Compound that restores mutant p53 function, and use thereof

Abstract

The present invention relates to a compound that restores the mutant p53 function, and the use thereof, and specifically relates to a compound as shown in formula A or B, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitrogen oxide, or metabolite of the compound, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably a deuterated compound) or prodrug thereof.

Description

Compounds restoring p53 mutant function and uses thereof

[0001] REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese Patent Application No. CN202411368654.X, filed September 27, 2024, Chinese Patent Application No. CN202411406017.7, filed October 09, 2024, Chinese Patent Application No. CN202411878093.8, filed December 17, 2024, Chinese Patent Application No. CN202510121435.X, filed January 24, 2025, and Chinese Patent Application No. CN202510486976.2, filed April 17, 2025, the contents of which are incorporated by reference in their entirety and for all purposes. TECHNICAL FIELD

[0003] The present application relates to the field of medicine, in particular to compounds restoring p53 mutant function and uses thereof. BACKGROUND

[0004] p53 is an important tumor suppressor gene, which was first reported in 1979. Initially, it was unanimously believed that the P53 gene was an oncogene, and with the deepening of research, the function of p53 as a tumor suppressor gene was gradually revealed. p53 is known as the guardian of the genome, which plays a key role in cell function and can maintain the stability of the genome when the cell is stressed.

[0005] p53 encodes p53 protein, which is a sequence-specific transcription factor that can regulate and participate in the expression of genes in many cell processes. The main functions of these target genes include inducing cell cycle arrest, DNA repair, regulating cell metabolism, cell senescence, apoptosis, and the newly discovered induction of ferroptosis in cells.

[0006] p53 has the highest mutation frequency of any protein in human cancer, with mutations present in 50% of cancer patients. p53 mutations are most common in ovarian (47.8%), colon (43.2%), esophageal (43.1%), head and neck (40.6%), and laryngeal (40.4%) tumors, while the lowest p53 mutation frequencies are found in cervical (5.8%), hematopoietic (12.7%), and endocrine gland (14.6%) tumors.

[0007] p53 is considered as one of the most difficult targets to target, and there is no effective therapy targeting p53 in the world. The difficulties in developing p53-targeting therapy are: 1) unlike traditional inhibitor development, drugs targeting p53 need to restore rather than inhibit the normal activity of the protein; 2) the positions of p53 point mutations are relatively scattered; 3) p53 is not an enzyme, so there is no hydrophobic pocket to bind small molecule ligands.

[0008] The tyrosine at position 220 of the p53 Y220C mutant is replaced by cysteine, and this mutation brings a crack on the protein, so that the mutant protein cannot maintain the conformation and function of wild-type p53.

[0009] Therefore, the compounds that can restore the normal function of the p53 Y220C mutant also need further research. SUMMARY

[0010] The inventors of the present application have obtained new compounds that can restore the normal function of the p53 Y220C mutant through in-depth research and creative discovery. These compounds target the small gap produced on the protein surface by the p53 Y220C mutation, thereby restoring the normal function of the p53 Y220C mutant and exerting an anticancer effect. These compounds can be used for the treatment of various diseases caused by the p53 Y220C mutation (such as gastric adenocarcinoma, pancreatic cancer, etc.).

[0011] To this end, in a first aspect of the present application, the present application provides a compound represented by Formula A or B, or an enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug of the compound,

[0012] wherein:

[0013] Ring A is a 5-membered heteroaromatic ring;

[0014] One of X1, X2 is N, and the other is C;

[0015] X3, X4, X5 are each independently selected from N, CR X ;

[0016] R X are each independently selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0017] with the proviso that X2, X3are not simultaneously N; with the proviso that X1, X3are simultaneously N, only one of X4, X5is N;

[0018] R1is selected from OR, SR;

[0019] R is selected from C 1-6 alkyl, C 1-6 haloalkyl;

[0020] Z1is selected from CR Z1 R Z2 , O, S(O)2;

[0021] R Z1 is selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl;

[0022] R Z2 is selected from halogen, -N(R’)2, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; said 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1- 6alkyl, C 1-6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0023] or, R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R”)2, cyano, C 1-6 6alkyl, C 1-6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0024] each R’ is independently selected from H, C 1-6 alkyl, 4-7 membered saturated heterocyclyl; said C 1-6 alkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from deuterium, halogen, C 1-6substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy;

[0025] each R” is independently selected from H, C1-6alkyl; 1-6 C1-6alkyl; said C1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; 1-6 C1-6alkyl; said C1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen;

[0026] R2is selected from H, halogen, hydroxyl, -CN, C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy;

[0027] Y1, Y2are each independently selected from N, CH;

[0028] R Y are each independently selected from H, halogen, -OR Y’ , cyano, C1-6alkyl, -CO-C1-6alkyl; 1-6 C1-6alkyl; said C1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; 1-6 C1-6alkyl; said C1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; 1-6 C1-6alkyl, -CO-C1-6alkyl; 1-6 C1-6alkyl; said C1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy;

[0029] R Y’ is selected from H, C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 3-6 Cycloalkyl, 4-7 membered heterocyclyl; said C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 3-6 Cycloalkyl, 4-7 membered heterocyclyl; said C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy; 1-6 C1-6alkyl, C1-6alkoxy;

[0030] n is selected from 0, 1, 2, 3;

[0031] R3is selected from -CON(R 1 )2, -PO(R 2 )2, -SO2R 3 , -SO(=NR 4 )R 5, -COOR 6 , halogen, cyano, C 1-6 alkyl, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 , -SO2NR 8 COR 11 ; said C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, 4-7 membered heterocyclyl;

[0032] R 1 , R 2 are each independently selected from the group consisting of H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, and at most one of R 1 , R 2 is selected from the group consisting of C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy;

[0033] or two R 1 form, together with the nitrogen atom to which they are attached, a 4-11 membered heterocyclyl; said 4-11 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy;

[0034] or two R 2 form, together with the phosphorus atom to which they are attached, a 4-11 membered heterocyclyl; said 4-11 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy;

[0035] optionally, 1 R 2 is attached to the ortho position of -PO(R 2 )2 to form a 5-6 membered heterocyclyl;

[0036] R 3 is selected from the group consisting of H, deuterium, C 1-6 alkyl, -N(R’)2, C 3-6 cycloalkyl, 4-11 membered heterocyclyl; or R 3with the ortho position to -SO2R 3 forming a 5-6 membered heterocyclyl;

[0037] R 4 , R 5 are each independently selected from the group consisting of H, deuterium, C 1-6 alkyl, cyano, C 3-7 cycloalkyl, 4-7 membered heterocyclyl; or R 4 , R 5 and the -S=N- to which they are attached form a 4-8 membered heterocyclyl; or R 5 and the ortho position to -SO(=NR 4 )R 5 form a 5-6 membered heterocyclyl;

[0038] R 6 is selected from the group consisting of H, deuterium, C 1-6 alkyl, C 3-6 haloalkyl;

[0039] R 8 , R 10 are each independently selected from the group consisting of H, C 1-6 alkyl;

[0040] R 9 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0041] R 11 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -C 1- 6alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups.

[0042] In some implementations, R3 is selected from -CON(R 1 )2、-PO(R 2 )2、-SO2R 3 -SO(=NR) 4 )R 5 -COOR 6 Halogen, cyano, C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally surrounded by one or more radicals selected from deuterium, halogen, cyano, hydroxyl, C. 1-6 Alkyl, C 1-6 Substitution with alkoxy groups or 4-7 membered heterocyclic groups.

[0043] In some implementation schemes, R Z1 Selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl;

[0044] R Z2 Selected from -N(R')2, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, and 5-10 membered bridged heterocyclic groups; wherein the 4-7 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, and 5-10 membered bridged heterocyclic group are optionally surrounded by one or more elements selected from halogen, oxo, hydroxyl, -N(R')2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0045] Or, R Z1 R Z2 The carbon atoms bonded to them form 4-7 membered heterocyclic groups; said 4-7 membered heterocyclic groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, -N(R”)2, cyano groups, C… 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0046] In some implementation schemes, R 3 Selected from H, deuterium, C1-6 alkyl, -N(R')2, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; or R 3 -SO2R 3 to form a 5-6 membered heterocyclyl ring.

[0047] In some embodiments, the compound has the structure shown in Formula A.

[0048] In some embodiments, the compound has the structure shown in Formula B.

[0049] In some embodiments, R X each independently selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy.

[0050] In some embodiments, R X each independently selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; more preferably, R X each independently selected from H, halogen. More preferably, R X is H.

[0051] In some embodiments, X3is selected from N, CR X ; R X selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0052] In some embodiments, X3is selected from N, CH.

[0053] In some embodiments, X3is CH.

[0054] In some embodiments, X4is selected from N, CR X ; R X selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy. Preferably, R X is selected from H, halogen.

[0055] In some embodiments, X4is selected from CR X .

[0056] In some embodiments, X4is selected from CH, CF. More preferably, X4is selected from CH.

[0057] In some embodiments, X5is selected from N, CR X ; RX H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0058] In some embodiments, X5is selected from N, CH, CF.

[0059] In some embodiments, X5is selected from N, CH.

[0060] In some embodiments, X5is CH.

[0061] In some embodiments, the group is selected from:

[0062] In some embodiments, the group is selected from:

[0063] In some embodiments, the group is selected from:

[0064] In some embodiments, the group is selected from:

[0065] In some embodiments, the group is selected from:

[0066] In some embodiments, the group is selected from:

[0067] In some embodiments, R1is selected from OR, SR.

[0068] In some embodiments, R1is selected from SR.

[0069] In some embodiments, R1is selected from OR.

[0070] In some embodiments, R is selected from C 1-3 alkyl, C 1-3 haloalkyl.

[0071] In some embodiments, R1is selected from OR, SR; R is selected from C 1-3 alkyl, C 1-3 haloalkyl.

[0072] In some embodiments, R is selected from methyl, ethyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F.

[0073] In some embodiments, R is selected from C 1-3 haloalkyl.

[0074] In some embodiments, R is selected from -CF3, -CHF2.

[0075] In some embodiments, R is selected from -CF3.

[0076] In some embodiments, R1is selected from SR; R is selected from C 1-3 haloalkyl.

[0077] In some embodiments, R Z1 is selected from H, halogen, hydroxyl, -CN, C 1-3 alkyl.

[0078] In some embodiments, R Z2 is selected from -N(R’)2, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2. 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0079] In some embodiments, R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2. 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0080] In some embodiments, each R’ is independently selected from H, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-3 Substitution of the alkoxy group; or the two R' groups and the N atom attached to them form a 4-7 member saturated monocyclic heterocyclic group, a 7-11 member saturated bicyclic spirocyclic group, or a 5-10 member saturated bicyclic bridged heterocyclic group; wherein the 4-7 member saturated monocyclic heterocyclic group, the 7-11 member saturated bicyclic spirocyclic group, or the 5-10 member saturated bicyclic bridged heterocyclic group is optionally replaced by one or more elements selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0081] In some implementations, in -N(R')2, one R' is selected from H, C 1-3 Alkyl group, the other R' being selected from 4-7 membered saturated monocyclic heterocyclic groups; the C 1-3 Alkyl groups, 4-7 saturated monocyclic heterocyclic groups optionally surrounded by one or more elements selected from halogens, C 1-3 Substitution of the alkoxy group; or the two R' groups and the N atom attached to them form a 4-7 member saturated monocyclic heterocyclic group, a 7-11 member saturated bicyclic spirocyclic group, or a 5-10 member saturated bicyclic bridged heterocyclic group; wherein the 4-7 member saturated monocyclic heterocyclic group, the 7-11 member saturated bicyclic spirocyclic group, or the 5-10 member saturated bicyclic bridged heterocyclic group is optionally replaced by one or more elements selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1- The 3-alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0082] In some implementation schemes, "R" is independently selected from H and C. 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from deuterium and halogens.

[0083] In some implementations, Z1 is selected from CR Z1 R Z2 、S(O)2.

[0084] In some implementation schemes, R Z1 Selected from H, halogens; R Z2-N(R’)2, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O. 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O. Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O. 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0085] In some embodiments, R Z1 is selected from H; R Z2 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O. 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0086] In some embodiments, R Z1 is selected from H; R Z2 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3substituted with substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0087] In some embodiments, R Z1 is selected from H; R Z2 is selected from -N(R')2, both R' with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O. 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0088] In some embodiments, R Z1 is selected from H; R Z2 is selected from -N(R')2, both R' with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O. 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0089] In some embodiments, R Z1 is selected from H; R Z2 is selected from -N(R')2, both R' with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl group has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O. 1-3 substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl group has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O. 1-3 substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl group has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0090] In some embodiments, R Z1 selected from H; R Z2 selected from -N(R')2, R ’ selected from C 1-3 alkyl, or, two R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms, and the heteroatoms are each independently selected from N, O (preferably O).

[0091] In some embodiments, R Z1 selected from H; R Z2 selected from -N(R')2, two R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0092] In some embodiments, R Z1 selected from H; R Z2 selected from -N(R')2, two R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms, and the heteroatoms are each independently selected from N, O (preferably O).

[0093] In some embodiments, R 8 , R 10 are each independently selected from H, C 1-3 alkyl.

[0094] In some embodiments, R 8 , R 10 are each H.

[0095] In some embodiments, R 9 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4Deuterated alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl; the C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Substituents of haloalkoxy groups.

[0096] In some implementation schemes, R 9 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl; the C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Substitution of deuterated alkyl groups.

[0097] In some implementation schemes, R 9 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0098] In some implementation schemes, R 9 Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl.

[0099] In some implementation schemes, R 9 Selected from C 1-4 Alkyl, C 3-6 Saturated cycloalkyl groups.

[0100] In some implementation schemes, R 9 Selected from C 1-4 alkyl.

[0101] In some implementation schemes, R 9selected from methyl, isopropyl, cyclopropyl, -CH2CF3, - methylene-cyclopropyl.

[0102] In some embodiments, R 11 selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy.

[0103] In some embodiments, R 11 selected from C 1-3 alkyl, C 3-6 cycloalkyl.

[0104] In some embodiments, R 11 selected from methyl, ethyl, cyclopropyl.

[0105] In some embodiments, R Z1 selected from H, F, methyl.

[0106] In some embodiments, R Z1 selected from H, F.

[0107] In some embodiments, R Z1 selected from H.

[0108] In some embodiments, R Z2 selected from F, -NHCH3, -N(CH3)2,

[0109] In some embodiments, R Z2 selected from F, -N(CH3)2,

[0110] In some embodiments, R Z2 selected from -N(CH3)2,

[0111] In some embodiments, R is selected from Z2

[0112] In some embodiments, R is selected from Z2

[0113] In some embodiments, R is selected from Z2

[0114] In some embodiments, R is selected from Z2

[0115] In some embodiments, R is selected from Z2

[0116] In some embodiments, R is selected from Z2

[0117] In some embodiments, R is selected from Z2

[0118] In some embodiments, R is selected from Z1 , R is selected from Z2 and the carbon atom to which they are attached form a 4-7 membered saturated heterocyclyl group, which is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; preferably, the 4-7 membered saturated heterocyclyl group contains 1 or 2 heteroatoms each independently selected from N or O; preferably, the 4-7 membered saturated heterocyclyl group is selected from: * indicates the carbon atom to which R Z1 , R is selected from Z2 is attached.

[0119] In some embodiments, R is selected from Z1 , R is selected from Z2 and the carbon atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl group, which is optionally substituted with one or more substituents selected from halogen, C 1-6 ​​​​​​​substituted with substituents selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, -CN, -ORa, -N(Ra)2, -C(=O)Rb, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Rb, and -NRbC(=O)N(Rb)2; preferably said 4-7 membered saturated monocyclic heterocyclyl contains 1 or 2 heteroatoms each independently selected from N or O; preferably said 4-7 membered saturated monocyclic heterocyclyl is selected from: * indicates the carbon atom to which R Z1 , R Z2 are attached.

[0120] In some embodiments, R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is selected from: * indicates the carbon atom to which R Z1 , R Z2 are attached.

[0121] In some embodiments, R2is selected from H, halogen, hydroxyl, -CN, C 1-3 alkyl, C 1-3 alkoxy.

[0122] In some embodiments, R2is selected from H, halogen.

[0123] In some embodiments, R2is selected from halogen (e.g., F). In some embodiments, R2is selected from H, F.

[0124] In some embodiments, R2is F.

[0125] In some embodiments, the group is selected from:

[0126] In some embodiments, the group is selected from:

[0127] In some embodiments, the group is selected from:

[0128] In some embodiments, the group is selected from:

[0129] In some embodiments, the group is selected from:

[0130] In some embodiments, the group is selected from:

[0131] In some embodiments, the group is selected from: (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ),

[0132] In some embodiments, the group selected from: (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ).

[0133] In some embodiments, the group is selected from: (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ).

[0134] In some embodiments, the group is selected from: (e.g. ), (e.g. ).

[0135] In some embodiments, the group is selected from (e.g. ), (e.g. ).

[0136] In some embodiments, R Y each is independently selected from H, halogen, -ORY’ , cyano, C 1-3 alkyl, -CO-C 1-3 alkyl; said C 1-3 alkyl, -CO-C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy.

[0137] In some embodiments, R Y each is independently selected from H, halogen, -OR Y’ , cyano, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen.

[0138] In some embodiments, R Y each is independently selected from H, -OR Y’ .

[0139] In some embodiments, R Y is selected from -OR Y’ .

[0140] In some embodiments, R Y each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, -CD3, -CF3, -CHF2, -CH2F, methoxy, -OCD3, -OCF3, -OCHF2, -OCH2F, -OCH2CN, -OCH2CH2OH, -OCH2CH2F, ethoxy, -OCH2CF3, -OCH2CH2CN, -OCH2CH2OCH3, -O-cyclopropyl, -O-cyclobutyl, -C(O)CH3.

[0141] In some embodiments, R Y each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, -CD3, -CF3, -CHF2, -CH2F, methoxy, -OCD3, -OCF3, -OCHF2, -OCH2F, -OCH2CN, -OCH2CH2OH, -OCH2CH2F, ethoxy, -OCH2CF3, -OCH2CH2CN, -OCH2CH2OCH3, -O-cyclopropyl, -O-cyclobutyl.

[0142] In some embodiments, R Y each is independently selected from -OCH3, -OCD3, -OCF3, -OCHF2, -O-cyclopropyl.

[0143] In some embodiments, R Yeach independently selected from -OCD3, -OCF3, -OCHF2, -O-cyclopropyl.

[0144] In some embodiments, n is 1, R Y the carbon atom ortho to Y1.

[0145] In some embodiments, R Y’ selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0146] In some embodiments, R Y’ selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl.

[0147] In some embodiments, R Y’ selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g., F).

[0148] In some embodiments, R Y’ selected from C 1-3 alkyl; said C 1-3 alkyl optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g., F).

[0149] In some embodiments, R Y’ selected from C 1-3 alkyl; said C 1-3 alkyl optionally substituted with 1, 2, 3 deuterium.

[0150] In some embodiments, R Y’ selected from C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl.

[0151] In some embodiments, R Y’ selected from C 1-3 haloalkyl, C 1-3 deuterated alkyl.

[0152] In some embodiments, R Y’ is selected from C 1-3 alkyl.

[0153] In some embodiments, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, -CH2CH2F, cyclopropyl, cyclobutyl.

[0154] In some embodiments, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, -CH2CH2F, cyclopropyl, cyclobutyl.

[0155] In some embodiments, R Y’ is selected from -CD3, -CHF2, cyclopropyl.

[0156] In some embodiments, R Y’ is selected from -CD3, cyclopropyl.

[0157] In some embodiments, R Y’ is -CD3.

[0158] In some embodiments, one of Y1, Y2is N and the other is CH.

[0159] In some embodiments, Y1is N and Y2is CH.

[0160] In some embodiments, Y1, Y2are both CH.

[0161] In some embodiments, Y1, Y2are both N.

[0162] In some embodiments, n is selected from 0, 1.

[0163] In some embodiments, n is 1.

[0164] In some embodiments, R 1 , R 2 are each independently selected from H, deuterium, C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl, and no more than one of R 1 , R 2 are both C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, C 3-6saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; and

[0165] or two R 1 atoms connected to the same nitrogen atom form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; and

[0166] or two R 2 atoms connected to the same phosphorus atom form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; and

[0167] optionally, 1 R 2 is attached to the ortho position of -PO(R 2 )2 to form a 5-6 membered heterocyclyl.

[0168] In some embodiments, R 1 , R 2 are each independently selected from H, methyl, -CD3, ethyl, -CH2CF3, -CH2CHF2, -CH2CH2OCH3, isopropyl, cyclopropyl, methoxy,

[0169] or two R 1 atoms connected to the same nitrogen atom form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is selected from: said 7-11 membered saturated bicyclic spiroheterocyclyl is selected from:

[0170] optionally, 1 R 2 is attached to the ortho position of -PO(R 2 )2 to form a 5-6 membered heterocyclyl; said 5-6 membered heterocyclyl is selected from:

[0171] In some embodiments, R 1 , R 2 are each independently selected from H, C 1-3 alkyl, said C1-3 alkyl is optionally substituted with one or more deuterium.

[0172] In some embodiments, R 1 , R 2 each is independently selected from H, methyl, -CD3, ethyl, -CH2CF3, -CH2CHF2, -CH2CH2OCH3, isopropyl, methoxy,

[0173] or two R 1 and the nitrogen atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; the 4-7 membered saturated monocyclic heterocyclyl is selected from: the 7-11 membered saturated bicyclic spiroheterocyclyl is selected from:

[0174] optionally, 1 R 2 is attached to form a 5-6 membered heterocyclyl with the ortho position of -PO(R 2 )2; the 5-6 membered heterocyclyl is selected from:

[0175] In some embodiments, R 3 is selected from H, deuterium, C 1-3 alkyl, -N(R’)2, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; or R 3 is attached to form a 5-6 membered heterocyclyl with the ortho position of -SO2R 3 .

[0176] In some embodiments, R 3 is selected from methyl, ethyl, isopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl,

[0177] or R 3 is attached to form a 5-6 membered heterocyclyl with the ortho position of -SO2R 3 , the 5-6 membered heterocyclyl is selected from:

[0178] In some embodiments, R 4 is selected from H, C 1-3 alkyl; R 5 is selected from H, C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 saturated monocyclic membered heterocyclyl; or R 4 , R 5And the -S=N- links connected to them form 4-8 member monocyclic heterocyclic groups; or R 5 With -SO(=NR) 4 )R 5 The adjacent connections form 5-6 member heterocyclic groups.

[0179] In some implementation schemes, R 4 Selected from H, methyl, cyano; R 5 Selected from H, methyl, cyclopropyl; or R 4 R 5 The -S=N- links connected to them form 4-8 cyclic monocyclic heterocyclic groups, wherein the 4-8 cyclic monocyclic heterocyclic groups are selected from: Or R 5 With -SO(=NR) 4 )R 5 The adjacent connections form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is selected from:

[0180] In some implementation schemes, R 6 Selected from H, deuterium, C 1-3 Alkyl, C 3-6 Saturated cycloalkyl groups.

[0181] In some implementation schemes, R 6 Selected from H, methyl, ethyl, and cyclopropyl.

[0182] In some implementation schemes, R 6 Selected from H, methyl, and ethyl.

[0183] In some embodiments, the compound has the structure shown in Formula I.

[0184] The rings A, X1, X2, Y1, Y2, R1, R2, R3, Z1, R X R Y The definitions of and n are as described in any of the above schemes;

[0185] Preferably, ring A is a 5-membered heteroaromatic ring; X1 is N, and X2 is C;

[0186] R X It is H or halogen (preferably H);

[0187] R1 is selected from SR;

[0188] R is selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl (preferably C) 1-3 (Halogenated alkyl);

[0189] R2is selected from H or halogen (preferably halogen, e.g. F);

[0190] Z1is selected from CR Z1 R Z2 ;

[0191] R Z1 is selected from H, halogen or C 1-3 alkyl (preferably H);

[0192] R Z2 is selected from -N(R’)2;

[0193] R ’ is selected from C 1-3 alkyl, or, two R’ and the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O) (preferably two R’ and the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O));

[0194] Y1is selected from CH or N;

[0195] Y2is selected from CH or N (preferably CH);

[0196] n is selected from 0 or 1 (preferably 1);

[0197] R Y is selected from -OR Y’ ;

[0198] R Y’ is selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g. F) (preferably C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g. F); preferably C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 deuterium; preferably C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl; preferably C 1-3 haloalkyl, C 1-3deuteroalkyl; more preferably C 1-3 deuteroalkyl) ;

[0199] R Y carbon atom ortho to Y1;

[0200] R3is selected from -CON(R 1 )2, -PO(R 2 )2, -CONR 8 SO2R 9 , -CONR 8 SO( = NR 10 )R 9 (preferably -CON(R 1 )2, -CONR 8 SO2R 9 ; more preferably -CONR 8 SO2R 9 ) ;

[0201] of the two R 1 , one R 1 is selected from H and the other R 1 is selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with one or more deuterium;

[0202] each R 2 is independently selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with one or more deuterium;

[0203] R 8 is selected from H, C 1-3 alkyl (preferably H) ;

[0204] R 9 is selected from C 1-4 alkyl, C 3-6 saturated cycloalkyl (preferably C 1-4 alkyl) ;

[0205] R 10 is selected from H, C 1-3 alkyl (preferably H).

