Compound for recovering p53 mutation function and application thereof

Abstract

The invention relates to a compound capable of recovering a p53 mutation function and application thereof, in particular to a compound as shown in a formula M, or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, a crystal form, nitrogen oxide, a metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope labeled compound or prodrug of the compound. # imgabs0 #

Description

Compounds for restoring p53 mutation function and their applications

[0001] This application claims priority to Chinese patent application CN202210866557.8, filed on July 22, 2022, and Chinese patent application CN202310257457.X, filed on March 6, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to a compound for restoring the p53 mutation function and an application thereof. Background Art

[0003] p53 is a crucial tumor suppressor gene, first described in 1979. When it was first discovered, it was generally believed to be an oncogene. However, with increasing research, p53's function as a tumor suppressor gene has gradually been revealed. Known as the guardian of the genome, p53 plays a critical role in cellular function, maintaining genomic stability during periods of cellular stress.

[0004] p53 encodes the p53 protein, a sequence-specific transcription factor that regulates the expression of genes involved in numerous cellular processes. These target genes primarily function in inducing cell cycle arrest, DNA repair, regulating cellular metabolism, cellular senescence, apoptosis, and, more recently, inducing ferroptosis.

[0005] p53 is mutated more frequently than any other protein in human cancer, with mutations occurring in 50% of cancer patients. p53 mutations are most common in tumors of the ovary (47.8%), colon (43.2%), esophagus (43.1%), head and neck (40.6%), and larynx (40.4%), while p53 mutations are least frequent in tumors of the cervix (5.8%), hematopoietic (12.7%), and endocrine glands (14.6%).

[0006] p53 is considered one of the most difficult targets to target, and currently no effective p53-targeting therapy exists globally. The challenges in developing p53-targeted therapies lie in: 1) Unlike traditional inhibitor development, drugs targeting p53 need to restore, rather than inhibit, the protein's normal activity; 2) p53 point mutations are relatively dispersed; and 3) p53 is not an enzyme, so it has not evolved a hydrophobic pocket for small molecule ligand binding.

[0007] In the p53 Y220C mutant, tyrosine at position 220 is replaced by cysteine. This mutation creates a crack in the protein, making it impossible for the mutant protein to maintain the conformation and function of wild-type p53.

[0008] Therefore, further investigation is needed to determine the compounds that can restore the normal function of the p53 Y220C mutant.

[0009] Summary of the Invention

[0010] Through in-depth research and creative discoveries, the inventors of this application have developed novel compounds that can restore the normal function of the p53 Y220C mutant. These compounds target the small cleft on the protein surface caused by the p53 Y220C mutation, thereby restoring the normal function of the p53 Y220C mutant and exerting its tumor-suppressing effects. These compounds can be used to treat a variety of diseases caused by the p53 Y220C mutation, such as gastric adenocarcinoma and pancreatic cancer.

[0011] To this end, in a first aspect of the present invention, the present invention provides a compound represented by formula M, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound) or prodrug thereof,

[0012] in:

[0013] Ring A is selected from in,# N is the connection point between ring A and NH, $ L1 A ring and L 1 connected junctions;

[0014] Each are each independently a single bond or a double bond;

[0015] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C(=O), N, NH, S;

[0016] Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8Each independently selected from S, N, C, CH, CR d NR d ;

[0017] Each R a 、R d Independently selected from deuterium, C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl are each independently optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, or C3-C7 cycloalkyl;

[0018] Each R b independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano;

[0019] Each R c independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano;

[0020] L 1 Selected from 5-6 membered heteroarylene; wherein, # A For L 1 The connection point with the A ring, $ L2 For L 1 With L 2 connected junctions;

[0021] L 2 Selected from

[0022] L 3 Selected from NH, -NHC(=O)-, -NHC(=O)NH-;

[0023] Ring B is selected from phenyl, 5-10 membered heteroaryl;

[0024] Each R B Independently selected from: hydrogen, deuterium, halogen, cyano, amino, C1-C6 alkyl, R 3 O-、R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkoxy, and phenyl;B for The connection point with the B ring;

[0025] n is selected from 0, 1, 2, 3;

[0026] Each R 3 Independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkyl-C(=O)-; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C6 alkoxy;

[0027] R e 、R f Each is independently selected from hydrogen, deuterium, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, or 4-8 membered heterocyclic group; or, R e 、R f Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring, wherein the 4-8 membered saturated heterocyclic ring or the 7-11 membered spiroheterocyclic ring is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0028] Each R g is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl and C3-C7 cycloalkyl are optionally substituted by substituents selected from deuterium, halogen, hydroxyl, amino, and cyano;

[0029] Each R h is selected from hydrogen, deuterium, amino, C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered saturated heterocyclic group; or R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring;

[0030] R i 、R j are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring;

[0031] R kR is selected from hydrogen, deuterium, C1-C6 alkyl, cyano, C3-C7 cycloalkyl, 4-8 membered heterocyclic group; k’ is selected from hydrogen, deuterium, C1-C6 alkyl, cyano, C3-C7 cycloalkyl; or, R k 、R k’ and -S=N- connected thereto to form a 4-8 membered heterocyclic ring; or R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0032] R l 、R m are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl; or, R l 、R m and the P atoms to which they are connected form a 4-8 membered saturated heterocyclic ring; or R l 、R m One of the The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0033] R 6 is selected from hydrogen, deuterium, hydroxyl, halogen, and cyano;

[0034] R 11 is selected from hydrogen, deuterium, and C1-C6 alkyl;

[0035] Z 2 Selected from N(R 7 )、C(R 8 )2, O, S(O)2;

[0036] R 7 is selected from hydrogen, deuterium, and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0037] Each R 8 independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R pN-; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, 5-10 membered bridged heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; provided that: there is at most 1 R 8 is selected from 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-8 membered heterocyclic group; wherein the 4-8 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0038] R o 、R p are each independently selected from hydrogen, deuterium, C1-C6 alkyl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocyclic ring, a 7-11 membered spiro heterocyclic ring or a 5-10 membered bridged heterocyclic ring; wherein the 4-8 membered heterocyclic ring, the 7-11 membered spiro heterocyclic ring, the 5-10 membered bridged heterocyclic ring are optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0039] The compound of formula M must satisfy conditions 1) and 2) at the same time:

[0040] 1) When ring A is not: When R 0Selected from C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl are each independently optionally substituted with deuterium, halogen, hydroxyl, amino, or cyano, and must meet at least one of the following conditions:

[0041] a)L 1 is selected from 5-6 membered heteroarylene;

[0042] b)L 3 Selected from -NHC(=O)-, -NHC(=O)NH-;

[0043] c) Ring B is R h S(=O)2-substituted, and R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring; or

[0044] B ring is Replace, and R k 、R k’ and the -S=N- to which they are attached form a 4-8 membered heterocyclic ring; or

[0045] B ring is Replace, and R k and The ortho positions of the amines are connected to form a 5-6 membered heterocyclic ring; or

[0046] B ring is Replace, and R l 、R m and the P atoms to which they are connected form a 4-8 membered saturated heterocyclic ring, or R l 、R m One of the The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0047] d)Z 2 Selected from C(R 8 )2, and there is only one R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-, R o 、R pTogether with the N atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiroheterocycle or a 5-10 membered bridged heterocycle; wherein the 7-11 membered spiroheterocyclyl, the 7-11 membered spiroheterocycle, the 5-10 membered bridged heterocyclyl, the 5-10 membered bridged heterocycle, the 4-8 membered saturated heterocycle is optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0048] 2) The compound represented by formula M does not include the following compounds:

[0049] In some embodiments, the condition 2) is: the compound represented by formula M does not include the compounds specifically listed in the aforementioned condition 2), and their enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers, for example:

[0050] In some embodiments, Ring A is selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0051] Preferably, R 0 R is selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0052] More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; R 9 is selected from hydrogen, hydroxyl; R 10 Selected from hydrogen and fluorine.

[0053] Most preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-.

[0054] In some embodiments, Ring A is selected from R0 Has the definitions given herein.

[0055] Preferably, R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl.

[0056] More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0057] Most preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-.

[0058] In some embodiments, Ring A is selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0059] Preferably, R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0060] More preferably, R 9 and R 10 Each is independently selected from hydrogen, hydroxy, and halogen.

[0061] Preferably, ring A is selected from

[0062] R 0 R is selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; 9 is selected from hydrogen, hydroxyl; R 10 Selected from hydrogen and fluorine.

[0063] More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0064] Most preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; R 9 and R 10 For hydrogen.

[0065] In some embodiments, Ring A is selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0066] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0067] More preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; R 9 and R 10 For hydrogen.

[0068] In some embodiments, L 1 Selected from 5-membered heteroarylene.

[0069] Preferably, L 1 Selected from 1,3,4-thiadiazole substituent, 1,2,4-oxadiazole substituent, 1,3,4-oxadiazole substituent, thiazolyl substituent.

[0070] More preferably, L 1 Selected from

[0071] More preferably, L 1 Selected from

[0072] More preferably, L 1 Selected from

[0073] In some embodiments, R 11 Selected from hydrogen, deuterium, and C1-C4 alkyl.

[0074] Preferably, R 11 Selected from hydrogen and methyl.

[0075] In some embodiments, L 3 Selected from NH,# L2 -NHC(=O)-$ B 、# L2 -NHC(=O)NH-$ B ,in,# L2 For L 3With L 2 Connected connection points, $ B For L 3 Connection point to the B ring.

[0076] Preferably, L 3 For NH.

[0077] In some embodiments, R 3 O-、R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl as optional substituent R on ring B B , can only be selected once at most; that is, when the substituent R on the B ring B When there are multiple, R 3 O-、R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl group as optional substituents, they cannot be selected 2 or more times independently.

[0078] In some embodiments, Ring B is selected from phenyl, pyridyl, a 5-membered heteroaryl ring, # L3 For B ring and L 3 Connected connection points.

[0079] Preferably, the B ring is selected from phenyl, pyridyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, furyl.

[0080] More preferably, the B ring is selected from phenyl and pyridyl.

[0081] More preferably, Ring B is selected from thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, furyl.

[0082] Most preferably, the B ring is selected from phenyl.

[0083] In some embodiments, Ring B is selected from phenyl,

[0084] n is 2 or 3, each RB are independently selected from halogen, R 3 O-、R h S(=O)2-, And each R B Not the same.

[0085] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene-, hydroxy-C1-C2 alkylene-, C1-C2 alkoxy-C1-C2 alkylene-, C1-C2 alkyl-C(=O)-.

[0086] Preferably, R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring;

[0087] R k’ Selected from hydrogen, R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0088] R l is selected from C1-C6 alkyl (preferably C1-C3 alkyl), R m and The ortho positions of the two rings are connected to form a 5-6 membered heterocyclic ring.

[0089] Preferably, R 3 O-、R h S(=O)2-, As an optional substituent R on the B ring B , can only be selected once at most.

[0090] Preferably, the B ring is selected from phenyl, n is 2, 1 R B R 3 O-, another R B Selected from R h S(=O)2-,

[0091] More preferably, the B ring is selected from phenyl, n is 2, 1 R B R 3 O-, another R B Selected from R h S(=O)2-,

[0092] More preferably, R 3Selected from hydrogen, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-.

[0093] Most preferably, R 3 Selected from methyl.

[0094] Preferably, the B ring is selected from phenyl, n is 3, 1 R B is hydrogen or fluorine, 1 R B R 3 O-, 1 R B Selected from R h S(=O)2-,

[0095] More preferably, R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-.

[0096] Most preferably, R 3 Selected from methyl.

[0097] In some embodiments, Selected from

[0098] n is selected from 0, 1, 2;

[0099] Z 1 Selected from N, CR 4 ;

[0100] R 1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, C1-C6 alkyl, R 3 O-; wherein the C1-C6 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, and amino;

[0101] R 2 Selected from hydrogen, deuterium, cyano, halogen, C1-C6 alkyl, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group is optionally substituted with 0, 1, 2, or 3 substituents selected from: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkoxy, and phenyl;

[0102] R 4 is selected from hydrogen, deuterium, hydroxyl, halogen, and cyano;

[0103] R 5 is selected from hydrogen, deuterium, R'-NH-C(=O)-, C1-C6 alkyl, 4-8 membered saturated heterocyclyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclyl, C3-C7 cycloalkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C3 alkyl, and phenyl;

[0104] R' is selected from hydrogen, deuterium, and C1-C6 alkyl.

[0105] Preferably, n is selected from 0, 1.

[0106] Preferably, Selected from

[0107] Z 1 Selected from N, CR 4 ;

[0108] R 1 Selected from R 3 O-;

[0109] R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group is optionally substituted with 0, 1, 2, or 3 substituents selected from: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkoxy, and phenyl;

[0110] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl-C(=O)-; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C6 alkoxy;

[0111] R4 is selected from hydrogen and halogen;

[0112] More preferably, Z 1 Selected from N, CR 4 ;

[0113] R 1 Selected from R 3 O-;

[0114] R 2 is selected from cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 4-8 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group; wherein the 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group is optionally substituted by 0, 1, 2, or 3 substituents selected from: halogen, hydroxyl, amino, cyano, and C1-C6 alkoxy;

[0115] R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-.

[0116] R 4 is selected from hydrogen and halogen;

[0117] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl (e.g., oxazolyl, thiazolyl, pyridinyl).

[0118] More preferably, R 1Selected from methoxy; R 2 Selected from CH3NHC(=O)-; Z 1 Selected from CF or CH.

[0119] In some embodiments, Selected from

[0120] Preferably, Selected from

[0121] In some embodiments, R 5 is selected from hydrogen, R'-NH-C(=O)-, C1-C6 alkyl, 4-6 membered saturated heterocyclyl, C3-C6 cycloalkyl, wherein C1-C6 alkyl, 4-6 membered saturated heterocyclyl, C3-C6 cycloalkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen, cyano, C1-C3 alkyl, and phenyl;

[0122] R' is selected from C1-C3 alkyl.

[0123] Preferably, Selected from

[0124] In some embodiments, for

[0125] R 1 Selected from hydroxy, halogen, C1-C2 haloalkyl, R 3 O-;

[0126] Z 1 Selected from N, CR 4 ;

[0127] R 2 is selected from cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 4-8 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0128] R 4 Selected from hydrogen, deuterium, and fluorine.

[0129] Preferably, R 1 Selected from hydroxy, fluorine, trifluoromethyl, R 3 O-;R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-;

[0130] R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0131] R 4 is selected from hydrogen and fluorine;

[0132] More preferably, R 1 selected from methoxy;

[0133] R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl.

[0134] Most preferably, R 1 Selected from methoxy; R 2 Selected from CH3NHC(=O)-; Z 1 Selected from CF or CH.

[0135] In some embodiments, ring B is selected from phenyl, n is 2 or 3, and each R B are independently selected from halogen, R 3 O-、R e R fNC(=O)-;R 3 、R e 、R f Has the definitions given herein.

[0136] Preferably, each R B Not the same.

[0137] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene-, hydroxy-C1-C2 alkylene-, C1-C2 alkoxy-C1-C2 alkylene-, C1-C2 alkyl-C(=O)-.

[0138] More preferably, R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, monofluoromethyl, difluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-.

[0139] Most preferably, R 3 Selected from methyl.

[0140] Preferably, R e 、R f Each is independently selected from hydrogen, deuterium, and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, or a 4-8 membered heterocyclic group.

[0141] More preferably, R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl.

[0142] Most preferably, R e 、R f Each is independently selected from hydrogen and methyl.

[0143] Preferably, n is 2 or 3, each R B are independently selected from fluorine, methoxy, CH3NHC(=O)-, and each R B Not the same.

[0144] More preferably, n is 2, 1 R B is a methoxy group, and the other R B It is CH3NHC(=O)-.

[0145] More preferably, n is 3, R B They are fluorine, methoxy and CH3NHC(=O)- respectively.

[0146] In some embodiments, Selected from

[0147] Preferably, Selected from

[0148] In some embodiments, Z 2 Selected from C(R 8 )2;

[0149] 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-;R o 、R p Together with the N atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiro heterocycle or a 5-10 membered bridged heterocycle; wherein the 7-11 membered spiro heterocyclic group, the 7-11 membered spiro heterocyclic group, the 5-10 membered bridged heterocyclic group, the 5-10 membered bridged heterocyclic group, the 4-8 membered saturated heterocycle is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0150] Preferably, the 7-11 membered spiro heterocyclic group is selected from

[0151] The 5-10 membered bridged heterocyclic group is selected from

[0152] in,# Z2 R 8 With Z 2 The connection point where the 6-membered ring is connected.

[0153] Preferably, 1 R 8is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-;R o 、R p Together with the N atom to which they are commonly attached, they form a 7-11-membered spiroheterocyclic ring or a 5-10-membered bridged heterocyclic ring; wherein the 7-11-membered spiroheterocyclic ring, the 7-11-membered spiroheterocyclic ring, the 5-10-membered bridged heterocyclic ring, and the 5-10-membered bridged heterocyclic ring are optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0154] Preferably, 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, R o R p N-;R o 、R p Together with the N atom to which they are commonly attached, they form a 7-11 membered spiroheterocyclic ring; wherein the 7-11 membered spiroheterocyclic ring and the 7-11 membered spiroheterocyclic ring are optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0155] More preferably, 1 R 8is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, R o R p N-;R o 、R p Together with the N atom to which they are commonly connected, they form a 7-11 membered spiroheterocycle; wherein the 7-11 membered spiroheterocyclic group and the 7-11 membered spiroheterocycle are optionally substituted by substituents selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0156] Preferably, 1 R 8 is hydrogen, and the other R 8 is selected from 5-10 membered bridged heterocyclic groups; R o 、R p Together with the N atom to which they are commonly attached, they form a 5-10 membered bridged heterocycle; wherein the 5-10 membered bridged heterocyclic group and the 5-10 membered bridged heterocycle are optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0157] Preferably, 1 R 8 is hydrogen, and the other R 8 Selected from R o R p N-;R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocyclic ring; wherein the 4-8 membered saturated heterocyclic ring is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0158] Preferably, Selected from Among them, $ A It is the connection point between NH and A ring.

[0159] In some embodiments, Z2 Selected from N(R 7 );R 7 is selected from C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by a substituent selected from hydroxyl, C1-C6 alkoxy, and hydroxyl-substituted C1-C6 alkoxy. 7 is selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups; more preferably, R 7 Selected from methyl,

[0160] In some embodiments, R 6 Selected from hydrogen and fluorine.

[0161] In some embodiments, each R a 、R d Independently selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene.

[0162] In some embodiments, each R b Independently selected from hydrogen, hydroxy, halogen, cyano.

[0163] In some embodiments, each R c Independently selected from hydrogen and halogen.

[0164] In some embodiments, each R a 、R d Independently selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-.

[0165] In some embodiments, each R b Independently selected from hydrogen, hydroxy.

[0166] In some embodiments, each R c Independently selected from hydrogen and fluorine.

[0167] In some embodiments, Selected from

[0168] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from NR 7 , where R 7is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by a substituent selected from halogen, hydroxy and / or C1-C6 alkoxy.

[0169] More preferably, the C1-C6 alkyl group is substituted with a substituent selected from fluorine, hydroxyl and / or C1-C3 alkoxy.

[0170] Preferably, Selected from

[0171] Preferably, Selected from

[0172] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from C(R 8 )2, each R 8 independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, 5-10 membered bridged heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; provided that: there is at most 1 R 8 is selected from 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-8 membered heterocyclic group; wherein the 4-8 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0173] R o 、R p are each independently selected from hydrogen, deuterium, C1-C6 alkyl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy; or, Ro 、R p Together with the N atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiro heterocycle or a 5-10 membered bridged heterocycle; wherein the 4-8 membered heterocycle, the 7-11 membered spiro heterocycle, the 5-10 membered bridged heterocycle is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0174] More preferably, 1 R 8 is hydrogen or halogen, and the other R 8 is selected from halogen, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0175] Preferably, Selected from

[0176] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from C(R 8 )2, 2 R 8 Together with the carbon atom to which they are attached, they form a 4-8 membered heterocyclic group.

[0177] More preferably, 2 R 8 Together with the carbon atom to which they are attached, they form a 4-7 membered heterocyclic group.

[0178] More preferably, 2 R 8 Together with the carbon atom to which they are attached, they form a 4-6 membered heterocyclic group.

[0179] More preferably, 2 R 8 Together with the carbon atom to which they are attached, they form a 5-membered heterocyclic group.

[0180] More preferably, Selected from

[0181] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from C(R 8 )2, 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, R o R p N-;R o 、R p Together with the nitrogen atom to which they are attached, they form a 7-11 membered spiroheterocyclic ring.

[0182] More preferably, another R 8 is selected from 7-9 membered spiro heterocyclic group, R o R p N-;R o 、R p Together with the nitrogen atom to which they are attached, they form a 7-9 membered spiroheterocyclic ring.

[0183] More preferably, Selected from

[0184] More preferably, Selected from

[0185] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from C(R 8 )2, 1 R 8 is hydrogen, and the other R 8 Selected from 5-10 membered heterocyclic group, R o R p N-; among them, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-10 membered bridged heterocyclic ring.

[0186] More preferably, another R 8 is selected from 7-9 membered heterocyclic group, R o R p N-; among them, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 7-9 membered bridged heterocyclic ring.

[0187] More preferably, Selected from

[0188] Preferably, Medium R 6 is selected from hydrogen, fluorine; Z 2 Selected from C(R 8 )2, of which 1 R 8 is hydrogen, and the other R 8 is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic groups are substituted by halogen and / or C1-C6 alkyl.

[0189] More preferably, the 4-7 membered heterocyclic group is substituted by halogen and / or C1-C3 alkyl.

[0190] More preferably, Selected from

[0191] In some embodiments, the compound is represented by formula MI-1 or MI-2:

[0192] Among them, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 、L 1 、L 3 , Ring B, R B ,n,R 6 、R 11 、Z 2 Has the definitions given herein.

[0193] Preferably, L 1 for

[0194] More preferably, L 1 It is a 5-membered heteroarylene group.

[0195] More preferably, L 1 Selected from

[0196] Preferably, Selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0197] More preferably, Selected from R 0 Has the definitions given herein.

[0198] More preferably, Selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0199] More preferably, Selected from

[0200] R 0 R is selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; 9 is selected from hydrogen, hydroxyl; R 10 Selected from hydrogen and fluorine.

[0201] More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0202] Most preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; R 9 and R 10 For hydrogen.

[0203] More preferably, Selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0204] More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; R 9 and R10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0205] More preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; R 9 and R 10 For hydrogen.

[0206] In some embodiments, the compound is represented by formula MI-1-1:

[0207] Among them, L 1 、L 3 , Ring B, R B ,n,R 0 、R 6 、R 11 、Z 2 、R 9 、R 10 Has the definitions given herein.

[0208] In some embodiments, the compound is represented by formula MI-1-1A or MI-1-1B:

[0209] Among them, L 1 、L 3 , Ring B, R B ,n,R 0 、R 6 、R 11 、Z 2 、R 9 、R 10 Has the definitions given herein.

