Macrocyclic compound and medical application thereof

Abstract

The invention relates to a macrocyclic compound and medical application thereof. The structure of the macrocyclic compound is shown as a formula (I). The disclosure also relates to methods of preparation of the compounds, pharmaceutical compositions and their use as p53 mutant weight activators in the treatment of cancer. X1 to X6, Q1 to Q3, R1, RB, A, ring B, L and n in the formula (I) are as defined in the specification. # imgabs0 #

Description

Macrocyclic compounds and their medical uses

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits to Chinese Patent Application No. 202211294235.7 filed with the State Intellectual Property Office of China on October 21, 2022, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to a macrocyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use of the macrocyclic compound as a p53 mutant reactivator in the treatment of cancer. Background Art

[0004] p53 is a transcription factor that binds to the promoters of its target genes in a sequence-specific manner and regulates their expression, thereby controlling the cell cycle and cell death. p53 is activated when it detects DNA damage and oxidative or other cellular stresses that exceed the thresholds that normal cells can tolerate. Activated p53 promotes the repair of damaged DNA or eliminates damaged cells by triggering programmed cell death, apoptosis, thereby preventing the cancerous transformation and proliferation of damaged cells.

[0005] In normal cells, p53 levels are typically maintained at low levels because cells promote p53 degradation through expression of the ubiquitin ligase MDM2 (murine double minute 2). The activation of p53 is strictly controlled, with MDM2 being the most important negative regulator of p53. Upon activation by damaged DNA and other types of stress, p53 expression is upregulated, blocking the proliferation of precancerous and malignant cells or eliminating them by inducing apoptosis. Mutant p53, however, loses the ability to eliminate precancerous and malignant cells. Given that the mutational status of p53 in tumors significantly influences sensitivity to commonly used anticancer drugs and radiotherapy, p53 is both an important biomarker and a novel therapeutic target.

[0006] Summary of the Invention

[0007] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Each are independently selected from a single bond or a double bond;

[0010] R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12Alkylthio, C 1-12 Alkylamino, di-C 1- 12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0011] X 1 Selected from CR 2 , CR 2 R 3 、N、NR 2 , O, S, C(O), or connected to Q 1 of carbon atoms;

[0012] X 2 Selected from CR 4 , CR 4 R 5 、N、NR 4 , O, S, C(O), or connected to Q 1 of carbon atoms;

[0013] X 3 Selected from CR 6 , CR 6 R 7 、N、NR 6 , O, S, C(O), or connected to Q 1 of carbon atoms;

[0014] X 4 Selected from CR 8 , CR 8 R 9 、N、NR 8 , O, S, C(O), or connected to Q 1 of carbon atoms;

[0015] The premise is that X 1 、X 2 、X 3 and X 4 There is only one connection to Q 1 of carbon atoms;

[0016] X 5 Selected from CR 10 , N, or NR 10 ;

[0017] X 6 selected from CH, or N;

[0018] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1- 12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0019] Q 1 is selected from a single bond, -CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -O-, -S-, -S(O)-, -S(O)NH-, -NHS(O)-, -S(O)2-, -NHS(O)2-, or -S(O)2NH-;

[0020] A is selected from a single bond, or

[0021] Ring Cy is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0022] m is selected from 1, 2, 3, or 4;

[0023] Each R A Each independently selected from H, oxo, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -C(O)R A1、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0024] R A1 、R A2 Each independently selected from H or C 1-12 alkyl;

[0025] L is selected from a single bond or C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: heteroatom groups, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl groups, 3-12 membered heterocyclyl groups, 6-14 membered aryl groups, or 5-14 membered heteroaryl groups, wherein the C 1-20 Alkylene, heteroatom group, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl are each independently optionally substituted by one or more R L replace;

[0026] Each R L Each independently selected from oxo, halogen, cyano, hydroxy, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1- 12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0027] Q 2is selected from a single bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -S(O)-, -S(O)NH-, -NHS(O)-, -S(O)2-, -NHS(O)2-, or -S(O)2NH-;

[0028] Ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0029] n is selected from 1, 2, 3, or 4;

[0030] Each R B Each independently selected from H, oxo, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0031] R B1 、R B2 Each independently selected from H or C 1-12 alkyl;

[0032] Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-12 Alkylene, C 1-12 Heteroalkylene, C 2-12 Alkenylene, or C 1-12 heteroalkenylene;

[0033] Each R Q3 Each independently selected from oxo, halogen, cyano, hydroxy, amino, alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0034] Each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R A 、R A1 、R A2 、R L 、R B 、R B1 、R B2 , or R Q3 Each is independently optionally substituted with one or more substituents.