[0206] In some embodiments, the compound has the structure of Formula II,

[0207] the definitions of Y1, Y2, R1, R2, R3, R X , R Y , R Z1 , R Z2 , n are as described in any of the above aspects.

[0208] In some embodiments, Z1is selected from CR Z1 R Z2 .

[0209] In some embodiments, R X is selected from H, halogen.

[0210] In some embodiments, R X is H.

[0211] In some embodiments, R Z1 is H.

[0212] In some embodiments, R Z2 is selected from -N(R’)2, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0213] In some embodiments, R Z2 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0214] In some embodiments, R Z2 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, C 1-3substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0215] In some embodiments, R Z2 is selected from -N(R')2; both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2.

[0216] In some embodiments, R Z2 is selected from -N(R')2; both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0217] In some embodiments, R Z2 is selected from -N(R')2; both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, C 1-3 alkyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O.

[0218] In some embodiments, R Z1 is selected from H; R Z2Selected from -N(R')2, R ’ Selected from C 1-3 Alkyl groups, or two R' groups, together with the N atom attached to them, form 4-7 membered saturated monocyclic heterocyclic groups or 7-11 membered saturated bicyclic spirocyclic heterocyclic groups; said 4-7 membered saturated monocyclic heterocyclic groups or 7-11 membered saturated bicyclic spirocyclic heterocyclic groups are optionally surrounded by 1, 2, or 3 atoms selected from halogens (e.g., F), C 1-3 Alkyl substituents; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group optionally has one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N or O (preferably O).

[0219] In some implementation schemes, R Z1 Selected from H;R Z2 Selected from -N(R')2, R ’ Selected from C 1-3 Alkyl groups, or two R's, together with the N atoms attached to them, form 4-7 saturated monocyclic heterocyclic groups or 7-11 saturated bicyclic spirocyclic heterocyclic groups; provided that the 4-7 saturated monocyclic heterocyclic groups or 7-11 saturated bicyclic spirocyclic heterocyclic groups optionally have one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N and O (preferably O).

[0220] In some implementation schemes, R Z1 Selected from H;R Z2 Selected from -N(R')2, the two R' atoms and the N atoms attached to them form a 4-7 membered saturated monocyclic heterocyclic group or a 7-11 membered saturated bicyclic spirocyclic heterocyclic group; provided that the 4-7 membered saturated monocyclic heterocyclic group or the 7-11 membered saturated bicyclic spirocyclic heterocyclic group optionally has one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N and O (preferably O). In some embodiments, R1 is selected from -SCF3 and -OCF3.

[0221] In some implementations, R1 is -SCF3.

[0222] In some implementations, R2 is selected from H or halogens.

[0223] In some implementations, R2 is selected from halogens.

[0224] In some implementations, R2 is selected from F.

[0225] In some implementations, R3 is selected from -CON(R 1 )2、-CONR 8 SO2R 9 .

[0226] In some implementations, R3 is selected from -CON(R1 )2.

[0227] In some embodiments, R3is selected from -CONR 8 SO2R 9 .

[0228] In some embodiments, R Y is each independently selected from H, halogen, -OR Y’ .

[0229] In some embodiments, R Y is selected from -OR Y’ . In some embodiments, R Y’ is selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl; said C 1- 6alkyl, C 3-6 saturated cycloalkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0230] In some embodiments, R Y’ is selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl; said C 1-6 alkyl is optionally substituted with one or more (e.g. 1, 2, or 3) substituents selected from deuterium, halogen (e.g. F).

[0231] In some embodiments, R Y’ is selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen.

[0232] In some embodiments, R Y’ is selected from C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g. F).

[0233] In some embodiments, R Y’ is selected from C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 deuterium.

[0234] In some embodiments, n is selected from 0, 1, 2.

[0235] In some embodiments, n is selected from 1.

[0236] In some embodiments, R Y is located at the ortho position of Y1or Y2.

[0237] In some embodiments, at most 1 of Y1, Y2is N.

[0238] In some embodiments, n is 1, R Y is located at the ortho position of Y1.

[0239] In some embodiments, Y1is N and Y2is CH.

[0240] In some embodiments, Y1and Y2are both CH.

[0241] In some embodiments, R3is selected from -CON(R 1 )2, -PO(R 2 )2, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 . In some embodiments, R3is selected from -CON(R 1 )2, -PO(R 2 )2, -SO2R 3 , -SO(=NR 4 )R 5 .

[0242] In some embodiments, R3is selected from -CON(R 1 )2, -CONR 8 SO2R 9 .

[0243] In some embodiments, R3is selected from -CON(R 1 )2.

[0244] In some embodiments, R3is selected from -PO(R 2 )2.

[0245] In some embodiments, R3is selected from -CONR 8 SO2R 9 .

[0246] In some embodiments, R3is selected from -CONR 8 SO(=NR 10 )R 9 .

[0247] In some embodiments, R 1 , R 2 are each independently selected from H, deuterium, C 1-3 alkyl, C3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl, and both R 1 , R 2 each independently selected from the group consisting of C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy;

[0248] or two R 1 and the nitrogen atom attached thereto form a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy;

[0249] or two R 2 and the phosphorus atom attached thereto form a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy;

[0250] optionally, 1 R 2 forms a 5-6 membered heterocyclyl with the ortho position of -PO(R 2 )2. In some embodiments, R 1 , R 2 are each independently selected from H, C 1-3 alkyl, C 3-6 saturated cycloalkyl, and both R 1 , R 2 are each independently selected from the group consisting of C 3-6 saturated cycloalkyl; said C 1-3 alkyl, C 3- 6 saturated cycloalkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy;

[0251] or two R 1 and the nitrogen atom attached thereto form a 4-7 membered monocyclic heterocyclyl; said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, C 1-3 alkyl;

[0252] or two R 2 form a 4-7 membered monocyclic heterocyclyl with the phosphorus atom to which they are attached; said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halo, C 1-3 alkyl;

[0253] optionally, 1 R 2 is attached to form a 5-6 membered heterocyclyl with the ortho position of -PO(R 2 )2.

[0254] In some embodiments, each R 1 is independently selected from H, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium.

[0255] In some embodiments, two R 1 , 1 R 1 is selected from H and the other R 1 is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium.

[0256] In some embodiments, each R 2 is independently selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium.

[0257] In some embodiments, R 3 is selected from C 1-3 alkyl, -N(R’)2, C 3-6 saturated cycloalkyl, 4-7 saturated monocyclic heterocyclyl; R’ is selected from H, C 1-3 alkyl; or R 3 is attached to form a 5-6 membered heterocyclyl with the ortho position of -SO2R 3 .

[0258] In some embodiments, R 4 is selected from H, C 1-3 alkyl; R 5 is selected from H, C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 saturated monocyclic heterocyclyl; or R 4 , R 5 and the -S=N- to which they are attached form a 4-7 membered monocyclic heterocyclyl; or R 5 is attached to form a 5-6 membered heterocyclyl with the ortho position of -SO(=NR 4 )R 5 .

[0259] In some embodiments, R 8 is selected from H, C 1-3 alkyl.

[0260] In some embodiments, R 8 is H.

[0261] In some embodiments, R 10 is selected from H, C 1-3 alkyl.

[0262] In some embodiments, R 10 is H.

[0263] In some embodiments, R 9 is selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl.

[0264] In some embodiments, R 9 is selected from C 1-4 alkyl, C 3-6 saturated cycloalkyl.

[0265] In some embodiments, R 9 is selected from C 1-4 alkyl.

[0266] In some embodiments, the compound is represented by Formula II-1:

[0267] (preferably )

[0268] wherein Y1, Y2, R1, R2, R3, R’ are as defined in any embodiment of the present application;

[0269] Preferably, R1is selected from SR;

[0270] Preferably, R is selected from C 1-6 haloalkyl (e.g. C 1-3 haloalkyl, e.g. CF3);

[0271] Preferably, R2is selected from H, halogen; preferably, R2is selected from halogen (e.g. F);

[0272] Preferably, Y1, Y2are both CH, or one of Y1, Y2is selected from CH and the other is selected from N;

[0273] Preferably, Y1, Y2are both CH;

[0274] Preferably, Y1is N and Y2is CH;

[0275] Preferably, R Y is selected from -ORY’ ;

[0276] Preferably, R Y’ Selected from C 1-6 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-6 Alkyl, C 3-6 The saturated cycloalkyl group is optionally substituted by one or more substituents selected from deuterium and halogens;

[0277] Preferably, R Y’ Selected from C 1-6 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-6 The alkyl group is optionally substituted by one or more (e.g., 1, 2 or 3) substituents selected from deuterium and halogens (e.g., F);

[0278] Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted by one or more (e.g., 1, 2 or 3) substituents selected from deuterium and halogens (e.g., F);

[0279] Preferably, R Y’ Selected from C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens (e.g., F);

[0280] Preferably, R Y’ Selected from C 1-3 Alkyl; the C 1-3 Alkyl groups are optionally substituted with 1, 2, or 3 deuteriums;

[0281] Preferably, R3 is selected from -CON(R 1 )2、-PO(R 2 )2、-CONR 8 SO2R 9 -CONR 8 SO(=NR 10 )R 9 ;

[0282] Preferably, R3 is selected from -CON(R 1 )2;

[0283] Preferably, R3 is selected from -PO(R 2 )2;

[0284] Preferably, R3 is selected from -CONR 8 SO2R 9 ;

[0285] Preferably, R3is selected from -CONR 8 SO(=NR 10 )R 9 ;

[0286] Preferably, when R3is selected from -CON(R 1 )2or -PO(R 2 )2, Y1, Y2are both CH;

[0287] Preferably, when R3is selected from -CONR 8 SO2R 9 or -CONR 8 SO(=NR 10 )R 9 , Y1is N and Y2is CH;

[0288] Preferably, each R 1 is independently selected from H, C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more deuterium;

[0289] Preferably, one R 1 is selected from H and the other R 1 is selected from C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more deuterium;

[0290] Preferably, each R 2 is independently selected from C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more deuterium;

[0291] Preferably, R 8 is selected from H, C 1-3 alkyl;

[0292] Preferably, R 8 is H;

[0293] Preferably, R 10 is selected from H, C 1-3 alkyl;

[0294] Preferably, R 10 is H;

[0295] Preferably, R 9 is selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl;

[0296] Preferably, R 9 is selected from C 1-4 alkyl, C 3-6Saturated cycloalkyl groups;

[0297] Preferably, R ’ Selected from C 1-3 Alkyl groups, or two R' groups, together with the N atoms attached to them, form 4-7 nucleotide saturated monocyclic heterocyclic groups or 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic groups; provided that the 4-7 nucleotide saturated monocyclic heterocyclic groups or 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic groups optionally have one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N and O (preferably O);

[0298] Preferably, the two R' atoms and the N atoms connected to them form a 4-7 nucleotide saturated monocyclic heterocyclic group or a 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic group; provided that the 4-7 nucleotide saturated monocyclic heterocyclic group or the 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic group optionally has one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N and O (preferably O).

[0299] In some implementation schemes, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups, 7-11 member saturated bicyclic spirocyclic groups, and 5-10 member saturated bicyclic bridged heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0300] In some implementation schemes, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups, 7-11 member saturated bicyclic spirocyclic groups, and 5-10 member saturated bicyclic bridged heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2; provided that the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group have 1, 2, or 3 heteroatoms, and each heteroatom is independently selected from N and O.

[0301] In some implementation schemes, RZ3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0302] In some implementation schemes, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O.

[0303] In some implementation schemes, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and the 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more elements selected from halogens, C 1-3 Alkyl substituents; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O.

[0304] In some implementation schemes, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic groups; the 4-7 member saturated monocyclic heterocyclic group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl substituents; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O.

[0305] In some implementation schemes, R Z3is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0306] In some embodiments, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl; the 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2. 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2.

[0307] In some embodiments, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl; the 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; provided that the 4-7 membered saturated monocyclic heterocyclyl has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0308] In some embodiments, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0309] In some embodiments, R Z3 is selected from 7-11 membered saturated bicyclic spiroheterocyclyl; the 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2. 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2.

[0310] In some embodiments, R Z3 is selected from 7-11 membered saturated bicyclic spiroheterocyclyl; the 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; provided that the 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and the heteroatoms are each independently selected from N, O.

[0311] In some embodiments, RZ3 selected from 7-11 membered saturated bicyclic spiro heterocyclyl; provided that the 7-11 membered saturated bicyclic spiro heterocyclyl has 1 or 2 heteroatoms, and each of the heteroatoms is independently selected from N, O.

[0312] In some embodiments, R Z3 attached to ring B through a nitrogen atom.

[0313] In some embodiments, R Z3 selected from

[0314] In some embodiments, R Z3 selected from

[0315] In some embodiments, R Z3 selected from

[0316] In some embodiments, R Z3 selected from

[0317] In some embodiments, R Z3 selected from

[0318] In another aspect of the present application, the present application provides a compound represented by Formula C or D, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically-labeled compound (preferably deuterated compound), or prodrug of the compound,

[0319] wherein:

[0320] ring A is a 5-membered heteroaromatic ring; and each of X1, X2, X3, X4, X5is independently selected from N, CR X ;

[0321] R X is each independently selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0322] R1is selected from OR, SR;

[0323] R is selected from C 1-6 alkyl, C 1-6 haloalkyl;

[0324] Z2is selected from CR Z4 R Z5 , O, S, NR Z6 ;

[0325] R Z4 is selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl;

[0326] R Z5 is selected from halogen, C 1-6 alkyl, -N(R’)2, -OR 12 , -S(O)R 13 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0327] R 12 , R 13 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl;

[0328] or, R Z4 , R Z5 and the carbon atom to which they are attached form a 4-7 membered heterocyclyl; the 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R”)2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0329] R Z6 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, 5-10 membered bridged heterocyclic groups; wherein, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, 7-11 spirocyclic groups, and 5-10 bridged heterocyclic groups are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0330] R' is independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclic groups; the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4-7 saturated heterocyclic group are optionally surrounded by one or more elements selected from deuterium, halogen, C. 1-6 The alkoxy group is substituted; or the two R' groups and the N atom attached to them form a 4-7 membered saturated heterocyclic group, a 7-11 membered spiroheterocyclic group, a 5-10 membered bridged heterocyclic group, or a 7-11 membered fused heterocyclic group; wherein the 4-7 membered saturated heterocyclic group, the 7-11 membered spiroheterocyclic group, the 5-10 membered bridged heterocyclic group, or the 7-11 membered fused heterocyclic group is optionally substituted by one or more elements selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2;

[0331] "R" is independently selected from H and C. 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from deuterium and halogens;

[0332] Y1 and Y2 are each independently selected from N and CH;

[0333] R Y Each is independently selected from H, halogen, -OR Y’ , cyano, C 1-6 Alkyl, -CO-C 1-6 Alkyl; the C 1-6 Alkyl, -CO-C 1-6alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-6alkyl, 1-6 substituents of the alkoxy group;

[0334] R Y’ selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 substituents of the alkoxy group;

[0335] n is selected from 0, 1, 2, 3;

[0336] L is selected from: -CONR 8 SO2- R4 , -CONR 8 SO(=NR 10 )- R4 , -SO2NR 8 CO- R4 ; R4 attached to R4;

[0337] R 8 , R 10 each independently selected from H, C 1-6 alkyl;

[0338] R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -C 1- 6alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0339] each R5is independently selected from H, halogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6Haloalkoxy group; optionally, the two R5 atoms attached to the same carbon atom form a C-H group with that carbon atom. 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, wherein the C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, and 7-11 spiroheterocyclic groups are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl substituents; optionally, the two R5s attached to different carbon atoms are interconnected such that the ring containing Z2 forms a 7-10 membered bridged cycloalkyl, a 7-10 membered bridged heterocyclic group, a 7-10 membered fused and cycloalkyl, or a 7-10 membered fused and heterocyclic group, wherein the 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclic group, 7-10 membered fused and cycloalkyl, or 7-10 membered fused and heterocyclic group is optionally replaced by one or more elements selected from halogens, C 1-6 Alkyl substituents;

[0340] m is selected from 0, 1, 2, and 3;

[0341] R6 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0342] In some embodiments, the compound is as shown in Formula C.

[0343] In some implementations, one of X1 and X2 is N and the other is C; X3, X4, and X5 are each independently selected from N and C. X .

[0344] In some implementations, X2 and X3 are not both N; when X1 and X3 are both N, only one of X4 and X5 is N.

[0345] In some implementations, one of X1 and X2 is N and the other is C; X3, X4, and X5 are each independently selected from N and C. X The conditions are: X2 and X3 are not N at the same time; when X1 and X3 are N at the same time, only one of X4 and X5 is N.

[0346] In some embodiments, the compound is as shown in Formula D.

[0347] In some implementation schemes, R X Each is independently selected from H, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups.

[0348] In some implementation schemes, R X Each is independently selected from H, halogen, hydroxyl, and C. 1-3 Alkyl, C1-3 alkoxy.

[0349] In some embodiments, R X each is independently selected from H, halogen.

[0350] In some embodiments, R X is H.

[0351] In some embodiments, X3is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0352] In some embodiments, X3is selected from N, CH.

[0353] In some embodiments, X3is CH.

[0354] In some embodiments, X4is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0355] In some embodiments, R X is selected from H, halogen.

[0356] In some embodiments, X4is selected from CR X .

[0357] In some embodiments, X4is selected from CH, CF.

[0358] In some embodiments, X4is CH.

[0359] In some embodiments, X5is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0360] In some embodiments, X5is selected from N, CH, CF.

[0361] In some embodiments, X5is CH.

[0362] In some embodiments, the group is selected from:

[0363] In some embodiments, the group is selected from:

[0364] In some embodiments, the group is selected from:

[0365] In some embodiments, the group is selected from:

[0366] In some embodiments, the group is selected from:

[0367] In some embodiments, the group is selected from:

[0368] In some embodiments, R1is selected from OR, SR.

[0369] In some embodiments, R1is selected from SR.

[0370] In some embodiments, R1is selected from OR.

[0371] In some embodiments, R is selected from C 1-3 alkyl, C 1-3 haloalkyl.

[0372] In some embodiments, R is selected from methyl, ethyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F.

[0373] In some embodiments, R is selected from C 1-3 haloalkyl.

[0374] In some embodiments, R is selected from -CF3, -CHF2.

[0375] In some embodiments, R1is selected from SR; R is selected from C 1-3 haloalkyl.

[0376] In some embodiments, R6is selected from C 1-3 alkyl, C 1-3 haloalkyl.

[0377] In some embodiments, R6is selected from C 1-3 haloalkyl.

[0378] In some embodiments, R6is selected from -CH2CF3.

[0379] In some embodiments, Z2is selected from CR Z4 RZ5 NR Z6 .

[0380] In some embodiments, R Z4 is selected from H, halogen, C 1-3 alkyl (preferably R Z4 is H);

[0381] R Z5 is selected from halogen, C 1-3 alkyl, -N(R’)2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein said C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl;

[0382] or, R Z4 , R Z5 and the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0383] In some embodiments, R Z4 is selected from H, halogen, C 1-3 alkyl;

[0384] R Z5 is selected from halogen, C 1-3 alkyl, -N(R’)2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl; wherein said C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl;

[0385] or, R Z4 , RZ5 with the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C1-6alkyl, C1-6alkoxy; wherein said C1-6alkyl, C1-6alkoxy are optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2. 1-3 with the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C1-6alkyl, C1-6alkoxy; wherein said C1-6alkyl, C1-6alkoxy are optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0386] In some embodiments, R Z5 is selected from -N(R’)2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein said C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 alkyl, C 1-6 alkoxy; wherein said C 1-6 alkyl, C 1-6 alkoxy are optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2.

[0387] In some embodiments, R Z5 is selected from 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl; wherein said 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 alkyl.

[0388] In some embodiments, R Z5 is selected from 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiro heterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; wherein said 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiro heterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl.

[0389] In some embodiments, R Z5 is selected from -N(R’)2.

[0390] In some embodiments, R Z5 is selected from -N(R’)2; one of R’ is selected from H, C 1-3 alkyl, the other is selected from C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C

[0391] In some embodiments, R Z5 selected from -N(R’)2; in 2 R’, 1 is H, and the other is selected from C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 3-6 cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl; said C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C

[0392] In some embodiments, R Z5 selected from -N(R’)2; in 2 R’, 1 is H, and the other is selected from C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 3-6 cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl; said C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C 1-3 substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C

[0393] In some embodiments, RZ5 -N(R')2; R' is selected from C 1-3 alkyl; or both R' and the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halo or C 1-3 alkyl; provided that said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O).

[0394] In some embodiments, R Z5 -N(R')2; both R' and the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O). 1-3 alkyl; provided that said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O).

[0395] In some embodiments, R Z5 -N(R')2; both R' and the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O).

[0396] In some embodiments, the 4-6 membered monocyclic saturated heterocyclyl is selected from preferably, the 4-6 membered monocyclic saturated heterocyclyl is selected from the 7-11 membered saturated bicyclic spiroheterocyclyl is selected from preferably, the 7-11 membered saturated bicyclic spiroheterocyclyl is selected from the 5-10 membered saturated bicyclic bridged heterocyclyl is selected from the 7-11 membered saturated bicyclic fused heterocyclyl is

[0397] In some embodiments, R Z6 is selected from H, C1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, 5-10 membered bridged heterocyclic groups; wherein, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, 7-11 spirocyclic groups, and 5-10 bridged heterocyclic groups are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2.

[0398] In some implementation schemes, R Z6 Selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-7 membered saturated heterocyclic groups; wherein, the C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-7 saturated heterocyclic groups optionally surrounded by one or more elements selected from halogens, hydroxyl groups, C 1-3 Substitution of alkoxy groups.

[0399] In some implementation schemes, R 12 R 13 Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 5-6 membered heteroaryl groups, phenyl, wherein the C 3-6 Cycloalkyl, 4-7 saturated heterocyclic group, 5-6 heteroaryl group, phenyl optionally surrounded by one or more halogens, C 1-3 Alkyl substituents.

[0400] In some implementation schemes, R 12 R 13 Each is independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 5-6 membered heteroaryl groups, phenyl, wherein the C 3-6 Cycloalkyl, 4-7 saturated heterocyclic group, 5-6 heteroaryl group, phenyl group optionally surrounded by one or more halogens, C 1-3 Alkyl substituents.

[0401] In some implementation schemes, R 12 R 13 Each is independently selected from C 1-3 Alkyl, C 3-6cycloalkyl.

[0402] In some embodiments, each R' is independently selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from halogen, C

[0403] In some embodiments, each R" is independently selected from H, C 1-3 alkyl; said C 1-3 alkyl optionally substituted with one or more substituents selected from deuterium, halogen.

[0404] In some embodiments, each R5is independently selected from H, halogen, oxo, C 1-3 alkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, wherein said C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is formed is a 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl, wherein said 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl.

[0405] In some embodiments, each R5is independently selected from halogen, C 1-3 alkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, wherein said C 3- 6cycloalkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from halo, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl, wherein said 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl is optionally substituted with one or more substituents selected from halo, C 1-3 alkyl.

[0406] In some embodiments, each R5is independently selected from halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halo, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered fused cycloalkyl, wherein said 7-10 membered bridged cycloalkyl, 7-10 membered fused cycloalkyl is optionally substituted with one or more substituents selected from halo, C 1-3 alkyl.

[0407] In some embodiments, each R5is independently selected from halo, C 1-3 alkyl. 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkyl.

[0408] In some embodiments, each R5is independently selected from halo, C 1-3 alkyl.

[0409] In some embodiments, each R5is independently selected from halo.

[0410] In some embodiments, selected from:

[0411] In some embodiments, is selected from:

[0412] In some embodiments, is selected from: (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ),

[0413] In some embodiments, is selected from (e.g. )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、

[0414] In some embodiments, is selected from (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example ).

[0415] In some embodiments, is selected from:

[0416] In some embodiments, is selected from:

[0417] In some embodiments, is selected from (For example )、 (For example ).

[0418] In some embodiments, R Y is each independently selected from H, halogen, -OR Y’ , cyano, C 1-3alkyl, -CO-C 1-3 alkyl; said C 1-3 alkyl, -CO-C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy.

[0419] In some embodiments, R Y each is independently selected from H, halogen, -OR Y’ , cyano, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen.

[0420] In some embodiments, R Y each is independently selected from H, -OR Y’ .

[0421] In some embodiments, R Y is selected from -OR Y’ .

[0422] In some embodiments, R Y each is independently selected from H, F, Cl, hydroxyl, cyano, methyl, -CD3, -CF3, -CHF2, -CH2F, methoxy, -OCD3, -OCF3, -OCHF2, -OCH2F, -OCH2CN, -OCH2CH2OH, -OCH2CH2F, ethoxy, -OCH2CF3, -OCH2CH2CN, -OCH2CH2OCH3, -O-cyclopropyl, -O-cyclobutyl, -C(O)CH3.