[0210] Preferably, L 1 It is a 5-membered heteroarylene group.

[0211] More preferably, L 1 Selected from

[0212] Preferably, L 1 for

[0213] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0214] Preferably, R 9 is selected from hydrogen, hydroxyl. Most preferably, R9 For hydrogen.

[0215] Preferably, R 10 is selected from hydrogen and fluorine. Most preferably, R 10 For hydrogen.

[0216] Preferably, R 11 Selected from hydrogen and methyl.

[0217] Preferably, L 3 For NH.

[0218] Preferably, Z 2 Selected from N(R 7 )、C(R 8 )2;

[0219] R 7 Selected from hydrogen, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0220] Each R 8 independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, 5-10 membered bridged heterocyclic group is optionally substituted by a substituent selected from halogen, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl; provided that: there is at most one R 8 is selected from 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-8 membered heterocyclic group; wherein the 4-8 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0221] R o 、R pare each independently selected from hydrogen, deuterium, C1-C6 alkyl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiro heterocycle or a 5-10 membered bridged heterocycle; wherein the 4-8 membered heterocycle, the 7-11 membered spiro heterocycle and the 5-10 membered bridged heterocycle are optionally substituted by a substituent selected from halogen, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl and amino-substituted C1-C6 alkyl.

[0222] More preferably, Z 2 Selected from N(R 7 )、C(R 8 )2;

[0223] R 7 Selected from hydrogen, C1-C3 alkyl;

[0224] 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-;R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 7-11-membered spiroheterocyclic ring or a 5-10-membered bridged heterocyclic ring; wherein the 7-11-membered spiroheterocyclic ring, the 7-11-membered spiroheterocyclic ring, the 5-10-membered bridged heterocyclic ring, or the 5-10-membered bridged heterocyclic ring is optionally substituted with a substituent selected from halogen, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, or amino-substituted C1-C6 alkyl; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy.

[0225] Further preferably, the 7-11 membered spiro heterocyclic group is selected from

[0226] The 5-10 membered bridged heterocyclic group is selected from

[0227] in,# Z2 R 8 With Z 2 The connection point where the 6-membered ring is connected.

[0228] More preferably, Selected from

[0229] Among them, $ A It is the connection point between NH and A ring.

[0230] More preferably, Selected from

[0231] More preferably, Selected from

[0232] More preferably, Selected from

[0233] Further preferably, Ring B is selected from phenyl, pyridine, and a 5-membered heteroaryl. More preferably, Ring B is selected from phenyl and pyridine. Most preferably, Ring B is selected from phenyl.

[0234] In some embodiments, the compound is represented by formula MI-1-1-2, MI-1-1-2A, or MI-1-1-2B:

[0235] Among them, R 0 、R 6 、R 9 、R 10 、Z 2 , n have the definitions described herein.

[0236] In some embodiments, the compound is represented by formula MI-1-1-1, MI-1-1-1A, or MI-1-1-1B:

[0237] Among them, R 0 、R 1 、R 2 、R 6 、R 9 、R 10 、R 11 、L 1 、L 3 、Z 2, n have the definitions described herein.

[0238] Preferably, L 1 for

[0239] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0240] Preferably, R 1 Selected from hydrogen, hydroxy, halogen, C1-C2 haloalkyl, R 3 O-;R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene-, hydroxy-C1-C2 alkylene-, C1-C2 alkoxy-C1-C2 alkylene-, C1-C2 alkyl-C(=O)-. More preferably, R 1 is selected from hydrogen, hydroxyl, halogen. Most preferably, R 1 Selected from hydrogen and fluorine.

[0241] Preferably, R 9 is selected from hydrogen, hydroxyl. Most preferably, R 9 For hydrogen.

[0242] Preferably, R 10 is selected from hydrogen and fluorine. Most preferably, R 10 For hydrogen.

[0243] Preferably, R 11 Selected from hydrogen and methyl.

[0244] Preferably, L 3 For NH.

[0245] Preferably, Z 2 Selected from C(R 8 )2;

[0246] Each R 8 independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, 5-10 membered bridged heterocyclic group is optionally substituted by a substituent selected from halogen, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl; provided that: there is at most one R 8 is selected from 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group; or, 2 R 8Together with the carbon atoms to which they are attached, they form a 4-8 membered heterocyclic group; wherein the 4-8 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy;

[0247] R o 、R p are each independently selected from hydrogen, deuterium, C1-C6 alkyl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiro heterocycle or a 5-10 membered bridged heterocycle; wherein the 4-8 membered heterocycle, the 7-11 membered spiro heterocycle and the 5-10 membered bridged heterocycle are optionally substituted by a substituent selected from halogen, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl and amino-substituted C1-C6 alkyl.

[0248] More preferably, Z 2 Selected from C(R 8 )2;

[0249] 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-;R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 7-11-membered spiroheterocyclic ring or a 5-10-membered bridged heterocyclic ring; wherein the 7-11-membered spiroheterocyclic ring, the 7-11-membered spiroheterocyclic ring, the 5-10-membered bridged heterocyclic ring, or the 5-10-membered bridged heterocyclic ring is optionally substituted with a substituent selected from halogen, cyano, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, hydroxyl-substituted C1-C3 alkyl, or amino-substituted C1-C3 alkyl; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy, hydroxy-substituted C1-C3 alkoxy, and amino-substituted C1-C3 alkoxy.

[0250] More preferably, the 7-11 membered spiro heterocyclic group, 7-11 membered spiro heterocyclic ring (ie, another R 8 )

[0251] The 5-10 membered bridged heterocyclic group, the 5-10 membered bridged heterocyclic ring (ie, another R 8 )

[0252] in,# Z2 R 8 With Z 2 The connection point where the 6-membered ring is connected.

[0253] More preferably, Selected from

[0254] Among them, $ A It is the connection point between NH and A ring.

[0255] More preferably, Selected from

[0256] More preferably, Selected from

[0257] More preferably, Selected from

[0258] Preferably, R 2 Selected from R h S(=O)2-,

[0259] R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring;

[0260] R k 、R k’ and -S=N- connected thereto to form a 5-7 membered heterocyclic ring, or R k’ Selected from hydrogen, R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0261] R lis selected from C1-C6 alkyl (preferably C1-C3 alkyl), R m and The ortho positions of the two rings are connected to form a 5-6 membered heterocyclic ring.

[0262] Preferably, L 1 It is a 5-membered heteroarylene group.

[0263] More preferably, L 1 is a 5-membered heteroarylene group; R 1 is selected from halogen, preferably fluorine or chlorine; n is selected from 0 or 1;

[0264] R 2 Selected from R h S(=O)2-,

[0265] R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring;

[0266] R k 、R k’ and -S=N- connected thereto to form a 5-7 membered heterocyclic ring, or R k’ Selected from hydrogen, R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring;

[0267] R l is selected from C1-C6 alkyl (preferably C1-C3 alkyl), R m and The ortho positions of the two rings are connected to form a 5-6 membered heterocyclic ring.

[0268] In some embodiments, the compound is represented by Formula T:

[0269] In formula T, X 3 、X 4 、X 5 、R 6 、R 8 、R 9 、R 10 、R B 、R a As defined in any one of claims 1 to 15, n and p are independently 0, 1, 2 or 3; or

[0270] In formula T, X 3 CH or N, X 4 CH or N, X 5 is CH or N, preferably, X 4 and / or X 3 is N;

[0271] R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 alkoxy, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl, -O-C3-C6 heterocycloalkyl; preferably, R B Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C6 deuterated alkyl;

[0272] R 1-1 、R 1-2 R is independently selected from H, deuterium, C1-C6 alkyl, -O-C1-C6 alkyl, -C1-C3 alkylene-O-C1-C3 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl; preferably H or C1-C6 deuterated alkyl; or R 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from:

[0273] R 1-3 Selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl;

[0274] R 8 Selected from-NR 2-1 R 2-2 , 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged cycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl; R 2-1 、R 2-2 are independently C1-C6 alkyl or 4-7 membered monoheterocyclic alkyl;

[0275] R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl;

[0276] R a are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; preferably, Ra is selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; more preferably, R a is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-;

[0277] R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0278] In some embodiments, in Formula T, R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 heterocycloalkyl;

[0279] R 1-1 、R 1-2 independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, -O-C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, or R 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from:

[0280] R 1-3 Selected from H, C1-C6 alkyl;

[0281] R 8 is selected from 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0282] R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl;

[0283] R a are independently selected from C1-C6 alkyl, C1-C6 haloalkyl; preferably, R a is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, Ra Selected from CF3CH2-;

[0284] R 9 and R 10 are each independently selected from hydrogen and deuterium.

[0285] In some embodiments, in Formula T, R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl; preferably, R 1 Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C6 deuterated alkyl;

[0286] R 1-1 、R 1-2 R is independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl; preferably H or C1-C6 deuterated alkyl; or 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from:

[0287] R 1-3 Selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl;

[0288] R 8 Selected from-NR 2-1 R 2-2 , 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged cycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl; R 2-1 、R 2-2 are independently C1-C6 alkyl or 4-7 membered monoheterocyclic alkyl;

[0289] R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl;

[0290] R aare independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; preferably, R a is selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; more preferably, R a is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-;

[0291] R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0292] In some embodiments, in Formula T,

[0293] R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 heterocycloalkyl;

[0294] R 1-1 、R 1-2 R is independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, -O-C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; or 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from

[0295] R 1-3 Selected from H, C1-C6 alkyl;

[0296] R 8 is selected from 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0297] R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl;

[0298] R aare independently selected from C1-C6 alkyl, C1-C6 haloalkyl; preferably, R a is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-;

[0299] R 9 and R 10 are each independently selected from hydrogen and deuterium.

[0300] In some embodiments, in Formula T,

[0301] R B Independently selected from -CONR 1-1 R 1-2 , -SO2R1-3, -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl; preferably, R B Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C6 deuterated alkyl;

[0302] R 1-1 、R 1-2 R is independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl; preferably H or C1-C6 deuterated alkyl; or 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from

[0303] R 1-3 Selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl;

[0304] R 8 Selected from 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted by halogen.

[0305] Preferably, in formula T,

[0306] R B Independently selected from -CONR 1-1 R1-2 、-SO2R 1-3 , -O-C1-C3 alkyl, -O-C1-C3 deuterated alkyl, -O-C1-C3 haloalkyl, -O-C3-C6 cycloalkyl; preferably, R1 is selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C3 deuterated alkyl;

[0307] R 1-1 、R 1-2 、R 1-3 Independently selected from H, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl; preferably H or C1-C3 deuterated alkyl;

[0308] R 6 Independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl;

[0309] R a Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl;

[0310] R 9 and R 10 are each independently selected from hydrogen and deuterium.

[0311] The formula T is selected from formulas T-1 to T-9:

[0312] In formula T-1 to formula T9, the definitions of the symbols are the same as those in formula T; R 1a and R 1b Define R in the same formula T B , and R 1a and R 1b different;

[0313] Preferably, R 1a Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 ; Further preferably, R 1a Selected from -CONHCD3, -CONHCH3, -SO2CH3, -SO2CD3;

[0314] Preferably, R 0 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl; more preferably, R 0 are independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl; more preferably, R 0is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-;

[0315] Preferably, R 1b is selected from -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 deuterated alkyl, -O-C3-C6 cycloalkyl; further preferably, R 1b Selected from -OCH3, -OCD3, -OCH2F,

[0316] In Formula T, Formula T-1 to Formula T9, preferably, R 8 Selected from

[0317] In Formula T, Formula T-1 to Formula T11, preferably, R 8 Selected from

[0318] In Formula T, Formula T-1 to Formula T11, preferably, R 6 It is selected from halogen, more preferably fluorine.

[0319] In some embodiments, the compound is represented by Formula MII:

[0320] Among them, A ring, L 1 、L 2 、L 3 、R 1 、R k 、R k’ 、R 6 、Z 1 、Z 2 Has the definitions given herein.

[0321] Preferably, R k 、R k’ and -S=N- connected thereto to form a 4-8 membered heterocyclic ring, or R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring.

[0322] Preferably, ring A is selected from

[0323] R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

[0324] More preferably, Ring A is selected from

[0325] More preferably, Ring A is selected from

[0326] Preferably, L 1 Selected from

[0327] Preferably, L 2 Selected from CH2, CH(CH3).

[0328] Preferably, L 3 Selected from NH.

[0329] Preferably, Z 1 Selected from N, CR 4 ; R 4 Selected from hydrogen and halogen.

[0330] More preferably, Z 1 Selected from N, CH, CF.

[0331] Preferably, R 1 Selected from hydrogen, hydroxy, halogen, C1-C4 alkyl, R 3 O-; wherein the C1-C4 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from halogen and hydroxy;

[0332] R 3 Independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkyl-C(=O)-; wherein the C1-C4 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C4 alkoxy.

[0333] More preferably, R 1 Selected from hydrogen, hydroxyl, F, R 3 O-;

[0334] R 3 Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkyl-C(=O)-; wherein the C1-C3 alkyl is optionally substituted by F, hydroxy, cyano, or C1-C3 alkoxy.

[0335] Most preferably, R 1 It is a methoxy group.

[0336] In some embodiments, the compound is represented by formula MII-1, MII-2 or MII-3:

[0337] Among them, X 1 、X 2 、X 3 、X4 、X 5 、X 6 、X 7 、X 8 、X 9 、L 1 、L 2 、L 3 、R 1 、R k’ 、R 6 、Z 1 、Z 2 has the definitions described herein; r is selected from 1, 2, 3 or 4.

[0338] Preferably, Selected from R 0 、R 9 、R 10 Has the definitions given herein.

[0339] More preferably, Selected from

[0340] Preferably, L 1 Selected from

[0341] Preferably, L 2 Selected from CH2, CH(CH3).

[0342] Preferably, L 3 Selected from NH.

[0343] Preferably, Z 1 Selected from N, CR 4 ; R 4 Selected from hydrogen and halogen.

[0344] More preferably, Z 1 Selected from N, CH, CF.

[0345] Preferably, R 1 Selected from hydrogen, hydroxy, halogen, C1-C4 alkyl, R 3 O-; wherein the C1-C4 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from halogen and hydroxy;

[0346] R 3 Independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkyl-C(=O)-; wherein the C1-C4 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C4 alkoxy.

[0347] More preferably, R 1 Selected from hydrogen, hydroxyl, F, R 3 O-;

[0348] R 3 Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkyl-C(=O)-; wherein the C1-C3 alkyl is optionally substituted by F, hydroxy, cyano, or C1-C3 alkoxy.

[0349] Most preferably, R 1 It is a methoxy group.

[0350] Preferably, r is selected from 1, 2 or 3.

[0351] In some embodiments, the compound is represented by formula MII-1-1, MII-1-2, MII-2-1, MII-2-2, MII-3-1 or MII-3-2:

[0352] Among them, L 1 、R 0 、R 9 、R 10 、R 11 、R 1 、R k’ 、R 6 、Z 1 、Z 2 , r have the definitions described herein.

[0353] Preferably, L 1 Selected from

[0354] Preferably, R 11 Selected from hydrogen and methyl.

[0355] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-.

[0356] Preferably, R 9 is selected from hydrogen, hydroxyl. Most preferably, R 9 For hydrogen.

[0357] Preferably, R 10 is selected from hydrogen and fluorine. Most preferably, R 10 For hydrogen.

[0358] Preferably, Z 1 Selected from N, CR 4 ; R 4 Selected from hydrogen and halogen.

[0359] More preferably, Z1 Selected from N, CH, CF.

[0360] Most preferably, Z 1 Selected from CH.

[0361] Preferably, R 1 Selected from hydrogen, hydroxy, halogen, C1-C4 alkyl, R 3 O-; wherein the C1-C4 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from halogen and hydroxy;

[0362] R 3 Independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkyl-C(=O)-; wherein the C1-C4 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C4 alkoxy.

[0363] More preferably, R 1 Selected from hydrogen, hydroxyl, F, R 3 O-;

[0364] R 3 Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkyl-C(=O)-; wherein the C1-C3 alkyl is optionally substituted by F, hydroxy, cyano, or C1-C3 alkoxy.

[0365] Most preferably, R 1 It is a methoxy group.

[0366] Preferably, r is selected from 1, 2 or 3.

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

[0368] In another aspect, the present invention provides a compound of formula O, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound.

[0369] in:

[0370] Ring A is selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0371] Each are each independently a single bond or a double bond;

[0372] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[0373] a)X 4 and X 5 Any one of them is N,

[0374] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[0375] Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 Each independently selected from S, N, C, CH, CR d NR d , and the following conditions c) or d) are met:

[0376] c)Y 4 and Y 5 Any one of them is N,

[0377] d)Y 4 and Y 5When both are not N, Y 6 、Y 7 Any one of them is S;

[0378] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, C3-C6 cycloalkyl, C3-C6 halocycloalkyl;

[0379] Preferably, R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0380] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0381] More preferably, R a Selected from

[0382] Most preferably, R a for

[0383] R b is selected from hydrogen, hydroxy, halogen, and cyano;

[0384] Preferably, R b Selected from hydrogen, hydroxyl;

[0385] Preferably, R b is hydrogen;

[0386] R c is selected from hydrogen, hydroxy, halogen, and cyano;

[0387] Preferably, R c is selected from hydrogen and halogen;

[0388] Preferably, R c is selected from hydrogen and fluorine;

[0389] More preferably, R c is hydrogen;

[0390] R d Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, C3-C6 cycloalkyl, C3-C6 halocycloalkyl

[0391] Preferably, R d Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0392] Preferably, R dSelected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0393] More preferably, R d Selected from

[0394] Most preferably, R d for

[0395] Preferably, ring A is selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0396] More preferably, Ring A is Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0397] Ring B is selected from

[0398] Preferably, Ring B is

[0399] L 1 Selected from 5-6 membered heteroarylene;

[0400] Preferably, L 1 Selected from 5-membered heteroarylene;

[0401] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[0402] More preferably, L 1 Selected from The left site is connected to the A ring, and the right site is connected to the L ring. 2 connected;

[0403] Most preferably, L 1 for

[0404] L 2 Selected from

[0405] Z 1 Selected from N, CR 4 ;

[0406] Z 2 Selected from

[0407] Preferably, Z 2 Selected from

[0408] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, C3-C6 cycloalkyl, C3-C6 halocycloalkyl;

[0409] Preferably, R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0410] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0411] More preferably, R 0 Selected from

[0412] Most preferably, R 0 for

[0413] R 1 Selected from C1-C6 alkyl, C1-C6 haloalkyl, R 3 O-;

[0414] Preferably, R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0415] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0416] More preferably, R 1 Selected from F3C-, R 3 O-;

[0417] Most preferably, R 1 Selected from R 3 O-;

[0418] R 2 is selected from cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 4-8 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R iR j NS(=O)2-, 5-6 membered heteroaryl;

[0419] Preferably, R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0420] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0421] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0422] R e 、R f are independently selected from hydrogen, C1-C6 alkyl, cyano-C1-C6 alkylene, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 1-3 hydroxy groups; or, R e 、R fTogether with the nitrogen atom to which they are attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring;

[0423] Preferably, R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0424] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0425] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0426] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[0427] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0428] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0429] R g Selected from hydrogen, C1-C6 alkyl, cyano-C1-C6 alkylene, C1-C6 haloalkyl, hydroxy-C1-C6 alkylene, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, hydroxy-C3-C6 cycloalkylene;

[0430] Preferably, R g Selected from hydrogen, C1-C6 alkyl;

[0431] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0432] More preferably, R gis selected from hydrogen, methyl, and ethyl;

[0433] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0434] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0435] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0436] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring;

[0437] Preferably, R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0438] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0439] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0440] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0441] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0442] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[0443] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0444] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[0445] R k Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0446] R l 、R m are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; or, R l 、R m and the P atoms to which they are attached form a 4-6 membered heterocyclic ring;

[0447] Preferably, R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0448] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0449] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[0450] Most preferably, R k 、R l 、R m is methyl;

[0451] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0452] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0453] Preferably, R 3Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0454] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[0455] Most preferably, R 3 is methyl;

[0456] R 4 is selected from hydrogen, hydroxy, halogen, and cyano;

[0457] Preferably, R 4 is selected from hydrogen and halogen;

[0458] Preferably, R 4 is selected from hydrogen and fluorine;

[0459] More preferably, R 4 is hydrogen;

[0460] R 5 selected from R'-NH-C(=O)-;

[0461] R' is selected from C1-C6 alkyl;

[0462] Preferably, R 5 Selected from

[0463] R 6 is selected from hydrogen, hydroxy, halogen, and cyano;

[0464] Preferably, R 6 is selected from hydrogen and halogen;

[0465] Preferably, R 6 is selected from hydrogen and fluorine;

[0466] More preferably, R 6 For fluorine;

[0467] R 7 Selected from hydrogen, C1-C6 alkyl, cyano, cyano-C1-C6 alkylene, C1-C6 haloalkyl, C1-C6 alkyl substituted by 1-3 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0468] Preferably, R 7Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0469] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0470] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0471] More preferably, R 7 Selected from methyl,

[0472] Most preferably, R 7 is methyl;

[0473] R 8 Selected from R o R p N-;

[0474] R o 、R p Each is independently selected from hydrogen, cyano-C1-C6 alkylene, C1-C6 haloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-7 membered saturated heterocyclic ring, a 7-11 membered spiroheterocyclic ring or a 7-11 membered bridged heterocyclic ring;

[0475] Preferably, R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[0476] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0477] More preferably, R ois selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[0478] Most preferably, R o is methyl, R p Selected from methyl,

[0479] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[0480] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[0481] Preferably, R 8 Selected from

[0482] R 9 is selected from hydrogen, hydroxy, halogen, and cyano;

[0483] Preferably, R 9 Selected from hydrogen, hydroxyl;

[0484] Preferably, R 9 is hydrogen;

[0485] R 10 is selected from hydrogen, hydroxy, halogen, and cyano;

[0486] Preferably, R 10 is selected from hydrogen and halogen;

[0487] Preferably, R 10 is selected from hydrogen and fluorine;

[0488] More preferably, R 10 is hydrogen;

[0489] R 11 Selected from hydrogen, C1-C6 alkyl;

[0490] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0491] More preferably, R 11 is selected from hydrogen, methyl;

[0492] Most preferably, R 11 For hydrogen.