[0035] In some embodiments, the structural unit It is an aromatic ring structure.

[0036] In some embodiments, the structural unit It is a heteroaromatic ring structure.

[0037] In some embodiments, R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0038] In some embodiments, R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0039] In some embodiments, R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0040] In some embodiments, R 1 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0041] In some embodiments, R 1is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino.

[0042] In some embodiments, R 1 Selected from H, methyl, ethyl, trifluoromethyl, or -CH2CF3.

[0043] In some embodiments, X 1 Selected from CR 2 , CR 2 R 3 、N、NR 2 , O, S, or C(O).

[0044] In some embodiments, X 1 Selected from CR 2 , N, or connect to Q 1 of carbon atoms.

[0045] In some embodiments, X 1 is N.

[0046] In some embodiments, X 1 Selected from CR 2 .

[0047] In some embodiments, X 1 For CH.

[0048] In some embodiments, X 1 To connect to Q 1 of carbon atoms.

[0049] In some embodiments, X 2 Selected from CR 4 , CR 4 R 5 、N、NR 4 , O, S, or C(O).

[0050] In some embodiments, X 2 Selected from CR 4 , N, or connect to Q 1 of carbon atoms.

[0051] In some embodiments, X 2 is N.

[0052] In some embodiments, X 2 Selected from CR 4 .

[0053] In some embodiments, X2 For CH.

[0054] In some embodiments, X 2 To connect to Q 1 of carbon atoms.

[0055] In some embodiments, X 3 Selected from CR 6 , CR 6 R 7 、N、NR 6 , O, S, or C(O).

[0056] In some embodiments, X 3 Selected from CR 6 , N, or connect to Q 1 of carbon atoms.

[0057] In some embodiments, X 3 is N.

[0058] In some embodiments, X 3 Selected from CR 6 .

[0059] In some embodiments, X 3 For CH.

[0060] In some embodiments, X 3 To connect to Q 1 of carbon atoms.

[0061] In some embodiments, X 4 Selected from CR 8 , N, or connect to Q 1 of carbon atoms.

[0062] In some embodiments, X 4 is N.

[0063] In some embodiments, X 4 Selected from CR 6 .

[0064] In some embodiments, X 4 For CH.

[0065] In some embodiments, X 4 To connect to Q 1 of carbon atoms.

[0066] In some embodiments, X 1 、X 2 、X 3 、X 4 One of them is N.

[0067] In some embodiments, X 1 、X 2 、X 3 、X 4 Two of them are N.

[0068] In some embodiments, X 1 Selected from CR 2 ;X 2 Selected from CR 4 ;X 3 Selected from CR 6 ;X 4 To connect to Q 1 of carbon atoms.

[0069] In some embodiments, X 5 is selected from CH, N, or NH.

[0070] In some embodiments, X 5 For CH.

[0071] In some embodiments, X 6 is N.

[0072] In some embodiments, X 5 CH; X 6 is N.

[0073] In some embodiments, X 1 Selected from CR 2 ;X 2 Selected from CR 4 ;X 3 Selected from CR 6 ;X 4 To connect to Q 1 The carbon atom of X 5 Selected from CR 10 ;X 6 is N.

[0074] In some embodiments, X 1 、X 2 and X 3 All are CH, X 4 To connect to Q 1 of carbon atoms.

[0075] In some embodiments, X 1 、X 2 and X 3 All are CH, X 4 To connect to Q 1 The carbon atom, X 5 CH, X 6 is N.