[0423] In some embodiments, R Y each is independently selected from -OCD3, -OCF3, -OCHF2, -O-cyclopropyl.

[0424] In some embodiments, R Y’ is selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy.

[0425] In some embodiments, R Y’ is selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl.

[0426] In some embodiments, R Y’ selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen.

[0427] In some embodiments, R Y’ selected from C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen.

[0428] In some embodiments, R Y’ selected from C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 deuterium.

[0429] In some embodiments, R Y’ selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, CH2CH2F, cyclopropyl, cyclobutyl.

[0430] In some embodiments, R Y’ selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, CH2CH2F, cyclopropyl, cyclobutyl.

[0431] In some embodiments, one of Y1, Y2 is N, and the other is CH.

[0432] In some embodiments, Y1 is N, and Y2 is CH.

[0433] In some embodiments, Y1, Y2 are both CH.

[0434] In some embodiments, Y1, Y2 are both N.

[0435] In some embodiments, n is selected from 0, 1.

[0436] In some embodiments, n is 1.

[0437] In some embodiments, m is selected from 1, 2, 3.

[0438] In some embodiments, m is selected from 1 or 2.

[0439] In some embodiments, m is 1.

[0440] In some embodiments, R6is selected from C 1-3 alkyl, C 1-3 haloalkyl.

[0441] In some embodiments, R6is selected from C 1-3 haloalkyl.

[0442] In some embodiments, R6is selected from -CH2CF3.

[0443] In some embodiments, the compound is of Formula III,

[0444] the definitions of ring A, X1, X2, Y1, Y2, R1, R4, R5, Z2, L, R X , R Y , n, m are as described in any of the preceding embodiments. In some embodiments, the compound is of Formula IV,

[0445] the definitions of Y1, Y2, R1, R4, R5, Z2, L, R Y , n, m are as described in any of the preceding embodiments.

[0446] In some embodiments, the compound is of Formula V,

[0447] the definitions of Y1, Y2, R1, R4, R5, L, R Y , R Z5 , n, m are as described in any of the preceding embodiments.

[0448] In some embodiments, the compound is of Formula VI,

[0449] the definitions of Y1, Y2, R1, R4, R5, L, R Y , R Z5 are as described in any of the preceding embodiments.

[0450] In some embodiments, the compound is of Formula VII,

[0451] the definitions of Y1, Y2, R1, R4, R5, L, R Y , R Z5 are as described in any of the preceding embodiments.

[0452] In some embodiments, R Z5 is selected from halogen, C 1-6alkyl, -N(R')2, -OR 12 -S(O)R 13 -S(O)2R 13 C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0453] R 12 , R 13 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl.

[0454] In some embodiments, R Z5 is selected from halogen, C 1-3 alkyl, -N(R')2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C 1-3 alkyl, C 13 alkoxy;

[0455] R 12 , R 13 are each independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-3substituted by one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl,

[0456] In some embodiments, R is selected from -N(R')2. Z5 selected from -N(R')2, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl, 1-3 substituted by one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl,

[0457] In some embodiments, R is selected from -N(R')2. Z5 selected from 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-6alkyl, 1-6 substituted by one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl,

[0458] In some embodiments, R is selected from -N(R')2. Z5 selected from 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; wherein the 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-6alkyl, 1-3 substituted by one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl,

[0459] In some embodiments, R is selected from -N(R')2. Z5 selected from -N(R')2.

[0460] In some embodiments, R is selected from -N(R')2. Z5 selected from -N(R')2; of the 2 R', 1 is selected from H, C1-6alkyl, 1-3 C1-6alkyl, the other is selected from C1-6alkyl, C3-6cycloalkyl, 1-3 C1-6alkyl, C3-6cycloalkyl, 3-6 C1-6alkyl, C3-6cycloalkyl, 4-7 membered saturated heterocyclyl; the C1-6alkyl, C3-6cycloalkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl, 1-3 C1-6alkyl, C3-6cycloalkyl, 3-6 C1-6alkyl, C3-6cycloalkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl, 1-3 C1-6alkyl, C3-6cycloalkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl, 1-3 C1-6alkyl, C3-6cycloalkyl, 1-3 substituted by one or more substituents selected from halogen, oxo, hydroxyl, C1-6alkyl,

[0461] In some embodiments, R is selected from -N(R')2. Z5Selected from -N(R')2; of the two R's, one is H, and the other is selected from C. 1-3 Alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclic groups; the C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-7 saturated heterocyclic groups optionally surrounded by one or more groups selected from halogen, oxo, C 1-3 The alkoxy group is substituted; or the two R' groups and the N atom attached to them form a 4-7 membered saturated heterocyclic group, a 7-11 membered spiroheterocyclic group, a 5-10 membered bridged heterocyclic group, or a 7-11 membered fused heterocyclic group; wherein the 4-7 membered saturated heterocyclic group, the 7-11 membered spiroheterocyclic group, the 5-10 membered bridged heterocyclic group, or the 7-11 membered fused heterocyclic group is optionally substituted by one or more elements selected from halogen, oxo, hydroxyl, C 1-3 Alkyl, C 1-3 Substitution of alkoxy groups.

[0462] In some implementation schemes, R Z5 Selected from -N(R')2; of the two R's, one is H, and the other is selected from C. 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered monocyclic saturated heterocyclic groups; the C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-6 saturated heterocyclic groups optionally surrounded by one or more groups selected from halogen, oxo, C 1-3 Substituents of the alkoxy group; or the two R' atoms and the N atom attached to them form a 4-6 member saturated monocyclic heterocyclic group, a 7-11 member saturated bicyclic spirocyclic group, a 5-10 member saturated bicyclic bridged heterocyclic group, or a 7-11 member saturated bicyclic fused heterocyclic group; wherein the 4-6 member saturated monocyclic heterocyclic group, the 7-11 member saturated bicyclic spirocyclic group, the 5-10 member saturated bicyclic bridged heterocyclic group, or the 7-11 member saturated bicyclic fused heterocyclic group is optionally replaced by one or more atoms selected from C 1-3 Alkyl substituents.

[0463] In some implementation schemes, R Z5 Selected from -N(R')2; R' is selected from C 1-3 Alkyl group; or two R' atoms and the N atom attached to them form a 4-6 member saturated monocyclic heterocyclic group or a 7-11 member saturated bicyclic spirocyclic heterocyclic group; wherein the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group is optionally surrounded by one or more elements selected from halogen or C. 1-3 Alkyl substituents; provided that the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group optionally has one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N or O (preferably O).

[0464] In some implementation schemes, R Z5selected from -N(R')2; both R' and the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally having 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O). 1-3 substituted with one or more substituents selected from halo or C1-6alkyl; provided that said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O).

[0465] In some embodiments, R Z5 selected from -N(R')2; both R' and the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally having 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O).

[0466] In some embodiments, L is selected from -CONR 8 SO2-$ R4 , -CONR 8 SO(=NR 10 )-$ R4 ;$ R4 attached to R4.

[0467] In some embodiments, L is selected from -CONR 8 SO2-$ R4 ;$ R4 attached to R4.

[0468] In some embodiments, R 8 , R 10 are each independently selected from H, C 1-3 alkyl.

[0469] In some embodiments, R 8 , R 10 are selected from H.

[0470] In some embodiments, R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl.

[0471] In some embodiments, R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C1-6 deuteroalkyl, C 3-6 saturated cycloalkyl.

[0472] In some embodiments, the compound is selected from Table 1 or Table 2.

[0473] In some embodiments, the compound is selected from Table 1.

[0474] In some embodiments, the compound is selected from Table 2.

[0475] Table 1

[0476] In some embodiments, the compound is selected from

[0477] In some embodiments, the compound is selected from

[0478] In some embodiments, the compound is selected from

[0479] In some embodiments, the compound is selected from

[0480] In some embodiments, the compound is selected from

[0481] In some embodiments, the compound is selected from

[0482] In a second aspect of the present application, the present application provides a pharmaceutical composition comprising the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically-labeled compound (preferably deuterated) or prodrug thereof of the compound, and optionally a pharmaceutically acceptable excipient.

[0483] In a third aspect of the present application, the present application provides a combination drug comprising:

[0484] 1) a first drug which is the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically-labeled compound (preferably deuterated) or prodrug thereof of the compound;

[0485] 2) a second drug which is a PD-1 inhibitor or a PD-L1 inhibitor.

[0486] In some embodiments, the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, camrelizumab, sintilimab, toripalimab, penpulimab, zimberelimab, Pucotenlimab.

[0487] In some embodiments, the PD-L1 inhibitor is selected from atezolizumab, avelumab, durvalumab.

[0488] In a fourth aspect of the present application, the present application provides use of the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically-labeled compound (preferably deuterated) or prodrug thereof of the compound, or the aforementioned pharmaceutical composition, or the aforementioned combination drug, in the manufacture of a medicament.

[0489] In some embodiments, the medicament is for treating and / or preventing a disease.

[0490] In some embodiments, the disease is a disease caused by a p53 Y220C mutation.

[0491] In some embodiments, the disease caused by a p53 Y220C mutation is a cancer.

[0492] In some embodiments, the cancer is selected from gastric adenocarcinoma, pancreatic cancer, breast cancer, liver cancer, prostate cancer, cervical cancer, ovarian cancer, oral cancer, esophageal cancer, stomach cancer, colorectal cancer, nasopharyngeal cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), bladder cancer, soft tissue sarcoma, brain tumor, lymphocytic tumor, osteosarcoma, endometrial cancer, head and neck cancer.

[0493] In some embodiments, the disease is selected from gastric adenocarcinoma, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, endometrial cancer, head and neck cancer, small cell lung cancer.

[0494] In a fifth aspect of the present application, the present application provides the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug of the compound, or the aforementioned pharmaceutical composition, or the aforementioned combination drug, for use in the treatment and / or prevention of a disease.

[0495] In some embodiments, the disease is a disease caused by a p53 Y220C mutation.

[0496] In some embodiments, the disease caused by a p53 Y220C mutation is a cancer.

[0497] In some embodiments, the cancer is selected from gastric adenocarcinoma, pancreatic cancer, breast cancer, liver cancer, prostate cancer, cervical cancer, ovarian cancer, oral cancer, esophageal cancer, stomach cancer, colorectal cancer, nasopharyngeal cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), bladder cancer, soft tissue sarcoma, brain tumor, lymphocytic tumor, osteosarcoma, endometrial cancer, head and neck cancer.

[0498] In some embodiments, the disease is selected from gastric adenocarcinoma, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, endometrial cancer, head and neck cancer, small cell lung cancer.

[0499] In some embodiments, the first drug and the second drug in the combination drug are administered simultaneously, or sequentially.

[0500] In a sixth aspect of the present application, the present application provides a method of treating and / or preventing a disease caused by p53 Y220C mutation, comprising: administering to a subject an effective amount of a compound as described above, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug thereof of the compound, or a pharmaceutical composition as described above, or a combination drug as described above.

[0501] In some embodiments, the disease is selected from gastric adenocarcinoma, pancreatic cancer, breast cancer, liver cancer, prostate cancer, cervical cancer, ovarian cancer, oral cancer, esophageal cancer, gastric cancer, colorectal cancer, nasopharyngeal cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), bladder cancer, soft tissue sarcoma, brain tumor, lymphocytic tumor, osteosarcoma, endometrial cancer, head and neck cancer.

[0502] In some embodiments, the disease is selected from gastric adenocarcinoma, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, endometrial cancer, head and neck cancer, small cell lung cancer.

[0503] In some embodiments, when the combination drug as described above is administered, the first drug and the second drug are administered simultaneously or sequentially.

[0504] In a seventh aspect of the present application, the present application provides a method of inducing apoptosis in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound that binds to a mutant p53 mutant, wherein the compound is a compound as described above, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug thereof of the compound, or a pharmaceutical composition as described above, or a combination drug as described above.

[0505] In some embodiments, the compound increases the ability of the p53 mutant to bind to DNA.

[0506] In some embodiments, the p53 mutant is p53 Y220C.

[0507] In some embodiments, the compound induces a conformational change in the p53 mutant.

[0508] In some embodiments, the compound increases the stability of the biologically active conformation of the p53 mutant relative to the stability of the biologically active conformation of the p53 mutant in the absence of the compound. Beneficial effects

[0509] 1、The compound of the present application has excellent in vitro activity, and can increase the binding ability of Y220C mutant P53 protein to DNA.

[0510] 2、The compound of the present application can significantly inhibit the proliferation of NUGC-3 gastric adenocarcinoma cells containing p53 Y220C mutation.

[0511] 3、The compound of the present application can significantly inhibit the proliferation of BxPC-3 pancreatic cancer cells containing p53 Y220C mutation.

[0512] 4、At least part of the compounds of the present application have good cell permeability and low efflux properties.

[0513] 5、At least part of the compounds of the present application have good PK properties and good efficacy in mouse in vivo efficacy test experiments. DETAILED DESCRIPTION

[0514] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Furthermore, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods, devices and materials are now described.

[0515] In the present application, unless otherwise explicitly indicated, the description "… are each independently selected from" used throughout this text can mean that the specific options expressed between the same or different symbols in different groups are independent of each other, or that the specific options expressed between the same or different symbols in the same group are independent of each other.

[0516] The term "optionally", "optionally" or "any", "any" means that the event or situation described later can or can not occur, and the description includes the case where the event or situation described is present and the case where it is not present. For example, "optionally substituted" means that the substitution can exist or can not exist.

[0517] The term "independent of each other" is used in combination with "optionally", for example, "independent of each other, optionally substituted" means that the specific options are independent of each other, or not substituted.

[0518] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the "Handbook of Chemistry and Physics", 75thEd., 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0519] Substituents of the compounds of the present application are disclosed according to group type or range. It is specifically intended that the present application include each and every independent combination of members of the groups and ranges specified. For example, the term "C 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0520] The term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups, having the number of carbon atoms specified. For example, "C 1-6 "alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, preferably "C 1-4 "alkyl", more preferably "C 1-3 "alkyl", most preferably "C 1-2 "alkyl". "C 1-6 Examples of "C 1-4 Examples of "C 1-3 Examples of "C 1-2 Examples of "C

[0521] The term "alkylene" refers to a divalent radical resulting from the loss of a hydrogen atom from one of the above-mentioned alkyl groups, for example, C 1-6 alkylene.

[0522] The term "alkoxy" refers to any of the above-mentioned alkyl groups that are attached to a ring, for example, C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2alkyl, etc.) is attached to the rest of the molecule by an oxygen atom (i.e., -O-), such as C 1-6 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy, C

[0523] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0524] The term "C 1-6 haloalkyl" refers to a group in which one or more hydrogen atoms of any of the above-mentioned alkyl groups (e.g., C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, etc.) is replaced by a halogen (preferably fluorine), such as monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, -CH2CF3, -CH2CH2F, -CH2CHF2, etc.

[0525] The term "heteroatom" refers to N, O, S, or P; in some embodiments, the heteroatom is selected from N, O, or S; in some embodiments, the heteroatom is selected from N or O.

[0526] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic) monovalent hydrocarbon ring group, preferably containing 3-15 ring carbon atoms or 3-10 ring carbon atoms, for example, can be "C 3-7 cycloalkyl," "C 4-9 cycloalkyl," "C 3-6 cycloalkyl," the cycloalkyl group can be in the form of a monocyclic ring, a fused ring, a bridged ring, a spiro ring, or any reasonable combination thereof, etc. The term "C 3-6 Examples of "cycloalkyl" include

[0527] The term "halocycloalkyl" refers to a group in which one or more hydrogen atoms of any of the above-mentioned cycloalkyl groups (e.g., C 3-7 cycloalkyl, C 4-9 cycloalkyl, C 3-6 cycloalkyl, etc.) is replaced by a halogen (preferably fluorine), such as C 3-6 halocycloalkyl.

[0528] The term "cycloalkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) monovalent hydrocarbon ring group having 1 or more double bonds within the ring, for example, a monocyclic ring, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, or a bicyclic ring. The "cycloalkenyl" group preferably has 3 to 10 carbon atoms, for example, 3-8, 3-7, 3-6, 4-6, or 5-6 carbon atoms.

[0529] The term "bridged cycloalkyl" refers to a cyclic group formed from two cycloalkyl groups as defined above connected by sharing two ring carbon atoms via a carbon chain of 1 or more (e.g., 2) carbon atoms. In some embodiments, the "bridged cycloalkyl" has, for example, 5-10 ring carbon atoms (C 5-10 ), for example, 6 (C6), 7 (C7), 8 (C8), or 9 (C9) ring carbon atoms. Enumerated examples of the bridged cycloalkyl group include, but are not limited to: bicyclo[l. l. l]pentyl, for example, bicyclo[2. l. l]hexyl, for example, bicyclo[2.2. l]heptyl, for example, bicyclo[3.2. l]octyl; bicyclo[5.2.0]nonyl;

[0530] The term "spirocycloalkyl" refers to a cyclic group formed from two cycloalkyl groups as defined above sharing 1 ring carbon atom, which cyclic group can be saturated or partially unsaturated. In some embodiments, the "spirocycloalkyl" has, for example, 5-11 ring carbon atoms (C 5-11 ), for example, 6 (C6), 7 (C7), 8 (C8), 9 (C9), or 10 (C 10 ) ring carbon atoms. Spirocycloalkyl groups include, but are not limited to: C 5-11 spirocycloalkyl, C 6-10 spirocycloalkyl, C 7-10 spirocycloalkyl; and C 5-11 spirocycloalkenyl, C 6-10 spirocycloalkenyl, C 7-10 spirocycloalkenyl. Single spirocyclic hydrocarbyl groups can include, for example, 3- membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5- membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, where the count of each ring includes the spiro atom. Enumerated examples of the spirocycloalkyl group include, but are not limited to:

[0531] The terms "heterocycle," "heterocyclyl," or "heterocycloalkyl" are used interchangeably and refer to a radical that has at least one heteroatom in at least one ring of the above- defined cycloalkyl radical, such as 3- to 7-membered (preferably 4- to 7-membered, more preferably 5- to 6-membered or 4- to 6-membered) monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, which can include one or more double bonds but at least one ring does not have a conjugated pi-electon system. The heterocyclyl can be attached through any available ring nitrogen or carbon atom of the ring. Exemplary heterocyclic examples include, but are not limited to, the following moieties (without the bond to the other radical shown):

[0532] Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolanyl, and the like.

[0533] The terms "saturated heterocyclyl" and "saturated heterocycle" are used interchangeably to mean a heterocyclyl group as defined above that does not contain an unsaturated bond, such as a double bond, for example, examples of "4-8 membered saturated heterocycle" include, but are not limited to, hexahydropyrimidine, hexahydropyrazine, and the like. For another example, examples of "6 membered saturated heterocyclyl" include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, hexahydropyrimidinyl, hexahydropyrazinyl, specifically, for example,

[0534] The terms "bridged heterocyclyl", "bridged heterocycle", "bridged heterocycloalkyl" are used interchangeably to mean a heterocyclyl group as defined above containing at least one heteroatom on at least one ring of the bridged cycloalkyl group, which can contain one or more double bonds, specifically exemplified as "7 membered bridged heterocyclyl". Wherein "membered" refers to the total number of ring atoms of the bridged heterocyclyl group. Further, it is classified as diheterocyclyl, triheterocyclyl, tetraheterocyclyl, and the like, according to the number of rings that make up. For example, "7 membered bridged heterocyclyl" can be

[0535] The terms "spiroheterocyclyl" and "spiroheterocycle" are used interchangeably to mean a heterocyclyl group as defined above containing at least one heteroatom on at least one ring of the spirocycloalkyl group, which can contain one or more double bonds, specifically exemplified as "7-11 membered spiroheterocycle", "7-9 membered spiroheterocycle". Wherein "7-11 membered spiroheterocycle" can be, for example: Specifically, "7-9 membered spiroheterocycle" can be, for example,

[0536] The terms "aryl" and "aromatic ring" are used interchangeably to mean a fully carbon mononuclear or fused ring polynuclear aromatic group having a conjugated pi-electron system throughout the ring. For example, C 6-14 "Aryl" means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl.

[0537] The terms "heteroaryl" and "heteroaromatic" are used interchangeably and refer to aromatic groups having at least one heteroatom in at least one ring of the above-mentioned aryl groups, such as 5- or 6-membered monocyclic groups, 8-, 9-, or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups, the heteroatom-containing rings optionally further having 1, 2, or 3 heteroatoms selected from N, O, S, or P. Among these, the aromatic 8-, 9-, or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups having at least one heteroatom in at least one ring are "fused heteroaryl" or "fused heteroaromatic". The bicyclic or tricyclic heteroaryl or heteroaromatic rings require the bicyclic or tricyclic structure as a whole to form an aromatic system. The heteroaryl or heteroaromatic groups can be attached to other groups at any available nitrogen or carbon atom of any of the rings. And as will be understood by those skilled in the art, each two rings in a fused ring share two adjacent atoms (preferably carbon atoms) between them. Exemplary monocyclic heteroaryl or heteroaromatic rings include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyridazinyl, and the like. Exemplary bicyclic heteroaryl groups include, but are not limited to, indolyl, 5-azaindolyl, pyrrolo[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridinyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridinyl, isoindolyl, and the like.

[0538] The terms "heteroarylene" and "heteroaromatic ring" are used interchangeably and refer to divalent groups derived from any of the above-mentioned heteroaryl groups by the loss of one hydrogen atom, such as 5-6 membered heteroarylenes which can be 1,3,4-thiadiazolylene, 1,2,4-oxadiazolylene, 1,3,4-oxadiazolylene, or thiazolylene, and the like, and specifically can be

[0539] From all the above descriptions, it will be apparent to those skilled in the art that any group whose name is a composite name, such as "cyano-C 1-6 alkylene", should refer to the moiety conventionally built from left to right from which it is derived, such as from a "C 1-6 alkylene" substituted with a cyano group, wherein "C 1-6 alkylene" is as defined above. Specifically, "cyano-C 1-6 ​"alkylene" can be, for example, -CH2CN. Similarly, "hydroxyl-C" 1-6 Alkylene, C 1-6 Alkoxy-C 1-6 Alkylene, 5-6 membered saturated heterocyclic group -C 1-6 "alkylene" should conventionally refer to the part derived from it from left to right, such as from the part with hydroxyl, C 1-6 alkoxy or 5-6 membered saturated heterocyclic groups substituted with "C" 1-6 The structure is constructed using "alkylene", where "C1-C6 alkylene" is as defined above. Specifically, "hydroxyl-C..." 1-6 "alkylene" can be, for example, -CH2CH2OH, "C 1-6 Alkoxy-C 1-6 "alkylene" can be, for example, -CH2CH2OCH3, "5-6 membered saturated heterocyclic group -C 1-6 "alkylene" can be, for example, Other similar complex groups can be understood by referring to the foregoing content.

[0540] The term "substituted" or "substituted by a substituent" refers to the selective substitution of one or more hydrogen atoms on a specified atom or group by a specified group, provided that the substitution does not exceed the normal valence state of the specified atom. For example, "hydroxyl-substituted C..." 1-6 "alkyl" can be hydroxymethyl. For example, "C0" can be a C0 substituted with two hydroxyl groups. 1-6 "alkyl" can be For example, "R" 7 Selected from C 1-6 Alkoxy-C 1-6 Alkylene, the C 1-6 Alkoxy-C 1-6 "If the alkylene group is replaced by a hydroxyl group", then R 7 For example, it can be...

[0541] The term "one or more" means one or more under reasonable conditions, such as two, three, four, five or ten.

[0542] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0543] When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.

[0544] As used herein, "treatment" generally means obtaining a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a patient, including: (a) preventing the disease or symptom from occurring in an individual that is predisposed to the disease or symptom but has not yet been diagnosed with the disease; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.

[0545] As used herein, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, farm animals (such as cows), domestic pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0546] As used herein, "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A "therapeutically effective amount" of a substance / molecule of the present application can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount of the substance / molecule that has therapeutic benefits in comparison to any toxic or detrimental effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, but not necessarily, since a prophylactic dose is used in subjects prior to or at the early stages of disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer.

[0547] The pharmaceutical compositions of the present application can contain pharmaceutically acceptable excipients including, but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, and the like.

[0548] The pharmaceutical compositions described herein can be prepared in various forms according to different routes of administration. For example, the pharmaceutical compositions described herein can be administered in any of the following ways: orally, spray inhalation, rectally, nasally, buccally, vaginally, topically, parenterally, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or by means of an implanted reservoir. Oral or intravenous administration is preferred.

[0549] The compounds described herein optionally can also be used in combination with other active ingredients, each in amounts and ratios that are adjusted according to the particular condition and patient, and the clinical needs of the patient, etc., by those skilled in the art.

[0550] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative of a compound of the present application that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Prodrugs are inactive until they are converted to the active form of the compound by the reaction. They can have no or only low activity in their form that does not react, or they become active compounds only after they have reacted. Prodrugs can be prepared from the known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th ed.).

[0551] The term "enantiomer" refers to two isomers of a compound that are non-superimposable mirror images of each other.

[0552] The term "diastereomer" refers to two or more stereoisomers of a compound that are not mirror images of each other and which have different physical properties.