[0493] In the third aspect of the present invention, the present invention provides a compound of formula I, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0494] in:

[0495] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0496] Each are each independently a single bond or a double bond;

[0497] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[0498] a)X 4 and X 5 Any one of them is N,

[0499] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[0500] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0501] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0502] More preferably, R a Selected from

[0503] Most preferably, R a for

[0504] R bSelected from hydrogen, hydroxyl;

[0505] Preferably, R b is hydrogen;

[0506] R c is selected from hydrogen and halogen;

[0507] Preferably, R c is selected from hydrogen and fluorine;

[0508] More preferably, R c is hydrogen;

[0509] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0510] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[0511] Ring B is selected from

[0512] Preferably, Ring B is

[0513] L 1 Selected from 5-6 membered heteroarylene;

[0514] Preferably, L 1 Selected from 5-membered heteroarylene;

[0515] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[0516] More preferably, L 1 Selected from Among them, the site on the left is related to A 1 The ring is connected, and the site on the right is connected to L 2 connected;

[0517] Most preferably, L 1 for

[0518] L 2 Selected from

[0519] Z2 Selected from

[0520] Z 1 Selected from N, CR 4 ;

[0521] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0522] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0523] More preferably, R 0 Selected from

[0524] Most preferably, R 0 for

[0525] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0526] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0527] More preferably, R 1 Selected from F3C-, R 3 O-;

[0528] Most preferably, R 1 Selected from R 3 O-;

[0529] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0530] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, Re R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0531] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0532] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0533] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0534] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0535] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[0536] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0537] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0538] R g Selected from hydrogen, C1-C6 alkyl;

[0539] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0540] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[0541] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0542] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0543] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0544] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0545] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0546] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0547] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0548] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0549] Most preferably, R i is selected from hydrogen, methyl, Rj Selected from hydrogen, methyl,

[0550] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0551] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[0552] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0553] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0554] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[0555] Most preferably, R k 、R l 、R m is methyl;

[0556] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0557] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0558] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0559] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[0560] Most preferably, R 3 is methyl;

[0561] R 4 is selected from hydrogen and halogen;

[0562] Preferably, R 4 is selected from hydrogen and fluorine;

[0563] More preferably, R 4 is hydrogen;

[0564] R 5 selected from R'-NH-C(=O)-;

[0565] R' is selected from C1-C6 alkyl;

[0566] Preferably, R 5 Selected from

[0567] R 6 is selected from hydrogen and halogen;

[0568] Preferably, R 6 is selected from hydrogen and fluorine;

[0569] More preferably, R 6 For fluorine;

[0570] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0571] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0572] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0573] More preferably, R 7 Selected from methyl,

[0574] Most preferably, R 7 is methyl;

[0575] R 8 Selected from R o R p N-;

[0576] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[0577] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0578] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[0579] Most preferably, R o is methyl, R p Selected from methyl,

[0580] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[0581] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[0582] Preferably, R 8 Selected from

[0583] R 9 Selected from hydrogen, hydroxyl;

[0584] Preferably, R 9 is hydrogen;

[0585] R 10 is selected from hydrogen and halogen;

[0586] Preferably, R 10 is selected from hydrogen and fluorine;

[0587] More preferably, R 10 is hydrogen;

[0588] R 11 Selected from hydrogen, C1-C6 alkyl;

[0589] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0590] More preferably, R 11 is selected from hydrogen, methyl;

[0591] Most preferably, R 11 For hydrogen.

[0592] In a fourth aspect of the present invention, the present invention provides a compound represented by formula I-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0593] in:

[0594] L 1 Selected from 5-6 membered heteroarylene;

[0595] Preferably, L 1 Selected from 5-membered heteroarylene;

[0596] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[0597] More preferably, L 1 Selected from Among them, the site on the left is connected to the imidazole ring, and the site on the right is connected to L 2 connected;

[0598] Most preferably, L 1 for

[0599] L 2 Selected from

[0600] Z 2 Selected from

[0601] Z 1 Selected from N, CR 4 ;

[0602] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0603] Preferably, R 0Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0604] More preferably, R 0 Selected from

[0605] Most preferably, R 0 for

[0606] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0607] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0608] More preferably, R 1 Selected from F3C-, R 3 O-;

[0609] Most preferably, R 1 Selected from R 3 O-;

[0610] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0611] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0612] More preferably, R 2is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0613] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0614] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0615] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0616] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[0617] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0618] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0619] R g Selected from hydrogen, C1-C6 alkyl;

[0620] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0621] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[0622] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0623] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0624] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0625] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0626] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0627] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0628] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0629] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0630] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[0631] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0632] Or more preferably, R i 、R jTogether with the N atoms they are connected to, they form

[0633] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0634] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0635] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[0636] Most preferably, R k 、R l 、R m is methyl;

[0637] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0638] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0639] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0640] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[0641] Most preferably, R 3 is methyl;

[0642] R 4 is selected from hydrogen and halogen;

[0643] Preferably, R 4 is selected from hydrogen and fluorine;

[0644] More preferably, R 4 is hydrogen;

[0645] R 6 is selected from hydrogen and halogen;

[0646] Preferably, R 6 is selected from hydrogen and fluorine;

[0647] More preferably, R 6 For fluorine;

[0648] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0649] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0650] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0651] More preferably, R 7 Selected from methyl,

[0652] Most preferably, R 7 is methyl;

[0653] R 8 Selected from R o R p N-;

[0654] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[0655] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0656] More preferably, R o is selected from C1-C4 alkyl, R pSelected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[0657] Most preferably, R o is methyl, R p Selected from methyl,

[0658] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[0659] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[0660] Preferably, R 8 Selected from

[0661] R 9 Selected from hydrogen, hydroxyl;

[0662] Preferably, R 9 is hydrogen;

[0663] R 10 is selected from hydrogen and halogen;

[0664] Preferably, R 10 is selected from hydrogen and fluorine;

[0665] More preferably, R 10 is hydrogen;

[0666] R 11 Selected from hydrogen, C1-C6 alkyl;

[0667] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0668] More preferably, R 11 is selected from hydrogen, methyl;

[0669] Most preferably, R 11 For hydrogen.

[0670] In the fifth aspect of the present invention, the present invention provides a compound represented by formula I-1-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein:

[0671] in:

[0672] Z 2 Selected from

[0673] Z 1 Selected from N, CR 4 ;

[0674] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0675] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0676] More preferably, R 0 Selected from

[0677] Most preferably, R 0 for

[0678] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0679] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0680] More preferably, R 1 Selected from F3C-, R 3 O-;

[0681] Most preferably, R 1 Selected from R 3 O-;

[0682] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0683] Preferably, R 2is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0684] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0685] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0686] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0687] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0688] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[0689] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0690] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0691] R g Selected from hydrogen, C1-C6 alkyl;

[0692] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0693] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[0694] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0695] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0696] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0697] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0698] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0699] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0700] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0701] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0702] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[0703] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0704] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[0705] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0706] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0707] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[0708] Most preferably, R k 、R l 、R m is methyl;

[0709] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0710] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0711] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0712] More preferably, R 3Selected from hydrogen, methyl, F3C-,

[0713] Most preferably, R 3 is methyl;

[0714] R 4 is selected from hydrogen and halogen;

[0715] Preferably, R 4 is selected from hydrogen and fluorine;

[0716] More preferably, R 4 is hydrogen;

[0717] R 6 is selected from hydrogen and halogen;

[0718] Preferably, R 6 is selected from hydrogen and fluorine;

[0719] More preferably, R 6 For fluorine;

[0720] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0721] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0722] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0723] More preferably, R 7 Selected from methyl,

[0724] Most preferably, R 7 is methyl;

[0725] R 8 Selected from R o R p N-;

[0726] R o 、R pEach independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[0727] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0728] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[0729] Most preferably, R o is methyl, R p Selected from methyl,

[0730] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[0731] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[0732] Preferably, R 8 Selected from

[0733] R 9 Selected from hydrogen, hydroxyl;

[0734] Preferably, R 9 is hydrogen;

[0735] R 10 is selected from hydrogen and halogen;

[0736] Preferably, R 10 is selected from hydrogen and fluorine;

[0737] More preferably, R 10 is hydrogen;

[0738] R 11 Selected from hydrogen, C1-C6 alkyl;

[0739] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0740] More preferably, R 11 is selected from hydrogen, methyl;

[0741] Most preferably, R 11 For hydrogen.

[0742] In the sixth aspect of the present invention, the present invention provides a compound represented by formula I-1-1-1, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0743] in:

[0744] Z 1 Selected from N, CR 4 ;

[0745] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0746] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0747] More preferably, R 0 Selected from

[0748] Most preferably, R 0 for

[0749] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0750] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0751] More preferably, R 1 Selected from F3C-, R 3 O-;

[0752] Most preferably, R 1 Selected from R 3 O-;

[0753] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R fNC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0754] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0755] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0756] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0757] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0758] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R fSelected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0759] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[0760] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0761] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0762] R g Selected from hydrogen, C1-C6 alkyl;

[0763] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0764] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[0765] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0766] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0767] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0768] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0769] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0770] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0771] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0772] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0773] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[0774] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0775] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[0776] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0777] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0778] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[0779] Most preferably, R k 、R l 、R m is methyl;

[0780] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0781] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0782] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0783] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[0784] Most preferably, R 3 is methyl;

[0785] R 4 is selected from hydrogen and halogen;

[0786] Preferably, R 4 is selected from hydrogen and fluorine;

[0787] More preferably, R 4 is hydrogen;

[0788] R 6 is selected from hydrogen and halogen;

[0789] Preferably, R 6 is selected from hydrogen and fluorine;

[0790] More preferably, R 6 For fluorine;

[0791] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0792] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0793] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0794] More preferably, R 7 Selected from methyl,

[0795] Most preferably, R 7is methyl;

[0796] R 9 Selected from hydrogen, hydroxyl;

[0797] Preferably, R 9 is hydrogen;

[0798] R 10 is selected from hydrogen and halogen;

[0799] Preferably, R 10 is selected from hydrogen and fluorine;

[0800] More preferably, R 10 is hydrogen;

[0801] R 11 Selected from hydrogen, C1-C6 alkyl;

[0802] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0803] More preferably, R 11 is selected from hydrogen, methyl;

[0804] Most preferably, R 11 For hydrogen.

[0805] In the seventh aspect of the present invention, the present invention provides a compound represented by formula I-1-1-1a, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0806] in:

[0807] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0808] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0809] More preferably, R 0 Selected from

[0810] Most preferably, R 0 for

[0811] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0812] Preferably, R 1Selected from C1-C2 haloalkyl, R 3 O-;

[0813] More preferably, R 1 Selected from F3C-, R 3 O-;

[0814] Most preferably, R 1 Selected from R 3 O-;

[0815] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0816] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[0817] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[0818] R e 、R fare each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0819] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[0820] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[0821] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl,

[0822] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0823] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[0824] R g Selected from hydrogen, C1-C6 alkyl;

[0825] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[0826] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[0827] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0828] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[0829] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[0830] Ri 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[0831] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[0832] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[0833] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[0834] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[0835] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[0836] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[0837] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[0838] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[0839] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[0840] More preferably, R k 、R l 、Rm Each independently selected from C1-C4 alkyl;

[0841] Most preferably, R k 、R l 、R m is methyl;

[0842] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[0843] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[0844] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[0845] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[0846] Most preferably, R 3 is methyl;

[0847] R 4 is selected from hydrogen and halogen;

[0848] Preferably, R 4 is selected from hydrogen and fluorine;

[0849] More preferably, R 4 is hydrogen;

[0850] R 6 is selected from hydrogen and halogen;

[0851] Preferably, R 6 is selected from hydrogen and fluorine;

[0852] More preferably, R 6 For fluorine;

[0853] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0854] Preferably, R7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[0855] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[0856] More preferably, R 7 Selected from methyl,

[0857] Most preferably, R 7 is methyl;

[0858] R 9 Selected from hydrogen, hydroxyl;

[0859] Preferably, R 9 is hydrogen;

[0860] R 10 is selected from hydrogen and halogen;

[0861] Preferably, R 10 is selected from hydrogen and fluorine;

[0862] More preferably, R 10 is hydrogen;

[0863] R 11 Selected from hydrogen, C1-C6 alkyl;

[0864] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0865] More preferably, R 11 is selected from hydrogen, methyl;

[0866] Most preferably, R 11 For hydrogen.

[0867] In the eighth aspect of the present invention, the present invention provides a compound represented by formula I-1-1-1b, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0868] in:

[0869] R 0 Selected from C1-C6 haloalkyl;

[0870] Preferably, R 0 Selected from C1-C2 haloalkyl;

[0871] More preferably, R 0 for

[0872] R 1 Selected from R 3 O-;

[0873] R 2 Selected from cyano, R e R f NC(=O)-;

[0874] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0875] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[0876] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[0877] Most preferably, R e is hydrogen, R f Selected from ethyl, isopropyl;

[0878] Preferably, R 2 Selected from cyano,

[0879] R 3 Selected from C1-C6 alkyl;

[0880] Preferably, R 3 Selected from C1-C4 alkyl;

[0881] More preferably, R 3 is methyl;

[0882] R 6 selected from halogen;

[0883] Preferably, R 6 For fluorine;

[0884] R 7 Selected from C1-C6 alkyl;

[0885] Preferably, R 7 Selected from C1-C4 alkyl;

[0886] More preferably, R 7 is methyl;

[0887] R 11 Selected from hydrogen, C1-C6 alkyl;

[0888] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0889] More preferably, R 11 is selected from hydrogen, methyl;

[0890] Most preferably, R 11 For hydrogen.

[0891] In the ninth aspect of the present invention, the present invention provides a compound of formula I-1-1-2, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0892] in:

[0893] R 0 Selected from C1-C6 haloalkyl;

[0894] Preferably, R 0 Selected from C1-C2 haloalkyl;

[0895] More preferably, R 0 for

[0896] R 1 Selected from R 3 O-;

[0897] R 2 Selected from R e R f NC(=O)-;

[0898] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0899] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[0900] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[0901] Most preferably, R e is hydrogen, R f is methyl;

[0902] Preferably, R 2 for

[0903] R 3 Selected from C1-C6 alkyl;

[0904] Preferably, R 3 Selected from C1-C4 alkyl;

[0905] More preferably, R 3 is methyl;

[0906] R 8 Selected from R o R p N-;

[0907] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[0908] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0909] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[0910] Most preferably, R o is methyl, R p Selected from methyl,

[0911] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[0912] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[0913] Preferably, R 8 Selected from

[0914] R 11 Selected from hydrogen, C1-C6 alkyl;

[0915] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0916] More preferably, R 11 is selected from hydrogen, methyl;

[0917] Most preferably, R 11 For hydrogen.

[0918] In the tenth aspect of the present invention, the present invention provides a compound represented by formula I-1-2, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0919] in:

[0920] L 11 is selected from 5-6 membered heteroarylene;

[0921] Preferably, L 11 is selected from 5-membered heteroarylene groups;

[0922] More preferably, L 11 Selected from 1,3,4-thiadiazole substituent, 1,2,4-oxadiazole substituent, 1,3,4-oxadiazole substituent, thiazolyl substituent;

[0923] Most preferably, L 11 Selected from Among them, the left site is connected to the imidazole ring, and the right site is connected to the alkylene / alkylene group;

[0924] R 0 Selected from C1-C6 haloalkyl;

[0925] Preferably, R 0 Selected from C1-C2 haloalkyl;

[0926] More preferably, R 0 for

[0927] R 1 Selected from R 3 O-;

[0928] R 2 Selected from R e R f NC(=O)-;

[0929] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0930] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[0931] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[0932] Most preferably, R e is hydrogen, R f is methyl;

[0933] Preferably, R 2 for

[0934] R 3 Selected from C1-C6 alkyl;

[0935] Preferably, R 3 Selected from C1-C4 alkyl;

[0936] More preferably, R 3 is methyl;

[0937] R 7 Selected from C1-C6 alkyl;

[0938] Preferably, R 7 Selected from C1-C4 alkyl;

[0939] More preferably, R 7 is methyl;

[0940] R 11 Selected from hydrogen, C1-C6 alkyl;

[0941] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0942] More preferably, R 11 is selected from hydrogen, methyl;

[0943] Most preferably, R 11 For hydrogen.

[0944] In the eleventh aspect of the present invention, the present invention provides a compound of formula I-2, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0945] in:

[0946] A 11 Ring selected from Among them, the lower left site is connected to NH, and the upper right site is connected to the alkynyl group;

[0947] R 0 Selected from C1-C6 haloalkyl;

[0948] Preferably, R 0 Selected from C1-C2 haloalkyl;

[0949] More preferably, R 0 for

[0950] R 1 Selected from R 3 O-;

[0951] R 2 Selected from R e R f NC(=O)-、R h S(=O)2-;

[0952] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0953] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[0954] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[0955] Most preferably, R e is hydrogen, R f is methyl;

[0956] R h Selected from C1-C6 alkyl;

[0957] Preferably, R h Selected from C1-C4 alkyl;

[0958] More preferably, R h is methyl;

[0959] Preferably, R 2 for

[0960] R 3 Selected from C1-C6 alkyl;

[0961] Preferably, R 3 Selected from C1-C4 alkyl;

[0962] More preferably, R 3is methyl;

[0963] R 7 Selected from C1-C6 alkyl;

[0964] Preferably, R 7 Selected from C1-C4 alkyl;

[0965] More preferably, R 7 is methyl;

[0966] R 11 Selected from hydrogen, C1-C6 alkyl;

[0967] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[0968] More preferably, R 11 is selected from hydrogen, methyl;

[0969] Most preferably, R 11 For hydrogen.

[0970] In the twelfth aspect of the present invention, the present invention provides a compound represented by formula I-3, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0971] in:

[0972] A 1 Ring selected from Among them, the lower left site is connected to NH, and the upper right site is connected to the alkynyl group;

[0973] Each are each independently a single bond or a double bond;

[0974] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[0975] a)X 4 and X 5 Any one of them is N,

[0976] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[0977] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0978] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0979] More preferably, R a Selected from

[0980] Most preferably, R a for

[0981] R b Selected from hydrogen, hydroxyl;

[0982] Preferably, R b is hydrogen;

[0983] R c is selected from hydrogen and halogen;

[0984] Preferably, R c is selected from hydrogen and fluorine;

[0985] More preferably, R c is hydrogen;

[0986] Preferably, A 1 Ring selected from Among them, the lower left site is connected to NH, and the upper right site is connected to the alkynyl group;

[0987] More preferably, A 1 Ring Among them, the lower left site is connected to NH, and the upper right site is connected to the alkynyl group;

[0988] Ring B is selected from

[0989] Preferably, Ring B is

[0990] Z 2 Selected from

[0991] Z 1 Selected from N, CR 4 ;

[0992] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[0993] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[0994] More preferably, R 0 Selected from

[0995] Most preferably, R 0 for

[0996] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[0997] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[0998] More preferably, R 1 Selected from F3C-, R 3 O-;

[0999] Most preferably, R 1 Selected from R 3 O-;

[1000] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1001] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R jNS(=O)2-, 5-6 membered heteroaryl;

[1002] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2- Oxazolyl, thiazolyl, pyridinyl;

[1003] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1004] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1005] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1006] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1007] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1008] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1009] R g Selected from hydrogen, C1-C6 alkyl;

[1010] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1011] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1012] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1013] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1014] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1015] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1016] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1017] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1018] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1019] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1020] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1021] Or preferably, R i 、R jTogether with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1022] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[1023] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1024] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[1025] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1026] Most preferably, R k 、R l 、R m is methyl;

[1027] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[1028] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1029] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1030] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[1031] Most preferably, R 3 is methyl;

[1032] R 4 is selected from hydrogen and halogen;

[1033] Preferably, R 4 is selected from hydrogen and fluorine;

[1034] More preferably, R 4 is hydrogen;

[1035] R 5 selected from R'-NH-C(=O)-;

[1036] R' is selected from C1-C6 alkyl;

[1037] Preferably, R 5 Selected from

[1038] R 6 is selected from hydrogen and halogen;

[1039] Preferably, R 6 is selected from hydrogen and fluorine;

[1040] More preferably, R 6 For fluorine;

[1041] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1042] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1043] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[1044] More preferably, R 7 Selected from methyl,

[1045] Most preferably, R 7 is methyl;

[1046] R 8 Selected from R o R p N-;

[1047] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, Ro 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[1048] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[1049] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[1050] Most preferably, R o is methyl, R p Selected from methyl,

[1051] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[1052] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[1053] Preferably, R 8 Selected from

[1054] R 9 Selected from hydrogen, hydroxyl;

[1055] Preferably, R 9 is hydrogen;

[1056] R 10 is selected from hydrogen and halogen;

[1057] Preferably, R 10 is selected from hydrogen and fluorine;

[1058] More preferably, R 10 is hydrogen;

[1059] R 11 Selected from hydrogen, C1-C6 alkyl;

[1060] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1061] More preferably, R 11is selected from hydrogen, methyl;

[1062] Most preferably, R 11 For hydrogen.

[1063] In the thirteenth aspect of the present invention, the present invention provides a compound represented by formula I-4, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1064] in:

[1065] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 11 connected;

[1066] Each are each independently a single bond or a double bond;

[1067] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[1068] a)X 4 and X 5 Any one of them is N,

[1069] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[1070] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1071] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1072] More preferably, R a Selected from

[1073] Most preferably, R a for

[1074] R b Selected from hydrogen, hydroxyl;

[1075] Preferably, R b is hydrogen;

[1076] R c is selected from hydrogen and halogen;

[1077] Preferably, R c is selected from hydrogen and fluorine;

[1078] More preferably, R c is hydrogen;

[1079] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 11 connected;

[1080] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 11 connected;

[1081] Most preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 11 connected;

[1082] Ring B is selected from

[1083] Preferably, Ring B is

[1084] L 11 is selected from 5-6 membered heteroarylene;

[1085] Preferably, L 11 is selected from 5-membered heteroarylene groups;

[1086] More preferably, L 11 Selected from 1,3,4-thiadiazole substituent, 1,2,4-oxadiazole substituent, 1,3,4-oxadiazole substituent, thiazolyl substituent;

[1087] More preferably, L 11 Selected from Among them, the site on the left is related to A 1 The rings are connected, and the right side is connected to the alkylene / alkylidene group;

[1088] Z 2 Selected from

[1089] Preferably, Z 2 Selected from

[1090] Z 1 Selected from N, CR 4 ;

[1091] Preferably, Z 1 Selected from CR 4 ;

[1092] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1093] Preferably, R 0 Selected from C1-C6 haloalkyl;

[1094] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1095] Preferably, R 0 Selected from C1-C2 haloalkyl;

[1096] More preferably, R 0 Selected from

[1097] Most preferably, R 0 for

[1098] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[1099] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[1100] More preferably, R 1 Selected from F3C-, R 3 O-;

[1101] Most preferably, R 1 Selected from R 3 O-;

[1102] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e Rf NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1103] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1104] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[1105] More preferably, R 2 Selected from R e R f NC(=O)-;

[1106] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1107] Preferably, R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[1108] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1109] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1110] More preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[1111] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[1112] More preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1113] Most preferably, R e is hydrogen, R f is methyl;

[1114] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1115] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1116] R g Selected from hydrogen, C1-C6 alkyl;

[1117] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1118] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1119] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1120] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1121] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1122] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1123] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1124] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1125] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1126] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1127] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1128] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1129] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[1130] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1131] Preferably, R k 、R l 、R mEach independently selected from C1-C6 alkyl;

[1132] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1133] Most preferably, R k 、R l 、R m is methyl;

[1134] More preferably, R 2 Selected from chlorine, cyano, F3C-,

[1135] Most preferably, R 2 for

[1136] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1137] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1138] Preferably, R 3 Selected from C1-C6 alkyl;

[1139] Preferably, R 3 Selected from C1-C4 alkyl;

[1140] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[1141] Most preferably, R 3 is methyl;

[1142] R 4 is selected from hydrogen and halogen;

[1143] Preferably, R 4 is selected from hydrogen and fluorine;

[1144] More preferably, R 4 is hydrogen;

[1145] R 5selected from R'-NH-C(=O)-;

[1146] R' is selected from C1-C6 alkyl;

[1147] Preferably, R 5 Selected from

[1148] R 6 is selected from hydrogen and halogen;

[1149] Preferably, R 6 is selected from hydrogen and fluorine;

[1150] More preferably, R 6 For fluorine;

[1151] Or more preferably, R 6 is hydrogen;

[1152] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1153] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1154] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[1155] More preferably, R 7 Selected from C1-C6 alkyl;

[1156] More preferably, R 7 Selected from C1-C4 alkyl;

[1157] More preferably, R 7 Selected from methyl,

[1158] Most preferably, R 7 is methyl;

[1159] R 8 Selected from R o R p N-;

[1160] R o 、Rp Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[1161] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[1162] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[1163] Most preferably, R o is methyl, R p Selected from methyl,

[1164] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[1165] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[1166] Preferably, R 8 Selected from

[1167] R 9 Selected from hydrogen, hydroxyl;

[1168] Preferably, R 9 is hydrogen;

[1169] R 10 is selected from hydrogen and halogen;

[1170] Preferably, R 10 is selected from hydrogen and fluorine;

[1171] More preferably, R 10 is hydrogen;

[1172] R 11 Selected from hydrogen, C1-C6 alkyl;

[1173] Preferably, R 11Selected from hydrogen, C1-C4 alkyl;

[1174] More preferably, R 11 is selected from hydrogen, methyl;

[1175] Most preferably, R 11 For hydrogen.