[0076] In some embodiments, the structural unit for

[0077] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0078] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0079] In some embodiments, R 2 、R 3 、R 4 、R 5 、R6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0080] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each is independently selected from H, fluorine, chlorine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino.

[0081] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each is independently selected from H, fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0082] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R10 Selected from H.

[0083] In some embodiments, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R 10 Both are H.

[0084] In some embodiments, Q 1 is selected from a single bond, -CH2-, -C(O)-, -NH-, or -O-.

[0085] In some embodiments, Q 1 For a single bond.

[0086] In some embodiments, Q 1 is selected from -CH2-, -NH-, or -O-.

[0087] In some embodiments, Q 1 It is -NH-.

[0088] In some embodiments, A is a single bond.

[0089] In some embodiments, A is selected from

[0090] In some embodiments, ring Cy is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0091] In some embodiments, ring Cy is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0092] In some embodiments, ring Cy is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0093] In some embodiments, the "heterocyclyl" involved in the ring Cy is selected from heterocycloalkyl, for example, a 3-12 membered heterocyclyl can be selected from 3-12 membered heterocycloalkyl, a 3-10 membered heterocyclyl can be selected from 3-10 membered heterocycloalkyl, and a 3-8 membered heterocyclyl can be selected from 3-8 membered heterocycloalkyl.

[0094] In some embodiments, the “heterocyclyl” and “heteroaryl” involved in the ring Cy each independently contain 1, 2 or 3 heteroatoms each independently selected from N, O or S.

[0095] In some embodiments, the "heterocyclyl" and "heteroaryl" involved in the ring Cy each independently contain 1 or 2 N atoms.

[0096] In some embodiments, ring Cy is selected from 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl.

[0097] In some embodiments, ring Cy is selected from 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl containing 1 or 2 N atoms.

[0098] In some embodiments, ring Cy is selected from 5-8 membered cycloalkyl, or 5-8 membered heterocycloalkyl, wherein the 5-8 membered heterocycloalkyl contains 1 or 2 N atoms.

[0099] In some embodiments, ring Cy is selected from cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl.

[0100] In some embodiments, ring Cy is selected from cyclohexanyl, spiro[3.3]heptyl, piperidinyl, or azaspiro[3.3]heptyl.

[0101] In some embodiments, ring Cy is selected from cyclohexanyl, spiro[3.3]heptyl, pyrrolidinyl, piperidinyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl.

[0102] In some embodiments, A is selected from

[0103] In some embodiments, A is selected from

[0104] In some embodiments, m is selected from 1 or 2.

[0105] In some embodiments, m is 1.

[0106] In some embodiments, each R A Each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6Alkoxy, halogenated C 1- 6-alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0107] In some embodiments, each R A Each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1- 6-alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0108] In some embodiments, each R A Each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-4Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1- 4-alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0109] In some embodiments, each R A each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, halodimethylamino, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.

[0110] In some embodiments, each R AEach is independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 , or -S(O)2NR A1 R A2 .

[0111] In some embodiments, each R A Each is independently selected from H, oxo, fluoro, chloro, cyano, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy.

[0112] In some embodiments, each R A are each independently selected from H or fluorine.

[0113] In some embodiments, R A1 、R A2 Each independently selected from H or C 1-6 alkyl.

[0114] In some embodiments, R A1 、R A2 Each independently selected from H or C 1-4 alkyl.

[0115] In some embodiments, R A1 、R A2 Each is independently selected from H, methyl, or ethyl.

[0116] In some embodiments, A is selected from

[0117] In some embodiments, A is selected from

[0118] In some embodiments, A is selected from

[0119] In some embodiments, L is selected from a single bond.

[0120] In some embodiments, the "heteroatom group" involved in the L group is selected from NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, ONHC(O), NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, or =NO-.

[0121] In some embodiments, the "heteroatom group" involved in the L group is selected from NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON= or =NO-.

[0122] In some embodiments, the "heteroatom group" referred to in the L group is selected from NH, O, C(O), C(O)NH or NHC(O).