[0553] The term "racemate", "racemic" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

[0554] The term "tautomer" or "tautomerism" refers to structural isomers that differ in energy by a low energy barrier and can interconvert. If tautomerism is possible (as in solution), a chemical equilibrium of tautomers can be achieved. For example, protontautomer (also known as prototropic tautomer) includes interconversion by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversion by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0555] The term "stereoisomer" refers to compounds having the same chemical constitution, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0556] The term "geometric isomer" is also known as "cis-trans isomer", which results from the inability of a single bond (including double bond of alkene, C=N double bond and N=N double bond) or ring carbon atom to rotate freely, where for example, represents the cis configuration, i.e., both substituents on the cyclobutyl ring are on the same side.

[0557] A solid line may be used herein to represent a single bond or a dashed line Chemical bonds of the compounds of the invention are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers, including particular enantiomers, racemic mixtures, and the like, at that carbon atom are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the depicted stereoisomer is present. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis- and trans-isomers, optical isomers (for example R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention can exhibit more than one type of isomerism, and consist of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).

[0558] As used herein, the term "chiral carbon atom" refers to a carbon atom that is attached to four non-identical groups. As used herein, the term "chiral carbon atom" refers to a carbon atom that is attached to four non-identical groups. As used herein, the term "chiral carbon atom" refers to a carbon atom that is attached to four non-identical groups. As used herein, the term "chiral carbon atom" refers to a carbon atom that is attached to four non-identical groups. As used herein, the term "chiral carbon atom" refers to a carbon atom that is attached to four non-identical groups.

[0559] The stereochemical definitions and rules used herein generally follow S. P. 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. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. One specific stereoisomer is the enantiomeric form, and mixtures of such isomers are called enantiomeric mixtures. A 50:50 mixture of enantiomeric forms is called a racemic mixture or racemate, and can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0560] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present application can exist in the form of a racemic or enantiomeric enrichment, e.g., (R)-, (S)-, or (R,S)-configurational forms. In certain embodiments, each asymmetric atom has at least a 50% enantiomeric excess in the (R)- or (S)- configuration, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least an 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0561] Depending on the choice of starting materials and methods, the compounds of the present application can be present in the form of one or more of possible isomers, such as racemates and mixtures of diastereomers, depending on the number of asymmetric carbon atoms (see, e.g., WO 91 / 06283). The optically active forms of (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compounds contain a double bond, the substituents can be in the E or the Z configuration; if the compounds contain a disubstituted cycloalkyl, the substituents on the cycloalkyl can have a cis- or trans-configuration.

[0562] Any mixture of stereoisomers can be separated into their individual isomers by conventional techniques, such as HPLC or fractional crystallization, and any enantiomers can be converted into each other following conventional procedures.

[0563] Any resulting racemate of an end product or intermediate can be separated using known methods to obtain the optical antipodes by methods well known to those skilled in the art, such as by separation of the resulting diastereomeric salts thereof. The racemate product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0564] The compounds described herein include all possible isotopically labeled compounds described herein. The term "isotopically labeled compound" refers to compounds wherein any atom of the compound is replaced by its isotope.

[0565] "Solvate" or "solvate" are used interchangeably to refer to a compound that exists in combination with one or more solvent molecules. The combination can include stoichiometric amounts of solvent molecules, for example, when the solvent is water, a "hydrate" such as a monohydrate or dihydrate is formed, or it can include any amount of solvent molecules; for example, when the solvent is an alcohol such as methanol or ethanol, an "alcoholate" can be formed, which can also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in solution of a solvent, although it can be solvated, is not a solvate as the term is used herein.

[0566] The term "hydrate" refers to an association of one or more water molecules with a compound of the application.

[0567] The term "nitroso compound" refers to the oxidation of one or more than one nitrogen atom to form an N-oxide when the compound contains several amine functions. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen heterocycle ring nitrogen atoms. N-oxides can be formed by treatment of the corresponding amines with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. peroxycarboxylic acids) (see Advanced Organic Chemistry, Wiley Interscience, 4thedition, Jerry March, pages 622-623). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA) for example in an inert solvent such as dichloromethane.

[0568] As used herein, the term "metabolite" refers to a derivative of a compound formed upon metabolism of the compound. The term "metabolism" refers to the sum of the processes by which particular substances are changed by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions).

[0569] As used herein, the term "ester" refers to an ester formed from the presence of -COOH in a compound provided herein and an appropriate alcohol, or an ester formed from the presence of -OH in a compound provided herein and an appropriate acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, stearyl or palmitoyl. Esters can undergo hydrolysis in the presence of an acid or a base to form the corresponding acid or alcohol.

[0570] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated with it. Preferably, the "pharmaceutically acceptable" of the present application means approved or approvable by a regulatory agency of the Federal or a state government or the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.

[0571] As used herein, the term "pharmaceutically acceptable salt" refers to (i) salts of acidic functional groups present in the compounds provided herein with appropriate inorganic or organic cations (bases), and include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salts, and the like; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, and the like; inorganic base salts, such as ammonium salts; organic base salts, such as tertiary octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts, and (ii) salts of basic functional groups present in the compounds provided herein with appropriate inorganic or organic anions (acids), and include, but are not limited to, hydrogen halide salts, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, and the like; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, and the like; lower alkylsulfonic acid salts, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, and the like; arylsulfonic acid salts, such as benzenesulfonates, p-toluenesulfonates, and the like; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, and the like; amino acid salts, such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts, and the like.

[0572] As used herein, the term "crystal form" refers to the crystal structure of a substance. When a substance crystallizes, the way the intramolecular or intermolecular bonds are changed due to various factors, so that the molecules or atoms are arranged differently in the crystal lattice space, forming different crystal structures. The compounds of the present application can exist in one crystal structure, or in multiple crystal structures, i.e., have "polymorphism". The compounds of the present application can exist in different crystal forms.

[0573] As used herein, the term "about" refers to within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

[0574] In the present application, for each group in the Markush general formula compound, the definition thereof, including each embodiment, each preferred level (or preferred range), and the listed level (or listed range), are all independent of each other, and the above-mentioned definitions of different groups, including each embodiment, each preferred level, and the listed level, can be independently selected and arbitrarily combined.

[0575] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The experimental methods in the following examples are generally according to the conventional conditions of such reactions, or according to the conditions suggested by the manufacturers, unless otherwise specified. The percentages and parts are weight percentages and weight parts, unless otherwise specified. The ratio of liquids is volume ratio, unless otherwise specified. The experimental materials and reagents used in the following examples are commercially available, unless otherwise specified.

[0576] Nomenclature:

[0577] DABCO: 1,4-Diazabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane

[0578] DPPA: diphenylphosphoryl azid, diphenyl phosphoryl azide

[0579] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex

[0580] BrettPhos Pd G3: (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methane sulfonate

[0581] Preparation Example:

[0582] Preparation of Intermediate A

[0583] Step 1: Compound A-1 (34.72 mL, 297.24 mmol) was added to toluene (500 mL), triethylamine (45 mL, 324.64 mmol) and diphenyl phosphoryl azide (68 mL, 313.81 mmol) were added. The reaction was stirred at 25 °C under nitrogen protection for 1.5 hours. Then heated to 110 °C and stirred for another 2.5 hours. Benzyl alcohol (34.00 mL, 326.97 mmol) was added to the reaction, which was stirred at 110 °C for 12 hours. The reaction was concentrated and diluted with N,N-dimethylformamide (100 mL) and water (1000 mL). The mixture was filtered, and the filter cake was washed with water (200 mL x 2). The filter cake was dried under vacuum to obtain compound A-2. 1H NMR (400 MHz, CDC13) δ 7.34 - 7.22 (m, 5H), 5.64 - 5.56 (m, 1H), 5.55 - 5.48 (m, 1H), 5.02 (s, 2H), 3.81 (d, J = 9.2 Hz, 1H), 2.36 - 2.30 (m, 1H), 2.12 - 1.99 (m, 2H), 1.85 - 1.78 (m, 2H), 1.59 - 1.43 (m, 1H).

[0584] Step 2: To a solution of compound A-2 (83.0 g, 358.86 mmol) in dichloromethane (1000 mL) was added m-chloroperoxybenzoic acid (169.64 mL, 467.95 mmol). The mixture was stirred at 25 °C for 3 hours. The mixture was quenched with saturated sodium thiosulfate (500 mL), washed with saturated sodium bicarbonate (300 mL x 2). The organic phase was concentrated to give compound A-3.

[0585] Step 3: A solution of compound A-3 (189 g, 764.28 mmol) in triethylamine hydrofluoride (622 mL, 3821.42 mmol) was stirred at 100 °C for 2 hours. The mixture was quenched with potassium carbonate (528.12 g) in water (1000 mL), extracted with ethyl acetate (500 mL x 3). The combined organic phase was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound A-4. 1 H NMR (400 MHz, CDC13) δ 7.34 - 7.22 (m, 5H), 5.64 - 5.56 (m, 1H), 5.55 - 5.48 (m, 1H), 5.02 (s, 2H), 3.81 (d, J = 9.2 Hz, 1H), 2.36 - 2.30 (m, 1H), 2.12 - 1.99 (m, 2H), 1.85 - 1.78 (m, 2H), 1.59 - 1.43 (m, 1H).

[0586] Step 4: A solution of compound A-4 (80.0 g, 299.29 mmol), phthalimide (46.96 g, 319.45 mmol), triphenylphosphine (100 g, 381.26 mmol) and diisopropyl azodicarboxylate (77 mL, 388.41 mmol) in tetrahydrofuran (500 mL) was stirred at 45 °C for 12 hours. The resulting mixture was concentrated, diluted with acetonitrile (300 mL) and filtered. The filter cake was washed with acetonitrile (100 mL x 3) and dried under vacuum to give compound A-5. MS m / z (ESI): 397.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.82 (m, 4H), 7.43-7.28 (m, 5H), 5.13-4.98 (m, 2H), 4.95-4.75 (m, 1H), 4.26-4.00 (m, 1H), 3.74-3.62 (m, 1H), 2.99-2.85 (m, 1H), 2.23-2.13 (m, 1H), 2.04-1.94 (m, 1H), 1.84-1.76 (m, 1H), 1.74-1.32 (m, 2H).

[0587] Step 5: Compound A-5 (42.0 g, 105.95 mmol) was added into hydrazine hydrate (100 mL, 1646.02 mmol, 85%) and ethanol (420 mL), and the reaction solution was stirred at 80 °C for 2 hours. The reaction solution was concentrated and diluted with dichloromethane (500 mL). The mixture was filtered, and the filter cake was washed with dichloromethane (100 mL). The organic phase was concentrated to obtain compound A-6. MS m / z (ESI): 267.2 [M+H] + .

[0588] Step 6: Compound A-6 (3.0 g, 11.26 mmol), di-tert-butyl dicarbonate (5.0 mL, 23.37 mmol) and triethylamine (5.0 mL, 36.07 mmol) were added into dichloromethane (30 mL), and the mixture was stirred at 25 °C for 18 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound A-7. 1 H NMR (400 MHz, CD3OD) δ 7.26-7.16 (m, 5H), 4.96 (s, 2H), 4.83-4.61 (m, 1H), 3.66-3.58 (m, 1H), 3.44-3.32 (m, 1H), 2.26-2.06 (m, 1H), 1.89-1.84 (m, 1H), 1.68-1.55 (m, 2H), 1.57-1.21 (m, 11H).

[0589] Step 7: Compound A-7 (4.0 g, 10.92 mmol) was dissolved in a mixture of methanol (100 mL) and tetrahydrofuran (100 mL), and palladium hydroxide (3.0 g, 4.27 mmol) was added. The mixture was stirred at 25 °C for 4 hours under the protection of hydrogen gas at normal pressure. The reaction solution was filtered through diatomite, and the filter cake was washed with methanol (20 mL x 3). The filtrate was concentrated to obtain compound A-8. 1H NMR (400 MHz, DMSO-d6) δ 6.81 (d, J = 7.6 Hz, 1H), 4.72 (dd, J = 4.0, 52.4 Hz, 1H), 3.50 - 3.31 (m, 1H), 2.81 - 2.69 (m, 1H), 2.10 - 1.99 (m, 1H), 1.79 - 1.70 (m, 1H), 1.58 - 1.49 (m, 2H), 1.39 (s, 9H), 1.36 - 1.18 (m, 1H), 1.18 - 1.03 (m, 1H).

[0590] Step 8: To compound A-8 (6.0 g, 24.60 mmol), 3,3-bis(chloromethyl)oxetane (4.0 g, 25.83 mmol) and sodium carbonate (2.74 g, 25.83 mmol) was added acetonitrile (10 mL) and the mixture was stirred at 80 °C for 18 hours. The reaction was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound A-9. 1 H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 7.6 Hz, 1H), 4.82 - 4.63 (m, 1H), 4.57 (s, 4H), 3.49 - 3.41 (m, 1H), 3.23 - 3.15 (m, 4H), 2.16 - 2.04 (m, 1H), 1.99 - 1.93 (m, 1H), 1.73 - 1.62 (m, 1H), 1.55 - 1.45 (m, 2H), 1.38 (s, 9H), 1.26 - 1.05 (m, 1H), 1.03 - 0.90 (m, 1H).

[0591] Step 9: Compound A-9 (2.5 g, 7.95 mmol) was added to a mixture of trifluoroacetic acid (4 mL) and dichloromethane (20 mL) and the reaction was stirred at 25 °C for 2 hours. The reaction was concentrated and diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give intermediate A. 1 H NMR (400 MHz, DMSO-d6) δ 4.73 - 4.53 (m, 5H), 3.20 (s, 4H), 2.67 - 2.52 (m, 1H), 2.14 - 2.04 (m, 1H), 1.98 - 1.90 (m, 1H), 1.65 - 1.42 (m, 4H), 1.36 - 1.03 (m, 2H), 0.99 - 0.86 (m, 1H).

[0592] Preparation of Intermediate B

[0593] The synthesis of intermediate B can be prepared according to the preparation method of intermediate A, for example, in step 8, replace 3,3-bis(chloromethyl)oxetane with 2,2'-dibromo-diethyl ether to carry out the reaction, and replace compound A-9 in step 9 with the product obtained by the reaction to finally prepare intermediate B.

[0594] Intermediate B: MS m / z (ESI): 203.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 4.72 (d, J = 50.0, 1H), 3.69-3.59 (m, 4H), 2.68-2.56 (m, 1H), 2.50-2.43 (m, 4H), 2.28-2.18 (m, 1H), 1.91-1.82 (m, 1H), 1.77-1.68 (m, 1H), 1.55-1.13 (m, 4H).

[0595] Preparation of intermediate C

[0596] Step 1: To a solution of compound C-1 (10.0 g, 50.72 mmol) in N,N-dimethylformamide (100 mL) was added deuterated methyl iodide (6.31 mL, 101.45 mmol) and potassium carbonate (10.52 g, 76.08 mmol), and the reaction was stirred at 60 °C for 18 hours. After the reaction was cooled to room temperature, it was diluted with water (150 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound C-2. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 8.4, 1.6 Hz, 1H), 3.91 (s, 3H).

[0597] Step 2: To a solution of compound C-2 (4.8 g, 22.41 mmol) in a mixture of ethanol (40 mL) and water (20 mL) was added iron powder (6.26 g, 112.05 mmol) and ammonium chloride (5.99 g, 112.05 mmol), and the mixture was heated to 80 °C under nitrogen protection and stirred for 3 hours. The reaction was filtered through diatomite while hot, and the diatomite was washed with methanol. The reaction was concentrated under reduced pressure, poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 2). The organic phase was concentrated under reduced pressure to give compound C-3. MS m / z (ESI): 185.0 [M+H] + .

[0598] Step 3: To a solution of compound C-3 (4.0 g, 21.71 mmol) in N,N- dimethylformamide (70 mL) was added potassium carbonate (9.0 g, 65.14 mmol) and bromopropynyl (2.81 mL, 32.57 mmol), the mixture was heated to 70 °C under nitrogen protection and stirred for 18 hours. The reaction was poured into water (200 mL) and extracted with ethyl acetate (60 mL x 2), the combined organic phase was washed with saturated brine (40 mL), the organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound C-4. MS m / z (ESI): 223.0 [M+H] + .

[0599] Step 4: To a mixture of compound C-4 (20.0 g, 89.98 mmol) in methanol (120 mL), water (40 mL) and tetrahydrofuran (40 mL) was added lithium hydroxide (10.78 g, 449.92 mmol), the mixture was stirred at 40 °C for 18 hours. The reaction was adjusted to pH about 5 with 1M dilute hydrochloric acid and extracted with ethyl acetate (400 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound C-5. MS m / z (ESI): 209.0 [M+H] + .

[0600] Step 5: To a solution of compound C-5 (20.0 g, 96.05 mmol) in acetonitrile (200 mL) was added methylamine-d3-amine hydrochloride (10.1 g, 143.20 mmol), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (40.40 g, 143.99 mmol) and 1-methylimidazole (45 mL, 564.56 mmol), the mixture was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure, diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give intermediate C. MS m / z (ESI): 225.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.79 (t, J = 6.4 Hz, 1H), 3.95 (dd, J = 6.4, 2.4 Hz, 2H), 3.07 - 3.01 (m, 1H).

[0601] Preparation of Intermediate D

[0602] Step 1: To a solution of compound D-1 (10.0 g, 49.4 mmol) in dimethyl sulfoxide (100 mL) was added deuterated methanol (2.14 g, 61.0 mmol) and cesium carbonate (48.3 g, 148 mmol), the mixture was stirred at 60 °C for 18 h under nitrogen atmosphere. The reaction was cooled to room temperature, then adjusted to pH about 3 by 1 M hydrochloric acid, the mixture was filtered, the filter cake was concentrated to give compound D-2, which was used directly in the next step. MS m / z (ESI): 202.1 [M+H] + .

[0603] Step 2: To a solution of compound D-2 (4.8 g, 22.41 mmol) and cesium carbonate (23.3 g, 71.6 mmol) in dimethyl sulfoxide (50 mL) was added iodomethane (10.2 g, 71.6 mmol), the mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The reaction was quenched by saturated ammonium chloride solution (200 mL), extracted by ethyl acetate (80 mL x 3), the combined organic phase was washed by saturated brine (100 mL x 2), the organic phase was concentrated under reduced pressure, the crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound D-3. MS m / z (ESI): 216.0 [M+H] + .

[0604] Step 3: To a solution of compound D-3 (4.6 g, 21.4 mmol) in ethyl acetate (46 mL) was added wet palladium on carbon (1.8 g, 5% content), the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The reaction was filtered, the filter cake was washed by ethyl acetate (60 mL x 2), the combined filtrate was concentrated under reduced pressure to give compound D-4. MS m / z (ESI): 186.1 [M+H] + .

[0605] Step 4: To a solution of compound D-4 (4.0 g, 21.6 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (4.78 g, 34.6 mmol) and bromopropargyl (2.06 g, 17.3 mmol), the mixture was stirred at 70 °C for 18 h under nitrogen atmosphere. The reaction was poured into water (100 mL), extracted by ethyl acetate (60 mL x 2), the combined organic phase was washed by saturated brine (40 mL), the organic phase was concentrated under reduced pressure, the crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give intermediate D. MS m / z (ESI): 224.1 [M+H] + .

[0606] Preparation of intermediate E

[0607] Step 1: To a solution of compound E-1 (5.0 g, 52.6 mmol) in chloroform (50 mL) was added triethylamine (14.6 mL, 105.1 mmol) and tert-butyldimethylsilyl chloride (11.9 g, 78.9 mmol), the reaction was stirred at 20 °C for 18 hours under nitrogen protection. The reaction was quenched with aqueous solution (100 mL), extracted with ethyl acetate (80 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), then dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound E-2. 1 H NMR (400 MHz, CDCl3) δ 4.55 (s, 1H), 3.04 (s, 3H), 0.97 (d, J = 1.2 Hz, 9H), 0.32 (d, J = 1.2 Hz, 6H).

[0608] Step 2: A solution of triphenylphosphine (0.6 g, 2.29 mmol) and hexachloroethane (0.6 g, 2.53 mmol) in chloroform (15 mL) was heated to 70 °C for 18 hours, after the temperature was recovered to room temperature, triethylamine (0.5 mL, 3.58 mmol) was added, and stirred at room temperature for half an hour. The reaction was cooled to 0 °C, compound E-2 (0.5 g, 2.39 mmol) was added, and stirred for half an hour. Then ammonia was bubbled for 1 hour. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), the organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound E-3. MS m / z (ESI): 209.1 [M+H] + .

[0609] Step 3: Compound E-3 (50 mg, 0.24 mmol) was dissolved in hydrochloric acid dioxane (1 mL, 4N), and stirred at room temperature for 1 hour. The reaction was concentrated to give intermediate E. The crude product was directly used in the next step.

[0610] Preparation of intermediate F

[0611] Step 1: To a solution of compound F-1 (1.0 g, 4.31 mmol) in N,N- dimethylformamide (20 mL) was added sodium difluorochloroacetate (1.3 g, 8.53 mmol) and potassium carbonate (1.8 g, 13.02 mmol), and the reaction was stirred at 100 °C for 18 h under nitrogen atmosphere. The reaction was quenched with water solution (100 mL), extracted with ethyl acetate (80 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), then dried over anhydrous sodium sulfate, filtered through a filter paper, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound F-2. MS m / z (ESI): 281.9 [M+H] + .

[0612] Step 2: To a solution of compound F-2 (1.1 g, 3.90 mmol) and tert-butyl carbamate (460 mg, 3.90 mmol) in 1,4-dioxane (20 mL) was added cesium carbonate (3.8 g, 11.7 mmol) and BrettPhos Pd G3 (350 mg, 0.39 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered through a filter paper, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound F-3. MS m / z (ESI): 319.0 [M+H] + .

[0613] Step 3: To a solution of compound F-3 (220 mg, 0.69 mmol) in N,N- dimethylformamide (5 mL) was added sodium hydride (34 mg, 0.85 mmol) at 0 °C under nitrogen atmosphere, and the mixture was stirred at 0 °C for 1 h. Propargyl bromide (135 mg, 1.13 mmol) was added to the reaction, and the stirring was continued for 1 h. The reaction was quenched with water solution (30 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered through a filter paper, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound F-4. MS m / z (ESI): 357.2 [M+H] + .

[0614] Step 4: To a solution of compound F-4 (210 mg, 0.59 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL, 13.07 mmol), the mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure, then neutralized with saturated sodium bicarbonate (12 mL), extracted with ethyl acetate (2 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 3 / 1) to give intermediate F.

[0615] Preparation of intermediate G

[0616] Step 1: To a solution of compound D-1 (5.0 g, 24.69 mmol) in dimethyl sulfoxide (40 mL) was added cyclopropanol (1.58 g, 27.15 mmol) and cesium carbonate (24.13 g, 74.06 mmol), the mixture was stirred at 60 °C for 18 h under nitrogen atmosphere. The reaction was cooled to room temperature, then poured into water (200 mL), the pH was adjusted to 5 using 2 M diluted hydrochloric acid, extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound G-2 which was used directly in the next step. MS m / z (ESI): 225.0 [M+H] + .

[0617] Step 2: To a solution of compound G-2 (2.42 g, 10.8 mmol) in dimethyl sulfoxide (15 mL) was added iodomethane (1.7 g, 11.87 mmol) and cesium carbonate (10.55 g, 32.39 mmol) at 0 °C, the mixture was stirred at 20 °C for 1 h under nitrogen atmosphere. The reaction was poured into saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound G-3. MS m / z (ESI): 239.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 4.77-4.68 (m, 1H), 4.04 (s, 3H), 0.92 (d, J = 5.2 Hz, 4H).

[0618] Step 3: To a solution of compound G-3 (1.42 g, 6.00 mmol) in ethyl acetate (50 mL) was added palladium on carbon (1.5 g, 14.10 mmol), the mixture was stirred at room temperature for 36 hours under hydrogen atmosphere. The reaction was filtered with celite, rinsed with ethyl acetate (50 mL x 2), the organic phase was concentrated under reduced pressure to give compound G-4. MS m / z (ESI): 209.0 [M+H] + .

[0619] Step 4: To a solution of compound G-4 (490 mg, 2.35 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (2.66 mL, 2.66 mmol) at -78 °C under nitrogen atmosphere, the mixture was stirred at -78 °C for 1 hour. Di-tert-butyl dicarbonate (254 mg, 1.16 mmol) was added to the reaction, the stirring was continued for 2 hours. The reaction was poured into water (50 mL) after it was allowed to recover to room temperature, extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound G-5. MS m / z (ESI): 309.2 [M+H] + .

[0620] Step 5: To a solution of compound G-5 (220 mg, 0.71 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (34 mg, 0.86 mmol) at 0 °C under nitrogen atmosphere, the mixture was stirred at 0 °C for 1 hour. Bromopropargyl (135 mg, 1.13 mmol) was added to the reaction, the stirring was continued for 2 hours. The reaction was poured into water (30 mL) after it was allowed to recover to room temperature, extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound G-6. MS m / z (ESI): 347.2 [M+H] + .