[1176] In the fourteenth aspect of the present invention, the present invention provides a compound of formula I-5, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1177] in:

[1178] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1179] Each are each independently a single bond or a double bond;

[1180] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[1181] a)X 4 and X 5 Any one of them is N,

[1182] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[1183] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1184] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1185] More preferably, R a Selected from

[1186] Most preferably, R a for

[1187] R b Selected from hydrogen, hydroxyl;

[1188] Preferably, R b is hydrogen;

[1189] R c is selected from hydrogen and halogen;

[1190] Preferably, R c is selected from hydrogen and fluorine;

[1191] More preferably, R c is hydrogen;

[1192] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1193] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1194] Ring B is selected from

[1195] Preferably, Ring B is

[1196] L 1 Selected from 5-6 membered heteroarylene;

[1197] Preferably, L 1 Selected from 5-membered heteroarylene;

[1198] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[1199] More preferably, L 1 Selected from Among them, the site on the left is related to A 1 The rings are connected, and the right side is connected to the alkylene / alkylidene group;

[1200] Most preferably, L 1 for

[1201] Z 1 Selected from N, CR 4 ;

[1202] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1203] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1204] More preferably, R 0 Selected from

[1205] Most preferably, R 0 for

[1206] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[1207] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[1208] More preferably, R 1 Selected from F3C-, R 3 O-;

[1209] Most preferably, R 1 Selected from R 3 O-;

[1210] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1211] Preferably, R 2is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1212] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[1213] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1214] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1215] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1216] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1217] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1218] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1219] R g Selected from hydrogen, C1-C6 alkyl;

[1220] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1221] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1222] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1223] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1224] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1225] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1226] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1227] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1228] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1229] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1230] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1231] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1232] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[1233] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1234] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[1235] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1236] Most preferably, R k 、R l 、R m is methyl;

[1237] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[1238] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1239] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1240] More preferably, R 3Selected from hydrogen, methyl, F3C-,

[1241] Most preferably, R 3 is methyl;

[1242] R 4 is selected from hydrogen and halogen;

[1243] Preferably, R 4 is selected from hydrogen and fluorine;

[1244] More preferably, R 4 is hydrogen;

[1245] R 5 selected from R'-NH-C(=O)-;

[1246] R' is selected from C1-C6 alkyl;

[1247] Preferably, R 5 Selected from

[1248] R 6 is selected from hydrogen and halogen;

[1249] Preferably, R 6 is selected from hydrogen and fluorine;

[1250] More preferably, R 6 For fluorine;

[1251] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1252] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1253] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[1254] More preferably, R 7 Selected from methyl,

[1255] Most preferably, R 7 is methyl;

[1256] R 9 Selected from hydrogen, hydroxyl;

[1257] Preferably, R 9 is hydrogen;

[1258] R 10 is selected from hydrogen and halogen;

[1259] Preferably, R 10 is selected from hydrogen and fluorine;

[1260] More preferably, R 10 is hydrogen;

[1261] R 11 Selected from hydrogen, C1-C6 alkyl;

[1262] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1263] More preferably, R 11 is selected from hydrogen, methyl;

[1264] Most preferably, R 11 For hydrogen.

[1265] In the fifteenth aspect of the present invention, the present invention provides a compound represented by formula I-6, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1266] in:

[1267] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1268] Each are each independently a single bond or a double bond;

[1269] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c, C=O, N, NH, S, and meets the following conditions a) or b):

[1270] a)X 4 and X 5 Any one of them is N,

[1271] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[1272] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1273] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1274] More preferably, R a Selected from

[1275] Most preferably, R a for

[1276] R b Selected from hydrogen, hydroxyl;

[1277] Preferably, R b is hydrogen;

[1278] R c is selected from hydrogen and halogen;

[1279] Preferably, R c is selected from hydrogen and fluorine;

[1280] More preferably, R c is hydrogen;

[1281] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1282] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1283] Most preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L1 connected;

[1284] Ring B is selected from

[1285] Preferably, Ring B is

[1286] L 1 Selected from 5-6 membered heteroarylene;

[1287] Preferably, L 1 Selected from 5-membered heteroarylene;

[1288] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[1289] More preferably, L 1 Selected from Among them, the site on the left is related to A 1 The rings are connected, and the right side is connected to the alkylene / alkylidene group;

[1290] Most preferably, L 1 for

[1291] Z 1 Selected from N, CR 4 ;

[1292] Preferably, Z 1 CR 4 ;

[1293] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1294] Preferably, R 0 Selected from C1-C6 haloalkyl;

[1295] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1296] Preferably, R 0 Selected from C1-C2 haloalkyl;

[1297] More preferably, R 0 Selected from

[1298] Most preferably, R 0 for

[1299] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[1300] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[1301] More preferably, R 1 Selected from F3C-, R 3 O-;

[1302] Most preferably, R 1 Selected from R 3 O-;

[1303] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1304] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1305] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R iR j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[1306] More preferably, R 2 Selected from R e R f NC(=O)-;

[1307] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1308] Preferably, R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[1309] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1310] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[1311] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1312] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[1313] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1314] Or most preferably, R e is hydrogen, R f is methyl;

[1315] Or preferably, R e 、R fTogether with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1316] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1317] R g Selected from hydrogen, C1-C6 alkyl;

[1318] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1319] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1320] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1321] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1322] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1323] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1324] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1325] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1326] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1327] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1328] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1329] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1330] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[1331] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1332] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[1333] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1334] Most preferably, R k 、R l 、R m is methyl;

[1335] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[1336] Or most preferably, R 2 for

[1337] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1338] Preferably, R 3 Selected from C1-C6 alkyl;

[1339] Preferably, R 3Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1340] Preferably, R 3 Selected from C1-C4 alkyl;

[1341] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[1342] Most preferably, R 3 is methyl;

[1343] R 4 is selected from hydrogen and halogen;

[1344] Preferably, R 4 is selected from hydrogen and fluorine;

[1345] More preferably, R 4 is hydrogen;

[1346] R 5 selected from R'-NH-C(=O)-;

[1347] R' is selected from C1-C6 alkyl;

[1348] Preferably, R 5 Selected from

[1349] R 6 is selected from hydrogen and halogen;

[1350] Preferably, R 6 is selected from hydrogen and fluorine;

[1351] More preferably, R 6 For fluorine;

[1352] R 8 Selected from R o R p N-;

[1353] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[1354] Preferably, R o Selected from C1-C6 alkyl, Rp Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[1355] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[1356] Most preferably, R o is methyl, R p Selected from methyl,

[1357] Or preferably, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[1358] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[1359] Preferably, R 8 Selected from

[1360] R 9 Selected from hydrogen, hydroxyl;

[1361] Preferably, R 9 is hydrogen;

[1362] R 10 is selected from hydrogen and halogen;

[1363] Preferably, R 10 is selected from hydrogen and fluorine;

[1364] More preferably, R 10 is hydrogen;

[1365] R 11 Selected from hydrogen, C1-C6 alkyl;

[1366] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1367] More preferably, R 11 is selected from hydrogen, methyl;

[1368] Most preferably, R 11 For hydrogen.

[1369] In the sixteenth aspect of the present invention, the present invention provides a compound represented by formula I-7, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1370] in:

[1371] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1372] Each are each independently a single bond or a double bond;

[1373] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[1374] a)X 4 and X 5 Any one of them is N,

[1375] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[1376] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1377] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1378] More preferably, R a Selected from

[1379] Most preferably, R a for

[1380] Rb Selected from hydrogen, hydroxyl;

[1381] Preferably, R b is hydrogen;

[1382] R c is selected from hydrogen and halogen;

[1383] Preferably, R c is selected from hydrogen and fluorine;

[1384] More preferably, R c is hydrogen;

[1385] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1386] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1387] L 1 Selected from 5-6 membered heteroarylene;

[1388] Preferably, L 1 Selected from 5-membered heteroarylene;

[1389] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[1390] More preferably, L 1 Selected from In the left side, the site is the same as A 1 The loop is connected, and the site on the right is connected to the sub / sub;

[1391] Most preferably, L 1 for

[1392] Z 2 Selected from

[1393] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1394] Preferably, R 0Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1395] More preferably, R 0 Selected from

[1396] Most preferably, R 0 for

[1397] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[1398] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[1399] More preferably, R 1 Selected from F3C-, R 3 O-;

[1400] Most preferably, R 1 Selected from R 3 O-;

[1401] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1402] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1403] More preferably, R 2is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[1404] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1405] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1406] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1407] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1408] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1409] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1410] R g Selected from hydrogen, C1-C6 alkyl;

[1411] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1412] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1413] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1414] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1415] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1416] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1417] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1418] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1419] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1420] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1421] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1422] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1423] Or more preferably, R i 、R jTogether with the N atoms they are connected to, they form

[1424] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1425] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[1426] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1427] Most preferably, R k 、R l 、R m is methyl;

[1428] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[1429] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1430] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1431] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[1432] Most preferably, R 3 is methyl;

[1433] R 4 is selected from hydrogen and halogen;

[1434] Preferably, R 4 is selected from hydrogen and fluorine;

[1435] More preferably, R 4 is hydrogen;

[1436] R 6 is selected from hydrogen and halogen;

[1437] Preferably, R 6 is selected from hydrogen and fluorine;

[1438] More preferably, R 6 For fluorine;

[1439] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1440] Preferably, R 7 Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1441] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[1442] More preferably, R 7 Selected from methyl,

[1443] Most preferably, R 7 is methyl;

[1444] R 8 Selected from R o R p N-;

[1445] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[1446] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[1447] More preferably, R o is selected from C1-C4 alkyl, R pSelected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[1448] Most preferably, R o is methyl, R p Selected from methyl,

[1449] Or preferably, R o 、R p Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiro heterocyclic group, or a 7-membered bridged heterocyclic group;

[1450] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[1451] Preferably, R 8 Selected from

[1452] R 9 Selected from hydrogen, hydroxyl;

[1453] Preferably, R 9 is hydrogen;

[1454] R 10 is selected from hydrogen and halogen;

[1455] Preferably, R 10 is selected from hydrogen and fluorine;

[1456] More preferably, R 10 is hydrogen;

[1457] R 11 Selected from hydrogen, C1-C6 alkyl;

[1458] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1459] More preferably, R 11 is selected from hydrogen, methyl;

[1460] Most preferably, R 11 For hydrogen.

[1461] In the seventeenth aspect of the present invention, the present invention provides a compound represented by formula I-8, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1462] in:

[1463] A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1464] Each are each independently a single bond or a double bond;

[1465] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C=O, N, NH, S, and meets the following conditions a) or b):

[1466] a)X 4 and X 5 Any one of them is N,

[1467] b)X 4 and X 5 When both are not N, X 1 、X 3 Any one of them is S;

[1468] R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1469] Preferably, R a Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1470] More preferably, R a Selected from

[1471] Most preferably, R a for

[1472] R b Selected from hydrogen, hydroxyl;

[1473] Preferably, R b is hydrogen;

[1474] R c is selected from hydrogen and halogen;

[1475] Preferably, R cis selected from hydrogen and fluorine;

[1476] More preferably, R c is hydrogen;

[1477] Preferably, A 1 Ring selected from Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1478] More preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1479] Most preferably, A 1 Ring Among them, the site at the lower left end is connected to NH, and the site at the upper right end is connected to L 1 connected;

[1480] L 1 Selected from 5-6 membered heteroarylene;

[1481] Preferably, L 1 Selected from 5-membered heteroarylene;

[1482] More preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit;

[1483] More preferably, L 1 Selected from Among them, the site on the left is related to A 1 The rings are connected, and the right side is connected to the alkylene / alkylidene group;

[1484] Most preferably, L 1 for

[1485] Z 2 Selected from

[1486] Preferably, Z 2 for

[1487] R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene;

[1488] Preferably, R 0Selected from C1-C6 haloalkyl;

[1489] Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene;

[1490] Preferably, R 0 Selected from C1-C2 haloalkyl;

[1491] More preferably, R 0 Selected from

[1492] Most preferably, R 0 for

[1493] R 1 Selected from C1-C6 haloalkyl, R 3 O-;

[1494] Preferably, R 1 Selected from C1-C2 haloalkyl, R 3 O-;

[1495] More preferably, R 1 Selected from F3C-, R 3 O-;

[1496] Most preferably, R 1 Selected from R 3 O-;

[1497] R 2 is selected from cyano, halogen, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkylene, cyano-C1-C6 alkylene, 5-6 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl;

[1498] Preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i Rj NS(=O)2-, 5-6 membered heteroaryl;

[1499] More preferably, R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholinyl-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl;

[1500] More preferably, R 2 Selected from cyano, R e R f NC(=O)-;

[1501] R e 、R f are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups; or, R e 、R f Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1502] Preferably, R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[1503] Preferably, R e is selected from hydrogen, C1-C6 alkyl, R f Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl substituted with 2 hydroxy groups;

[1504] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[1505] More preferably, R e is selected from hydrogen, C1-C4 alkyl, R f Selected from hydrogen, C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene, C1-C4 alkyl substituted with 2 hydroxyl groups;

[1506] More preferably, R e is hydrogen, Rf Selected from C1-C4 alkyl;

[1507] Most preferably, R e is selected from hydrogen, methyl, R f Selected from hydrogen, methyl, ethyl, isopropyl,

[1508] Or most preferably, R e is hydrogen, R f Selected from ethyl, isopropyl;

[1509] Or preferably, R e 、R f Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1510] Or more preferably, R e 、R f Together with the N atoms they are connected to, they form

[1511] R g Selected from hydrogen, C1-C6 alkyl;

[1512] Preferably, R g Selected from hydrogen, C1-C4 alkyl;

[1513] More preferably, R g is selected from hydrogen, methyl, and ethyl;

[1514] R h Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[1515] Preferably, R h Selected from C1-C4 alkyl, C3-C6 cycloalkyl;

[1516] More preferably, R h Selected from methyl, ethyl, cyclopropyl;

[1517] R i 、R j are each independently selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiroheterocyclic ring;

[1518] Preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-6 membered heteroaryl;

[1519] More preferably, R iis selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, 5-membered heteroaryl;

[1520] More preferably, R i is selected from hydrogen, C1-C6 alkyl, R j is selected from hydrogen, C1-C6 alkyl, isoxazolyl;

[1521] More preferably, R i is selected from hydrogen, C1-C4 alkyl, R j Selected from hydrogen, C1-C4 alkyl,

[1522] Most preferably, R i is selected from hydrogen, methyl, R j Selected from hydrogen, methyl,

[1523] Or preferably, R i 、R j Together with the nitrogen atom to which they are attached, they form a 6-membered saturated heterocyclic ring or a 7-membered spiroheterocyclic ring;

[1524] Or more preferably, R i 、R j Together with the N atoms they are connected to, they form

[1525] R k 、R l 、R m Each is independently selected from hydrogen, C1-C6 alkyl;

[1526] Preferably, R k 、R l 、R m Each independently selected from C1-C6 alkyl;

[1527] More preferably, R k 、R l 、R m Each independently selected from C1-C4 alkyl;

[1528] Most preferably, R k 、R l 、R m is methyl;

[1529] Most preferably, R 2 Selected from chlorine, cyano, F3C-,

[1530] Or most preferably, R 2 Selected from cyano,

[1531] R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene, hydroxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkyl-C(=O)-;

[1532] Preferably, R 3 Selected from C1-C6 alkyl;

[1533] Preferably, R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene, hydroxy-C1-C2 alkylene, C1-C2 alkoxy-C1-C2 alkylene, C1-C2 alkyl-C(=O)-;

[1534] Preferably, R 3 Selected from C1-C4 alkyl;

[1535] More preferably, R 3 Selected from hydrogen, methyl, F3C-,

[1536] Most preferably, R 3 is methyl;

[1537] R 5 selected from R'-NH-C(=O)-;

[1538] R' is selected from C1-C6 alkyl;

[1539] Preferably, R 5 Selected from

[1540] R 6 is selected from hydrogen and halogen;

[1541] Preferably, R 6 selected from halogen;

[1542] Preferably, R 6 is selected from hydrogen and fluorine;

[1543] More preferably, R 6 For fluorine;

[1544] R 7 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1545] Preferably, R 7Selected from C1-C6 alkyl, C1-C6 alkyl substituted by 2 hydroxyl groups, C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by hydroxyl groups;

[1546] Preferably, R 7 Selected from C1-C6 alkyl;

[1547] More preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkylene, wherein the C1-C2 alkoxy-C1-C4 alkylene is substituted by hydroxyl groups;

[1548] More preferably, R 7 Selected from C1-C4 alkyl;

[1549] More preferably, R 7 Selected from methyl,

[1550] Most preferably, R 7 is methyl;

[1551] R 8 Selected from R o R p N-;

[1552] R o 、R p Each independently selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 5-6 membered saturated heterocyclic ring, a 7-9 membered spiro heterocyclic ring or a 7 membered bridged heterocyclic ring;

[1553] Preferably, R o Selected from C1-C6 alkyl, R p Selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[1554] More preferably, R o is selected from C1-C4 alkyl, R p Selected from C1-C4 alkyl, C1-C2 alkoxy-C1-C2 alkylene;

[1555] Most preferably, R o is methyl, R p Selected from methyl,

[1556] Or preferably, R o 、R pTogether with the nitrogen atom to which they are commonly attached, they form a 6-membered saturated heterocyclic group, a 7-9-membered spiroheterocyclic group, or a 7-membered bridged heterocyclic group;

[1557] Or more preferably, R o 、R p Together with the N atoms they are connected to, they form

[1558] Preferably, R 8 Selected from

[1559] R 9 Selected from hydrogen, hydroxyl;

[1560] Preferably, R 9 is hydrogen;

[1561] R 10 is selected from hydrogen and halogen;

[1562] Preferably, R 10 is selected from hydrogen and fluorine;

[1563] More preferably, R 10 is hydrogen;

[1564] R 11 Selected from hydrogen, C1-C6 alkyl;

[1565] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1566] More preferably, R 11 is selected from hydrogen, methyl;

[1567] Most preferably, R 11 For hydrogen.

[1568] In the eighteenth aspect of the present invention, the present invention provides a compound represented by formula II, or a stereoisomer, tautomer, prodrug, crystal form, hydrate, isotope-labeled compound, metabolite, ester, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[1569] in:

[1570] A 2 Ring selected from Among them, the lower left site is connected to NH, and the upper right site is connected to the alkynyl group;

[1571] R 0 Selected from C1-C6 haloalkyl;

[1572] Preferably, R 0Selected from C1-C2 haloalkyl;

[1573] More preferably, R 0 for

[1574] R 1 Selected from R 3 O-;

[1575] R 2 Selected from R e R f NC(=O)-;

[1576] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[1577] Preferably, R e is hydrogen, R f Selected from C1-C6 alkyl;

[1578] More preferably, R e is hydrogen, R f Selected from C1-C4 alkyl;

[1579] Most preferably, R e is hydrogen, R f is methyl; preferably, R 2 for

[1580] R 3 Selected from C1-C6 alkyl;

[1581] Preferably, R 3 Selected from C1-C4 alkyl;

[1582] More preferably, R 3 is methyl;

[1583] R 7 Selected from C1-C6 alkyl;

[1584] Preferably, R 7 Selected from C1-C4 alkyl;

[1585] More preferably, R 7 is methyl;

[1586] R 11 Selected from hydrogen, C1-C6 alkyl;

[1587] Preferably, R 11 Selected from hydrogen, C1-C4 alkyl;

[1588] More preferably, R 11 is selected from hydrogen, methyl;

[1589] Most preferably, R 11 For hydrogen.

[1590] In some embodiments, the compound is selected from:

[1591] In some embodiments, the compound is selected from:

[1592] In the nineteenth aspect of the present invention, the present invention provides a pharmaceutical composition comprising the aforementioned compound, or the enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug of the compound, and optional pharmaceutically acceptable excipients.

[1593] In the twentieth aspect of the present invention, the present invention provides a combination drug comprising:

[1594] 1) A first drug, which is the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof;

[1595] 2) A second drug, wherein the second drug is a PD-1 inhibitor or a PD-L1 inhibitor.

[1596] In some embodiments, the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, camrelizumab, sintilimab, toripalimab, penpulimab, zimberelimab, and Pucotenlimab.

[1597] In some embodiments, the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab.

[1598] In the twenty-first aspect of the present invention, the present invention provides the aforementioned compound, or the enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug of the compound, or the aforementioned pharmaceutical composition, or the use of the aforementioned combination drug in the preparation of a drug.

[1599] In some embodiments, the medicament is for treating and / or preventing a disease.

[1600] In some embodiments, the disease is a disease caused by a p53 Y220C mutation.

[1601] In some embodiments, the disease caused by the p53 Y220C mutation is cancer.

[1602] 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, 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, osteogenic sarcoma, endometrial cancer, head and neck cancer.

[1603] 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.

[1604] In the twenty-second aspect of the present invention, the present invention provides the aforementioned compound, or the enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug of the compound, or the aforementioned pharmaceutical composition, or the aforementioned combination drug, for use in treating and / or preventing a disease.

[1605] In some embodiments, the disease is a disease caused by a p53 Y220C mutation.

[1606] In some embodiments, the disease caused by the p53 Y220C mutation is cancer.

[1607] 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, 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, osteogenic sarcoma, endometrial cancer, head and neck cancer.

[1608] 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.

[1609] In some embodiments, the first drug and the second drug in the combination are administered simultaneously, or are administered sequentially.