[0123] In some embodiments, L is selected from C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-20 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0124] In some embodiments, L is selected from C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-20 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0125] In some embodiments, L is selected from C 1-16 Alkylene, the C 1-16 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-16 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0126] In some embodiments, L is selected from C 1-16 Alkylene, the C 1-16 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-16 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L In some embodiments, L is selected from C 1-14 Alkylene, the C 1-14 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-14 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0127] In some embodiments, L is selected from C 1-14 Alkylene, the C 1-14One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-14 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0128] In some embodiments, the "heterocyclyl" involved in L is selected from heterocycloalkyl, for example, a 3-12 membered heterocyclyl can be selected from 3-12 membered heterocycloalkyl, a 3-10 membered heterocyclyl can be selected from 3-10 membered heterocycloalkyl, and a 3-8 membered heterocyclyl can be selected from 3-8 membered heterocycloalkyl.

[0129] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-12 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0130] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-12 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0131] In some embodiments, the "one or more" referred to in L is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or 1, 2, 3, 4, 5, or 6; or 1, 2, or 3.

[0132] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted with one or more R L replace.

[0133] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0134] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-121, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0135] In some embodiments, L is selected from C 1-12 Alkylene, the C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, OC(O), C(O)NH, NHC(O), 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0136] In some embodiments, L is selected from C 2-8 Alkylene, the C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, OC(O), C(O)NH, NHC(O), 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0137] In some embodiments, the "alkylene" mentioned in L is selected from a linear alkylene or a branched alkylene.

[0138] In some embodiments, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-121, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -CH=CH-, -C≡C-, cyclobutane, cyclobutyl, cyclopentane ... pentyl, cyclohexyl, cycloheptyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl, wherein C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, spiro[3.3]heptane, spiro[3.4]octane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptane, azabicyclo[3.3.0]octane, azaspiro[3.3]heptane, or azaspiro[3.4]octane, each independently optionally substituted with one or more R L replace.

[0139] In some embodiments, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -CH=CH-, -C≡C-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.3]heptyl, oxidized azaphosphorinyl, or pyrazolyl, said C 1-12alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, spiro[3.3]heptane, spiro[3.4]octane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptane, azabicyclo[3.3.0]octane, azaspiro[3.3]heptane, azaspiro[3.4]octane, diazaspiro[3.3]heptane, oxidized azaphosphorinyl, or pyrazolyl are each independently optionally substituted with one or more R L replace.

[0140] In some embodiments, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 One, two or three CH2 groups on the alkylene group are each independently optionally replaced by NH, O, C(O), azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0141] In some embodiments, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl, wherein the C 1-12 Alkylene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl are each independently optionally substituted by one or more R L In some embodiments, L is selected from a linear C 2-8 Alkylene, the straight chain C 2-8 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl, wherein the C 2-8 Alkylene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl are each independently optionally substituted by one or more R L replace.

[0142] In some embodiments, each R L Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0143] In some embodiments, each R L Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0144] In some embodiments, each R L Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0145] In some embodiments, each R LEach is independently selected from oxo, fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino.

[0146] In some embodiments, each R L Each is independently selected from oxo, fluoro, chloro, cyano, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0147] In some embodiments, R L Selected from oxo.

[0148] In some embodiments, R L Selected from oxo, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy.

[0149] In some embodiments, R L is selected from oxo, hydroxy, methyl or methoxy.

[0150] In some embodiments, L is selected from

[0151] In some embodiments, L is selected from

[0152] In some embodiments, L is selected from

[0153] In some embodiments, Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, or -S(O)2-.

[0154] In some embodiments, Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-.

[0155] In some embodiments, Q 2 It is -S(O)2-.

[0156] In some embodiments, Ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0157] In some embodiments, Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0158] In some embodiments, Ring B is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0159] In some embodiments, the "heterocyclyl" involved in the ring B is selected from heterocycloalkyl, for example, a 3-12 membered heterocyclyl can be selected from 3-12 membered heterocycloalkyl, a 3-10 membered heterocyclyl can be selected from 3-10 membered heterocycloalkyl, and a 3-8 membered heterocyclyl can be selected from 3-8 membered heterocycloalkyl.

[0160] In some embodiments, Ring B is selected from a 6-10 membered aryl or a 5-10 membered heteroaryl.