[0621] Step 6: To a solution of compound G-6 (220 mg, 0.64 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL, 13.07 mmol), the mixture was stirred at 25 °C for 3 hours. The reaction was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give intermediate G. MS m / z (ESI): 247.0 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 8.0, 1.4 Hz, 1H), 6.90 (dd, J = 8.1, 1.4 Hz, 1H), 6.42 (t, J = 6.2 Hz, 1H), 4.44 (qd, J = 4.4, 2.4 Hz, 1H), 4.01 - 3.96 (m, 2H), 3.80 (d, J = 1.5 Hz, 3H), 3.15 (q, J = 2.1 Hz, 1H), 0.89 - 0.71 (m, 4H).

[0622] Preparation of intermediate H

[0623] Step 1: To a solution of compound H-1 (10.0 g, 45.87 mmol) in N,N- dimethylformamide (60 mL) was added deuteromethyl iodide (2.85 mL, 45.87 mmol) and potassium carbonate (9.51 g, 68.81 mmol), the reaction was stirred at 50 °C for 5 hours. The reaction was cooled to room temperature, poured into ice water (100 mL) and filtered, the filter cake was washed with ice water (50 mL) for three times to give compound H-2. 1 H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 8.8, 3.2 Hz, 1H), 7.27 (t, J = 1.6 Hz, 1H), 7.24 - 7.18 (m, 1H).

[0624] Step 2: To a solution of compound H-2 (9.5 g, 40.4 mmol) in a mixture of ethanol (180 mL) and water (90 mL) was added iron powder (12.19 g, 218.2 mmol) and ammonium chloride (22.83 g, 426.9 mmol), the mixture was heated to 85 °C and stirred for 1 hour under nitrogen protection. The reaction was filtered through celite while hot, the celite was washed with methanol, the reaction was concentrated under reduced pressure, poured into water (300 mL) and extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), the organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give compound H-3. MS m / z (ESI): 206.9 [M+H] + .

[0625] Step 3: To a solution of compound H-3 (1.0 g, 4.88 mmol) in N,N- dimethylformamide (20 mL) was added palladium acetate (0.28 g, 1.27 mmol), N,N- diisopropylethylamine (1.98 mL, 11.36 mmol) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (0.62 g, 1.07 mmol), the mixture was heated to 120 °C under nitrogen protection and stirred for half an hour. Then dimethyl phosphine oxide (1.24 g, 15.95 mmol) was added slowly dropwise, and the reaction was continued to stir at 120 °C for 1 hour. The reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound H-4. MS m / z (ESI): 203.1 [M+H] + .

[0626] Step 4: To a solution of compound H-4 (0.94 g, 4.65 mmol) in N-methylpyrrolidone (25 mL) was added bromo propargyl (0.5 mL, 5.76 mmol) and N,N- diisopropylethylamine (1.51 g, 8.69 mmol), the mixture was stirred at 50 °C for 6 hours. The reaction was purified by reverse phase HPLC preparation (ASA-AZZOTA-C18-7 μm-30*150 mm, A: 0.1% FA / H2O B: ACN, flow rate: 35 mL / min) to give intermediate H. MS m / z (ESI): 241.0 [M+H] + .

[0627] Preparation of intermediate I

[0628] Step 1: To a solution of compound I-1 (10.0 g, 50.72 mmol) in N,N- dimethylformamide (100 mL) was added deuterated methyl iodide (4.73 mL, 76.09 mmol) and cesium carbonate (10.52 g, 76.09 mmol), the reaction was stirred at 40 °C for 18 hours. The reaction was cooled to room temperature and poured into ice water (100 mL) and filtered, the filter cake was washed with ice water (50 mL) three times to give crude compound I-2 which was used directly in the next step. MS m / z (ESI): 215.0 [M+H] + .

[0629] Step 2: To a solution of compound I-2 (8.0 g, 37.18 mmol) in ethyl acetate (180 mL) was added palladium on carbon (8.0 g, 75.17 mmol), the mixture was stirred at room temperature for 36 hours under hydrogen protection. The reaction was filtered through celite, washed with ethyl acetate (50 mL) for three times, the organic phase was concentrated under reduced pressure to give the crude compound I-3 which was used directly in the next step. MS m / z (ESI): 185.2 [M+H] + .

[0630] Step 3: To a solution of compound I-3 (0.5 g, 2.71 mmol) in N,N-dimethylformamide (15 mL) was added potassium iodide (0.5 g, 0.27 mmol), N,N-diisopropylethylamine (1.42 mL, 8.14 mmol) and bromopropargyl (0.65 g, 5.43 mmol) was added dropwise into the mixture, the mixture was heated to 75 °C and stirred for 18 hours under nitrogen protection. The reaction was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate I. MS m / z (ESI): 223.0 [M+H] + .

[0631] Preparation of intermediate J

[0632] Step 1: To a solution of compound A-8 (1.00 g, 4.30 mmol) and 1,4-dibromobutane (1.10 g, 5.19 mmol) in acetonitrile (10 mL) was added sodium carbonate (912 mg, 8.60 mmol), the reaction was stirred at 80 °C for 16 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound J-2. MS m / z (ESI): 287.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 7.6 Hz, 1H), 4.78 (ddt, J = 50.0, 4.4, 2.0 Hz, 1H), 3.44 (dd, J = 31.2, 8.4 Hz, 1H), 2.56 (t, J = 5.6 Hz, 3H), 2.43 - 2.32 (m, 1H), 2.24 (td, J = 10.2, 7.6, 4.0 Hz, 1H), 1.94 (dt, J = 12.0, 3.2 Hz, 1H), 1.71 - 1.69 (m, 4H), 1.62 - 1.44 (m, 3H), 1.42 - 1.38 (m, 11H).

[0633] Step 2: Compound J-2 (240 mg, 0.84 mmol) was dissolved in hexafluoroisopropanol (5 mL), the mixture was stirred at 80 °C for 48 hours. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate J. MS m / z (ESI): 187.2 [M+H] + .

[0634] Preparation of intermediate K

[0635] Step 1: To a solution of compound A-8 (1.00 g, 4.30 mmol) and paraformaldehyde (0.65 g, 21.65 mmol) in methanol (10 mL) was added sodium cyanoborohydride (1.4 g, 22.28 mmol) and acetic acid (0.04 g, 0.67 mmol), the reaction was stirred at 45 °C for 16 hours. The reaction was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound K-2. MS m / z (ESI): 261.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 7.6 Hz, 1H), 4.93 - 4.72 (m, 1H), 2.18 (s, 6H), 2.05 (td, J = 10.8, 8.4, 4.0 Hz, 1H), 1.78 (dt, J = 12.8, 3.2 Hz, 1H), 1.65 - 1.46 (m, 3H), 1.40 (s, 9H), 1.38 - 1.22 (m, 3H).

[0636] Step 2: Compound K-2 (1.1 g, 4.16 mmol) was dissolved in a solution of hexafluoroisopropanol (10 mL), and the mixture was stirred at 80 °C for 48 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate K.

[0637] Preparation of intermediate L

[0638] Step 1: To a solution of compound A-8 (420 mg, 1.81 mmol) and 1,1- dibromomethylcyclobutane (482 mg, 1.99 mmol) in acetonitrile (6 mL) was added sodium iodide (543 mg, 3.62 mmol) and potassium carbonate (1.2 g, 9.04 mmol), and the reaction was stirred at 80 °C for 48 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound L-2. MS m / z (ESI): 313.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 7.6 Hz, 1H), 4.81 - 4.66 (m, 1H), 3.07 (s, 4H), 2.16 (s, 1H), 2.01 (q, J = 14.8, 11.2 Hz, 5H), 1.80 - 1.67 (m, 3H), 1.56 - 1.46 (m, 2H), 1.39 (s, 9H), 1.36 - 1.10 (m, 2H), 0.99 (dd, J = 11.6, 4.4 Hz, 1H).

[0639] Step 2: Compound L-2 (220 mg, 0.63 mmol) was dissolved in a solution of hexafluoroisopropanol (5 mL), and the mixture was stirred at 80 °C for 48 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate L. MS m / z (ESI): 213.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 7.6 Hz, 1H), 4.81 - 4.66 (m, 1H), 3.07 (s, 4H), 2.16 (s, 1H), 2.01 (q, J = 14.8, 11.2 Hz, 5H), 1.80 - 1.67 (m, 3H), 1.56 - 1.46 (m, 2H), 1.39 (s, 9H), 1.36 - 1.10 (m, 2H), 0.99 (dd, J = 11.6, 4.4 Hz, 1H).

[0640] Preparation of intermediate M

[0641] Step 1: To a solution of lithium aluminum hydride (6.0 g, 158.09 mmol) in tetrahydrofuran (120 mL) was added compound M-1 (8.0 g, 39.56 mmol) at 0 °C, and the reaction was stirred at 25 °C for 16 h. To the reaction was added water (6 mL), 15% sodium hydroxide aqueous solution (6 mL), and water (18 mL) successively at 0 °C. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound M-2. MS m / z (ESI): 147.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 3.73 - 3.66 (m, 4H), 3.56 (s, 4H), 1.55 - 1.47 (m, 4H).

[0642] Step 2: To a solution of compound M-2 (1.3 g, 7.11 mmol) in pyridine (15 mL) was added p-toluenesulfonyl chloride (3.4 g, 17.83 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound M-3. MS m / z (ESI): 323.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.79 (m, 2H), 7.54 - 7.47 (m, 2H), 4.72 (d, J = 1.6 Hz, 1H), 3.93 (d, J = 1.6 Hz, 2H), 3.47 - 3.28 (m, 6H), 2.44 (s, 3H), 1.38 - 1.29 (m, 4H).

[0643] Step 3: To a solution of compound M-3 (600 mg, 1.99 mmol) in dichloromethane (5 mL) was added Dess-Martin oxidizing reagent (1.7 g, 3.98 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound M-4. MS m / z (ESI): 299.0 [M+H] + .

[0644] Step 4: To a solution of compound M-4 (200 mg, 0.41 mmol) in methanol (2 mL) was added compound A-8 (100 mg, 0.43 mmol) and 2 drops of acetic acid, the mixture was stirred at 60 °C for 4 h. The reaction was cooled, 2-methylpyridine borane (89 mg, 0.83 mmol) was added, the mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound M-6. MS m / z (ESI): 343.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.20 - 6.82 (m, 1H), 4.80 (d, J = 50.0 Hz, 1H), 3.73 (t, J = 7.2 Hz, 1H), 3.62 - 3.45 (m, 7H), 2.97 - 2.64 (m, 2H), 2.26 (brs, 1H), 1.91 - 1.51 (m, 7H), 1.42 - 1.44 (m, 10H), 1.24 (d, J = 4.0 Hz, 1H).

[0645] Step 5: Compound M-6 (180 mg, 0.52 mmol) was dissolved in a solution of hexafluoroisopropanol (4 mL), the mixture was stirred at 80 °C for 48 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate M. MS m / z (ESI): 243.2 [M+H] + .

[0646] Preparation of compound 1

[0647] Step 1: A solution of compound 1-1 (5.0 g, 28.9 mmol) in ethyl bromoacetate (25 mL) was stirred at 50 °C for 18 h under nitrogen protection. After the reaction was naturally cooled to room temperature, it was filtered, the filter cake was washed with petroleum ether (20 mL x 2), and the filter cake was concentrated under reduced pressure to give compound 1-2. MS m / z (ESI): 259.1, 261.1 [M+H] + .

[0648] Step 2: A mixture of compound 1-2 (4.1 g, 12.06 mmol) in phosphorus oxychloride (20 mL) was stirred at 105 °C for 3 h under nitrogen. The reaction mixture was concentrated under reduced pressure to give a crude product, which was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (70 mL x 2). The organic phase was washed with saturated brine (70 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound 1-3. MS m / z (ESI): 232.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.55 (dd, J = 6.8, 1.2 Hz, 1H), 8.22 (s, 1H), 7.70 (dd, J = 7.6, 1.2 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H).

[0649] Step 3: To a mixture of compound 1-3 (500 mg, 2.16 mmol) and sodium iodide (1.62 g, 10.80 mmol) in acetonitrile (3 mL) was added hydroiodic acid (2.2 mL) under nitrogen. The reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 12 with 12 M sodium hydroxide and saturated sodium thiosulfate solution (2:1) in an ice bath. The mixture was filtered, and the filter cake was washed with petroleum ether (5 mL x 2). The filter cake was concentrated under reduced pressure to give compound 1-4. MS m / z (ESI): 322.9, 324.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.54 (dd, J = 6.6, 1.2 Hz, 1H), 8.28 (s, 1H), 7.62 (dd, J = 7.2, 1.2 Hz, 1H), 6.87 (dd, J = 7.2, 6.8 Hz, 1H).

[0650] Step 4: To a mixture of compound 1-4 (600 mg, 2.16 mmol) and Shimoyama reagent (631 mg, 2.23 mmol) in acetonitrile (10 mL) was added trimethylsilyl chloride (283 mg, 2.60 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 1-5. MS m / z (ESI): 422.9, 424.9 [M+H] + .

[0651] Step 5: To a solution of compound 1-5 (50 mg, 0.12 mmol) in dimethyl sulfoxide (0.5 mL) was added cuprous iodide (10 mg, 0.05 mmol), tetrakis triphenylphosphine palladium (14 mg, 0.01 mmol) and diisopropyl amine (112 mg, 1.11 mmol). The mixture was purged with nitrogen for 3 times before intermediate C (32 mg, 0.14 mmol) was added. The reaction was stirred at room temperature for 15 min under nitrogen atmosphere. The reaction was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to give compound 1-6. MS m / z (ESI): 519.0, 521.0 [M+H] + .

[0652] Step 6: To a solution of compound 1-6 (30 mg, 0.06 mmol) and intermediate A (19 mg, 0.09 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (56 mg, 0.17 mmol), tris-dibenzylideneacetone palladium (8 mg, 0.01 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (6 mg, 0.01 mmol). The mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL) and then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase HPLC (Waters-SunFire-C18-10 μm-19 x 250 mm, A: 0.1% FA / H2O B: ACN, flow rate: 25 mL / min) to give compound 1. MS m / z (ESI): 653.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br s, 2H), 8.09 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.00 (s, 1H), 5.58 (d, J = 8.8 Hz, 1H), 4.95 (dt, J = 49.6, 2.4 Hz, 1H), 4.60 (br s, 4H), 4.33 (d, J = 6.4 Hz, 2H), 3.27 - 3.22 (m, 4H), 2.26 - 1.04 (m, 6H).

[0653] Preparation of compound 2

[0654] Step 1: To a solution of compound 2-1 (50 g, 268 mmol) and ethyl acrylate (43.8 mL, 403 mmol) in water (500 mL) and dioxane (500 mL) was added DABCO (18.1 g, 161 mmol). The mixture was stirred at 20 °C for 18 h. The reaction mixture was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with saturated aqueous sodium chloride solution (500 mL) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, eluted with petroleum ether / ethyl acetate = 5:1 to give compound 2-2. MS m / z (ESI): 286, 288.0 [M+H] + .

[0655] Step 2: A solution of compound 2-2 (35.0 g, 122 mmol) in acetic anhydride (500 mL) was stirred at 120 °C for 18 h. After the reaction solution was cooled, it was concentrated to give a crude product, which was poured into saturated aqueous NaOH solution (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL) twice. The combined organic phase was washed with saturated aqueous sodium chloride solution (500 mL) and then dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, eluted with petroleum ether / ethyl acetate = 5:1 to give compound 2-3. 1 H NMR (400 MHz, CDCl3) δ 7.92-7.83 (m, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.44 (t, J = 7.2 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0656] Step 3: To a mixture of compound 2-3 (650 mg, 2.42 mmol) and Shimoyama reagent (686 mg, 2.42 mmol) in acetonitrile (7 mL) was added trimethylsilyl chloride (368 mg, 3.39 mmol) under nitrogen protection. The reaction solution was stirred at room temperature for 18 h. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 1) to give compound 2-4. MS m / z (ESI): 367.8, 369.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 0.8 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0657] Step 4: To a solution of compound 2-4 (0.95 g, 2.58 mmol) in methanol (16 mL) and water (4 mL) was added lithium hydroxide (0.43 g, 10.32 mmol). The reaction mixture was stirred at 50 °C for 1 h. The pH value of the reaction mixture was adjusted to 5 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-5. MS m / z (ESI): 339.7, 341.7 [M+H] + .

[0658] Step 5: To a mixture of compound 2-5 (700 mg, 2.06 mmol) and DPPA (1.11 mL, 5.15 mmol) in toluene (10 mL) and tert-butyl alcohol (10 mL) was added triethylamine (1.08 mL, 7.82 mmol) under nitrogen protection. The reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 5 / 1) to give compound 2-6. MS m / z (ESI): 411.0, 413.0 [M+H] + .

[0659] Step 6: To a solution of compound 2-6 (650 mg, 1.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL, 39.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly concentrated to dryness, diluted with saturated aqueous sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 3 / 1) to give compound 2-7. MS m / z (ESI): 310.8, 312.8 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.27 (d, J = 6.8 Hz, 1H), 7.15 (dd, J = 7.2, 0.8 Hz, 1H), 6.49 (t, J = 7.2 Hz, 1H), 6.19 (s, 1H).

[0660] Step 7: To a solution of compound 2-7 (450 mg, 1.45 mmol), p-toluenesulfonic acid (348 mg, 2.02 mmol), copper bromide (32.2 mg, 0.14 mmol), tetrabutylammonium iodide (1.28 g, 3.47 mmol) in acetonitrile (10 mL) was added n-pentyl nitrite (237 mg, 2.02 mmol). The reaction was stirred at 50 °C for 5 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 10 / 1) to give compound 2-8. MS m / z (ESI): 421.8, 423.8 [M+H] + .

[0661] Step 8: To a solution of compound 2-8 (60 mg, 0.14 mmol) and intermediate C (42.2 mg, 0.17 mmol) in dimethyl sulfoxide (1.5 mL) was added cuprous iodide (27.1 mg, 0.14 mmol), Pd(dppf)Cl2(11 mg, 0.01 mmol) and diisopropyl amine (143 mg, 1.42 mmol). The mixture was purged with nitrogen for 3 times. The reaction was stirred at 45 °C for 2 h under nitrogen atmosphere. The reaction was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 2-9. MS m / z (ESI): 517.9, 519.9 [M+H] + .

[0662] Step 9: To a solution of compound 2-9 (25 mg, 0.05 mmol) and Intermediate A (15.5 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (47 mg, 0.14 mmol), tris-dibenzylideneacetone palladium (4.4 mg, 0.01 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (3 mg, 0.01 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL), then dried over sodium sulfate, filtered over filter paper and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase HPLC (Waters-SunFire-C18-10 μm-19*250 mm, A: 0.1% FA / H2O B: ACN, flow rate: 25 mL / min) to give compound 2. Compound 2: MS m / z (ESI): 652.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.05 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.17 (s, 1H), 6.78 - 6.69 (m, 2H), 6.09 (d, J = 7.6 Hz, 1H), 5.92 (t, J = 6.4 Hz, 1H), 5.79 (d, J = 8.4 Hz, 1H), 4.91 (dt, J = 49.8, 2.5 Hz, 1H), 4.57 (brs, 4H), 4.26 (d, J = 6.2 Hz, 2H), 3.58 (dd, J = 29.5, 7.9 Hz, 1H), 3.26 - 3.17 (m, 4H), 2.17 (dd, J = 13.1, 9.5 Hz, 1H), 2.00 (brs, 1H), 1.72 (q, J = 9.3, 8.6 Hz, 3H), 1.31 (dt, J = 43.8, 12.5 Hz, 1H), 1.07 (dd, J = 13.7, 7.0 Hz, 1H).

[0663] Preparation of compound 3

[0664] To a solution of compound 2-9 (25 mg, 0.05 mmol) and intermediate B (19.5 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (47 mg, 0.14 mmol), tris-dibenzylideneacetone palladium (4.4 mg, 0.01 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (3 mg, 0.01 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL), then dried over anhydrous sodium sulfate, filtered through filter paper and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase HPLC (Waters-SunFire-C18-10 μm-19 x 250 mm, A: 0.1% FA / H2O B: ACN, flow rate: 25 mL / min) to give compound 3. Compound 3: MS m / z (ESI): 640.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.17 (s, 1H), 6.74 (t, J = 7.2 Hz, 2H), 6.10 (d, J = 7.8 Hz, 1H), 5.92 (t, J = 6.4 Hz, 1H), 5.83 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 50.6 Hz, 1H), 4.26 (d, J = 6.4 Hz, 2H), 3.65 - 3.45 (m, 5H), 2.55 (brs, 1H), 2.45 (d, J = 4.7 Hz, 4H), 2.10 (brs, 1H), 1.89 - 1.59 (m, 4H), 1.43 (d, J = 9.6 Hz, 1H).

[0665] Preparation of compound 4

[0666] To a solution of compound 1-6 (20 mg, 0.04 mmol) and intermediate B (12.5 mg, 0.06 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (38 mg, 0.12 mmol), tris-dibenzylideneacetone palladium (3.5 mg, 0.01 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (2.4 mg, 0.01 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL), then dried over anhydrous sodium sulfate, filtered through filter paper and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase HPLC (Waters-SunFire-C18-10 μm-19 x 250 mm, A: 0.1% TFA / H2O B: ACN, flow rate: 25 mL / min) to give compound 4. MS m / z (ESI): 641.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.09 (s, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.04 - 5.99 (m, 1H), 5.85 - 5.80 (m, 1H), 5.12 (d, J = 59.6 Hz, 1H), 4.33 (d, J = 5.2 Hz, 2H), 4.05 - 4.01 (m, 2H), 3.72 - 3.67 (m, 1H), 3.51 - 3.46 (m, 2H), 3.21 - 3.11 (m, 2H), 2.61 - 2.53 (m, 1H), 2.49 - 2.41 (m, 2H), 2.22 - 2.16 (m, 1H), 2.03 - 1.97 (m, 1H), 1.87 - 1.62 (m, 2H).

[0667] Preparation of compound 5

[0668] Step 1: To a solution of compound 2-8 (60 mg, 0.14 mmol) and intermediate D (48 mg, 0.21 mmol) in dimethyl sulfoxide (1.5 mL) was added cuprous iodide (27.1 mg, 0.14 mmol), Pd(dppf)Cl2(11 mg, 0.01 mmol) and diisopropyl amine (143 mg, 1.42 mmol). The mixture was purged with nitrogen for 3 times. The reaction was stirred at 45 °C for 2 h under nitrogen atmosphere. The reaction was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 5-1. MS m / z (ESI): 516.9, 518.9 [M+H] + .

[0669] Step 2: To a solution of compound 5-1 (50 mg, 0.10 mmol) and intermediate A (29 mg, 0.14 mmol) in 1,4-dioxane (1.5 mL) was added cesium carbonate (94 mg, 0.18 mmol), tris-dibenzylideneacetone palladium (8.8 mg, 0.02 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (6 mg, 0.02 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 5) to give compound 5-2. MS m / z (ESI): 651.2 [M+H] + .

[0670] Step 3: To a solution of compound 5-2 (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide monohydrate (3.2 mg, 0.08 mmol) in water (0.1 mL). The mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The reaction was poured into water (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 5-3. MS m / z (ESI): 637.2 [M+H] + .

[0671] Step 4: A solution of compound 5-3 (20 mg, 0.03 mmol) and N,N'- carbonyldiimidazole (10 mg, 0.06 mmol) in N,N'-dimethylformamide (1 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere. After the reaction was cooled to room temperature, methylsulfonamide (6 mg, 0.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10 mg, 0.06 mmol) were added, and the mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was diluted with acetonitrile (1 mL), filtered, and purified by reverse-phase HPLC (Waters-SunFire-C18-10 μm-19*250 mm, A: 0.1% TFA / H2O B: ACN, flow rate: 25 mL / min) to give compound 5. MS m / z (ESI): 714.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.20 - 6.05 (m, 2H), 5.83 (d, J = 8.2 Hz, 1H), 4.92 (d, J = 50.2 Hz, 1H), 4.58 (s, 4H), 4.26 (d, J = 6.2 Hz, 2H), 3.60 (m, 1H) 3.23 (d, J = 3.1 Hz, 4H), 2.93 (s, 3H), 2.18 (d, J = 11.5 Hz, 1H), 2.00 (s, 1H), 1.71 (d, J = 8.1 Hz, 3H), 1.42 - 1.27 (m, 1H), 1.07 (br s, 1H).

[0672] Preparation of compound 6

[0673] Compound 6 can be prepared according to the procedure for the preparation of compound 5, for example, by replacing intermediate A in step 2 of the preparation of compound 5 with intermediate B. Compound 6: MS m / z (ESI): 702.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 6.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.44 (s, 1H), 6.11 (d, J = 7.6 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 5.01 (d, J = 50.5 Hz, 1H), 4.29 (d, J = 6.1 Hz, 2H), 3.57 (t, J = 4.5 Hz, 5H), 3.11 (s, 3H), 2.58 (d, J = 12.5 Hz, 1H), 2.47 - 2.40 (m, 4H), 2.11 (s, 1H), 1.91 - 1.61 (m, 4H), 1.44 (q, J = 11.0, 9.9 Hz, 1H).