[1610] In the twenty-third aspect of the present invention, the present invention provides a method for treating and / or preventing a disease, comprising: administering to a subject an effective amount of the aforementioned compound, or the enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug of the compound, or the aforementioned pharmaceutical composition, or the aforementioned combination drug, wherein the disease is a disease caused by the p53 Y220C mutation.

[1611] 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, osteogenic sarcoma, endometrial cancer, head and neck cancer.

[1612] 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.

[1613] In some embodiments, when the aforementioned combination drug is administered, the first drug and the second drug are administered simultaneously, or are administered sequentially.

[1614] In the twenty-fourth aspect of the present invention, the present invention provides a method for inducing apoptosis in cells, which comprises contacting the cells with a therapeutically effective amount of a compound that binds to a mutant p53 mutant, wherein the compound is the aforementioned compound, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated substance) or prodrug of the compound, or the aforementioned pharmaceutical composition, or the aforementioned combination drug.

[1615] In some embodiments, the compound increases the ability of the p53 mutant to bind to DNA.

[1616] In some embodiments, the p53 mutant is p53 Y220C.

[1617] In some embodiments, the compound induces a conformational change in the p53 mutant.

[1618] 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

[1619] 1. The compounds of the present invention have excellent in vitro activity and can increase the binding ability of the Y220C mutated P53 protein to DNA.

[1620] 2. The compounds of the present invention can significantly inhibit the proliferation of NUGC-3 gastric adenocarcinoma cells containing the p53 Y220C mutation.

[1621] 3. The compounds of the present invention can significantly inhibit the proliferation of BxPC-3 pancreatic cancer cells containing the p53 Y220C mutation. DETAILED DESCRIPTION

[1622] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[1623] In the present invention, unless otherwise explicitly stated, the description method "... are independently selected from" used throughout this document can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[1624] The terms "optional," "optionally," or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with" means that the substitution may or may not occur.

[1625] When the term "each independently" is used in combination with "optionally", for example, "each independently arbitrarily replaced by..." means that the specific options are either replaced by... or not replaced by... without affecting each other.

[1626] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found 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.

[1627] The substituents of the compounds of the present invention are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[1628] The term "alkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, a "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably a "C1-C4 alkyl", more preferably a "C1-C3 alkyl", and most preferably a "C1-C2 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, a methyl group, an ethyl group, a propyl group (e.g., n-propyl, isopropyl), a butyl group (e.g., n-butyl, isobutyl, tert-butyl), a pentyl group (e.g., n-pentyl, isopentyl, neopentyl), and the like. Examples of "C1-C4 alkyl" include, but are not limited to, a methyl group, an ethyl group, a propyl group (e.g., n-propyl, isopropyl), a butyl group (e.g., n-butyl, isobutyl, tert-butyl), and the like. Examples of "C1-C3 alkyl" include, but are not limited to, a methyl group, an ethyl group, a propyl group (e.g., n-propyl, isopropyl), and the like. Examples of "C1-C2 alkyl" include, but are not limited to, a methyl group and an ethyl group.

[1629] The term "alkoxy" refers to any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, etc.) connected to the rest of the molecule through an oxygen atom -O-, such as C1-C6 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, and specifically methoxy, ethoxy, etc.

[1630] The term "cycloalkyl" refers to a saturated hydrocarbon monovalent ring containing 3-15 ring carbon atoms or 3-10 ring carbon atoms, for example, "C3-C7 cycloalkyl", "C4-C9 cycloalkyl", "C3-C6 cycloalkyl", etc. The cycloalkyl group may be in the form of a single ring, a fused ring, a bridged ring, or a spiro ring. Exemplary cycloalkyl groups include, but are not limited to, the following:

[1631] etc. Examples of the term "C3-C6 cycloalkyl" include

[1632] Halogen refers to fluorine, chlorine, bromine or iodine.

[1633] The term "C1-C6 haloalkyl" refers to a group in which one or more hydrogen atoms in any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, etc.) are replaced by halogen (preferably fluorine), for example, monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, wait.

[1634] The term "halogenated cycloalkyl" refers to a group in which one or more hydrogen atoms in any of the above cycloalkyl groups (e.g., C3-C7 cycloalkyl, C4-C9 cycloalkyl, C3-C6 cycloalkyl, etc.) are replaced by halogen (preferably fluorine), for example, it can be a C3-C6 halocycloalkyl group.

[1635] The heteroatom refers to N, O, S or P.

[1636] The terms "heteroaryl" and "heteroaromatic ring" are used interchangeably and refer to substituted and unsubstituted aromatic 5- or 6-membered monocyclic radicals, 8-, 9- or 10-membered bicyclic radicals, and 11- to 14-membered tricyclic radicals having at least one heteroatom (N, O, S, or P) in at least one ring, the heteroatom-containing ring optionally further having 1, 2, or 3 heteroatoms selected from N, O, S, or P. Among them, substituted and unsubstituted aromatic 8-, 9- or 10-membered bicyclic radicals and 11- to 14-membered tricyclic radicals having at least one heteroatom (N, O, S, or P) in at least one ring are "fused heteroaryls" or "fused heteroaromatic rings." Heteroaromatic radicals or heteroaromatic rings that are bicyclic or tricyclic require a bicyclic or tricyclic overall structure to form an aromatic system. The heteroaryl radical or heteroaromatic ring may be attached at any available nitrogen or carbon atom of either ring. It will be understood by those skilled in the art that two adjacent atoms (preferably carbon atoms) are shared between each two rings in the fused ring.

[1637] Exemplary monocyclic heteroaryl groups or monocyclic heteroaromatic rings include, but are not limited to, pyrrolyl / ring, pyrazolyl / ring, imidazolyl / ring, oxazolyl / ring, isoxazolyl / ring, thiazolyl / ring, thiadiazolyl / ring, isothiazolyl / ring, furanyl / ring, thienyl / ring, oxadiazolyl / ring, pyridinyl / ring, pyrazinyl / ring, pyrimidinyl / ring, pyridazinyl / ring, triazinyl / ring, triazolyl / ring, pyridazinyl / ring, 2-pyridone, and the like.

[1638] 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, benzothienyl, quinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridinyl, isoindolyl, and the like.

[1639] The terms "heteroarylene" and "heteroarylene ring" are used interchangeably and refer to a divalent group obtained by losing one hydrogen atom from any of the above heteroaryl groups or two hydrogen atoms from the above heteroaryl ring. For example, a 5-6 membered heteroarylene group may be a 1,3,4-thiadiazole group, a 1,2,4-oxadiazole group, a 1,3,4-oxadiazole group or a thiazolyl group, and may be specifically wait.

[1640] The terms "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered (preferably 4-7, more preferably 5-6 or 4-6) monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, which may contain one or more double bonds but do not constitute aromatic rings; wherein at least one ring has at least one heteroatom (N, O, S, or P). The fused, bridged, or spirocyclic rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated or partially saturated and do not constitute aromatic rings. The heterocyclic group may be attached at any available nitrogen or carbon atom. Exemplary heterocyclic examples include, but are not limited to, the following:

[1641] Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolanyl, and the like.

[1642] The terms "saturated heterocyclic group" and "saturated heterocycle" are used interchangeably and refer to the above-defined heterocyclic group that does not contain unsaturated bonds, such as double bonds. For example, examples of "4-8 membered saturated heterocycles" include, but are not limited to, hexahydropyrimidine, hexahydropyrazine,

[1643] For example, examples of "6-membered saturated heterocyclic group" include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, hexahydropyrimidinyl, and hexahydropyrazinyl.

[1644] The terms "bridged heterocyclic group" and "bridged heterocycle" are used interchangeably and refer to polycyclic hydrocarbons with 3-7 members sharing two or more carbon atoms between several monocyclic rings, wherein the ring atoms contain at least one heteroatom, which may contain one or more double bonds, but none of the rings have a conjugated π electron system, a specific example being a "7-membered bridged heterocyclic group". Wherein, "member" refers to the total number of ring atoms of the bridged heterocyclic group. In addition, it is divided into diheterocyclic hydrocarbons, triheterocyclic hydrocarbons, tetraheterocyclic hydrocarbons, etc. according to the number of rings. Preferred heteroatoms include N, O, S or P, more preferably N. Wherein, a "7-membered bridged heterocyclic group" can be, for example,

[1645] The terms "spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a polycyclic hydrocarbon ring having 3-7 members and a carbon atom shared between two monocyclic rings, wherein the ring atoms contain at least one heteroatom and may contain one or more double bonds, but neither ring has a conjugated π electron system. Specific examples include "7-11 membered spiroheterocycle" and "7-9 membered spiroheterocycle". Preferred heteroatoms include N, O, S or P.

[1646] Wherein, the "7-11 membered spiro heterocycle" can be, for example:

[1647] Specifically, the "7-9 membered spiro heterocycle" can preferably be

[1648] From all the above descriptions, it is obvious to a person skilled in the art that any group whose name is a composite name, such as "cyano-C1-C6 alkylene", should refer to the group conventionally constructed from the part derived therefrom from left to right, such as "C1-C6 alkylene" substituted with cyano, wherein "C1-C6 alkylene" is as defined above. Specifically, "cyano-C1-C6 alkylene" can be, for example, Similarly, "hydroxy-C1-C6 alkylene", "C1-C6 alkoxy-C1-C6 alkylene", "5-6 membered saturated heterocyclyl-C1-C6 alkylene" shall mean the moiety derived therefrom conventionally from left to right, for example, from "C1-C6 alkylene" substituted with hydroxy, C1-C6 alkoxy or 5-6 membered saturated heterocyclyl, wherein "C1-C6 alkylene" is as defined above. Specifically, "hydroxy-C1-C6 alkylene" can be, for example, "C1-C6 alkoxy-C1-C6 alkylene" can be, for example, "5-6 membered saturated heterocyclic-C1-C6 alkylene" can be, for example, Other similar composite groups can be understood by referring to the above content.

[1649] The term "substituted" or "substituted by a substituent..." means that any one or more hydrogen atoms on a designated atom or group are replaced by a selected designated group, provided that the normal valence of the designated atom is not exceeded. For example, "a C1-C6 alkyl group substituted with hydroxyl" can be a hydroxymethyl group. For another example, "a C1-C6 alkyl group substituted with two hydroxyl groups" can be For example, "R 7 is selected from C1-C6 alkoxy-C1-C6 alkylene, wherein the C1-C6 alkoxy-C1-C6 alkylene is substituted by a hydroxyl group, then R 7 For example, it can be

[1650] In the present invention, R 2 Re R f NC(=O)-,R e 、R f When, together with the nitrogen atoms to which they are commonly connected, they form a 5-6 membered saturated heterocyclic ring or a 7 membered spiro heterocyclic ring, if the 5-6 membered saturated heterocyclic ring is The 7-membered spiro heterocycle is It means that R 2 Can be Other similar definitions can be understood by referring to the above content.

[1651] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[1652] In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[1653] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the individual's disease state, age, sex and weight, and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Usually, but not necessarily, since a prophylactic dose is used for a subject before the onset of the disease or in the early stages of the disease, the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[1654] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, aluminum oxide, 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, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[1655] The pharmaceutical composition of the present invention can be prepared into various forms according to different routes of administration. For example, the pharmaceutical composition can be administered by any of the following methods: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or administration via an explanted reservoir. Oral and intravenous administration are preferred.

[1656] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, and the dosage and ratio of each can be adjusted by those skilled in the art according to the specific disease and patient conditions and clinical needs.

[1657] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only through this reaction under biological conditions, or they have no or only low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[1658] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[1659] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[1660] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[1661] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[1662] The term "stereoisomers" refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like. The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds, and N=N double bonds) or single bonds of ring carbon atoms to rotate freely. For example, it represents a cis configuration, that is, the two substituents on the cyclobutyl ring are located on the same side.

[1663] As used herein, from the perspective of a single chiral carbon atom, the connecting chain on the carbon atom and The meaning expressed is the same, that is and Both indicate that they include "R" and "S" configurations.

[1664] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, 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 l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[1665] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[1666] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[1667] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[1668] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, 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, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL 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).

[1669] The compounds described herein include all possible isotopically labeled compounds of all compounds described herein. The term "isotopically labeled compound" refers to a compound wherein any atom in the compound is replaced by an isotope thereof.

[1670] "Solvate" or "solvate" are used interchangeably to refer to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate" such as a monohydrate or dihydrate is formed, or it may include any amount of water; for example, when the solvent is an alcohol such as methanol or ethanol, an "alcoholate" may be formed, which may also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e., a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.

[1671] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[1672] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[1673] As used herein, the term "metabolite" refers to a derivative of a compound formed when the compound is metabolized. The term "metabolism" refers to the sum of processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions).

[1674] As used herein, the term "ester" refers to an ester formed between the -COOH group present in the compounds provided herein and a suitable alcohol, or an ester formed between the -OH group present in the compounds provided herein and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearic acid esters, or palmitates. Esters can undergo hydrolysis in the presence of an acid or base to produce the corresponding acid or alcohol.

[1675] 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 to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[1676] As used herein, the term "pharmaceutically acceptable salt" refers to (i) salts formed by acidic functional groups present in the compounds provided by the present invention with appropriate inorganic or organic cations (bases), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-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 formed by basic functional groups present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), including but not limited to hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; and amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[1677] As used herein, the term "crystalline form" refers to the crystal structure of a substance. During crystallization, various factors may alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms within the crystal lattice space, forming different crystal structures. The compounds of the present invention may exist in a single crystal structure or in multiple crystal structures, i.e., they may exhibit "polymorphism." The compounds of the present invention may exist in different crystalline forms.

[1678] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. In the following examples, if the experimental methods for specific conditions are not specified, they are generally based on the conventional conditions of this type of reaction, or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise stated, the ratio of liquids is volume ratio. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise stated.

[1679] Preparation Example: Synthesis of Compounds

[1680] Preparation Example 1. Preparation of Compound 1

[1681] Synthesis route:

[1682] Step 1: Preparation of compound 1-2

[1683] To a solution of compound 1-1 (10.0 g, 55.2 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (22.8 g, 165.6 mmol) and propargyl bromide (5.5 mL, 66.2 mmol). The mixture was heated to 70°C and stirred for 4 hours under nitrogen. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phases were concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 1-2. MS m / z (ESI): 219.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=1.6, 8.4Hz, 1H), 7.43 (d, J=1.6Hz, 1H), 6.65 (d, J= 8.4Hz, 1H), 4.02 (d, J = 2.4Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.24 (t, J = 2.4Hz, 1H).

[1684] Step 2: Synthesis of Compounds 1-3

[1685] Compound 1-2 (7.5 g, 34.2 mmol) was dissolved in a mixture of methanol (90 mL), water (30 mL), and tetrahydrofuran (30 mL). Lithium hydroxide (4.1 g, 171.2 mmol) was added and the mixture was heated to 40°C under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the mixture was dissolved in water (100 mL). The pH was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2) and concentrated under reduced pressure to obtain compound 1-3. MS m / z (ESI): 205.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),7.50(dd,J=1.6,8.4Hz,1H),7.32(d,J=1.6Hz,1H),6.66(d,J =8.4Hz, 1H), 6.12 (t, J = 6.0Hz, 1H), 3.98 (dd, J = 2.4, 6.0Hz, 2H), 3.83 (s, 3H), 3.08 (t, J = 2.4Hz, 1H).

[1686] Step 3: Synthesis of compound 1-4:

[1687] To a solution of compound 1-3 (7.2 g, 35.1 mmol) in N,N-dimethylformamide (100 mL) were added HATU (20.0 g, 52.7 mmol), methylamine hydrochloride (4.7 g, 70.2 mmol), and N,N-diisopropylethylamine (24.5 mL, 140.4 mmol) in sequence. The reaction mixture was stirred at room temperature under nitrogen for 4 hours. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 2) and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 1-4. MS m / z (ESI): 219.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.22-8.05(m,1H),7.38(dd,J=2.0,8.0Hz,1H),7.32(s,1H),6.62(d,J=8.4Hz,1H),5 .81(t,J=6.0Hz,1H),3.95(dd,J=2.4,6.4Hz,2H),3.82(s,3H),3.05(t,J=2.4Hz,1H),2.75(d,J=4.4Hz,3H).

[1688] Step 4: Synthesis of Compounds 1-6

[1689] Under nitrogen protection, N-methylimidazole (4.3 mL, 54.3 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (4.0 g, 14.3 mmol) were added to a solution of compound 1-5 (2.0 g, 15.4 mmol) and 4,4,4-trifluorobutyric acid (1.7 g, 11.9 mmol) in acetonitrile (31 mL). The mixture was heated to 85°C and stirred for 12 hours under nitrogen protection. The mixture was poured into water (150 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 1-6. MS m / z (ESI): 253.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.30 (d, J = 2.4Hz, 1H), 8.12 (d, J = 2.4Hz, 1H), 8.07 (s, 1H), 3.14-3.08 (m, 2H), 2.66-2.54 (m, 2H).

[1690] Step 5: Synthesis of Compounds 1-7

[1691] Under nitrogen protection, triethylamine (1.6 mL, 11.6 mmol) and thionyl chloride (0.8 mL, 11.6 mmol) were added dropwise to a solution of compound 1-6 (1.4 g, 5.5 mmol) in chloroform (10 mL). The mixture was heated to 90°C in a microwave oven under nitrogen protection and stirred for 15 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (100 mL) was added and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 1-7. MS m / z (ESI): 269.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 4.8 Hz, 1H), 7.84 (d, J = 4.8 Hz, 1H), 3.81 (q, J = 9.6 Hz, 2H).

[1692] Step 6: Synthesis of Compounds 1-8

[1693] Under nitrogen, 4-amino-1-methylpiperidine (0.09 mL, 0.74 mmol) was added to a solution of compound 1-7 (200 mg, 0.67 mmol) in pyridine (2.0 mL). The mixture was heated to 110°C and stirred for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 1-8. MS m / z (ESI): 348.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.45(d,J=4.8Hz,1H),7.25(d,J=4.8Hz,1H),5.86(d,J=8.0Hz,1H),4.16-4.01(m,1H),3 .68(q,J=9.6Hz,2H),2.89-2.85(m,2H),2.32(s,3H),2.26-2.16(m,2H),2.15-2.07(m,2H),1.76-1.68(m,2H).

[1694] Step 7: Synthesis of Compound 1

[1695] Under nitrogen protection, compound 1-4 (8.0 mg, 0.04 mmol) was added to a solution of compound 1-8 (10 mg, 0.03 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.0 mg, 0.01 mmol), bis(acetonitrile)palladium chloride (1.0 mg, 0.01 mmol), and Cs2CO3 (25 mg, 0.08 mmol) in acetonitrile (1.0 mL). The mixture was heated to 90°C and stirred for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with acetonitrile (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 1. MS m / z (ESI): = 530.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=4.4Hz,1H),7.71(d,J=4.8Hz,1H),7.45(d,J=8.0Hz,1H),7. 40(dd,J=2.0,8.0Hz,1H),7.35-7.33(m,2H),6.72(d,J=8.4Hz,1H),5.99(t,J=6.4Hz,1H),4.26 (d,J=6.4Hz,2H),4.01(q,J=10.4Hz,2H),3.95-3.87(m,1H),3.83(s,3H),2.81-2.71(m,2H),2. 74(d,J=4.4Hz,3H),2.16(s,3H),1.96(t,J=12.0Hz,2H),1.85-1.73(m,2H),1.70-1.57(m,2H).

[1696] Preparation Example 2, Preparation of Compound 2

[1697] Synthesis route:

[1698] Step 1: Synthesis of compound 2-2

[1699] Under nitrogen protection, N-methylimidazole (3.2 mL, 40.4 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.0 g, 10.6 mmol) were added to a solution of compound 2-1 (2.0 g, 11.5 mmol) and 4,4,4-trifluorobutyric acid (1.3 g, 8.8 mmol) in acetonitrile (22 mL). The mixture was heated to 85°C and stirred for 12 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was poured into water (150 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2) and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 2-2. MS m / z (ESI): 297.8 / 299.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.76 (d, J = 2.4Hz, 1H), 8.63 (d, J = 2.0Hz, 1H), 7.99 (s, 1H), 3.27-3.20 (m, 2H), 2.61-2.44 (m, 2H).

[1700] Step 2: Synthesis of compound 2-3

[1701] Under nitrogen protection, triethylamine (1.0 mL, 7.2 mmol) and thionyl chloride (0.5 mL, 7.2 mmol) were added dropwise to a chloroform (10 mL) solution of compound 2-2 (1.0 g, 3.4 mmol). The mixture was heated to 90 ° C in a microwave under nitrogen protection and stirred for 15 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (100 mL) was added and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2) and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 2-3. MS m / z (ESI): 313.8 / 315.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.86 (s, 1H), 8.25 (s, 1H), 3.86 (q, J = 9.6Hz, 2H).

[1702] Step 3: Synthesis of Compound 2-4

[1703] Under nitrogen, palladium acetate (251 mg, 1.12 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.07 g, 2.24 mmol) were added to a toluene (28 mL) solution of compound 2-3 (280 mg, 0.89 mmol), 4-amino-1-methylpiperidine (510 mg, 4.47 mmol), and sodium tert-butoxide (644 mg, 6.71 mmol). The mixture was heated to 110°C and stirred for 2 hours under nitrogen. After the reaction mixture cooled to room temperature, it was filtered, the filter cake was washed with methanol (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 2-4. MS m / z (ESI): = 348.0 [M+H] + .

[1704] Step 4: Synthesis of compound 2

[1705] Under nitrogen protection, compound 1-4 (38 mg, 0.17 mmol) was added to a solution of compound 2-4 (30 mg, 0.08 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol), bis(acetonitrile)palladium chloride (3.0 mg, 0.01 mmol) and cesium carbonate (73 mg, 0.22 mmol) in acetonitrile (1.0 mL). The mixture was heated to 90°C and stirred for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 2. MS m / z (ESI): 530.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.10 (d, J = 4.8Hz, 1H), 7.41 (dd, J = 2.0, 8.4Hz, 1H),7.35(d,J=2.0Hz,1H),7.18(s,1H),6.73(d,J=8.4Hz,1H),6.02-5.91(m,2H),4 .28(d,J=6.4Hz,2H),4.10(q,J=10.4Hz,2H),3.84(s,3H),3.83-3.80(m,1H),2.81- 2.68(m,5H),2.15(s,3H),2.04-1.93(m,2H),1.89-1.80(m,2H),1.63-1.48(m,2H).

[1706] Preparation Example 3, Preparation of Compound 3

[1707] Synthesis route:

[1708] Step 1: Synthesis of compound 3-2

[1709] Compound 3-1 (6.0 g, 35.1 mmol) was added to a mixed solution of 20% sodium thiomethoxide aqueous solution (16 mL) and N,N-dimethylformamide (50 mL) at 0°C. The reaction solution was stirred at room temperature for 2 hours under nitrogen. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (300 mL x 2) and concentrated under reduced pressure to obtain compound 3-2. MS m / z (ESI): 199.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 2.0, 8.4 Hz, 1H), 3.89 (s, 3H), 2.47 (s, 3H).