[0161] In some embodiments, Ring B is selected from phenyl or 5-6 membered heteroaryl.

[0162] In some embodiments, Ring B is selected from phenyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0163] In some embodiments, Ring B is selected from phenyl, thienyl, or pyridinyl.

[0164] In some embodiments, Ring B is selected from

[0165] In some embodiments, Ring B is selected from

[0166] In some embodiments, n is selected from 1 or 2.

[0167] In some embodiments, n is selected from 1.

[0168] In some embodiments, each R B Each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1- 6-alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, -C(O)R B1 、-C(O)NR B1 R B2、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0169] In some embodiments, each R B Each independently selected from H, oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1- 4-alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0170] In some embodiments, each R B Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1- 4 alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0171] In some embodiments, each R B each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, halodimethylamino, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0172] In some embodiments, each R B each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)ORB1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 , or -S(O)2NR B1 R B2 .

[0173] In some embodiments, each R B Each is independently selected from H, fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0174] In some embodiments, each R B Each is independently selected from H, methyl, methoxy, or ethoxy.

[0175] In some embodiments, each R B Each is independently selected from H, methyl, methoxy, ethoxy or -S(O)2CH3.

[0176] In some embodiments, R B1 、R B2 Each independently selected from H or C 1-6 alkyl.

[0177] In some embodiments, R B1 、R B2 Each independently selected from H or C 1-4 alkyl.

[0178] In some embodiments, R B1 、R B2 Each is independently selected from H, methyl, or ethyl.

[0179] In some embodiments, Ring B is selected from

[0180] In some embodiments, Ring B is selected from

[0181] In some embodiments, Ring B is

[0182] In some embodiments, Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-6 Alkylene, C 1-5 Heteroalkylene, C 2-6 Alkenylene, or C 1-5Heteroalkenylene.

[0183] In some embodiments, Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 Heteroalkenylene.

[0184] In some embodiments, Q 3 Selected from optionally one or more R Q3 Substituted with the following groups: C 1-4 Alkylene or C 1-3 Heteroalkylene.

[0185] In some embodiments, Q 3 Selected from optionally one or more R Q3 Substituted with the following groups: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-.

[0186] In some embodiments, Q 3 Selected from -CH2NH-.

[0187] In some embodiments, each R Q3 Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0188] In some embodiments, each R Q3 Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0189] In some embodiments, each R Q3 Each independently selected from oxo, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0190] In some embodiments, each R Q3 Each is independently selected from oxo, fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino.

[0191] In some embodiments, each R Q3 Each is independently selected from oxo, fluoro, chloro, cyano, hydroxy, amino, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0192] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-6-membered, 5-6-membered, 5-8-membered, or 5-10-membered.

[0193] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-8-membered, 3-6-membered, 5-6-membered, 5-8-membered, or 5-10-membered.

[0194] In some embodiments, the 3-12 membered heterocyclyl is selected from a 3-12 membered heterocycloalkyl or a benzo 4-6 membered heterocyclyl.

[0195] In some embodiments, the 3-12 membered heterocyclyl is selected from a 3-12 membered heterocycloalkyl or a benzo 4-6 membered heterocycloalkenyl.

[0196] In some embodiments, the 3-10 membered heterocyclyl is selected from a 3-10 membered heterocycloalkyl or a benzo 4-6 membered heterocyclyl.

[0197] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl or benzo 4-6 membered heterocycloalkenyl.

[0198] In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

[0199] In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0200] In some embodiments, the 3-12 membered, 3-10 membered, or 3-8 membered heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from N, O, or P.

[0201] In some embodiments, the heterocycloalkyl group contains 1 N atom.

[0202] In some embodiments, the heterocycloalkyl group contains 1 O atom.

[0203] In some embodiments, the 3-12 membered, 3-10 membered, or 3-8 membered heterocycloalkyl group contains 1 or 2 N atoms.

[0204] In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.

[0205] In some embodiments, the 3-12 membered, 3-10 membered, or 3-8 membered heterocycloalkyl group contains 1 N atom and 1 P atom.

[0206] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 heteroatoms selected from N, O, or S.