[0674] Preparation of compound 7

[0675] Compound 7 can be prepared according to the preparation method of compound 5, for example, replacing the methyl sulfonamide in step 4 of the preparation of compound 5 with cyclopropyl sulfonamide to obtain. Compound 7: MS m / z (ESI): 740.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 6.8 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.19 (s, 1H), 7.05 - 7.00 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 6.12 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.4 Hz, 1H), 4.94 (d, J = 50.4 Hz, 1H), 4.60 (s, 4H), 4.30 (d, J = 6.0 Hz, 2H), 3.30 - 3.23 (m, 6H), 3.03 (s, 1H), 2.22 (s, 1H), 2.03 (s, 1H), 1.73 (d, J = 8.4 Hz, 3H), 1.40 - 1.27 (m, 1H), 1.08 (d, J = 11.2 Hz, 1H), 0.99 (d, J = 8.8 Hz, 2H), 0.86 (d, J = 11.2 Hz, 2H).

[0676] Preparation of compound 8

[0677] Compound 8 can be prepared according to the preparation method of compound 5, for example, replacing the methyl sulfonamide in step 4 of the preparation of compound 5 with intermediate E to obtain. Compound 8: MS m / z (ESI): 713.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 7.83 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.37 (s, 1H), 6.10 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 4.92 (d, J = 49.6 Hz, 1H), 4.58 (s, 4H), 4.28 (d, J = 6.4 Hz, 2H), 3.75 - 3.78 (m, 1H), 3.22 (d, J = 3.2 Hz, 7H), 2.18 (s, 1H), 2.01 (s, 1H), 1.78 - 1.66 (m, 3H), 1.32 (dd, J = 57.0, 12.7 Hz, 1H), 1.07 (s, 1H).

[0678] Preparation of compound 9

[0679] Step 1: To a solution of compound 2-8 (60 mg, 0.14 mmol) and intermediate F (40 mg, 0.2 mmol) in dimethyl sulfoxide (1.5 mL) was added cuprous iodide (27.1 mg, 0.14 mmol), Pd(dppf)Cl2(11 mg, 0.01 mmol) and diisopropyl amine (143 mg, 1.42 mmol). The mixture was purged with nitrogen for 3 times. The reaction was stirred at 45 °C for 2 hours under nitrogen atmosphere. The reaction was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 9-1. MS m / z (ESI): 549.9 [M+H] + .

[0680] Step 2: To a solution of compound 9-1 (50 mg, 0.10 mmol) and Intermediate A (29 mg, 0.14 mmol) in 1,4-dioxane (1.5 mL) was added cesium carbonate (94 mg, 0.18 mmol), tris-dibenzylideneacetone palladium (8.8 mg, 0.02 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (6 mg, 0.02 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 5) to give compound 9-2. MS m / z (ESI): 684.1 [M+H] + .

[0681] Step 3: To a solution of compound 9-2 (40 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide monohydrate (6.4 mg, 0.16 mmol) in water (0.1 mL). The mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The reaction was poured into water (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 9-3. MS m / z (ESI): 670.0 [M+H] + .

[0682] Step 4: A solution of compound 9-3 (20 mg, 0.03 mmol) and N,N'-carbonyldiimidazole (10 mg, 0.06 mmol) in N,N'-dimethylformamide (1 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere. After the reaction was cooled to room temperature, methylsulfonamide (6 mg, 0.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10 mg, 0.06 mmol) were added. The mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was diluted with acetonitrile (1 mL) and filtered. The filtrate was purified by reverse phase HPLC preparative (Waters-SunFire-C18-10 μm-19*250 mm, A: 0.1% TFA / H2O B: ACN, flow rate: 25 mL / min) to give compound 9. MS m / z (ESI): 747.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.64 (m, 3H), 7.23 - 7.15 (m, 2H), 6.73 (t, J = 7.2 Hz, 1H), 6.42 (s, 1H), 6.09 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.4 Hz, 1H), 5.05 - 4.78 (m, 1H), 4.57 (s, 4H), 4.29 (d, J = 6.0 Hz, 2H), 3.72 - 3.68 (m, 1H), 3.25 (t, J = 5.6 Hz, 4H), 2.88 (s, 3H), 2.19 (d, J = 11.6 Hz, 1H), 2.01 (s, 1H), 1.73 (d, J = 7.2 Hz, 3H), 1.43 - 1.22 (m, 1H), 1.07 (dd, J = 15.3, 8.2 Hz, 1H).

[0683] Preparation of compound 10

[0684] Step 1: To a solution of compound 2-8 (294 mg, 0.7 mmol) and intermediate G (156 mg, 0.63 mmol) in dimethyl sulfoxide (3 mL) was added cuprous iodide (12 mg, 0.06 mmol), Pd(dppf)Cl2(46 mg, 0.06 mmol) and diisopropyl amine (641 mg, 6.33 mmol). The mixture was purged with nitrogen for 3 times. The reaction was stirred at 45 °C for 2 hours under nitrogen atmosphere. The reaction was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 10-1. MS m / z (ESI): 541.9 [M+H] + .

[0685] Step 2: To a solution of compound 10-1 (260 mg, 0.48 mmol) and Intermediate A (258 mg, 1.20 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (470 mg, 1.44 mmol), tris-dibenzylideneacetone palladium (88 mg, 0.10 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (60 mg, 0.10 mmol). The mixture was stirred at 100 °C for 18 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 10-2. MS m / z (ESI): 674.2 [M+H] + .

[0686] Step 3: To a solution of compound 10-2 (40 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide monohydrate (6.4 mg, 0.16 mmol) in water (0.1 mL). The mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The reaction was poured into water (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 10-3. MS m / z (ESI): 660.0 [M+H] + .

[0687] Step 4: A solution of compound 10-3 (20 mg, 0.03 mmol) and N,N'-carbonyldiimidazole (10 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere. After the reaction was cooled to room temperature, methylsulfonamide (6 mg, 0.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10 mg, 0.06 mmol) were added. The mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After the reaction was cooled to room temperature, it was diluted with acetonitrile (1 mL) and filtered. The filtrate was purified by reverse phase HPLC preparative (Waters-SunFire-C18-10 μm-19*250 mm, A: 0.1% TFA / H2O B: ACN, flow rate: 25 mL / min) to give compound 10. MS m / z (ESI): 737.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.60 (m, 2H), 7.19 (s, 1H), 6.95 - 6.72 (m, 2H), 6.13 - 5.86 (m, 3H), 5.00 - 4.84 (d, J = 64.8 Hz, 1H), 4.60 (brs, 4H), 4.28 - 4.20 (m, 2H), 3.29 - 3.21 (m, 6H), 2.86 (s, 3H), 2.25 - 2.19 (m, 2H), 2.05 (s, 1H), 1.75 (d, J = 7.2 Hz, 3H), 1.27 - 1.22 (m, 1H), 0.73 (d, J = 15.8 Hz, 4H).

[0688] Preparation of compound 11

[0689] Compound 11 can be prepared according to the preparation method of compound 2, for example, by replacing the intermediate C in step 8 of the preparation of compound 2 with intermediate H. Compound 11: MS m / z (ESI): 668.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.60 (m, 2H), 7.19 (s, 1H), 6.95 - 6.72 (m, 2H), 6.13 - 5.86 (m, 3H), 5.00 - 4.84 (d, J = 64.8 Hz, 1H), 4.60 (brs, 4H), 4.28 - 4.20 (m, 2H), 3.29 - 3.21 (m, 6H), 2.86 (s, 3H), 2.25 - 2.19 (m, 2H), 2.05 (s, 1H), 1.75 (d, J = 7.2 Hz, 3H), 1.27 - 1.22 (m, 1H), 0.73 (d, J = 15.8 Hz, 4H).

[0690] Preparation of compound 12

[0691] Compound 12 can be prepared according to the preparation method of compound 5, for example, by replacing the intermediate D in step 1 of the preparation of compound 5 with intermediate I. Compound 12: MS m / z (ESI): 713.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.19 (s, 1H), 6.80 - 6.74 (m, 2H), 6.14 (d, J = 7.6 Hz, 2H), 5.86 (d, J = 8.4 Hz, 1H), 5.03 - 4.91 (d, J = 49.6 Hz, 1H), 4.63 (s, 4H), 4.33 - 4.27 (m, 4H), 3.56 (s, 4H), 3.16 (s, 3H), 2.35 - 2.09 (m, 2H), 1.74 - 1.68 (m, 3H), 1.47 - 1.43 (m, 1H), 1.16 (s, 1H).

[0692] Preparation of compound 13

[0693] Compound 13 can be prepared according to the preparation method of compound 5, for example, replacing intermediate A in step 2 of the preparation of compound 5 with intermediate J to obtain. Compound 13: MS m / z (ESI): 686.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.19 (s, 1H), 6.80 - 6.74 (m, 2H), 6.14 (d, J = 7.6 Hz, 2H), 5.86 (d, J = 8.4 Hz, 1H), 5.03 - 4.91 (d, J = 49.6 Hz, 1H), 4.63 (s, 4H), 4.33 - 4.27 (m, 4H), 3.56 (s, 4H), 3.16 (s, 3H), 2.35 - 2.09 (m, 2H), 1.74 - 1.68 (m, 3H), 1.47 - 1.43 (m, 1H), 1.16 (s, 1H).

[0694] Preparation of compound 14

[0695] Compound 14 can be prepared according to the preparation method of compound 5, for example, replacing intermediate A in step 2 of the preparation of compound 5 with intermediate K to obtain. Compound 14: MS m / z (ESI): 660.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.62 (t, J = 6.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.89 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 50.4 Hz, 1H), 4.32 (d, J = 6.0 Hz, 2H), 3.23 (s, 3H), 2.76 (s, 1H), 2.38 - 2.29 (m, 7H), 2.17 (s, 1H), 1.96 - 1.67 (m, 5H), 1.48 (d, J = 10.8 Hz, 1H).

[0696] Preparation of compound 15

[0697] Compound 15 can be prepared according to the preparation method of compound 5, for example, by replacing intermediate A in step 2 of the preparation of compound 5 with intermediate L. Compound 15: MS m / z (ESI): 712.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.62 (t, J = 6.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.89 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 50.4 Hz, 1H), 4.32 (d, J = 6.0 Hz, 2H), 3.23 (s, 3H), 2.76 (s, 1H), 2.38 - 2.29 (m, 7H), 2.17 (s, 1H), 1.96 - 1.67 (m, 5H), 1.48 (d, J = 10.8 Hz, 1H).

[0698] Preparation of compound 16

[0699] Compound 16 can be prepared according to the preparation method of compound 5, for example, by replacing intermediate A in step 2 of the preparation of compound 5 with intermediate M. Compound 16: MS m / z (ESI): 742.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 6.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.76 (td, J = 7.2, 2.4 Hz, 1H), 6.23 (s, 1H), 6.14 - 6.10 (m, 1H), 5.87 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 50.0 Hz, 1H), 4.29 (d, J = 6.4 Hz, 2H), 3.50 (s, 2H), 2.99 (s, 4H), 2.42 - 2.23 (m, 4H), 1.99 (d, J = 12.8 Hz, 2H), 1.88 - 1.73 (m, 5H), 1.64 (t, J = 5.2 Hz, 3H), 1.43 - 1.09 (m, 4H). Refer to the preparation of Compound A

[0700] Compound A was prepared according to the procedure for the preparation of compound 74d in WO2024017384 (86d is 86b).

[0701] Preparation of Reference Compound B

[0702] Compound B was prepared according to the procedure for the preparation of compound 73d in WO2024017384 (72d is 72b).

[0703] The structure of the control compound is as follows:

[0704] Other compounds of the present application can be prepared by methods analogous to the foregoing Preparation Examples (with appropriate adjustments as necessary).

[0705] Biological tests:

[0706] Experimental Example 1: DNA binding experiment

[0707] To test the aforementioned compounds to increase the binding ability of P53 Y220C protein and DNA, the binding activity of p53 Y220C was measured by homogeneous time-resolved fluorescence (HTRF). Recombinant His-tagged p53 Y220C for HTRF assay was expressed in bacteria E. coli. The recombinant protein is a truncated mutant containing only amino acids 94-312 of p53, with the sequence SSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPCEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVHVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALSNNT. The sense strand of the DNA double strand is 5'-ATTAGGCATGTCTAGGCATGTCTAGG-3', with a biotin tag at 5' for activity assay, and the antisense strand is 5'-CCTAGACATGCCTAGACATGCCTAAT-3'.

[0708] Prepare 40 mL of assay buffer (20 mM Tris HCL, pH 7.5, 50 mM NaCl, 2 mM MgCl2, 0.02% Tween 20, 0.01% BSA, 1 mM DTT). Prepare 10 mM of compounds, 3-fold dilution to get 10 dose gradient dilutions of compounds, add 20 nL of compounds to 384-well assay plate (PerkinElmer 6007299) with Echo 655 Liquid Handler, prepare P53 Y220C protein with assay buffer, final concentration 150 nM, 5 µL per well, incubate at room temperature for 5 min; prepare DNA with assay buffer, final concentration 150 nM, 5 µL per well, incubate at room temperature for 15 min; prepare Anti 6HIS-XL665 (Cisbio 61HISXLB) with assay buffer, final concentration 20 nM, 5 µL per well; prepare Streptavidin-Eu cryptate (Cisbio 610SAKLA) with assay buffer, final concentration 0.625 nM, 5 µL per well, after incubation at 27 degrees Celsius for 1 hour, Envision (PerkinElmer 2105-0020) plate reader reads signal values at 665 nm and 615 nm respectively. Use GraphPad 9.0 to fit the activation rate and compound concentration into a non-linear regression curve (dose response-variable slope) to calculate EC 50 , EC50 The activation rate can be defined as the concentration required for the compound to obtain 50% effect. Activation rate = {(A-C) / (C)}x100%, A = (665nm signal value / 615nm signal value); C = average signal of negative control (wherein the negative control refers to 0.1% DMSO). The test results of some representative compounds are shown in Table 3.

[0709] Table 3 EC of some representative compounds in DNA binding experiment 50

[0710] A = 0 nM < EC 50 <100 nM; B = 100 nM < EC 50 <500 nM.

[0711] The experimental results show that at least some of the compounds of the present application exhibit excellent in vitro activity, which can increase the binding ability of Y220C mutant P53 protein to DNA. Among them, some compounds (such as compounds 1, 2, 4, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16) and reference compound A and reference compound B all have activation activity comparable to or better than the control compound. And some compounds (such as compounds 2, 7, 13, 14) have activation activity comparable to or better than reference compounds A and B.

[0712] Experimental Example 2: NUGC-3 cell proliferation experiment

[0713] In order to detect the effect of the aforementioned compounds on the proliferation ability of NUGC-3 cells, 250 NUGC-3 cells (Nanjing Kebai Biotechnology Co., Ltd., CBP60492) were inoculated into a 384-well plate (Corning 3765) at 35 μL per well and placed in a constant temperature incubator at 37°C, 5% CO2 overnight. Then 40 nL of compound was added to the 384-well plate using Echo 655 Liquid Handler, with a maximum final concentration of 10 μM, 1:3 serial dilution, a total of 10 doses. Incubate at 37°C, 5% CO2 for 6 days. Take the test plate out of the incubator and equilibrate at room temperature for 10 minutes. Add 20 μL of CTG (Promage G7572) to each well of the test plate according to the plate map. Centrifuge the plate at 1000 rpm for 1 minute. Mix for 2 minutes on a shaker to induce cell lysis. Centrifuge the plate at 1000 rpm for 1 minute. Incubate at room temperature for 10 minutes to stabilize the luminescence signal. Record the luminescence value by Envision (PerkinElmer 2105-0020). Using GraphPad 9.0, the inhibition rate activity and compound concentration were fitted into a non-linear regression curve (dose response-variable slope) to calculate GI50 , Inhibition = {1-(A-B) / (C-B)}x100%, A = signal value of compound; B = average signal of blank control; C = average signal of negative control (wherein the negative control is 0.1% DMSO). The test results of some representative compounds are shown in Table 4.

[0714] Table 4 GI of some representative compounds in NUGC-3 cell proliferation experiment 50

[0715] A = 0 nM < GI 50 <100 nM; B = 100 nM < GI 50 <300 nM; C = 300 nM < GI 50 <1000 nM.

[0716] The experimental results show that at least some of the compounds of the present application can significantly inhibit the proliferation of NUGC-3 gastric adenocarcinoma cells containing p53 Y220C mutation. Among them, some compounds (such as compounds 1-16) and reference compound A and reference compound B all have better cell proliferation inhibition activity than the control compounds; among the compounds of the present application, when the fused heteroaromatic ring is (i.e. X1 is N, X2 is C, X3, X4 and X5 are CH, such as compounds 2 and 3), the compound has better cell proliferation inhibition activity (2 times or more) than when the fused heteroaromatic ring is (i.e. X1 and X3 are N, X2 is C, X4 and X5 are CH, such as compounds 1 and 4); when R1 is -SCF3 (such as compounds 2 and 3), the compound has better cell proliferation inhibition activity (2 times or more) than when R1 is -CH2CF3 (such as reference compound A and reference compound B); when R Y is deuterated alkoxy (such as compound 5), the compound has better cell proliferation inhibition activity (more than 1.5 times) than when R1 is other substituents (such as compound 10); when R3 is -CONR 8 SO2R 9 or -L-R4 is -CONR 8 SO2R4, Y1 is N (such as compound 5), the compound has better cell proliferation inhibition activity (more than 2 times) than when Y1 is CH (such as compound 12).

[0717] Experimental Example 3: BxPC-3 cell proliferation experiment

[0718] In order to detect the influence of the aforementioned compounds on the proliferation ability of BxPC-3 cells, 125 BxPC-3 cells ( CRL-1687) were seeded into 384-well plates (Corning 3765) at 35 μL per well and placed in a 37 °C, 5% CO2 incubator overnight. Then 40 nL of compound was added to the 384-well plates using an Echo 655 Liquid Handler at a maximum final concentration of 10 μM in a 1:3 serial dilution for a total of 10 doses. The plates were incubated at 37 °C, 5% CO2 for 6 days. The test plates were removed from the incubator and equilibrated at room temperature for 10 minutes. 20 μL of CTG (Promega G7572) was added to each well of the test plates according to the plate map. The plates were centrifuged at 1000 rpm for 1 minute. The plates were mixed on a shaker for 2 minutes to induce cell lysis. The plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence values were recorded by Envision (PerkinElmer 2105-0020). The GI 50 , Inhibition = {1-(A-B) / (C-B)}x100%, A = compound signal value; B = average signal of blank controls; C = average signal of negative controls (where negative controls are 0.1% DMSO).

[0719] The experimental results show that at least part of the compounds of the present application can significantly inhibit the proliferation of BxPC-3 pancreatic cancer cells containing p53 Y220C mutation.

[0720] Experimental Example 4: Caco-2 cell permeability test

[0721] Caco-2 cells (ATCC, Cat. No. HTB-37) were seeded at 1.25 x 10 5 / cm 2Inoculate onto 96-well plates (Corning HTS Transwell, Cat. No. 3391) and replace the medium (DMEM + 10% FBS + 1% Penicillin-Streptomycin Liquid (100X) + 1% NEAA) every 3-4 days at 37 °C in a 5% CO2 incubator until a confluent cell monolayer is formed after 21-28 days. Before the start of the transport experiment, remove the medium from the cell culture plate and wash the plate twice with pre-warmed HBSS buffer (10 mM HEPES, pH 7.4) and add 100 μL of HBSS buffer per well. After incubation at 37 °C for 30 min, confirm the integrity and tightness of the monolayer by measuring the TEER value with a cell resistance meter (Millicell-ERS2). Discard the HBSS buffer and transfer the upper plate containing the cell monolayer membrane to the corresponding receiving plate. Dilute the 10 mM test compound stock solution to a 10 μM concentration in HBSS buffer containing 0.5% BSA and add to the apical (A side) and basolateral (B side) sides, respectively. Incubate at 37 °C in a 5% CO2, 95% relative humidity atmosphere for 120 min and determine the permeation of the test compound from A to B or B to A and the efflux rate of the compound. Analyze by LC-MS / MS according to the peak area ratio of analyte / internal standard. Calculate the apparent permeability coefficient Papp (cm / s) using the following formula: Papp = (dCr / dt) x Vr / (A x Co)

[0722] where dCr / dt is the function of the cumulative concentration of the compound in the receiving chamber and time; V is the solution volume in the receiving chamber (0.1 mL at the apical side and 0.25 mL at the basolateral side); A is the transport surface area, i.e. the area of the monolayer cell is 0.0804 cm 2 ; Co is the initial concentration of the compound in the donor chamber.

[0723] Calculate the efflux ratio using the following formula: Efflux Ratio = Papp(BA) / Papp(AB)

[0724] Calculate the percentage recovery using the following formula: %Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x Co) %Total Recovery = 100 x [(Vr x Cr) + (Vd x Cd) + (Vc x Cc)] / (Vd x Co)

[0725] Where Vd is the volume of the donor chamber (0.1 mL on the top side and 0.25 mL on the bottom side); C and Cr are the final concentrations of the transported compound in the donor and receiver chambers, respectively. Cc is the concentration of the compound in the cell lysate. Vc is the volume of the insert well (0.1 mL in this experiment).

[0726] The experimental data results show that at least part of the compounds of the present application have good cell permeability and low efflux properties. Among them, when the fused heteroaromatic ring is (i.e., X1 is N, X2 is C, and X3, X4 and X5 are CH), the compound has better cell permeability and lower efflux properties than the fused heteroaromatic ring is (i.e., X1 and X3 are N, X2 is C, and X4 and X5 are CH).

[0727] Experimental Example 5: Hepatic microsomal stability test

[0728] A 10 mM stock solution of the test compound / ketanserin was diluted with acetonitrile to a concentration of 0.5 mM of the test compound / ketanserin. A frozen 100 mM NADPH (MCE, Cat. No. HYF003 / CS-4998) was diluted with a phosphate buffer solution to a concentration of 6 mM; 20 mg / mL HLM (BioIVT, Cat. No. X008067) was diluted with a phosphate buffer solution to a concentration of 0.56 mg / mL, and was added to a 96-well round hole plate, which was shaken uniformly on a shaker at 600 rpm. The above uniformly shaken sample was blown with an electric blower for 3 times, and was aliquoted into a new 96-deep well plate (containing NADPH group (n=2), 0 and 45 min without NADPH group (n=1)), and was divided into 0, 5, 15, 30, and 45 min groups. After the 5 groups of samples were pre-incubated at 37°C for 5 min, the 0 min group was quickly precipitated with ice acetonitrile, and after quick vortex, K-Buffer or NADPH was added by an electric blower. The rest of the groups were added with 6 mM NADPH in the order of 45, 30, 15 and 5 min samples to start the reaction, and the group without NADPH was added with K-Buffer solution. After being mixed uniformly at 1000 rpm in a shaking mixer for 10 s, the reaction was continued to be incubated at 37°C for the corresponding time. Ice acetonitrile was quickly added by an electric blower to terminate the reaction, and after vortexing at 900 rpm for 10 s, it was heat-sealed, shaken on a shaker for 10 min, centrifuged at 4000 rpm for 20 min, and the supernatant was diluted with pure water. The test results are shown in Table 5.

[0729] Table 5

[0730] Wherein, represents that the compound is extremely stable in the liver microsomal experimental system, and almost no metabolic conversion occurs.

[0731] The experimental data results show that at least part of the compounds of the present application have good human, monkey and mouse liver microsomal metabolic stability, for example, compounds 5 and 6 have significantly superior liver microsomal stability compared to the reference compound and the control compound.

[0732] Experimental Example 6: Mouse pharmacokinetic test

[0733] The test animals of the present study were ICR male mice (15-35 g, 5-10 weeks old, Shanghai Xipu-Bike Experimental Animal Co., Ltd.), and the LC-MS / MS method was used to quantitatively determine the drug concentration in the plasma of the mice at different time points after intravenous injection or oral administration of the test compound, in order to evaluate the pharmacokinetic characteristics of the compound in mice. The clear solution of the test compound was injected into the ICR mice through the tail vein (without fasting, solvent: 40% hydroxypropyl-β-cyclodextrin), and was orally administered to the ICR mice (fasted for 10-14 hours, free drinking water, solvent: 0.2% hydroxypropyl cellulose, 0.5% Tween 80). The blood was collected from the submandibular venous plexus at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours after intravenous injection, and was placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed, and centrifuged at 2-8℃ and 6800g for 6 minutes to obtain the plasma; the blood was collected from the submandibular venous plexus at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after oral administration, and was placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed, and centrifuged at 2-8℃ and 6800g for 6 minutes to obtain the plasma. The blood drug concentration was determined by the LC-MS / MS method, and the Phoenix WinNonlin TM Version 7.0 (Pharsight, USA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by non-compartment model linear logarithmic trapezoidal method. The test results of part of the representative compounds are shown in Table 6.

[0734] Table 6 Mouse pharmacokinetic data of part of the representative compounds

[0735] The experimental results data show that at least part of the compounds of the present application have good PK properties (such as CL, Cmax, and / or AUC, etc.), which are comparable to or superior to the control compound.