[1710] Step 2: Synthesis of compound 3-3

[1711] To a mixed solution of compound 3-2 (3.5 g, 17.6 mmol) in acetone (30 mL), water (30 mL), and methanol (3 mL) was added Oxone (27.0 g, 43.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium thiosulfate solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (300 mL x 2). The organic phases were concentrated under reduced pressure to obtain compound 3-3. 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 1.6, 8.4 Hz, 1H), 3.99 (s, 3H), 3.04 (s, 3H).

[1712] Step 3: Synthesis of compound 3-4

[1713] To a solution of compound 3-3 (3.5 g, 15.14 mmol) in ethanol (30 mL) and water (10 mL) were added reduced iron powder (3.4 g, 60.55 mmol) and ammonium chloride (3.24 g, 60.55 mmol). The mixture was heated to 80°C and stirred for 2 hours under nitrogen. The reaction solution was filtered through celite while hot, and the celite was washed with methanol. The reaction solution was concentrated under reduced pressure and poured into water (50 mL). Extraction was performed with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phases were concentrated under reduced pressure to obtain compound 3-4. MS m / z (ESI): 201.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.39 (dd, J=2.0, 8.0Hz, 1H), 7.27 (d, J=0.8Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 4.44 (br s, 2H), 3.92 (s, 3H), 3.02 (s, 3H).

[1714] Step 4: Synthesis of Compound 3-5

[1715] Potassium carbonate (6.2 g, 14.91 mmol) and propargyl bromide (1.5 mL, 17.9 mmol) were added to a solution of compound 3-4 (3.0 g, 14.9 mmol) in N,N-dimethylformamide (10 mL). The mixture was heated to 70°C and stirred for 12 hours under nitrogen. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phases were concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography to obtain compound 3-5. MS m / z (ESI): 239.8 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.51(dd,J=2.0,8.4Hz,1H),7.26(s,1H),6.74(d,J=8.4H z, 1H), 4.04 (d, J = 2.4Hz, 2H), 3.92 (s, 3H), 3.03 (s, 3H), 2.26 (t, J = 2.4Hz, 1H).

[1716] Step 5: Synthesis of Compounds 3-7

[1717] Under nitrogen protection, N-methylimidazole (3.2 mL, 40.4 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.0 g, 10.6 mmol) were added to a solution of compound 3-6 (2.0 g, 11.5 mmol) and 4,4,4-trifluorobutyric acid (1.3 g, 8.8 mmol) in acetonitrile (22 mL). The mixture was stirred at 25 ° C for 12 hours under nitrogen protection. The reaction solution was dissolved in water (150 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phase was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 3-7. MS m / z (ESI): 296.8 / 298.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.76 (d, J = 3.2 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 3.25-3.22 (m, 2H), 2.56-2.50 (m, 2H).

[1718] Step 6: Synthesis of Compound 3-8

[1719] Under nitrogen protection, triethylamine (1.0 mL, 7.2 mmol) and thionyl chloride (0.5 mL, 7.2 mmol) were added dropwise to a solution of compound 3-7 (1.0 g, 3.4 mmol) in chloroform (10.0 mL) in sequence. The mixture was heated to 90°C in a microwave oven under nitrogen protection and stirred for 15 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (100 mL) was added and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2) and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 3-8. MS m / z (ESI): 312.8 / 314.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=6.8Hz,1H),7.79(dd,J=0.8,7.6Hz,1H),7.07(d,J=7.2Hz,1H),4.25(q,J=10.8Hz,2H).

[1720] Step 7: Synthesis of Compound 3-9

[1721] Under nitrogen protection, palladium acetate (34 mg, 0.15 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (143 mg, 0.3 mmol) were added to a solution of compound 3-8 (470 mg, 1.5 mmol), cis-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (390 mg, 1.8 mmol), and cesium carbonate (980 mg, 3.0 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 110°C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with methanol (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 3-9. MS m / z (ESI): 451.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.41(d,J=6.8Hz,1H),6.83(t,J=7.2Hz,1H),6.26(d,J=7.2Hz,1H),4.88-4.76(m,1H),4. 45-4.28(m,2H),3.72(q,J=10.0Hz,2H),3.68-3.62(m,1H),3.22-2.84(m,2H),1.95-1.92(m,2H),1.48(s,9H).

[1722] Step 8: Synthesis of Compound 3-10

[1723] Under nitrogen protection, compound 3-9 (160 mg, 0.35 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (51 mg, 0.11 mmol), bis(acetonitrile)palladium chloride (9 mg, 0.03 mmol) and cesium carbonate (297 mg, 0.91 mmol) in acetonitrile (1.0 mL) were added compound 3-5 (109 mg, 0.46 mmol). The mixture was heated to 90°C and stirred for 1.5 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 3-10. MS m / z (ESI): 654.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.52(dd,J=2.0,8.4Hz,1H),7.36(d,J=6.8Hz,1H),7.27-7.25(m,2H),6.84-6.80(m,2H),6.17(br s,1H),5.16(t,J=6.0Hz,1H),4.34(d,J=6.0Hz,2H),3.94-3.91(m,5H),3.71-3.64(m,3H),3.07-3.02(m,6H),1.92(br s,2H),1.48(s,9H).

[1724] Step 9: Synthesis of Compound 3-11

[1725] Under nitrogen protection, compound 3-10 (70 mg, 0.11 mmol) was dissolved in a hydrochloric acid-dioxane solution (5 mL, 4 M). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 2). The organic phases were concentrated under reduced pressure to give the crude product compound 3-11. MS m / z (ESI): 554.2 [M+H] + .

[1726] Step 10: Synthesis of compound 3

[1727] Under nitrogen protection, paraformaldehyde (13.5 mg, 0.45 mmol), sodium cyanoborohydride (27 mg, 0.45 mmol) and acetic acid (20 μL) were added to a solution of compound 3-11 (50 mg, 0.09 mmol) in methanol (5 mL). The mixture was heated to 50°C and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 2). The organic phases were concentrated under reduced pressure and the crude product was purified by reverse phase flash chromatography to obtain compound 3. MS m / z (ESI): 568.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.80(d,J=6.8Hz,1H),7.39(dd,J=2.0,8.4Hz,1H),7.25(d,J=2.0Hz,1H),6.87(d,J =8.4Hz,1H),6.83(t,J=7.2Hz,1H),6.50(t,J=6.0Hz,1H),6.40(d,J=7.6Hz,1H),5.38(d,J=9.2Hz,1H),4.8 8(d,J=52.0Hz,1H),4.31(d,J=6.0Hz,2H),4.04(q,J=10.4Hz,2H),3.89(s,3H),3.73(m,1H),3.10(s,3H),3 .03-3.00(m,1H),2.78-2.63(m,1H),2.30-2.26(m,1H),2.18(s,3H),2.11-2.06(m,1H),1.85-1.74(m,2H).

[1728] Preparation Example 4, Preparation of Compound 4

[1729] Synthesis route:

[1730] Step 1: Synthesis of compound 4-1

[1731] Under nitrogen protection, palladium acetate (17 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (72 mg, 0.15 mmol) were added to a solution of compound 3-8 (240 mg, 0.77 mmol), 4-amino-1-methylpiperidine (100 mg, 0.9 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 110°C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with methanol (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 4-1. MS m / z (ESI): 347.0 [M+H] + .

[1732] Step 2: Synthesis of compound 4

[1733] Under nitrogen protection, compound 3-5 (43 mg, 0.18 mmol) was added to a solution of compound 4-1 (50 mg, 0.14 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (20 mg, 0.04 mmol), bis(acetonitrile)palladium chloride (3.6 mg, 0.014 mmol) and cesium carbonate (119 mg, 0.36 mmol) in acetonitrile (1.0 mL). The mixture was heated to 90°C and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with acetonitrile (5.0 mL x 3) and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 4. MS m / z (ESI): 550.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.72(d,J=6.8Hz,1H),7.39(dd,J=2.0,8.4Hz,1H),7.25(d,J=2. 0Hz,1H),6.86(d,J=8.4Hz,1H),6.80(t,J=7.2Hz,1H),6.50(t,J=6.4Hz,1H),6.22(d,J=7.6Hz,1H),5 .72(d,J=8.4Hz,1H),4.31(d,J=6.4Hz,2H),4.03(q,J=10.8Hz,2H),3.89(s,3H),3.49-3.45(m,1H),3 .10(s,3H),2.75-2.67(m,2H),2.17(s,3H),2.05-2.00(m,2H),1.89-1.84(m,2H),1.60-1.51(m,2H).

[1734] Preparation Example 5, Preparation of Compound 5

[1735] Synthesis route:

[1736] Step 1: Synthesis of compound 5-1

[1737] Under nitrogen, trifluoroacetic acid (1.0 mL, 13.42 mmol) was added to a solution of compound 3-9 (600 mg, 0.64 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 0.5 hours under nitrogen. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (60 mL) and extracted with dichloromethane (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 5-1. MS m / z (ESI): 351.0 [M+H]+. 1H NMR (400MHz, CDCl3) δ7.39(d,J=6.8Hz,1H),6.78(t,J=7.2Hz,1H),6.21(d,J=7.6Hz,1H),5.38(d,J=9.2Hz,1H),4.84–4.81(m,1H),3.71(q,J=10 .0Hz,2H),3.66–3.57(m,1H),3.51–3.40(m,1H),3.29–3.21(m,1H),3.0 1–2.84(m,1H),2.84–2.74(m,1H),2.03–1.94(m,1H),1.88–1.75(m,1H).

[1738] Step 2: Synthesis of compound 5-2

[1739] Under nitrogen, sodium cyanoborohydride (48 mg, 0.76 mmol) was added to a solution of compound 5-1 (267 mg, 0.61 mmol), paraformaldehyde (114 mg, 3.80 mmol), and acetic acid (13 mg, 0.21 mmol) in methanol (6.0 mL). The reaction mixture was stirred at 50°C for 2 hours under nitrogen. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 5-2. MS m / z (ESI): 365.0 [M+H]+. 1H NMR (400MHz, CDCl3) δ7.38(d,J=6.8Hz,1H),6.81–6.75(m,1H),6.19(d,J=7.6Hz,1H),5.37(d,J=9.2Hz,1H),4.96–4.76(m,1H),3. 71(q,J=10.0Hz,2H),3.63–3.45(m,1H),3.29–3.14(m,1H),3.02–2.88(m,1H),2.35(s,3H),2.32–2.12(m,2H),2.08–1.92(m,2H).

[1740] Step 3: Synthesis of compound 5

[1741] Under nitrogen protection, compound 1-4 (120 mg, 0.55 mmol) was added to a solution of compound 5-2 (100 mg, 0.25 mmol), 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (40 mg, 0.08 mmol), cesium carbonate (224 mg, 0.69 mmol) and bis(acetonitrile)palladium chloride (8.0 mg, 0.03 mmol) in acetonitrile (4.0 mL). Under nitrogen protection, the reaction solution was stirred at 90 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered and the filter cake was washed with acetonitrile (10 mL x3). After the filtrate was concentrated, compound 5 was obtained by SFC preparation and reverse phase flash chromatography. MS m / z (ESI): 547.3 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.09(d,J=4.8Hz,1H),7.78(d,J=6.8Hz,1H),7.41(dd,J=2.0,8.4Hz,1H),7.34(d,J=2. 0Hz,1H),6.82(t,J=7.2Hz,1H),6.74(d,J=8.4Hz,1H),6.39(d,J=7.6Hz,1H),5.95(t,J=6.4Hz,1H),5.37(d,J= 9.2Hz,1H),4.81(d,J=49.2Hz,1H),4.26(d,J=6.4Hz,2H),4.01(q,J=10.8Hz,2H),3.84(s,3H),3.78–3.60(m,1 H),3.08–2.96(m,1H),2.81–2.70(m,4H),2.31–2.22(m,1H),2.19(s,3H),2.14–2.04(m,1H),1.87–1.67(m,2H).

[1742] Preparation Example 6, Preparation of Compound 6

[1743] Synthesis route:

[1744] Step 1: Synthesis of compound 6-1

[1745] Under nitrogen, palladium acetate (0.144 g, 0.64 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.611 g, 1.28 mmol) were added to a solution of compound 3-8 (2.0 g, 3.06 mmol), tert-butyl carbamate (1.13 g, 9.65 mmol), and cesium carbonate (2.09 g, 6.41 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 110°C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was filtered, the filter cake was washed with acetonitrile (20 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 6-1. 1H NMR (400 MHz, CDCl3) δ7.91 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J = 6.8 Hz, 1H), 6.92 (dd, J = 6.8, 7.6 Hz, 1H), 3.74 (q, J = 10.0 Hz, 2H), 1.53 (s, 9H).

[1746] Step 2: Synthesis of compound 6-2

[1747] Under nitrogen, trifluoroacetic acid (4.0 mL, 53.67 mmol) was added to a solution of compound 6-1 (1.55 g, 3.99 mmol) in dichloromethane (20 mL). The mixture was stirred at 25°C for 2 hours under nitrogen. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 6-2. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 6.8 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.43 (dd, J = 0.8, 7.6 Hz, 1H), 4.52 (s, 2H), 3.71 (q, J = 10.0 Hz, 2H).

[1748] Step 3: Synthesis of compound 6-3

[1749] To a solution of compound 6-2 (150 mg, 0.54 mmol) and 4,4-difluorocyclohexanone (190.92 mg, 1.35 mmol) in N,N-dimethylformamide (3 mL) was added trimethylsilyl chloride (0.17 mL, 1.35 mmol). The reaction mixture was stirred at 25°C for 2 hours under nitrogen. Borane in tetrahydrofuran (2.70 mL, 1 M) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 25°C for another 2 hours. The reaction mixture was quenched with saturated sodium carbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 6-3. MS m / z (ESI): 368.0 [M+H]+.

[1750] Step 4: Synthesis of compound 6

[1751] Under nitrogen, compound 1-4 (60 mg, 0.23 mmol) was added to a solution of compound 6-3 (50 mg, 0.13 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (40 mg, 0.08 mmol), cesium carbonate (112 mg, 0.34 mmol), and bis(acetonitrile)palladium chloride (8.0 mg, 0.03 mmol) in acetonitrile (2.0 mL). The reaction mixture was stirred at 90°C for 2 hours under nitrogen. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with acetonitrile (10 mL x 3). The filtrate was concentrated and purified by reverse-phase flash chromatography to yield compound 6. MS m / z (ESI): 550.2 [M+H]+. 1HNMR (400MHz, CDCl3) δ7.36 (d, J = 2.0Hz, 1H), 7.31 (d, J = 6.8Hz, 1H), 7.22 (dd, J =2.0,8.4Hz,1H),6.81–6.70(m,2H),6.14(d,J=7.6Hz,1H),6.06(brs,1H),5.19 –5.16(m,1H),4.90(brs,1H),4.29(s,2H),3.90(s,3H),3.63(q,J=10.0Hz,2H), 3.55–3.50(m,1H),2.99(d,J=4.8Hz,3H),2.22–2.08(m,4H),2.04–1.74(m,4H).

[1752] Preparation Example 7, Preparation of Compound 7

[1753] Synthesis route:

[1754] Step 1: Synthesis of compound 7-1

[1755] Under nitrogen protection, trimethylsilyl chloride (0.61 mL, 4.76 mmol) was added to a solution of compound 6-2 (500 mg, 1.90 mmol) and N-tert-butyloxycarbonyl-4-piperidone (134 mg, 0.95 mmol) in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at room temperature for 2 hours. Borane tetrahydrofuran (4.76 mL, 4.76 mmol) was then added dropwise to the reaction solution, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with saturated sodium carbonate solution (20 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 7-1. MS m / z (ESI): 433.2 [M+H] + .

[1756] Step 2: Synthesis of compound 7-2

[1757] To a solution of compound 7-1 (620 mg, 1.29 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2.5 mL, 33.55 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 7-2. MS m / z (ESI): 333.2 [M+H] + .

[1758] Step 3: Synthesis of compound 7-3

[1759] In an ice bath, potassium hydroxide (18 mg, 0.31 mmol) was added to a solution of compound 7-2 (0.03 mL, 0.27 mmol) in methanol (2 mL), and the reaction solution was stirred in an ice bath for 15 minutes. 1-Chloro-3-methoxy-2-propanol (33 mg, 0.09 mmol) was added to the reaction solution, and the reaction solution was stirred at 50°C for 3 hours. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain compound 7-3. MS m / z (ESI): 421.0 [M+H] + .

[1760] Step 4: Synthesis of compound 7

[1761] Under nitrogen protection, bis(acetonitrile)palladium chloride (1.6 mg, 0.01 mmol) was added to a mixture of compound 7-3 (30 mg, 0.06 mmol), cesium carbonate (52 mg, 0.16 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.01 mmol) in acetonitrile (2 mL). The reaction solution was stirred at 100°C for 10 minutes. Compound 1-4 (28 mg, 0.13 mmol) was added to the reaction solution, and the reaction solution was stirred at 100°C under nitrogen protection for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was washed with acetonitrile (4 mL x 3). The filtrate was concentrated and purified by reverse phase flash chromatography to obtain compound 7. MS m / z (ESI): 603.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=4.8Hz,1H),7.77(d,J=6.4Hz,1H),7.41(d,J=8.0Hz,1H), 7.35(s,1H),6.83(t,J=7.2Hz,1H),6.73(d,J=8.0Hz,1H),6.29(d,J=7.6Hz,1H),6.09(brs,1 H),5.98(brs,1H),5.77–5.66(m,1H),4.27(d,J=6.4Hz,2H),4.11–3.98(m,3H),3.85(s,3H), 3.68–3.53(m,2H).3.30(s,3H),3.21–2.98(m,7H),2.75(d,J=4.4Hz,3H),2.03–1.77(m,4H).

[1762] Preparation Example 8, Preparation of Compound 8

[1763] Synthesis route:

[1764] Step 1: Synthesis of compound 8-1

[1765] Under nitrogen, to a mixture of compound 3-8 (230 mg, 0.73 mmol), 4-aminotetrahydropyran (0.11 mL, 1.10 mmol), sodium tert-butoxide (211 mg, 2.20 mmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.07 mmol) in toluene (5 mL) was added methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (58 mg, 0.07 mmol). The reaction mixture was stirred at 80°C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 8-1. 1 H NMR(400MHz, CDCl3) δ7.29(d,J=6.8Hz,1H),6.76–6.63(m,1H),6.16(d,J=7.6Hz,1H),5.03–4.9 2(m,1H),3.98(dt,J=3.6,11.8Hz,2H),3.76–3.42(m,5H),2.04–1.97(m,2H),1.63–1.55(m,2H).

[1766] Step 2: Synthesis of compound 8

[1767] Under nitrogen protection, bis(acetonitrile)palladium chloride (4 mg, 0.02 mmol) was added to a solution of compound 8-1 (40 mg, 0.12 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol) and cesium carbonate (102 mg, 0.31 mmol) in acetonitrile (1 mL), and the reaction solution was stirred at 90°C for 20 minutes. Compound 1-4 (53 mg, 0.24 mmol) was added to the reaction solution. The reaction solution was stirred at 90°C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 8. MS m / z (ESI): 516.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=4.8Hz,1H),7.72(d,J=6.8Hz,1H),7.41(dd,J=2.0,8.4Hz,1H),7 .35(d,J=2.0Hz,1H),6.80(t,J=7.2Hz,1H),6.74(d,J=8.4Hz,1H),6.28(d,J=7.6Hz,1H),5.98(t,J= 6.4Hz,1H),5.86(d,J=8.4Hz,1H),4.27(d,J=6.4Hz,2H),4.02(d,J=10.4Hz,2H),3.91–3.82(m,5H) ,3.63–3.58(m,1H),3.51–3.46(m,2H),2.75(d,J=4.4Hz,3H),1.89–1.84(m,2H),1.60–1.55(m,2H).

[1768] Preparation Example 9, Preparation of Compound 9

[1769] Synthesis route:

[1770] Step 1: Synthesis of compound 9-1

[1771] To a solution of compound 3-8 (300 mg, 0.96 mmol) and tert-butyl trans-(4-aminocyclohexyl)carbamate (310 mg, 1.45 mmol) in 1,4-dioxane (10 mL) were added cesium carbonate (936 mg, 2.87 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (457 mg, 0.96 mmol), and palladium acetate (108 mg, 0.48 mmol). The mixture was stirred at 100°C under nitrogen for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 9-1. MS m / z (ESI): 447.2 [M+H] + .

[1772] Step 2: Synthesis of compound 9-2

[1773] To a solution of compound 9-1 (230 mg, 0.51 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.8 mL), and the reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution to quench the mixture, extracted with ethyl acetate (20 mL x 2), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 9-2. MS m / z (ESI): 347.0 [M+H] + .

[1774] Step 3: Synthesis of compound 9-3

[1775] To a solution of compound 9-2 (175 mg, 0.50 mmol) and 3,3-bis(bromomethyl)oxetane (310 mg, 1.27 mmol) in acetonitrile (4 mL) was added sodium carbonate (375 mg, 3.54 mmol), and the reaction mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (5 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 9-3. MS m / z (ESI): 429.2 [M+H] + .

[1776] Step 4: Synthesis of compound 9

[1777] Under nitrogen protection, bis(acetonitrile)palladium chloride (3 mg, 0.01 mmol) was added to a mixture of compound 9-3 (20 mg, 0.05 mmol), cesium carbonate (37 mg, 0.11 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9 mg, 0.02 mmol) in acetonitrile (2 mL), and the reaction solution was stirred at 90°C for 10 minutes. Compound 1-4 (41 mg, 0.19 mmol) was added to the reaction solution, and the reaction solution was stirred at 90°C for 3 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 9. MS m / z (ESI): 611.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.37(d,J=2.0Hz,1H),7.29(s,1H),7.22(dd,J=2.0,8.0Hz,1H),6 .78–6.69(m,2H),6.12(d,J=7.6Hz,1H),6.01(s,1H),5.05(d,J=8.0Hz,1H),4.89(t,J=6 .4Hz,1H),4.75(s,4H),4.29(d,J=6.4Hz,2H),3.91(s,3H),3.63(d,J=10.0Hz,2H),3.39 (s,6H),3.00(d,J=4.8Hz,3H),2.19–2.11(m,2H),1.91–1.83(m,2H),1.31–1.08(m,4H).

[1778] Preparation Example 10, Preparation of Compound 10

[1779] Synthesis route:

[1780] Step 1: Synthesis of compound 10-1

[1781] Under nitrogen protection, palladium acetate (15 mg, 0.07 mmol) was added to a mixture of compound 3-8 (200 mg, 0.64 mmol), 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (170 mg, 0.92 mmol), cesium carbonate (624 mg, 1.92 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (40 mg, 0.06 mmol) in toluene (5 mL). The reaction solution was stirred at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 10-1. MS m / z (ESI): 381.1 [M+H] + .