[0207] In some embodiments, the 3-12 membered, 3-10 membered, or 3-8 membered heterocyclyl, or the 5-14 membered, 5-10 membered, or 5-6 membered heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, or S.

[0208] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 N atoms.

[0209] In some embodiments, the heterocyclyl or heteroaryl contains 1 S atom.

[0210] In some embodiments, the heterocyclyl or heteroaryl group contains 1 N atom and 1 O atom.

[0211] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.

[0212] In some embodiments, the 3-12 membered, 3-10 membered, or 3-8 membered heterocyclyl, or 5-14 membered, 5-10 membered, or 5-6 membered heteroaryl contains 1 or 2 N atoms; or contains 1 S atom.

[0213] In some embodiments, the heterocyclic radical or heterocycloalkyl group includes a monocyclic, spirocyclic, cyclic or bridged ring form. In some embodiments, the heterocyclic radical or heterocycloalkyl group includes a monocyclic or spirocyclic form. In some embodiments, the heterocyclic radical or heterocycloalkyl group includes a monocyclic or bridged ring form.

[0214] In some embodiments, the C 1-20 Selected from C 1-18 、C 1-16 、C 1-14 、C 1-12 、C 1-10 、C 1-8 、C 1-6 、C 1-4 , or C 1-2 In some embodiments, the C 1-20 Selected from C 2-18 、C 2-16 、C 2-14 、C 2-12 、C 2-10 、C 2-8 、C 2-6 , or C 2-4 In some embodiments, the C 1-20 Selected from C 3-18 、C 3-16 、C 3-14 、C 3-12 、C 3-10 、C 3-8 、C 3-6 , or C 3-4 In some embodiments, the C 1-20 Selected from C 4- 18 、C 4-16 、C 4-14 、C 4-12 、C 4-10 、C 4-8 , or C 4-6In some embodiments, the C 1-20 Selected from C 4-11 .

[0215] In some embodiments, the C 1-12 Selected from C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 .

[0216] In some embodiments, the C 1-20 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0217] In some embodiments, the C 1-20 Alkylene is selected from C 1-16 Alkylene, C 1-14 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 2- 8 alkylene, C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0218] In some embodiments, the C 1-6 Alkyl is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0219] In some embodiments, the C 1-6 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0220] In some embodiments, the C 1-12 Heteroalkylene is selected from C 1-5 Heteroalkylene, C 1-4 Heteroalkylene, C 1-3 Heteroalkylene, or C 1-2 Heteroalkylene.

[0221] In some embodiments, the C 1-5 Heteroalkylene is selected from C 1-4 Heteroalkylene, C 1-3 Heteroalkylene, or C 1-2 Heteroalkylene.

[0222] In some embodiments, the C 2-6 Alkenylene is selected from C 2-5 Alkenylene, C 2-4 Alkenylene, or C 2-3 Alkenylene.

[0223] In some embodiments, the C 1-5 Heteroalkenylene is selected from C 1-4 Heteroalkenylene, C 1-3 Heteroalkenylene, or C 1-2 Heteroalkenylene.

[0224] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N, O, or S.

[0225] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N or O.

[0226] In some embodiments, the heteroalkylene group contains 1 N atom and 1 O atom.

[0227] In some embodiments, the heteroalkylene group contains 1 N atom.

[0228] In some embodiments, the heteroalkylene group contains 1 O atom.

[0229] In some embodiments, the heteroalkenylene group contains 1 or 2 heteroatoms selected from N, O, or S.

[0230] In some embodiments, the heteroalkenylene contains 1 or 2 heteroatoms selected from N or O.

[0231] In some embodiments, the heteroalkenylene contains 1 N atom and 1 O atom.

[0232] In some embodiments, the heteroalkenylene contains 1 N atom.

[0233] In some embodiments, the heteroalkenylene contains 1 O atom.

[0234] In some embodiments, the halogen is selected from fluorine, chlorine, bromine, or iodine.

[0235] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0236] In some embodiments, the "one or more" refers to an integer from one to ten, for example, "one or more" is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, 3, 4, or 5. In some embodiments, the "one or more" is selected from 1, 2, 3, or 4. In some embodiments, the "one or more" is selected from 1, 2, or 3.