[0736] Experimental Example 7: In vivo pharmacodynamic study of the compound in the NUGC3 subcutaneous tumor model

[0737] The use and welfare of the experimental animals in this experimental protocol were performed in compliance with the rules of the International Council for Laboratory Animal Evaluation and Accreditation (AAALAC).

[0738] The experimental animals (provided by Jixie Yaoke, Balb / c nude mice 6-8 weeks old) were started to be tested after being raised in the experimental environment for 7 days after arriving at the animal house. The experimental animals were all raised in the specific pathogen free (SPF) barrier animal house. Human gastric cancer NUGC3 tumor cells were cultured in vitro in monolayer in RPMI1640 complete medium (added with a final concentration of 10% fetal bovine serum) at 37°C in a constant temperature incubator containing 5% CO2. The tumor cells were routinely subcultured 2-3 times a week, and the cells in the exponential growth phase were collected and counted for tumor cell inoculation.

[0739] 10×10 6 NUGC3 tumor cells were resuspended in 0.1 mL RPMI1640 and Matrigel mixture and inoculated subcutaneously on the right side of the back of each mouse to establish a subcutaneous tumor model. When the average tumor volume of the tumor-bearing mice grew to about 100mm 3 , the appropriate mice were selected according to the tumor volume and body weight of the mice. The tumor-bearing mice after screening were randomly divided into groups, and the groups were respectively: blank solvent control group, control compound group (50mg / kg), control compound group (100mg / kg), compound 5 group (25mg / kg), compound 5 group (50mg / kg), compound 6 group (25mg / kg) and compound 6 group (50mg / kg). The blank control group was orally administered with solvent (0.2% HPC+0.5% Tween80), and the other groups were orally administered with the corresponding compounds. The administration frequency was once a day, and the administration lasted for 21 days. During the experiment, the tumor volume and animal body weight of each group were monitored every week, and the monitoring frequency was twice a week. The calculation formula of tumor volume (TV) was: TV = 1 / 2×a×b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively.

[0740] The animal body weight was weighed by using an electronic balance, and the relative body weight change rate (RCBW) was: RCBW (%) = (BW t -BW0) / BW0×100%; BW t was the animal body weight at the time of measurement, and BW0 was the animal body weight at the start of grouping.

[0741] The efficacy of the test product was evaluated by tumor growth inhibition rate TGI (%), and the tumor volume was statistically analyzed (Two-way ANOVA). The calculation formula of TGI (%) was: TGI (%) = [1-(T i -T0) / (V iV0)] x 100%, (T i V0 is the tumor volume of the control group at the beginning of the experiment, and V is the tumor volume of the control group at the time of measurement. i V0 is the tumor volume of the control group at the beginning of the experiment, and V is the tumor volume of the control group at the time of measurement). The test results of some compounds are shown in Table 7.

[0742] Table 7

[0743] *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0744] The test results show that at least some of the compounds of the present application exhibit excellent NUGC-3 subcutaneous transplanted tumor proliferation inhibition activity, for example, compounds 5 and 6 can significantly inhibit the growth of human gastric cancer NUGC-3 subcutaneous transplanted tumor, and the therapeutic effect is significantly better than that of the control compound.

[0745] Experimental Example 8: Hepatocyte stability test

[0746] First, the test compound and verapamil are dissolved in an appropriate solvent (such as DMSO) to prepare a 10 mM stock solution, and diluted to a 100 μM working solution. Then, the frozen hepatocytes are thawed using thawing medium (William's E medium supplemented with GlutaMAX), and after centrifugation to remove the supernatant, the cells are resuspended in medium to about 1.5 x 10 6 cells / mL, and the cell viability is ensured to be no less than 75% by AO / PI staining method. After diluting the cells to a working concentration of 0.5 x 10 6 viable cells / mL, 198 μL is aliquoted into a 96-well plate and equilibrated in a 37°C incubator. Then, 2 μL of 100 μM test compound or verapamil working solution is added to each well to start the reaction and sampled at set time points (such as 0.5, 15, 30, 60, 120 and 240 minutes). After sampling, the reaction is terminated by adding an internal standard-containing acetonitrile solution, vortexing, centrifuging, collecting the supernatant and diluting for LC-MS / MS analysis. All samples are repeated. Some of the test results are shown in Table 8.

[0747] Table 8

[0748] The test results show that at least some of the compounds of the present application have good metabolic stability in human, monkey and mouse hepatocytes.

[0749] Experimental Example 9: CYP3A4 enzyme multi-concentration inhibition curve determination

[0750] First, the test compound is prepared into a 10 mM stock solution with DMSO, and is diluted to 0, 0.02, 0.06, 0.2, 0.6, 2 and 6 mM in turn, so that the final concentration in the reaction system is 0, 0.1, 0.3, 1, 3, 10 and 30 μM; at the same time, a corresponding stock solution and working solution of ketoconazole are prepared for the CYP enzyme subtypes, and the final concentration of ketoconazole is 0, 0.0015, 0.005, 0.015, 0.05, 0.15 and 0.5 μM. Second, a substrate solution of CYP subtypes is prepared, and 40 μM testosterone is used for CYP3A4 (with testosterone as the substrate). Then, a 100 mM, pH 7.4 phosphate buffer solution is prepared for standby; a 10 mM NADPH solution is also prepared for standby. The NADPH is dissolved in the above phosphate buffer solution at a concentration of 10 mM. The main mixed solution is prepared in the following proportion: 168.5 μL of the above prepared 100 mM phosphate buffer solution is taken, 0.5 μL of a 20 mg / mL human liver microsomal solution is added, and the final concentration of the liver microsomes is ensured to be 0.05 mg / mL. The specific detection steps include: 169 μL of the main mixed solution is added to a 96 deep-well plate, 1 μL of the test compound or ketoconazole working solution of different concentrations is added, and then pre-warmed in a 37°C water bath for 15 minutes; then 10 μL of the substrate solution (CYP3A4-T needs to add 1 μL of the substrate and 9 μL of K-Mg buffer solution) is added, mixed well, and then 20 μL of 10 mM NADPH solution is added to start the reaction (the final concentration is 1 mM). The reaction is terminated by adding 400 μL of pre-cooled acetonitrile containing 200 nM tolbutamide and glibenclamide after 10 minutes, and centrifuged at 3,220 g for 30 minutes (4°C). Finally, 100 μL of the supernatant is transferred to a new plate, which can be diluted with 100 μL of pure water and mixed well, and then analyzed by UPLC-MS / MS. Part of the test results are shown in Table 9.

[0751] Table 9

[0752] The test results show that the compounds of the present application have no significant inhibitory activity on CYP3A4 enzyme, and some compounds are significantly better than the control compounds and reference compounds, for example, compounds 5 and 6 have no significant inhibitory activity on CYP3A4 enzyme, and the risk of drug interaction is significantly lower than that of the control compounds.

