: Preferably, the compound of formula VII is selected from any one of the structures represented by formula VII01, formula VII02 or formula VII03: Among them, in the general formula III01, the general formula IV01, the general formula V01 and the general formula VI03, G 1 Selected from O, NH or CH2, preferably G 1 Selected from O or CH2, preferably G 2 , G 3 , G 4 , G 5 are each independently selected from N or CH; Preferred Each independently selected from Preferred for Optimize each R a Each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, or -C(O)C1-C6 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, R e and R f Each independently selected from hydrogen, deuterium, halogen or C1-C6 alkyl, as R a The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, -C(O)C1-C6 alkyl, or two R groups connected to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 4-8 membered heterocyclic group, or R connected to different ring atoms a Together with the ring atoms to which they are attached, they form a C3-C8 cycloalkyl or a 4-8 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C6 alkyl; further preferably each R a Each independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, or -C(O)C1-C3 alkyl, or two R attached to the same carbon atom a Together with the carbon atoms to which they are attached, they form C=T, wherein T is selected from CR e R f , or two R attached to the same carbon atom a Together with the carbon atoms to which they are connected, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group. e and R f are each independently selected from hydrogen, deuterium or halogen, as R a The C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C(O)C1-C3 alkyl, or two R a Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group, optionally substituted by R a 'Replace, R a ' is selected from deuterium, halogen or C1-C3 alkyl; more preferably each R a Each is independently selected from F, Cl, cyano, -C(O)CH3, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, cyclobutane, cyclopentane, fluorocyclopropane, fluorocyclobutane, or two R attached to the same carbon atom a Together with the carbon atom to which they are connected, they form C=CF2, or two R a Together with the carbon atom to which they are attached, they form a cyclopropyl group; t is 0, 1, 2 or 3, preferably t is 0, 1 or 2; Preferred Each independently selected from Preferred Each independently In the general formula III02, the general formula III03, the general formula IV02, the general formula V2, the general formula VI01, the general formula VI02, the general formula VII01, the general formula VII02 and the general formula VII03, G 6 , G 7 , G 8 , G 9 , G 10 are each independently selected from N or CH; Preferred Each independently selected from Further optimization Selected from Each R a Each independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl, as R a The C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-10 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl; further preferably each R a Each independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl, as R a The C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, 5-6 membered heteroaryl group are optionally replaced by R a 'Replace, R a ' is selected from deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, preferably the 4-8 membered heterocyclic group is selected from saturated heterocyclic group, partially unsaturated heterocyclic group, monocyclic heterocyclic group, condensed ring heterocyclic group or bridged heterocyclic group; more preferably each R a Each independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, difluoromethoxy, Further optimization of each R a Each independently selected from F, Cl, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropane, fluorocyclopropane, methoxy, ethoxy, difluoromethoxy, or Preferably t is 1, 2 or 3, more preferably t is 1 or 2; Preferred Selected from Further optimization Selected from Preferred R 1 、R 2 is H; Preferred L 2 Selected from The end is connected to the B ring.

17. The compound according to any one of claims 1 to 16, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound is selected from any one of the following compounds:

18. A pharmaceutical composition comprising the compound of any one of claims 1 to 17, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt.

19. The pharmaceutical composition according to claim 18, characterized in that It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

20. Use of the compound of any one of claims 1 to 17, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 18 or 19 in the preparation of a medicament for preventing and / or treating cancer, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary unidentified cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

21. Use of the compound of any one of claims 1 to 17, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 18 or 19 in the preparation of a medicament for preventing and / or treating diseases or conditions caused by loss of function or mutation of BRG1 (SMARCA4).

22. The use according to claim 21, characterized in that The disease or disorder in which BRG1 (SMARCA4) is lost or mutated is cancer or tumor.

23. The use according to claim 22, characterized in that The cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary unknown cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal and gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal carcinoma, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer or penile cancer.

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