[1782] Step 2: Synthesis of compound 10:

[1783] Under nitrogen protection, bis(acetonitrile)palladium chloride (13 mg, 0.05 mmol) was added to a mixture of compound 10-1 (40 mg, 0.10 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (24 mg, 0.05 mmol) and cesium carbonate (88 mg, 0.27 mmol) in acetonitrile (2 mL), and the reaction solution was stirred at 90 ° C for 20 minutes. Compound 1-4 (100 mg, 0.46 mmol) was added to the reaction solution. The reaction solution was stirred at 90 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (3 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 10. MS m / z (ESI): 564.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6) δ8.11(d,J=4.8Hz,1H),7.75(d,J=6.8Hz,1H),7.41(d,J=8.4Hz,1H),7.34(d,J=2 .0Hz,1H),6.83(t,J=7.2Hz,1H),6.73(d,J=8.4Hz,1H),6.28–6.21(m,2H),5.97(t,J=6.4Hz ,1H),4.26(d,J=6.4Hz,2H),4.02(d,J=10.4Hz,2H),3.84(s,3H),3.83–3.79(m,1H),3.29–3 .23(m,2H),3.16–3.11(m,2H),2.75(d,J=4.4Hz,3H),2.17–2.13(m,2H),2.08–2.03(m,2H).

[1784] Preparation Example 11, Preparation of Compound 11

[1785] Synthesis route:

[1786] Step 1: Synthesis of compound 11-2

[1787] To a solution of compound 11-1 (200 mg, 1.35 mmol) in N,N-dimethylformamide (2 mL) were added 3-bromopropyne (0.17 mL, 2.02 mmol) and potassium carbonate (560 mg, 4.05 mmol). The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 11-1. MS m / z (ESI): 187.3 [M+H] + .

[1788] Step 2: Synthesis of compound 11

[1789] To a solution of compound 11-2 (25 mg, 0.07 mmol) in acetonitrile (1 mL) were added compound 4-2 (54 mg, 0.29 mmol), bis(acetonitrile)palladium chloride (3.7 mg, 0.01 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (21 mg, 0.04 mmol), and cesium carbonate (61 mg, 0.19 mmol). The reaction mixture was stirred at 90°C for 2 hours under nitrogen. After the reaction mixture was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (3 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 11. MS m / z (ESI): 497.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.27(brs,1H),7.27(d,J=6.8Hz,1H),7.18(d,J=2.0Hz,1H),6.8 9(d,J=2.0Hz,1H),6.73–6.65(m,2H),6.08(d,J=7.6Hz,1H),5.12(d,J=7.2Hz,1H),5.0 5(t,J=6.0Hz,1H),4.24(d,J=6.0Hz,2H),3.81(s,3H),3.59(q,J=10.0Hz,2H),3.52–3. 48(m,1H),3.03–2.97(m,2H),2.73–2.42(m,5H),2.20–1.86(m,2H),1.80–1.77(m,2H).

[1790] Preparation Example 12, Preparation of Compound 12

[1791] Synthesis route:

[1792] Step 1: Synthesis of compound 12-2

[1793] Compound 12-1 (900 mg, 3.58 mmol) and bis[(4-methoxyphenyl)methyl]amine (0.93 mL, 3.89 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.7 mL, 4.22 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (20 mL, 2 M) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 12-2. 1 H NMR(400MHz, CDCl3)δ7.78(d,J=8.4Hz,1H),7.36–7.30(m,1H),7.28(d,J=1.8Hz,1H) ,6.96(d,J=8.4Hz,4H),6.72(d,J=8.4Hz,4H),4.24(s,4H),3.83(s,3H),3.72(s,6H).

[1794] Step: Synthesis of compound 12-3

[1795] Iron powder (1.0 g, 17.91 mmol) was added to a mixture of compound 12-2 (2.0 g, 4.23 mmol) and ammonium chloride (496 mg, 9.35 mmol) in water (10 mL) and ethanol (40 mL). The mixture was stirred at 75°C for 2 hours. After the reaction mixture cooled to room temperature, it was filtered, the filter cake was washed with ethanol (20 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 12-3. MS m / z (ESI): 443.0 [M+H] + .

[1796] Step 3: Synthesis of compound 12-4

[1797] To a mixture of compound 12-3 (1.4 g, 3.16 mmol) and potassium carbonate (1.3 g, 9.41 mmol) in N,N-dimethylformamide (10 mL) was added 3-bromopropyne (0.54 mL, 6.32 mmol), and the reaction mixture was stirred at 75°C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 12-4. 1 H NMR (400MHz, CDCl3) δ7.38(dd,J=2.0,8.4Hz,1H),7.04(d,J=2.0Hz,1H),6.98–6.87(m,4H),6.75–6.66( m, 4H), 6.62 (d, J = 8.4Hz, 1H), 4.14 (s, 4H), 4.06 (d, J = 6.8Hz, 2H), 3.96 (s, 1H), 3.74 (s, 3H), 3.71 (s, 6H).

[1798] Step 4: Synthesis of compound 12-5

[1799] Under nitrogen, a mixture of compound 12-4 (40 mg, 0.12 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22 mg, 0.05 mmol), bis(acetonitrile)palladium chloride (6 mg, 0.02 mmol), cesium carbonate (80 mg, 0.25 mmol), and acetonitrile (1 mL) was stirred at 90°C for 20 minutes. Compound 4-2 (220 mg, 0.46 mmol) was added to the reaction solution, and the reaction solution was stirred at 90°C for another 2 hours. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (5 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 12-5. MS m / z (ESI): 791.2 [M+H] + .

[1800] Step 5: Synthesis of compound 12

[1801] Compound 12-5 (25 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography to obtain compound 12. MS m / z (ESI): 551.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.54(d,J=6.8Hz,1H),7.36(dd,J=2.0,8.4Hz,1H),7.23(d,J=2.0Hz,1H),6.82–6.73(m,2H),6.27(d,J=7.6Hz,1H),4 .25(s,2H),3.85–3.72(m,5H),3.04–3.00(m,1H),2.60–2.55(m,2H), 2.45(s,3H),2.12–2.07(m,2H),1.70–1.62(m,2H),1.53–1.49(m,2H).

[1802] Preparation Example 13, Preparation of Compound 13

[1803] Synthesis route:

[1804] Step 1: Synthesis of compound 13-2

[1805] To a solution of compound 13-1 (1.59 mL, 11.82 mmol) in N,N-dimethylformamide (10 mL) were added 3-bromopropyne (1.22 mL, 14.19 mmol) and potassium carbonate (4.90 g, 35.47 mmol). The reaction solution was stirred at 70°C for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 13-2. MS m / z (ESI): 208.0 [M+H] + .

[1806] Step 2: Synthesis of compound 13-3

[1807] To a mixture of compound 13-2 (900 mg, 4.34 mmol) in methanol (13.5 mL), water (4.5 mL), and tetrahydrofuran (4.5 mL) was added lithium hydroxide (920 mg, 21.93 mmol), and the reaction mixture was stirred at 45°C for 18 hours. The reaction mixture was quenched with dilute hydrochloric acid (40 mL, 1 M) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 13-3. MS m / z (ESI): 194.0 [M+H] + .

[1808] Step 3: Synthesis of compound 13-4

[1809] To a solution of compound 13-3 (0.80 g, 4.14 mmol) in N,N-dimethylformamide (16 mL) were added methylamine (0.31 g, 4.56 mmol), N,N-diisopropylethylamine (3.5 mL, 21.12 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.89 g, 4.97 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 13-4. MS m / z (ESI): = 207.2 [M+H] + .

[1810] Step 4: Synthesis of compound 13

[1811] To a solution of compound 4-2 (30 mg, 0.09 mmol) in acetonitrile (1 mL) were added cesium carbonate (70 mg, 0.22 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16 mg, 0.03 mol), and bis(acetonitrile)palladium chloride (5 mg, 0.02 mmol). The reaction solution was stirred at 90°C for 10 minutes under nitrogen. Compound 13-4 (75 mg, 0.36 mmol) was added to the reaction solution, and the reaction solution was stirred at 90°C for 4 hours under nitrogen. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (5 mL x 3), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 13. MS m / z (ESI): 517.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.48–7.35(m,2H),7.23(d,J=6.8Hz,1H),6.80(t,J=8.4Hz,1H), 6.68(t,J=7.2Hz,1H),6.07(d,J=7.6Hz,1H),5.91(brs,1H),5.09(d,J=7.6Hz,1H),4. 53(brs,1H),4.25(d,J=6.4Hz,2H),3.58(q,J=10.0Hz,2H),3.38–3.32(m,1H),2.92(d ,J=4.8Hz,3H),2.84–2.80(m,2H),2.28(s,3H),2.21–1.95(m,4H),1.26–1.22(m,2H).

[1812] Preparation Example 14, Preparation of Compound 14

[1813] Synthesis route:

[1814] Step 1: Synthesis of compound 14-2

[1815] Under nitrogen, potassium phosphate (2.01 mg, 9.48 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (499 mg, 0.86 mmol), and palladium acetate (194 mg, 0.86 mmol) were added sequentially to a solution of compound 14-1 (2.0 g, 8.62 mmol) and dimethylphosphine oxide (740 mg, 9.48 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at 130°C for 12 hours under nitrogen. After the reaction solution cooled to room temperature, it was filtered and the filter cake was washed with dichloromethane (30 mL x 2). The filtrate was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL) and the solution was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 14-2. MS m / z (ESI): 229.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.89 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 1.6 Hz, 1H), 7.19 (dd, J = 1.6, 8.0 Hz, 1H), 4.05 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H).

[1816] Step 2: Synthesis of compound 14-3

[1817] Iron powder (1660 mg, 29.67 mmol) and ammonium chloride (1590 mg, 29.67 mmol) were added to a solution of compound 14-2 (1700 mg, 7.42 mmol) in ethanol (30 mL). The mixture was stirred at 80°C for 2 hours under nitrogen. After the reaction solution cooled to room temperature, it was filtered, the filter cake was washed with methanol (30 mL x 2), and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane (300 ml) and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-3. MS m / z (ESI): 199.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.12–7.00(m,2H),6.69(dd,J=3.2,8.0Hz,1H),5.26(brs,2H),3.80(s,3H),1.57(s,3H),1.53(s,3H).

[1818] Step 3: Synthesis of compound 14-4

[1819] To a solution of compound 14-3 (1.0 g, 5.02 mmol) in N,N-dimethylformamide (15 mL) were added propargyl bromide (0.65 mL, 7.53 mmol) and potassium carbonate (2.08 g, 15.06 mmol). The mixture was stirred at 80°C under nitrogen for 2 hours. After the reaction mixture cooled to room temperature, it was filtered and the filter cake was washed with dichloromethane (30 mL x 2). The filtrate was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL) and the solution was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 14-4. 1 H NMR (400MHz, CDCl3) δ7.15(d,J=1.6Hz,1H),7.05(dd,J=1.6,8.0Hz,1H),6.67(d,J=8.0Hz,1H),4.83–4 .65(m,1H),3.94(dd,J=2.4,6.4Hz,2H),3.84(s,3H),2.17(t,J=2.4Hz,1H),1.65(s,3H),1.62(s,3H).

[1820] Step 4: Synthesis of compound 14

[1821] Under nitrogen protection, a mixed solution of compound 5-2 (100 mg, 0.26 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (32 mg, 0.07 mmol), cesium carbonate (72 mg, 0.22 mmol), and bis(acetonitrile)palladium chloride (6.0 mg, 0.02 mmol) in acetonitrile (3.0 mL) was stirred at 25°C for 10 minutes. Compound 14-4 (120 mg, 0.55 mmol) was added to the reaction solution under nitrogen protection, and the mixture was stirred at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (5 mL x 3), and the filtrate was concentrated under reduced pressure. Compound 14 was purified by flash silica gel column chromatography. MS m / z (ESI): 566.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=6.8Hz,1H),7.25–7.18(m,1H),7.13(d,J=8.0Hz,1H) ,6.86–6.79(m,2H),6.39(d,J=7.6Hz,1H),6.02(brs,1H),5.38(d,J=9.2Hz,1H),4.82(d ,J=49.2Hz,1H),4.27(d,J=6.4Hz,2H),4.00(q,J=10.8Hz,2H),3.85(s,3H),3.78–3.60 (m,1H),3.03(t,J=11.2Hz,1H),2.79–2.75(m,1H),2.32–2.28(m,1H),2.19(s,3H),2.14 –2.04(m,1H),1.88–1.73(m,2H),1.59(s,3H),1.55(s,3H).

[1822] Preparation Example 15, Preparation of Compound 15

[1823] Synthesis route:

[1824] Step 1: Synthesis of compound 15-1

[1825] To a solution of compound 3-2 (3.4 g, 17.07 mmol) and ammonium formate (4.17 g, 68.27 mmol) in methanol (50 mL) was added iodobenzene diacetate (10.99 g, 34.13 mmol), and the reaction mixture was stirred open at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with water (40 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 15-1. 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.4Hz, 1H), 7.64 (d, J = 1.6Hz, 1H), 7.54 (dd, J = 1.6, 8.4Hz, 1H), 3.98 (s, 3H), 3.19 (s, 3H).

[1826] Step 2: Synthesis of compound 15-2

[1827] Potassium tert-butoxide (2.63 g, 23.45 mmol) was added to a solution of compound 15-1 (2.70 g, 11.73 mmol) and di-tert-butyl dicarbonate (5.02 mL, 23.45 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 15-2. 1 H NMR (400MHz, CDCl3) δ7.96 (d, J = 8.4Hz, 1H), 7.70 (d, J = 1.6Hz, 1H), 7.61 (dd, J = 1.6, 8.4Hz, 1H), 4.04 (s, 3H), 3.26 (s, 3H), 1.41 (s, 9H).

[1828] Step 3: Synthesis of compound 15-3

[1829] To a mixture of compound 15-2 (1.7 g, 5.15 mmol) in ethanol (30 mL) and water (10 mL) were added iron powder (1.15 g, 20.58 mmol) and ammonium chloride (1.10 g, 20.58 mmol). The mixture was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with methanol (50 mL x 2), and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane (200 ml) and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-3. MS m / z (ESI): 301.2 [M+H] + .

[1830] Step 4: Synthesis of compound 15-4

[1831] Compound 15-3 (1500 mg, 4.99 mmol), 3-bromopropyne (2 mL, 23.20 mmol), and potassium carbonate (2100 mg, 15.20 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 75°C for 2 hours. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 15-4. 1H NMR(400MHz, CDCl3)δ 7.46(dd,J=2.0,8.4Hz,1H),7.20(d,J=2.4Hz,1H),6.68(d,J=8.4Hz,1H),4.9 7(brs,1H),3.96(s,2H),3.84(s,3H),3.14(s,3H),2.27(s,1H),1.35(s,9H).

[1832] Step 5: Synthesis of compound 15-5

[1833] Under nitrogen, acetonitrile (2 mL) was added to a mixture of compound 4-2 (90 mg, 0.26 mmol), bis(acetonitrile)palladium chloride (14 mg, 0.05 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (50 mg, 0.10 mmol), and cesium carbonate (170 mg, 0.52 mmol). The reaction solution was stirred at 90°C for 20 minutes. Compound 15-4 (180 mg, 0.53 mmol) was added to the reaction solution. The reaction solution was stirred at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 15-5. MS m / z (ESI): 649.2 [M+H] + .

[1834] Step 6: Synthesis of compound 15

[1835] To a solution of compound 15-5 (10 mg, 0.02 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to yield compound 15. MS m / z (ESI): 549.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.64(d,J=6.8Hz,1H),7.57(dd,J=2.0,8.4Hz,1H),7.40(d,J =2.0Hz,1H),6.98(d,J=8.4Hz,1H),6.87(t,J=7.2Hz,1H),6.38(d,J=7.6Hz,1H),4 .40(s,2H),3.97(s,3H),3.95–3.84(m,2H),3.62–3.59(m,1H),3.13(s,3H),3.02– 2.95(m,2H),2.55–2.50(m,2H),2.45(s,3H),2.18–2.14(m,2H),1.74–1.70(m,2H).

[1836] Preparation Example 16, Preparation of Compound 16

[1837] Synthesis route:

[1838] Step 1: Synthesis of compound 16-2

[1839] To a solution of compound 16-1 (2.00 g, 6.62 mmol) in N,N-dimethylformamide (24 mL) were added bis-pinacol borate (2.52 g, 9.93 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (0.48 g, 0.66 mmol), and potassium acetate (1.95 g, 19.86 mmol). The reaction mixture was stirred at 100°C under nitrogen for 18 hours. After the reaction mixture cooled to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 16-2. 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.82(d,J=8.0Hz,1H),7.24(dd,J=1.2,8.0Hz,1H),7.16(d,J=1.2Hz,1H),3.82(s,3H),1.46(s,9H),1.28(s,12H).

[1840] Step 2: Synthesis of compound 16-3

[1841] Compound 16-2 (1.96 g, 5.61 mmol) was dissolved in water (6 mL) and 1,4-dioxane (24 mL). 2-Bromo-1,3-thiazole (1.01 mL, 11.22 mmol), tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol), and potassium phosphate (3.57 g, 16.84 mmol) were added. The reaction solution was stirred at 100°C under nitrogen for 18 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 16-3. MS m / z (ESI): 307.0 [M+H] + .

[1842] Step 3: Synthesis of compound 16-4

[1843] To a solution of compound 16-3 (1.3 g, 4.24 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydroxide (0.34 g, 8.49 mmol, 60%) under ice-cooling. The reaction mixture was stirred at 0°C for 0.5 hours under nitrogen. 3-Bromoprop-1-yne (0.73 mL, 8.49 mmol) was added to the reaction mixture, and stirring was continued at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to yield compound 16-4. MS m / z (ESI): 345.0 [M+H] + .

[1844] Step 4: Synthesis of compound 16-5

[1845] Compound 4-2 (28 mg, 0.08 mmol) was dissolved in acetonitrile (1.5 mL), and cesium carbonate (65 mg, 0.20 mmol), bis(acetonitrile)palladium chloride (5 mg, 0.02 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (16 mg, 0.03 mmol) were added. The reaction solution was stirred at 90°C for 10 minutes under nitrogen protection. Compound 16-4 (110 mg, 0.32 mmol) was added to the reaction solution and stirred at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with acetonitrile (10 mL x 2), and the filtrate was concentrated under reduced pressure to obtain compound 16-5. MS m / z (ESI): 655.2 [M+H] + .

[1846] Step 5: Synthesis of compound 16

[1847] To a solution of compound 16-5 (40 mg, 0.06 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL, 26.84 mmol). The reaction mixture was stirred at 25°C under nitrogen for 0.5 hours. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography to yield compound 16. MS m / z (ESI): 555.3 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.70(d,J=3.2Hz,1H),7.45–7.37(m,2H),7.22(d,J=6.8Hz,1H) ,7.13(d,J=3.2Hz,1H),6.76–6.64(m,2H),6.06(d,J=7.6Hz,1H),5.10(d,J=7.6Hz,1 H),4.80(t,J=6.4Hz,1H),4.24(d,J=6.4Hz,2H),3.88(s,3H),3.66–3.54(m,2H),3.4 1–3.37(m,1H),2.84–2.81(m,2H),2.28(s,3H),2.17–2.02(m,4H),1.70–1.58(m,2H).

[1848] Preparation Example 17, Preparation of Compound 17

[1849] Synthesis route:

[1850] Step 1: Synthesis of compound 17-1

[1851] To a solution of compound 6-1 (3.0 g, 8.58 mmol), potassium ferrocyanide (3.16 g, 8.58 mmol), and potassium acetate (1.26 g, 12.87 mmol) in 1,4-dioxane (30 mL) and water (30 mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (0.54 g, 0.64 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.29 g, 0.60 mmol). The reaction mixture was stirred at 100°C under nitrogen for 4 hours. After the reaction mixture cooled to room temperature, it was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 17-1. MS m / z (ESI): 341.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.92 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J = 6.8 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 3.83 (q, J = 9.6 Hz, 2H), 1.48 (s, 9H).

[1852] Step 2: Synthesis of compound 17-2

[1853] Sodium carbonate (156 mg, 1.47 mmol) was added to a mixture of compound 17-1 (500 mg, 1.47 mmol) and hydroxylamine hydrochloride (102 mg, 1.47 mmol) in ethanol (5 mL). The reaction mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered, the filter cake was washed with ethanol (10 mL x 2), and the filtrate was concentrated under reduced pressure to obtain compound 17-2. MS m / z (ESI): 374.2 [M+H] + .

[1854] Step 3: Synthesis of compound 17-3

[1855] At room temperature, chloroacetyl chloride (1.33 g, 11.80 mmol) was added to a solution of compound 17-2 (2.20 g, 5.9 mmol) and sodium carbonate (0.63 g, 5.90 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 17-3. MS m / z (ESI): 450.1 [M+H] + .

[1856] Step 4: Synthesis of compound 17-4

[1857] A solution of compound 17-3 (2.65 g, 5.9 mmol) in toluene (30 mL) was added. The reaction mixture was stirred at 110°C for 1 hour. After the reaction mixture cooled to room temperature, it was filtered and the filter cake was washed with toluene (10 mL x 2). The filter cake was evaporated to dryness under reduced pressure to obtain compound 17-4. MS m / z (ESI): 432.0 [M+H] + .

[1858] Step 5: Synthesis of compound 17-5

[1859] To a solution of compound 17-4 (2.0 g, 4.63 mmol) in N,N-dimethylformamide (20 mL) was added potassium phthalimide (0.90 g, 4.86 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was evaporated to dryness under reduced pressure to obtain compound 17-5. MS m / z (ESI): 543.2 [M+H] + .

[1860] Step 6: Synthesis of compound 17-6

[1861] To a solution of compound 17-5 (2.0 g, 3.69 mmol) in ethanol (20 mL) was added hydrazine hydrate (180 mg, 3.69 mmol), and the reaction mixture was stirred at 90°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 17-6. MS m / z (ESI): 413.1 [M+H] + .

[1862] Step 7: Synthesis of compound 17-7

[1863] To a solution of compound 17-6 (200 mg, 0.49 mmol) in tetrahydrofuran (2 mL) were added 1-tert-butyl-1H-pyrrole-3-carboxylic acid (81 mg, 0.49 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.46 mmol), and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 17-7. MS m / z (ESI): 562.2 [M+H] + .

[1864] Step 8: Synthesis of compound 17-8

[1865] Trifluoroacetic acid (0.4 mL) was added to a solution of compound 17-7 (110 mg, 0.20 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure to give compound 17-8. MS m / z (ESI): 461.8 [M+H] + .

[1866] Step 9: Synthesis of compound 17

[1867] Under nitrogen protection, trimethylsilyl chloride (0.20 mL, 1.56 mmol) was added to a solution of compound 17-8 (90 mg, 0.20 mmol) and N-methyl-4-piperidone (176 mg, 1.56 mmol) in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 2 hours. After the reaction solution was cooled to room temperature, borane tetrahydrofuran (1.5 mL, 1.5 mmol) was added dropwise to the reaction solution, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography to obtain compound 17. MS m / z (ESI): 559.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.67(t,J=5.6Hz,1H),7.88(d,J=6.8Hz,1H),7.55(t,J=2.0Hz,1H),7. 00(t,J=2.8Hz,1H),6.90(t,J=7.2Hz,1H),6.50(dd,J=1.6,3.0Hz,1H),6.32(d,J=7.6Hz,1H),5 .77(d,J=8.4Hz,1H),4.75(d,J=5.6Hz,2H),4.53(q,J=10.4Hz,2H),3.47–3.42(m,1H),2.81–2 .76(m,2H),2.21(s,3H),2.12–2.05(m,2H),1.95–1.88(m,2H),1.67–1.58(m,2H),1.50(s,9H).