Claims

A compound of Formula A or B, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, wherein: ring A is a 5-membered heteroaromatic ring; one of X1, X2is N and the other is C; X3, X4, X5are each independently selected from N, CR X ; R X each independently selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; with the proviso that: X2, X3are not simultaneously N; X1, X3are simultaneously N, only one of X4, X5is N; R1is selected from OR, SR; R is selected from C 1-6 alkyl, C 1-6 haloalkyl; Z1is selected from CR Z1 R Z2 , O, S(O)2; R Z1 selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl; R Z2 selected from halogen, -N(R')2, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; said 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1- 6alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; wherein said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; or R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; R Z3 is selected from 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; said 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; each R' is independently selected from H, C 1-6 alkyl, 4-7 membered saturated heterocyclyl; said C 1-6 alkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C R" are each independently selected from the group consisting of H, C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; R2is selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 alkoxy; Y1, Y2are each independently selected from N, CH; R Y each independently is selected from H, halogen, -OR Y’ , cyano, C 1-6 alkyl, -CO-C 1-6 alkyl; said C 1-6 alkyl, -CO-C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkoxy; R Y’ selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; n is selected from 0, 1, 2, 3; R3is selected from -CON(R 1 )2, -PO(R 2 )2, -SO2R 3 , -SO(=NR 4 )R 5 , -COOR 6 , halogen, cyano, C 1-6 alkyl, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 , -SO2NR 8 COR 11 ; said C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, 4-7 membered heterocyclyl; R 1 , R 2 each independently is selected from H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, and two R 1 , R 2 each independently is selected from C 3-6 cycloalkyl, 4-7 membered heterocyclyl; each R 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; or two R 1 with the nitrogen atom to which they are attached form a 4-11 membered heterocyclyl; said 4-11 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; or two R 2 with the phosphorus atom to which it is attached forms a 4-11 membered heterocyclyl; said 4-11 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; Optionally, 1 R 2 with the ortho position of -PO(R 2 )2 forms a 5-6 membered heterocyclyl; R 3 selected from H, deuterium, C 1-6 alkyl, -N(R’)2, C 3-6 cycloalkyl, 4-11 membered heterocyclyl; or R 3 and the ortho-positioned R 3 form a 5-6 membered heterocyclyl; R 4 , R 5 each independently is selected from H, deuterium, C 1-6 1-6C-alkyl, cyano, C 3-7 3-6C-cycloalkyl, 4-7C-heterocyclyl; or R 4 , R 5 and the -S=N- to which they are attached form a 4-8C-heterocyclyl; or R 5 and the -SO(=NR 4 )R 5 to which they are attached form a 5-6C-heterocyclyl; R 6 selected from H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl; R 8 , R 10 are each independently selected from H, C 1-6 alkyl; R 9 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; R 11 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -C 1- alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy. The compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, said compound has a structure according to Formula A. The compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, said compound has a structure according to Formula B. The compound according to any one of claims 1-3, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R X each independently selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; Preferably, R X Each is independently selected from H, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy; preferably, R X Each is independently selected from H and halogens; more preferably, R X For H; and / or X3is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, X3is selected from N, CH; more preferably, X3is CH; and / or X4is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R X is selected from H, halogen; preferably, X4is selected from CR X ; preferably, X4is selected from CH, CF; more preferably, X4is selected from CH; and / or X5is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, X5is selected from N, CH, CF; more preferably, X5is CH; and / or group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: More preferably, the group selected from the group consisting of: Further preferably, the group selected from the group consisting of: The compound according to any one of claims 1-4, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R1is selected from OR, SR; Preferably, R1is selected from SR; Preferably, R1is selected from OR; Preferably, R is selected from C 1-3 alkyl, C 1-3 haloalkyl; Preferably, R is selected from methyl, ethyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F; Preferably, R is selected from C 1-3 haloalkyl; Preferably, R is selected from -CF3, -CHF2; Preferably, R1is selected from SR; R is selected from C 1-3 haloalkyl; Preferably, R1is selected from SCF3. The compound according to any one of claims 1-5, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R Z1 selected from H, halogen, hydroxyl, -CN, C 1-3 alkyl; R Z2 -N(R’)2, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; wherein said C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; or R Z1 , R Z2 form a 4-7 membered saturated monocyclic heterocyclyl with the carbon atom to which they are attached; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; and / or each R' is independently selected from H, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl optionally substituted with one or more substituents selected from halogen, C Preferably, in -N(R')2, one R' is selected from H, C 1-3 alkyl, the other R' is selected from 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkoxy; or both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxy, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, -N(R")2. and / or R" are each independently selected from the group consisting of H, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; Preferably, Z1is selected from CR Z1 R Z2 , S(O)2; R is selected from H, halogen; R Z1 R is selected from H, halogen; R Z2 R is selected from -N(R')2, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; or, R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl; said 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from -N(R’)2, two R’ with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; with the proviso that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl has 1, 2, or 3 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 -N(R’)2, both R’ with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; 1-3 alkyl, C 1-3 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 -N(R’)2, both R’ with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from halo, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halo, hydroxyl, -N(R”)2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and each of said heteroatoms is independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from H; R ’ R is selected from H; R 1-3 R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from R is selected from H; R Z1 R is selected from H; R Z2 R is selected from -N(R')2, two R' with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and each of the heteroatoms is independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from -N(R’)2, two R’ with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O); and / or R 8 , R 10 are each independently selected from the group consisting of H, C 1-3 alkyl; Preferably, R 8 , R 10 are each H; and / or R 9 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy; R is selected from the group consisting of hydrogen, C 9 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 cycloalkyl, -C 3-6 alkylene-C 1-3 alkylene-C 3-6 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl; Preferably, R 9 Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl; Preferably, R 9 Selected from C 1-4 Alkyl, C 3-6 Saturated cycloalkyl groups; and / or R 11 selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, -C 1- 3alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy. Preferably, R 11 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl. The compound according to any one of claims 1-6, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R Z1 is selected from H, F, methyl; preferably, R Z1 is selected from H; and / or R Z2 selected from F, -NHCH3, -N(CH3)2, Preferably, R Z2 selected from Preferably, R Z2 selected from -N(CH3)2, Preferably, R Z2 selected from -N(CH3)2, Preferably, R Z2 selected from -N(CH3)2, Preferably, R Z2 selected from Preferably, R Z2 selected from and / or R Z1 , R Z2 and the carbon atom to which they are attached form a 4-7 membered saturated heterocyclyl group, which is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; preferably, the 4-7 membered saturated heterocyclyl group contains 1 or 2 heteroatoms each independently selected from N or O; preferably, the 4-7 membered saturated heterocyclyl group is selected from: * denotes the carbon atom to which R Z1 , R Z2 are attached; R is preferably selected from the group consisting of H, C Z1 , R Z2 and a 4-7 membered saturated monocyclic heterocyclyl ring with and the carbon atoms to which they are attached, which 4-7 membered saturated monocyclic heterocyclyl ring is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; preferably the 4-7 membered saturated monocyclic heterocyclyl ring contains 1 or 2 heteroatoms each independently selected from N or O; preferably the 4-7 membered saturated monocyclic heterocyclyl ring is selected from the group consisting of: * denotes the carbon atom to which R Z1 , R Z2 are attached. The compound according to any one of claims 1-7, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R2is selected from H, halogen, hydroxyl, -CN, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R2is selected from H, halogen; Preferably, R2is selected from halogen (e.g. F); More preferably, R2is selected from H, F; and / or Preferably, R2is selected from H, halogen; group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 Preferably, the group selected from the group consisting of: (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )； Preferably, the group selected from the group consisting of: (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )； Preferably, the group selected from the group consisting of: (For example: )、 (For example: )； Preferably, the group selected from the group consisting of (For example )、 (For example )。 The compound according to any one of claims 1-8, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R Y each independently is selected from H, halogen, -OR Y’ , cyano, C 1-3 alkyl, -CO-C 1-3 alkyl; said C 1-3 alkyl, -CO-C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy; R is preferably selected from the group consisting of H, halogen, -OR Y each independently selected from the group consisting of H, halogen, -OR Y’ , cyano, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen; Preferably, R Y each independently is selected from H, -OR Y’ ; Preferably, R Y selected from -OR Y’ ; Preferably, R Y each independently is selected from H, F, CI, hydroxyl, cyano, methyl, -CD3, -CF3, -CHF2, -CH2F, methoxy, -OCD3, -OCF3, -OCHF2, -OCH2F, -OCH2CN, -OCH2CH2OH, -OCH2CH2F, ethoxy, -OCH2CF3, -OCH2CH2CN, -OCH2CH2OCH3, -O-cyclopropyl, -O-cyclobutyl, -C(O)CH3; Preferably, R Y each independently is selected from -OCH3, -OCD3, -OCF3, -OCHF2, -O-cyclopropyl; Preferably, R Y each independently is selected from -OCD3, -OCF3, -OCHF2, -O-cyclopropyl; Preferably, n is 1, R Y the carbon atom ortho to Y1; and / or R Y’ selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, or hydroxyl groups; Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens (e.g., F); Preferably, R Y’ Selected from C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens (e.g., F); R is selected from C Y’ C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C Preferably, R Y’ Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl groups; Preferably, R Y’ Selected from C 1-3 Haloalkyl, C 1-3 Deuterated alkyl groups; Preferably, R Y’ Selected from C 1-3 Deuterated alkyl groups; Preferably, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CH2OH, -CH2CN, -CH2CF3, -CH2CH2F, -CH2CH2CN, -CH2CH2OCH3, cyclopropyl, cyclobutyl; Preferably, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, -CH2CH2F, cyclopropyl, cyclobutyl; Preferably, R Y’ selected from -CD3, -CHF2, cyclopropyl; Preferably, R Y’ selected from -CD3, cyclopropyl; Preferably, R Y’ is -CD3; and / or one of Y1, Y2 is N, the other is CH; and / or Y1 is N, Y2 is CH; and / or Y1, Y2 are both CH; and / or Y1, Y2 are both N; and / or n is selected from 0, 1; preferably, n is 1. The compound according to any one of claims 1-9, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R 1 , R 2 each independently is selected from H, deuterium, C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl, and no more than one of R 1 , R 2 each is selected from C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl; said C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; or two R 1 with the nitrogen atom attached thereto forms a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; or two R 2 with the phosphorus atom to which it is attached forms a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Optionally, 1 R 2 with the ortho position of -PO(R 2 )2 forms a 5-6 membered heterocyclyl; R is preferably selected from H, C 1 , R 2 is each independently selected from H, C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more deuterium; R 1 , R 2 are each independently selected from the group consisting of H, methyl, -CD3, ethyl, -CH2CF3, -CH2CHF2, -CH2CH2OCH3, isopropyl, cyclopropyl, methoxy, or two R 1 with the nitrogen atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiro heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl is selected from: said 7-11 membered saturated bicyclic spiro heterocyclyl is selected from: optionally 1 R 2 with the ortho position of -PO(R 2 )2 to form a 5-6 membered heterocyclyl; said 5-6 membered heterocyclyl is selected from: and / or R 3 selected from H, deuterium, C 1-3 alkyl, -N(R’)2, C 3-6 saturated cycloalkyl, 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; or R 3 and the ortho-positioned R 3 form a 5-6 membered heterocyclyl; Preferably, R 3 is selected from methyl, ethyl, isopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, or R 3 with the adjacent -SO2R 3 form a 5-6 membered heterocyclyl selected from: and / or R 4 is selected from H, C 1-3 alkyl; R 5 is selected from H, C 1-3 alkyl, C 3-6 saturated cycloalkyl, 4-7 saturated monocyclic membered heterocyclyl; or R 4 , R 5 and the -S=N- to which they are attached form a 4-8 membered monocyclic heterocyclyl; or R 5 is attached to the ortho position of -SO(=NR 4 )R 5 forms a 5-6 membered heterocyclyl; Preferably, R 4 is selected from H, methyl, cyano; R 5 is selected from H, methyl, cyclopropyl; or R 4 , R 5 and the -S=N- to which they are attached form a 4-8 membered monocyclic heterocyclyl selected from the group consisting of: or R 5 with the ortho position of -SO(=NR 4 )R 5 form a 5-6 membered heterocyclyl selected from: and / or R 6 selected from H, deuterium, C 1-3 alkyl, C 3-6 saturated cycloalkyl; Preferably, R 6 is selected from H, methyl, ethyl, cyclopropyl. The compound according to any one of claims 1, 3-10, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, The compounds have a structure according to Formula I, A, X1, X2, Y1, Y2, R1, R2, R3, Z1, R X , R Y , n are as defined in any one of claims 1-7; preferably, ring A is a 5-membered heteroaromatic ring; X1 is N, X2 is C; R X is H or halogen (preferably H); R1 is selected from SR; R is selected from C 1-3 alkyl, C 1-3 haloalkyl (preferably C 1-3 haloalkyl); R2 is selected from H or halogen (preferably halogen, such as F); Z1is selected from CR Z1 R Z2 ; R Z1 selected from H, halogen or C 1-3 alkyl (preferably H); R Z2 -N(R’)2; R ’ selected from C 1-3 alkyl, or, two R' and the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O) (preferably two R' and the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O)); Y1 is selected from CH or N; Y2 is selected from CH or N (preferably CH); n is selected from 0 or 1 (preferably 1); R Y selected from -OR Y’ ; R Y’ selected from C 1-3 alkyl, C 3-6 saturated cycloalkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g. F); preferably C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen (e.g. F); preferably C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 deuterium; preferably C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl; preferably C 1-3 haloalkyl, C 1-3 deuteroalkyl; more preferably C 1-3 deuteroalkyl); R Y the carbon atom vicinal to Y1; R3is selected from -CON(R 1 )2, -PO(R 2 )2, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 (preferably -CON(R 1 )2, -CONR 8 SO2R 9 ; more preferably -CONR 8 SO2R 9 ); two R 1 , 1 R 1 selected from H, another R 1 selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium; each R is independently selected from the group consisting of C 2 independently selected from the group consisting of C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium; R 8 selected from H, C 1-3 alkyl (preferably H); R 9 selected from C 1-4 alkyl, C 3-6 saturated cycloalkyl (preferably C 1-4 alkyl); R 10 selected from H, C 1-3 alkyl (preferably H). The compound according to any one of claims 1, 3-11, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, The compound has a structure shown in Formula II, Y1, Y2, R1, R2, R3, R X , R Y , R Z1 , R Z2 , n are as defined in any one of claims 1-8; Preferably, R X selected from H, halogen; Preferably, R X is H; Preferably, R Z1 is H; Preferably, R Z2 Selected from -N(R')2, 4-7 member saturated monocyclic heterocyclic groups, 7-11 member saturated bicyclic spirocyclic groups, and 5-10 member saturated bicyclic bridged heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group are optionally surrounded by 1, 2, or 3 groups selected from halogen, oxo, hydroxyl, -N(R')2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, or -N(R”)2; More preferably, R Z2 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; 1-3 alkyl, C 1-3 alkoxy optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; More preferably, R Z2 selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, C 1-3 substituents of alkyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; More preferably, R Z2 is selected from -N(R')2; two R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridgedheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; More preferably, R Z2 is selected from -N(R')2; both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy; wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxyl, -N(R")2; with the proviso that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; more preferably, R Z2 is selected from -N(R')2; both R' form, together with the N atom to which they are attached, a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, oxo, C 1-3 alkyl; with the proviso that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; R is selected from H; R Z1 R is selected from H; R Z2 R is selected from -N(R’)2, R ’ R is selected from C 1-3 alkyl, or, two R’ together with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally substituted with 1, 2, 3 substituents selected from halogen (e.g. F), C 1-3 alkyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms, and said heteroatoms are each independently selected from N, O (preferably O); R is selected from H; R Z1 R is selected from H; R Z2 R is selected from H; R ’ R is selected from H; R 1-3 R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from H; R R is selected from R is selected from H; R Z1 R is selected from H; R Z2 R is selected from -N(R’)2, two R’ with the N atom to which they are attached form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O); preferably, R1 is selected from -SCF3, -OCF3; more preferably, R1 is -SCF3; preferably, R2 is selected from H, halogen; preferably, R2 is selected from halogen; more preferably, R2 is selected from F; Preferably, R Y each independently is selected from H, halogen, -OR Y’ ; more preferably, R Y is selected from -OR Y’ ; R is selected from C Y’ alkyl, C 1-6 alkyl, C 3-6 saturated cycloalkyl; said C 1-6 alkyl, C 3-6 saturated cycloalkyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R Y’ Selected from C 1-6 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-6 The alkyl group is optionally substituted by one or more (e.g., 1, 2 or 3) substituents selected from deuterium and halogens (e.g., F); Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens; Preferably, R Y’ Selected from C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens (e.g., F); R is selected from C Y’ C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C Preferably, n is selected from 0, 1, 2; more preferably, n is selected from 1 ; further preferably, R Y in ortho position to Y1or Y2; preferably, at most 1 of Y1, Y2 is N; Preferably, n is 1, R Y at the ortho position of Y1; preferably, Y1 is N, Y2 is CH; preferably, Y1, Y2 are both CH; Preferably, R3is selected from -CON(R 1 )2, -PO(R 2 )2, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 ; Preferably, R3is selected from -CON(R 1 )2, -PO(R 2 )2, -SO2R 3 , -SO(=NR 4 )R 5 ; Preferably, R3is selected from -CON(R 1 )2, -CONR 8 SO2R 9 ; Preferably, R3is selected from -CON(R 1 )2; Preferably, R3is selected from -PO(R 2 )2; Preferably, R3is selected from -CONR 8 SO2R 9 ; Preferably, R3is selected from -CONR 8 SO(=NR 10 )R 9 ; Preferably, R 1 R 2 Each is independently selected from H, deuterium, and C. 1-3 Alkyl, C 3-6 Saturated cycloalkyl groups, 4-7 membered saturated monocyclic heterocyclic groups, and two R groups 1 R 2 At most one of them is selected from C. 3-6 Saturated cycloalkyl groups, 4-7 membered saturated monocyclic heterocyclic groups; the C 1-3 Alkyl, C 3-6 Saturated cycloalkyl groups and 4-7 membered saturated monocyclic heterocyclic groups are optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, cyano, hydroxyl, C. 1-3 Alkyl, C 1-3 Substitution of alkoxy groups; or two R 1 with the nitrogen atom attached thereto forms a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; or two R 2 with the phosphorus atom to which it is attached forms a 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-7 membered monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with 1, 2, 3 substituents selected from halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Optionally, 1 R 2 with the ortho position of -PO(R 2 )2 forms a 5-6 membered heterocyclyl; More preferably, R 1 , R 2 are each independently selected from H, C 1-3 alkyl, C 3-6 saturated cycloalkyl, and two R 1 , R 2 each independently selected from H, C 3-6 saturated cycloalkyl; said C 1-3 alkyl, C 3-6 saturated cycloalkyl are optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen, hydroxy, C 1-3 alkyl, C 1- 3 alkoxy; or two R 1 with the nitrogen atom to which it is attached forms a 4-7 membered monocyclic heterocyclyl; said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3 substituents selected from the group consisting of halogen, C 1-3 substituted with 1, 2, 3 substituents selected from the group consisting of halogen, C or two R 2 with the phosphorus atom to which it is attached forms a 4-7 membered monocyclic heterocyclyl; said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3 substituents selected from the group consisting of halogen, C 1-3 substituted with 1, 2, 3 substituents selected from the group consisting of halogen, C Optionally, 1 R 2 with the ortho position of -PO(R 2 )2 forms a 5-6 membered heterocyclyl; R is independently selected from H, C 1 H, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium; Preferably, two R 1 In the middle, 1 R 1 Selected from H, and another R 1 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more deuterium groups; Preferably, each R 2 Selected independently from C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more deuterium groups; Preferably, R 3 Selected from C 1-3 Alkyl, -N(R')2, C 3-6 Saturated cycloalkyl groups, 4-7 membered saturated monocyclic heterocyclic groups; R' is selected from H, C 1-3 Alkyl; or R 3 With -SO2R 3 Adjacent connections form 5-6 membered heterocyclic groups; Preferably, R 4 Selected from H, C 1-3 Alkyl; R 5 Selected from H, C 1-3 Alkyl, C 3-6 Saturated cycloalkyl groups, 4-7 saturated monocyclic heterocyclic groups; or R 4 R 5 And the -S=N- links connected to them form 4-7 member monocyclic heterocyclic groups; or R 5 With -SO(=NR) 4 )R 5 Adjacent connections form 5-6 membered heterocyclic groups; Preferably, R 8 selected from H, C 1-3 alkyl; Preferably, R 8 is H; Preferably, R 10 selected from H, C 1-3 alkyl; Preferably, R 10 is H; Preferably, R 9 selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl; Preferably, R 9 selected from C 1-4 alkyl, C 3-6 saturated cycloalkyl; Preferably, R 9 selected from C 1-4 alkyl. The compound of claim 12, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, wherein, the compound has a structure shown in formula II-1, (preferably ) wherein Y1, Y2, R1, R2, R3, R’ are as defined in any one of claims 1-12; preferably, R1 is selected from SR; Preferably, R is selected from C 1-6 haloalkyl (e.g. C 1-3 haloalkyl, e.g. CF3); preferably, R2 is selected from H, halogen; preferably, R2 is selected from halogen (such as F); preferably, Y1, Y2 are both CH, or one of Y1, Y2 is selected from CH, the other is selected from N; preferably, Y1, Y2 are both CH; preferably, Y1 is N, Y2 is CH; Preferably, R Y selected from -OR Y’ ; Preferably, R Y’ Selected from C 1-6 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-6 Alkyl, C 3-6 The saturated cycloalkyl group is optionally substituted by one or more substituents selected from deuterium and halogens; Preferably, R Y’ Selected from C 1-6 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-6 The alkyl group is optionally substituted by one or more (e.g., 1, 2 or 3) substituents selected from deuterium and halogens (e.g., F); Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted by one or more (e.g., 1, 2 or 3) substituents selected from deuterium and halogens (e.g., F); Preferably, R Y’ Selected from C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium or halogens (e.g., F); R is selected from C Y’ C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C 1-3 C1-C6 alkyl; said C Preferably, R3is selected from -CON(R 1 )2, -PO(R 2 )2, -CONR 8 SO2R 9 , -CONR 8 SO(=NR 10 )R 9 ; Preferably, R3is selected from -CON(R 1 )2; Preferably, R3is selected from -PO(R 2 )2; Preferably, R3is selected from -CONR 8 SO2R 9 ; Preferably, R3is selected from -CONR 8 SO(=NR 10 )R 9 ; Preferably, when R3is selected from -CON(R 1 )2or -PO(R 2 )2, Y1, Y2are both CH. Preferably, when R3is selected from -CONR 8 SO2R 9 or -CONR 8 SO(=NR 10 )R 9 , Y1is N and Y2is CH. R is independently selected from H, C 1 H, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium; Preferably, 1 R 1 is selected from H, another R 1 is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more deuterium; Preferably, each R 2 Selected independently from C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more deuterium groups; Preferably, R 8 selected from H, C 1-3 alkyl; Preferably, R 8 is H; Preferably, R 10 selected from H, C 1-3 alkyl; Preferably, R 10 is H; Preferably, R 9 selected from C 1-6 alkyl, C 3-6 saturated cycloalkyl; Preferably, R 9 selected from C 1-4 alkyl, C 3-6 saturated cycloalkyl; Preferably, R ’ Selected from C 1-3 Alkyl groups, or two R' groups, together with the N atoms attached to them, form 4-7 nucleotide saturated monocyclic heterocyclic groups or 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic groups; provided that the 4-7 nucleotide saturated monocyclic heterocyclic groups or 7-11 nucleotide saturated bicyclic spirocyclic heterocyclic groups optionally have one or two (preferably one) additional heteroatoms, and each of the heteroatoms is independently selected from N and O (preferably O); preferably, both R’ form a 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl with the N atom to which they are attached; provided that the 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O). The compound according to any one of claims 1, 3-10, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; wherein said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups, 7-11 member saturated bicyclic spirocyclic groups, and 5-10 member saturated bicyclic bridged heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, and -N(R”)2; provided that the 4-7 member saturated monocyclic heterocyclic group, 7-11 member saturated bicyclic spirocyclic group, and 5-10 member saturated bicyclic bridged heterocyclic group have 1, 2, or 3 heteroatoms, and each heteroatom is independently selected from N and O. Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-3 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O. Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic heterocyclic groups; wherein the 4-7 member saturated monocyclic heterocyclic group and the 7-11 member saturated bicyclic spirocyclic heterocyclic group are optionally replaced by one or more elements selected from halogens, C 1-3 Alkyl substituents; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O; Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups and 7-11 member saturated bicyclic spirocyclic groups; the 4-7 member saturated monocyclic heterocyclic group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl substituents; provided that the 4-7 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O; Preferably, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; Preferably, R Z3 Selected from 4-7 membered saturated monocyclic heterocyclic groups; said 4-7 membered saturated monocyclic heterocyclic group is optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; Preferably, R Z3 Selected from 4-7 member saturated monocyclic heterocyclic groups; the 4-7 member saturated monocyclic heterocyclic group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl substituent substitution; provided that the 4-7 member saturated monocyclic heterocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O; Preferably, R Z3 is selected from 4-7 membered saturated monocyclic heterocyclyl; provided that said 4-7 membered saturated monocyclic heterocyclyl has 1 or 2 heteroatoms, and said heteroatoms are each independently selected from N, O; Preferably, R Z3 Selected from 7-11 nucleotide saturated bicyclic spiroheterocyclic groups; the 7-11 nucleotide saturated bicyclic spiroheterocyclic group is optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; Preferably, R Z3 Selected from 7-11 nucleotide saturated bicyclic spiroheterocyclic groups; the 7-11 nucleotide saturated bicyclic spiroheterocyclic group is optionally surrounded by one or more elements selected from halogens, C 1-3 Alkyl substituents; provided that the 7-11 member saturated bicyclic spirocyclic group has one or two heteroatoms, and each heteroatom is independently selected from N or O; Preferably, R Z3 selected from a 7-11 membered saturated bicyclic spiro heterocyclyl; provided that the 7-11 membered saturated bicyclic spiro heterocyclyl has 1 or 2 heteroatoms, and each of the heteroatoms is independently selected from N, O; Preferably, R Z3 through a nitrogen atom to ring B; Preferably, R Z3 selected from Preferably, R Z3 selected from Preferably, R Z3 selected from Preferably, R Z3 selected from Preferably, R Z3 selected from a compound of Formula C or Formula D, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, wherein: Ring A is a 5-membered heteroaromatic ring; and X1, X2, X3, X4, X5are each independently selected from N, CR X ; R X each independently selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; R1 is selected from OR, SR; R is selected from C 1-6 alkyl, C 1-6 haloalkyl; Z2is selected from CR Z4 R Z5 , O, S, NR Z6 ; R Z4 selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl; R Z5 halogen, C 1-6 alkyl, -N(R')2, -OR' 12 , -S(O)R 13 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; R 12 , R 13 each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; or R Z4 , R Z5 form a 4-7 membered heterocyclyl with the carbon atom to which they are attached; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; R Z6 selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; each R' is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, C 1-6 alkoxy; or two R' form, together with the N atom to which they are attached, a 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl, 7-11 membered fused heterocyclyl; said 4-7 membered saturated heterocyclyl, 7-11 membered spiro heterocyclyl, 5-10 membered bridged heterocyclyl, 7-11 membered fused heterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, -N(R")2, cyano, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; each R" is independently selected from H, C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen; Y1, Y2 are each independently selected from N, CH; R Y each independently is selected from H, halogen, -OR Y’ , cyano, C 1-6 alkyl, -CO-C 1-6 alkyl; said C 1-6 alkyl, -CO-C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkoxy; R Y’ selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; n is selected from 0, 1, 2, 3; L is selected from -CONR 8 SO2- R4 , -CONR 8 SO(=NR 10 )- R4 , -SO2NR 8 CO- R4 ; and R4 the terminal end is attached to R4; R 8 , R 10 are each independently selected from H, C 1-6 alkyl; R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -C 1- alkylene-C 3-6 cycloalkyl; said C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy. each R5is independently selected from H, halogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; optionally, 2 R5attached to the same carbon atom form a C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl, wherein the 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; m is selected from 0, 1, 2, 3; R6is selected from C 1-6 alkyl, C 1-6 haloalkyl. The compound according to claim 15, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, the compound is shown as formula C; Preferably, one of X1, X2is N and the other is C; each of X3, X4, X5is independently selected from N, CR X ; Preferably, X2, X3 are not simultaneously N; X1, X3 are simultaneously N, only one of X4, X5 is N. The compound according to claim 15, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, The compound is represented by formula D. The compound according to any one of claims 15-17, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R X each independently selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; Preferably, R X Each is independently selected from H, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkyloxy; more preferably, R X Each is independently selected from H and halogens; preferably, R X For H; and / or X3is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, X3 is selected from N, CH; more preferably, X3 is CH; and / or X4is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R X is selected from H, halogen; more preferably, X4is selected from CR X ; further preferably, X4is selected from CH, CF; preferably, X4 is CH; and / or X5is selected from N, CR X ; R X is selected from H, halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, X5 is selected from N, CH, CF; more preferably, X5 is CH; and / or group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: Preferably, the group selected from the group consisting of: More preferably, the group selected from the group consisting of: Further preferably, the group selected from the group consisting of: The compound according to any one of claims 15-18, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R1 is selected from OR, SR; Preferably, R1 is selected from SR; Preferably, R1 is selected from OR; Preferably, R is selected from C 1-3 alkyl, C 1-3 haloalkyl; Preferably, R is selected from methyl, ethyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F; Preferably, R is selected from C 1-3 haloalkyl; Preferably, R is selected from -CF3, -CHF2; Preferably, R1is selected from SR; R is selected from C 1-3 haloalkyl; and / or R6is selected from C 1-3 alkyl, C 1-3 haloalkyl; Preferably, R6is selected from C 1-3 haloalkyl; Preferably, R6 is selected from -CH2CF3. The compound according to any one of claims 15-19, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, Z2is selected from CR Z4 R Z5 , NR Z6 ; Preferably, R Z4 selected from H, halogen, C 1-3 alkyl (preferably R Z4 is H); R Z5 selected from halogen, C 1-3 alkyl, -N(R’)2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl; or R Z4 , R Z5 form a 4-7 membered heterocyclyl with the carbon atom to which they are attached; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, -N(R")2, cyano, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, -N(R")2; Preferably, R Z4 selected from H, halogen, C 1-3 alkyl; R Z5 selected from halogen, C 1-3 alkyl, -N(R’)2, -OR 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl; or R Z4 , R Z5 and the carbon atom to which they are attached form a 4-7 membered heterocyclyl; said 4-7 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; Preferably, R Z5 Selected from -N(R')2, -OR 12 -S(O)2R 13 C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, 5-10 membered bridged heterocyclic groups, 5-6 membered heteroaryl groups, phenyl; wherein, the C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, 7-11 spirocyclic groups, 5-10 bridged heterocyclic groups, 5-6 heteroaryl groups, phenyl groups optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Alkyl substituent substitution, wherein the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; Preferably, R Z5 is selected from 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; Preferably, R Z5 selected from 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; wherein the 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 substituents of alkyl; Preferably, R Z5 selected from -N(R')2; R is preferably selected from -N(R')2; in 2 R', 1 is selected from H, C Z5 alkyl, and the other is selected from C 1-3 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C R is preferably selected from -N(R')2; in 2 R', 1 is H and the other is selected from C Z5 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C Preferably, R Z5 Selected from -N(R')2; of the two R's, one is H, and the other is selected from C. 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered monocyclic saturated heterocyclic groups; the C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 4-6 saturated heterocyclic groups optionally surrounded by one or more groups selected from halogen, oxo, C 1-3 Substituents of the alkoxy group; or the two R' atoms and the N atom attached to them form a 4-6 member saturated monocyclic heterocyclic group, a 7-11 member saturated bicyclic spirocyclic group, a 5-10 member saturated bicyclic bridged heterocyclic group, or a 7-11 member saturated bicyclic fused heterocyclic group; wherein the 4-6 member saturated monocyclic heterocyclic group, the 7-11 member saturated bicyclic spirocyclic group, the 5-10 member saturated bicyclic bridged heterocyclic group, or the 7-11 member saturated bicyclic fused heterocyclic group is optionally replaced by one or more atoms selected from C 1-3 Alkyl substituents; R is selected from -N(R')2; R' is selected from C Z5 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl being optionally substituted with one or more substituents selected from halogen or C 1-3 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl being optionally substituted with one or more substituents selected from halogen or C 1-3 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl being optionally substituted with one or more substituents selected from halogen or C Preferably, R Z5 Selected from -N(R')2; the two R' atoms and the N atoms attached to them form a 4-6 member saturated monocyclic heterocyclic group or a 7-11 member saturated bicyclic spirocyclic heterocyclic group; the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl substituents; provided that the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group optionally has 1 or 2 (preferably 1) additional heteroatoms, and each of the heteroatoms is independently selected from N or O (preferably O); Preferably, R Z5 is selected from -N(R')2; two R' with the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O); Preferably, said 4-6 membered monocyclic saturated heterocyclyl is selected from Preferably, said 4-6 membered monocyclic saturated heterocyclyl is selected from said 7-11 membered saturated bicyclic spiro heterocyclyl is selected from Preferably, the 7-11 membered saturated bicyclic spiro heterocyclyl group is selected from said 5-10 membered saturated bicyclic heterocyclyl is selected from said 7-11 membered saturated bicyclic fused heterocyclyl is Preferably, R Z6 Selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, 5-10 membered bridged heterocyclic groups; wherein, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, 7-11 spirocyclic groups, and 5-10 bridged heterocyclic groups are optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-3 Alkyl substituent substitution, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, -N(R”)2; R is selected from H, C Z6 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; wherein said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-3 alkoxy; and / or R 12 , R 13 each independently is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; R 12 , R 13 are each independently selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; Preferably, R 12 R 13 Each was independently selected from C 1-3 Alkyl, C 3-6 cycloalkyl; and / or R' are each independently selected from the group consisting of H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl, C and / or R" are each independently selected from the group consisting of H, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen. The compound according to any one of claims 15-20, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, each R5is independently selected from H, halogen, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; optionally, 2 R5attached to the same carbon atom form a C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl, wherein the 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; R5is each independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; optionally, 2 R5attached to the same carbon atom form a C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, wherein said C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl, wherein said 7-10 membered bridged cycloalkyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused cycloalkyl, 7-10 membered fused heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl; R5is each independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; optionally, 2 R5attached to the same carbon atom form a C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl; optionally, 2 R5attached to different carbon atoms are connected to each other such that the ring on which Z2is located forms a 7-10 membered bridged cycloalkyl, 7-10 membered fused cycloalkyl, wherein said 7-10 membered bridged cycloalkyl, 7-10 membered fused cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl; R5is each independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy; Preferably, each R5is independently selected from halogen, C 1-3 alkyl; Preferably, R5 is each independently selected from halogen; and / or selected from the group consisting of: Preferably, selected from the group consisting of: Preferably, selected from the group consisting of: (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 Preferably, selected from the group consisting of (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 Preferably, selected from the group consisting of (For example )、 (For example )、 (For example )、 (For example )、 (For example )、 (For example )； Preferably, selected from the group consisting of: Preferably, selected from the group consisting of: Preferably, selected from the group consisting of (For example )、 (For example )。 The compound according to any one of claims 14-21, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, R Y each independently is selected from H, halogen, -OR Y’ , cyano, C 1-3 alkyl, -CO-C 1-3 alkyl; said C 1-3 alkyl, -CO-C 1-3 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy; R is preferably selected from H, halogen, -OR Y each independently selected from H, halogen, -OR Y’ , cyano, C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen; Preferably, R Y each independently is selected from H, -OR Y’ ; Preferably, R Y selected from -OR Y’ ; Preferably, R Y each independently selected from H, F, CI, hydroxyl, cyano, methyl, -CD3, -CF3, -CHF2, -CH2F, methoxy, -OCD3, -OCF3, -OCHF2, -OCH2F, -OCH2CN, -OCH2CH2OH, -OCH2CH2F, ethoxy, -OCH2CF3, -OCH2CH2CN, -OCH2CH2OCH3, -O-cyclopropyl, -O-cyclobutyl, -C(O)CH3; Preferably, R Y each independently selected from -OCD3, -OCF3, -OCHF2, -O-cyclopropyl; Preferably, n is 1, R Y the carbon atom ortho to Y1; and / or R Y’ selected from H, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy; Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, or hydroxyl groups; Preferably, R Y’ Selected from C 1-3 Alkyl, C 3-6 Saturated cycloalkyl; the C 1-3 The alkyl group is optionally substituted by 1, 2, or 3 substituents selected from deuterium or halogens; R is selected from C Y’ alkyl; said C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 substituents selected from deuterium, halogen; R is selected from C Y’ alkyl; said C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with 1, 2, 3 deuterium; Preferably, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CH2OH, -CH2CN, -CH2CF3, CH2CH2F, -CH2CH2CN, -CH2CH2OCH3, cyclopropyl, cyclobutyl; Preferably, R Y’ is selected from methyl, -CD3, -CF3, -CHF2, -CH2F, ethyl, -CH2CF3, CH2CH2F, cyclopropyl, cyclobutyl; Preferably, R Y’ selected from -CD3, cyclopropyl; and / or one of Y1, Y2 is N, the other is CH; and / or Y1 is N, Y2 is CH; and / or Y1, Y2 are both CH; and / or Y1, Y2 are both N; and / or n is selected from 0, 1; preferably, n is 1; and / or m is selected from 1, 2, 3; preferably, m is selected from 1 or 2; more preferably, m is 1; and / or R6is selected from C 1-3 alkyl, C 1-3 haloalkyl; preferably, R6is selected from C 1-3 haloalkyl; more preferably, R6is selected from -CH2CF3. The compound according to any one of claims 15-22, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, The compound is shown as formula III, The rings A, X1, X2, Y1, Y2, R1, R4, R5, Z2, L, R X R Y The definitions of , n, and m are as described in any of the claims 15-22. The compound according to any one of claims 15-23, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, wherein, The compound is shown as formula IV, Y1, Y2, R1, R4, R5, Z2, L, R Y , n, m are as defined in any one of claims 15-23; Preferably, the compound is as shown in formula V, Preferably, the compound is as shown in formula VI, Preferably, the compound is as shown in formula VII, The terms Y1, Y2, R1, R4, R5, L, and R Y R Z5 The definitions of , n, and m are as described in any of claims 15-23; Preferably, R Z5 Selected from halogens, C 1-6 Alkyl, -N(R')2, -OR 12 -S(O)R 13 -S(O)2R 13 C 3-6 Cycloalkyl, 4-7 membered saturated heterocyclic groups, 7-11 membered spiroheterocyclic groups, 5-10 membered bridged heterocyclic groups, 5-6 membered heteroaryl groups, phenyl; wherein, the C 3-6 Cycloalkyl, 4-7 saturated heterocyclic groups, 7-11 spirocyclic groups, 5-10 bridged heterocyclic groups, 5-6 heteroaryl groups, phenyl groups optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, -N(R”)2, cyano, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R 12 , R 13 each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; R is selected from the group consisting of halogen, C Z5 alkyl, -N(R’)2, -OR 1-3 , -S(O)2R 12 , -S(O)2R 13 , C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl; wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C 1- 3alkyl, C 13 alkoxy; R 12 , R 13 each independently is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl, wherein the C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl; Preferably, R Z5 is selected from -N(R')2, 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C 1-3 alkyl; Preferably, R Z5 is selected from 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl; wherein the 4-7 membered saturated heterocyclyl, 7-11 membered spiroheterocyclyl, 5-10 membered bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl; Preferably, R Z5 selected from 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl; wherein the 4-7 membered monocyclic saturated heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl, 5-10 membered saturated bicyclic bridged heterocyclyl is optionally substituted with one or more substituents selected from halogen, C 1-3 substituents of alkyl; Preferably, R Z5 selected from -N(R')2; R is preferably selected from -N(R')2; in 2 R', 1 is selected from H, C Z5 alkyl, and the other is selected from C 1-3 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C R is preferably selected from -N(R')2; in 2 R', 1 is H and the other is selected from C Z5 alkyl, C 1-3 alkyl, C 3-6 alkyl, C 1-3 alkyl, C 3-6 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C R is preferably selected from -N(R')2; in 2 R', 1 is H and the other is selected from C Z5 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl; said C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered saturated heterocyclyl optionally substituted with one or more substituents selected from halogen, oxo, C 1-3 alkyl, C 1-3 alkyl, C R is selected from -N(R')2; R' is selected from C Z5 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen or C 1-3 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen or C 1-3 alkyl; or two R' form, together with the N atom to which they are attached, a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; said 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl is optionally substituted with one or more substituents selected from halogen or C Preferably, R Z5 Selected from -N(R')2; the two R' atoms and the N atoms attached to them form a 4-6 member saturated monocyclic heterocyclic group or a 7-11 member saturated bicyclic spirocyclic heterocyclic group; the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl substituents; provided that the 4-6 member saturated monocyclic heterocyclic group or the 7-11 member saturated bicyclic spirocyclic heterocyclic group optionally has 1 or 2 (preferably 1) additional heteroatoms, and each of the heteroatoms is independently selected from N or O (preferably O); Preferably, R Z5 is selected from -N(R')2; two R' with the N atom to which they are attached form a 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl; provided that the 4-6 membered saturated monocyclic heterocyclyl, 7-11 membered saturated bicyclic spiroheterocyclyl optionally has 1 or 2 (preferably 1) additional heteroatoms each independently selected from N, O (preferably O); Preferably, L is selected from -CONR 8 SO2-$ R4 , -CONR 8 SO(=NR 10 )- R4 ; R4 and the other end is attached to R4; Preferably, L is selected from -CONR 8 SO2-$ R4 ;$ R4 the terminal end is attached to R4; Preferably, R 8 , R 10 are each independently selected from H, C 1-3 alkyl; Preferably, R 8 , R 10 is selected from H; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 3-6 saturated cycloalkyl. The compound according to any one of claims 1-24, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, wherein, The compound is selected from Table 1 or Table 2. A pharmaceutical composition comprising a compound of any one of claims 1-25, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug of the compound, and optionally a pharmaceutically acceptable excipient. A combination drug comprising: 1) a first drug which is a compound of any one of claims 1-25, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug of the compound; 2) a second drug which is a PD-1 inhibitor or a PD-L1 inhibitor; Preferably, the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, camrelizumab, sintilimab, toripalimab, penpulimab, zimberelimab, Pucotenlimab; Preferably, the PD-L1 inhibitor is selected from atezolizumab, avelumab, durvalumab. Use of a compound of any one of claims 1-25, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystal form, nitroso compound, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug of the compound, or a pharmaceutical composition of claim 26, or a combination drug of claim 27, in the manufacture of a medicament. Preferably, the medicament is for treating and / or preventing a disease; Preferably, the disease is a disease caused by p53 Y220C mutation; Preferably, the disease is selected from cancer; Preferably, the cancer is selected from gastric adenocarcinoma, pancreatic cancer, breast cancer, liver cancer, prostate cancer, cervical cancer, ovarian cancer, oral cancer, esophageal cancer, gastric cancer, colorectal cancer, nasopharyngeal cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), bladder cancer, soft tissue sarcoma, brain tumor, lymphocytic tumor, osteosarcoma, endometrial cancer, head and neck cancer; More preferably, the disease is selected from gastric adenocarcinoma, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, endometrial cancer, head and neck cancer, small cell lung cancer.

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