[1868] Preparation Example 18, Preparation of Compound 18

[1869] Synthesis route:

[1870] Step 1: Synthesis of compound 18-1

[1871] To a solution of compound 17-1 (1.5 g, 4.41 mmol) in methanol (20 mL) was added thionyl chloride (1.60 mL, 22.04 mmol). The reaction mixture was stirred at 80°C under nitrogen for 12 hours. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 18-1. MS m / z (ESI): 274.4 [M+H] + .

[1872] Step 2: Synthesis of compound 18-2

[1873] Under nitrogen protection at room temperature, trimethylsilyl chloride (1.49 mL, 11.90 mmol) was added to a solution of compound 18-1 (1.3 g, 4.76 mmol) and 2-methylpropane-2-yl 4-oxopyridine-1-carboxylate (0.66 g, 3.33 mmol) in N,N-dimethylformamide (8 mL), and the mixture was stirred at 25°C for 1 hour. Borane tetrahydrofuran (7.14 mL, 7.14 mmol) was added to the reaction solution at 0°C and stirring was continued for 1 hour. The reaction mixture was poured into water. The aqueous layer was extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 18-2. MS m / z (ESI): 457.2 [M+H] + .

[1874] Step 3: Synthesis of compound 18-3

[1875] To a solution of compound 18-2 (1.2 g, 2.63 mmol) in ethanol (5 mL) was added hydrazine hydrate (5 mL, 2.00 mmol) at room temperature, and the reaction mixture was stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 18-3. MS m / z (ESI): 457.2 [M+H] + .

[1876] Step 4: Synthesis of compound 18-4

[1877] To a solution of compound 18-3 (1.0 g, 2.19 mmol) and Fmoc-glycine (1.1 g, 3.7 mmol) in acetonitrile (10 mL) were added tetramethyluronium chloride hexafluorophosphate (1.23 g, 4.38 mmol) and 1-methylimidazole (0.70 mL, 8.76 mmol). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 18-4. MS m / z (ESI): 736.3 [M+H] + .

[1878] Step 5: Synthesis of compound 18-5

[1879] To a solution of compound 18-4 (1.2 g, 1.63 mmol) in toluene (20 mL) was added Lawesson's reagent (1.32 g, 3.26 mmol). The reaction mixture was stirred at 100°C for 2 hours. After the reaction solution cooled to room temperature, it was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 18-5. MS m / z (ESI): 734.2 [M+H] + .

[1880] Step 6: Synthesis of compound 18-6

[1881] To a solution of compound 18-5 (500 mg, 0.68 mmol) in acetonitrile (5 mL) was added diethylamine (0.33 mL, 2.04 mmol) at room temperature. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated and purified by flash silica gel column chromatography to afford compound 18-6. MS m / z (ESI): 512.2 [M+H] + .

[1882] Step 7: Synthesis of compound 18-7

[1883] To a solution of compound 18-6 (100 mg, 0.20 mmol) and 4-bromo-3-methoxy-N-methylbenzamide (72 mg, 0.29 mmol) in toluene (1 mL) were added methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (16 mg, 0.02 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (9 mg, 0.02 mmol), and sodium tert-butoxide (56 mg, 0.58 mmol). The reaction mixture was stirred at 100°C under nitrogen for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain compound 18-7. MS m / z (ESI): 675.4 [M+H] + .

[1884] Step 8: Synthesis of compound 18-8

[1885] Trifluoroacetic acid (0.2 mL) was added to a solution of compound 18-7 (80 mg, 0.12 mmol) in dichloromethane (0.5 mL), and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 18-8. MS m / z (ESI): 574.8 [M+H] + .

[1886] Step 9: Synthesis of compound 18

[1887] Sodium cyanoborohydride (23 mg, 0.37 mmol) and acetic acid (0.01 mL, 0.01 mmol) were...

Claims

1. A compound of formula M, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, in: Ring A is selected from in,# N is the connection point between ring A and NH, $ L1 A ring and L 1 connected junctions; Each are each independently a single bond or a double bond; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 Each independently selected from C, CH, CR a , CR b , CR c , C(=O), N, NH, S; Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 Each independently selected from S, N, C, CH, CR d NR d ; Each R a 、R d Independently selected from deuterium, C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl are each independently optionally substituted by deuterium, halogen, hydroxyl, amino, cyano, or C3-C7 cycloalkyl; Each R b independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano; Each R c independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano; L 1 Selected from 5-6 membered heteroarylene; wherein, # A For L 1 The connection point with the A ring, $ L2 For L 1 With L 2 connected junctions; L 2 Selected from L 3 Selected from NH, -NHC(=O)-, -NHC(=O)NH-; Ring B is selected from phenyl, 5-10 membered heteroaryl; Each R B Independently selected from: hydrogen, deuterium, halogen, cyano, amino, C1-C6 alkyl, R 3 O-、R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group, C3-C7 cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkoxy, and phenyl; B for The connection point with the B ring; n is selected from 0, 1, 2, 3; Each R 3 Independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkyl-C(=O)-; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C6 alkoxy; R e 、R f Each is independently selected from hydrogen, deuterium, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, or 4-8 membered heterocyclic group; or, R e 、R f Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring, wherein the 4-8 membered saturated heterocyclic ring or the 7-11 membered spiroheterocyclic ring is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; Each R g is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl and C3-C7 cycloalkyl are optionally substituted by a substituent selected from deuterium, halogen, hydroxyl, amino, and cyano; Each R h is selected from hydrogen, deuterium, amino, C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered saturated heterocyclic group; or R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring; R i 、R j are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C3-C7 halocycloalkyl, 5-6 membered heteroaryl; or, R i 、R j Together with the nitrogen atom to which they are attached, they form a 4-8 membered saturated heterocyclic ring or a 7-11 membered spiroheterocyclic ring; R k R is selected from hydrogen, deuterium, C1-C6 alkyl, cyano, C3-C7 cycloalkyl, 4-8 membered heterocyclic group; k’ is selected from hydrogen, deuterium, C1-C6 alkyl, cyano, C3-C7 cycloalkyl; or, R k 、R k’ and -S=N- connected thereto to form a 4-8 membered heterocyclic ring; or R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; R l 、R m are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C7 cycloalkyl; or, R l 、R m and the P atoms to which they are connected form a 4-8 membered saturated heterocyclic ring; or R l 、R m One of the The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; R 6 is selected from hydrogen, deuterium, hydroxyl, halogen, and cyano; R 11 is selected from hydrogen, deuterium, and C1-C6 alkyl; Z 2 Selected from N(R 7 )、C(R 8 )2, O, S(O)2; R 7 is selected from hydrogen, deuterium, and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; Each R 8 independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group, 7-11 membered spiroheterocyclic group, 5-10 membered bridged heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, amino-substituted C1-C6 alkoxy; provided that: there is at most 1 R 8 is selected from 4-8 membered saturated heterocyclic group, 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-8 membered heterocyclic group; wherein the 4-8 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; R o 、R p are each independently selected from hydrogen, deuterium, C1-C6 alkyl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxyl, amino, cyano, C1-C6 alkoxy; or, R o 、R p Together with the nitrogen atom to which they are commonly attached, they form a 4-8 membered saturated heterocyclic ring, a 7-11 membered spiro heterocyclic ring or a 5-10 membered bridged heterocyclic ring; wherein the 4-8 membered heterocyclic ring, the 7-11 membered spiro heterocyclic ring, the 5-10 membered bridged heterocyclic ring are optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; The compound of formula M must satisfy conditions 1) and 2) at the same time: 3) When Ring A is not: When R 0 Selected from C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-8 membered heterocyclyl, C5-C6 heteroaryl are each independently optionally substituted with deuterium, halogen, hydroxyl, amino, or cyano, and must meet at least one of the following conditions: e)L 1 is selected from 5-6 membered heteroarylene; f)L 3 Selected from -NHC(=O)-, -NHC(=O)NH-; g) Ring B is R h S(=O)2-substituted, and R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring; or B ring is Replace, and R k 、R k’ and -S=N- connected thereto to form a 4-8 membered heterocyclic ring, or R k and The ortho positions of the amines are connected to form a 5-6 membered heterocyclic ring; or B ring is Replace, and R l 、R m and the P atoms to which they are connected form a 4-8 membered saturated heterocyclic ring, or R l 、R m One of the The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; h)Z 2 Selected from C(R 8 )2, and there is only one R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-, R o 、R p Together with the N atom to which they are commonly attached, they form a 4-8 membered saturated heterocycle, a 7-11 membered spiroheterocycle or a 5-10 membered bridged heterocycle; wherein the 7-11 membered spiroheterocyclyl, the 7-11 membered spiroheterocycle, the 5-10 membered bridged heterocyclyl, the 5-10 membered bridged heterocycle, the 4-8 membered saturated heterocycle is optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; 2) The compound represented by formula M does not include the following compounds:

2. The compound according to claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Ring A is selected from R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; Preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; More preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-.

3. The compound according to claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Ring A is selected from R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, C1-C3 alkyl; Preferably, ring A is selected from R 9 is selected from hydrogen, hydroxyl; R 10 is selected from hydrogen and fluorine; R 0 Selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; More preferably, R 0 Selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; Most preferably, R 0 Selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; R 9 and R 10 For hydrogen.

4. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug, wherein: Ring A is selected from R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, and C1-C3 alkyl.

5. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: L 1 Selected from 5-membered heteroarylene; Preferably, L 1 Selected from 1,3,4-thiadiazole subunit, 1,2,4-oxadiazole subunit, 1,3,4-oxadiazole subunit, thiazolyl subunit; More preferably, L 1 Selected from 6. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: R 11 is selected from hydrogen, deuterium, and C1-C4 alkyl; Preferably, R 11 is selected from hydrogen, methyl; L 3 Selected from NH,# L2 -NHC(=O)-$ B 、# L2 -NHC(=O)NH-$ B ,in,# L2 For L 3 With L 2 Connected connection points, $ B For L 3 The connection point with the B ring; Preferably, L 3 For NH.

7. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Ring B is selected from phenyl, pyridyl, 5-membered heteroaromatic ring, # L3 For B ring and L 3 Connected connection points, Preferably, ring B is selected from phenyl, pyridyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, furyl; More preferably, Selected from n is selected from 0, 1, 2; preferably, n is selected from 0, 1; Z 1 Selected from N, CR 4 ; R 1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, C1-C6 alkyl, R 3 O-; wherein the C1-C6 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, and amino; R 2 Selected from hydrogen, deuterium, cyano, halogen, C1-C6 alkyl, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group; wherein the C1-C6 alkyl, 5-6 membered heteroaryl, 4-8 membered saturated heterocyclic group is optionally substituted with 0, 1, 2, or 3 substituents selected from: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkoxy, and phenyl; R 4 is selected from hydrogen, deuterium, hydroxyl, halogen, and cyano; R 5 is selected from hydrogen, deuterium, R'-NH-C(=O)-, C1-C6 alkyl, 4-8 membered saturated heterocyclyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, 4-8 membered saturated heterocyclyl, C3-C7 cycloalkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C3 alkyl, and phenyl; R' is selected from hydrogen, deuterium, and C1-C6 alkyl.

8. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Ring B is selected from phenyl, n is 2 or 3, each R B are independently selected from halogen, R 3 O-、R h S(=O)2-, And each R B are not the same; R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cyano-C1-C2 alkylene-, hydroxy-C1-C2 alkylene-, C1-C2 alkoxy-C1-C2 alkylene-, C1-C2 alkyl-C(=O)-; R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring; R k’ Selected from hydrogen, R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; R l is selected from C1-C6 alkyl (preferably C1-C3 alkyl), R m and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; Preferably, the B ring is selected from phenyl, n is 2, 1 R B R 3 O-, another R B Selected from R h S(=O)2-, or B ring is selected from phenyl, n is 3, 1 R B is hydrogen or fluorine, 1 R B R 3 O-, 1 R B Selected from R h S(=O)2-, Preferably, R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, monofluoromethyl, difluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-; More preferably, R 3 Selected from methyl.

9. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Selected from Preferably, Selected from 10. The compound of claim 7, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: R 5 is selected from hydrogen, R'-NH-C(=O)-, C1-C6 alkyl, 4-6 membered saturated heterocyclyl, C3-C6 cycloalkyl, wherein C1-C6 alkyl, 4-6 membered saturated heterocyclyl, C3-C6 cycloalkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen, cyano, C1-C3 alkyl, and phenyl; R' is selected from C1-C3 alkyl; Preferably, Selected from 11. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: for R 1 Selected from hydroxy, halogen, C1-C2 haloalkyl, R 3 O-; Z 1 Selected from N, CR 4 ; R 2 Selected from cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy-C1-C6 Alkylene, cyano-C1-C6 alkylene, 4-8 membered saturated heterocyclic-C1-C6 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl; R 4 selected from hydrogen, deuterium, and fluorine; Preferably, R 1 Selected from hydroxy, fluorine, trifluoromethyl, R 3 O-;R 3 Selected from hydrogen, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, CF3CH2-, CFH2CH2-, CNCH2-, CNCH2CH2-, C(OH)H2CH2-, CH3OCH2CH2-, CH3CH2C(=O)-; R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, 6-membered saturated heterocyclic-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, 5-6 membered heteroaryl; R 4 is selected from hydrogen and fluorine; More preferably, R 1 selected from methoxy; R 2 is selected from cyano, halogen, C1-C2 haloalkyl, C1-C2 alkoxy-C1-C2 alkylene, cyano-C1-C4 alkylene, morpholino-C1-C2 alkylene, R e R f NC(=O)-、R g OC(=O)-、R h S(=O)2-、R i R j NS(=O)2-, Oxazolyl, thiazolyl, pyridinyl; Most preferably, R 1 Selected from methoxy; R 2 Selected from CH3NHC(=O)-; Z 1 Selected from CF or CH.

12. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Z 2 Selected from C(R 8 )2; 1 R 8 is hydrogen, and the other R 8 is selected from 7-11 membered spiro heterocyclic group, 5-10 membered bridged heterocyclic group, R o R p N-;R o 、R p Together with the N atom to which they are commonly attached, they form a 7-11-membered spiroheterocycle or a 5-10-membered bridged heterocycle; wherein the 7-11-membered spiroheterocycle, the 7-11-membered spiroheterocycle, the 5-10-membered bridged heterocycle, or the 5-10-membered bridged heterocycle is optionally substituted with a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, or amino-substituted C1-C6 alkoxy; or, 2 R 8 Together with the carbon atoms to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by a substituent selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, and amino-substituted C1-C6 alkoxy; Preferably, the 7-11 membered spiro heterocyclic group is selected from The 5-10 membered bridged heterocyclic group is selected from in,# Z2 R 8 With Z 2 The connection point where the 6-membered ring is connected; More preferably, Selected from Among them, $ A It is the connection point between NH and A ring.

13. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: Z 2 Selected from N(R 7 ); R 7 Selected from C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by a substituent selected from hydroxy, C1-C6 alkoxy, and hydroxy-substituted C1-C6 alkoxy; Preferably, R 7 Selected from C1-C4 alkyl, C1-C4 alkyl substituted by 2 hydroxyl groups, C1-C2 alkoxy-C1-C4 alkyl, wherein the C1-C2 alkoxy-C1-C4 alkyl is substituted by hydroxyl groups; More preferably, R 7 Selected from methyl, 14. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: R 6 is selected from hydrogen and fluorine; Each R a 、R d Independently selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene; Each R b independently selected from hydrogen, hydroxy, halogen, cyano; Each R c independently selected from hydrogen, halogen; Preferably, each R a 、R d Independently selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; Each R b independently selected from hydrogen, hydroxyl; Each R c Independently selected from hydrogen and fluorine.

15. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compounds are shown in formula MI-1 and MI-2: L 1 is a 5-membered heteroarylene group; Preferably, L 1 Selected from 16. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compound is represented by formula MI-1-1, MI-1-1A, MI-1-1B, MI-1-1-2, MI-1-1-2A, MI-1-1-2B, MI-1-1-1, MI-1-1-1A, MI-1-1-1B or formula T: Preferably, the B ring is selected from phenyl and 5-membered heteroaryl; Preferably, the compound is represented by formula MI-1-1-2, MI-1-1-2A, or MI-1-1-2B: Preferably, the B ring is selected from phenyl and 5-membered heteroaryl; Preferably, the compound is as shown in formula MI-1-1-1, MI-1-1-1A, or MI-1-1-1B: R 1 is selected from halogen, preferably fluorine or chlorine; n is selected from 0 or 1; R 2 Selected from R h S(=O)2-, R h With R h The ortho-position of S(=O)2- forms a 5-6 membered heterocyclic ring; R k 、R k’ and -S=N- connected thereto to form a 5-7 membered heterocyclic ring, or R k’ Selected from hydrogen, R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; R l is selected from C1-C6 alkyl (preferably C1-C3 alkyl), R m and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; In formula T, X 3 、X 4 、X 5 、R 6 、R 8 、R 9 、R 10 、R B 、R a As defined in any one of claims 1 to 15, n and p are independently 0, 1, 2 or 3; or In formula T, X 3 CH or N, X 4 CH or N, X 5 is CH or N, preferably, X 4 and / or X 3 is N; R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 alkoxy, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl, -O-C3-C6 heterocycloalkyl; preferably, R B Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C6 deuterated alkyl; R 1-1 、R 1-2 R is independently selected from H, deuterium, C1-C6 alkyl, -O-C1-C6 alkyl, -C1-C3 alkylene-O-C1-C3 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl; preferably H or C1-C6 deuterated alkyl; or R 1-1 、R 1-2 Together with the nitrogen to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. 6-membered heterocycloalkyl is selected from R 1-3 Selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; R 8 Selected from-NR 2-1 R 2-2 , 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged cycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl; R 2-1 、R 2-2 are independently C1-C6 alkyl or 4-7 membered monoheterocyclic alkyl; R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl; R a are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkylene-, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; preferably, R a is selected from C1-C4 alkyl, C1-C2 haloalkyl, cyano-C1-C2 alkylene-; more preferably, R 4 is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-; R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, C1-C3 alkyl; Preferably, in formula T, R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 heterocycloalkyl; R 1-1 、R 1-2 independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, -O-C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, or R 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from: R 1-3 Selected from H, C1-C6 alkyl; R 8 is selected from 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl; R 6 Independently selected from H, halogen, preferably fluorine, C1-C6 alkyl, C1-C6 haloalkyl; R a are independently selected from C1-C6 alkyl, C1-C6 haloalkyl; preferably, R a is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-; R 9 and R 10 are each independently selected from hydrogen and deuterium; Preferably, in formula T, R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C6 alkyl, -O-C1-C6 deuterated alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl; preferably, R 1 Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , O-C1-C6 deuterated alkyl; R 1-1 、R 1-2 R is independently selected from H, C1-C6 alkyl, -C1-C3 alkyl-O-C1-C3 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered haloheterocycloalkyl; preferably H or C1-C6 deuterated alkyl; or 1-1 、R 1-2 Together with the N to which they are commonly connected, they form a 3-6 membered heterocycloalkyl group. Preferably, the 3-6 membered heterocycloalkyl group is selected from: R 1-3 Selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; R 8 is selected from 7-11 membered heterospirocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered fused heterocycloalkyl, 4-7 membered monoheterocycloalkyl, optionally substituted with halogen; Preferably, in formula T, R B Independently selected from -CONR 1-1 R 1-2 、-SO2R 1-3 , -O-C1-C3 alkyl, -O-C1-C3 deuterated alkyl, -O-C1-C3 haloalkyl, -O-C3-C6 cycloalkyl; preferably, R 1 Selected from -CONR 1-1 R 1-2 、-SO2R 1-3、 O-C1-C3 deuterated alkyl; R 1-1 、R 1-2 、R 1-3 Independently selected from H, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl; preferably H or C1-C3 deuterated alkyl; R 6 Independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl; R a Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl; R 9 and R 10 are each independently selected from hydrogen and deuterium; Preferably, the formula T is selected from formulas T-1 to T-9: In formula T-1 to formula T-9, the definitions of the symbols are the same as those in formula T; R 1a and R 1b Define R in the same formula T B , and R 1a and R 1b different; Preferably, R 1a Selected from -CONR 1-1 R 1-2 、-SO2R 1-3 ; Further preferably, R 1a Selected from -CONHCD3, -CONHCH3, -SO2CH3, -SO2CD3; Preferably, R 1b is selected from -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-C1-C6 deuterated alkyl, -O-C3-C6 cycloalkyl; further Preferably, R 1b Selected from -OCH3, -OCD3, -OCH2F, Preferably, R 8 Selected from Further optimization of R 8 Selected from Preferably, R 0 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl; more preferably, R 0 are independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl; more preferably, R 0 is selected from CF3CH2-, CH2FCH2-, CH3CH2CH2-, CNCH2-, CHF2CH2-; most preferably, R a Selected from CF3CH2-; preferably, R 6 It is selected from halogen, more preferably fluorine.

17. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compound is shown in formula MII: R 1 Selected from hydrogen, deuterium, hydroxyl, halogen, amino, C1-C6 alkyl, R 3 O-; wherein the C1-C6 alkyl group is optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, and amino; R 3 Independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkyl-C(=O)-; wherein the C1-C6 alkyl is optionally substituted by halogen, hydroxy, cyano, amino, or C1-C6 alkoxy; Z 1 Selected from N, CR 4 ; R 4 is selected from hydrogen, deuterium, hydroxyl, halogen, and cyano; Preferably, R k 、R k’ and -S=N- connected thereto to form a 4-8 membered heterocyclic ring, or R k and The ortho positions of the rings are connected to form a 5-6 membered heterocyclic ring; Preferably, ring A is selected from R 9 and R 10 Each is independently selected from hydrogen, deuterium, hydroxy, amino, halogen, cyano, C1-C3 alkyl; Preferably, L 1 Selected from Preferably, L 3 Selected from NH.

18. The compound of claim 17, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compound is represented by formula MII-1, MII-2 or MII-3: r is selected from 1, 2, 3 or 4; Preferably, r is selected from 1, 2 or 3.

19. The compound of claim 18, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compound is represented by formula MII-1-1, MII-1-2, MII-2-1, MII-2-2, MII-3-1 or MII-3-2:

20. The compound of claim 1, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, wherein: The compound is selected from:

21. A pharmaceutical composition comprising the compound of any one of claims 1 to 20, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound) or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

22. A combination drug comprising: 1) A first drug, which is a compound according to any one of claims 1 to 20, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, crystalline form, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof; 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, and Pucotenlimab; Preferably, the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab.

23. Use of the compound of any one of claims 1 to 20, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, crystalline forms, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds), or prodrugs, or the pharmaceutical composition of claim 21, or the combination drug of claim 22 in the preparation 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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