[0237] In some embodiments, the compound of formula (I), wherein

[0238] Each are independently selected from a single bond or a double bond;

[0239] R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl or halogenated C 1-12 alkyl;

[0240] X 1 Selected from CR 2 ;

[0241] X 2 Selected from CR 4 ;

[0242] X 3 Selected from CR 6 ;

[0243] X 4 Selected from Connect to Q 1 of carbon atoms;

[0244] X 5 Selected from CR 10 ;

[0245] X 6 Selected from N;

[0246] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-12 alkyl;

[0247] Q 1 Selected from -NH-;

[0248] A is selected from

[0249] Ring Cy is selected from 3-12 membered heterocyclic groups;

[0250] m is selected from 1 or 2;

[0251] Each R A are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-12 alkyl;

[0252] L is selected from C 1-12 Alkylene, the C 1-12 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), or a 3-12 membered heterocyclic group, wherein the C 1-12 The alkylene group is optionally substituted with one or more R L replace;

[0253] Each R L are each independently selected from oxo;

[0254] Q 2 Selected from -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-;

[0255] Ring B is selected from 6-14 membered aryl or 5-14 membered heteroaryl;

[0256] n is selected from 1 or 2;

[0257] Each R B Each independently selected from H, C 1-12 Alkyl, or C 1-12 alkoxy;

[0258] Q 3 Selected from C 1-12 heteroalkylene;

[0259] Each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R A 、R A1 、R A2 、R L 、R B 、R B1 、R B2 , or RQ3 Each is independently optionally substituted with one or more substituents.

[0260] In some embodiments, the compound of formula (I), wherein

[0261] Each are independently selected from a single bond or a double bond;

[0262] R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl or halogenated C 1-12 alkyl;

[0263] X 1 Selected from CR 2 ;

[0264] X 2 Selected from CR 4 ;

[0265] X 3 Selected from CR 6 ;

[0266] X 4 To connect to Q 1 of carbon atoms;

[0267] X 5 Selected from CR 10 ;

[0268] X 6 is N;

[0269] R 2 、R 4 、R 6 、R 10 are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-12 alkyl;

[0270] Q 1 Selected from -NH-;

[0271] A is selected from

[0272] Ring Cy is selected from 3-12 membered cycloalkyl or 3-12 membered heterocyclyl;

[0273] m is selected from 1 or 2;

[0274] Each R A are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-12 alkyl;

[0275] L is selected from C 1-12 Alkylene, the C 1-12One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), 3-12 membered heterocyclyl or 5-14 membered heteroaryl, wherein the C 1-12 Alkylene, 3-12 membered heterocyclyl and 5-14 membered heteroaryl are each independently optionally substituted by one or more R L replace;

[0276] Each R L Each independently selected from oxo, hydroxy, C 1-12 Alkyl, or C 1-12 alkoxy;

[0277] Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-;

[0278] Ring B is selected from 6-14 membered aryl or 5-14 membered heteroaryl;

[0279] n is selected from 1 or 2;

[0280] Each R B Each independently selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, or -S(O)2R B1 ;

[0281] R B1 Selected from C 1-12 alkyl;

[0282] Q 3 Selected from -CH2NH-.

[0283] In some embodiments, the compound of formula (I), wherein

[0284] Each are independently selected from a single bond or a double bond;

[0285] R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0286] X 1 Selected from CR 2 ;

[0287] X 2 Selected from CR 4 ;

[0288] X 3 Selected from CR 6 ;

[0289] X 4 To connect to Q 1 of carbon atoms;

[0290] X 5 Selected from CR 10 ;

[0291] X 6 is N;

[0292] R 2 、R 4 、R 6 、R 10 are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-6 alkyl;

[0293] Q 1 Selected from -NH-;

[0294] A is selected from

[0295] Ring Cy is selected from 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;

[0296] m is selected from 1 or 2;

[0297] Each R A are each independently selected from H, halogen, cyano, hydroxyl, amino, or C 1-6 alkyl;

[0298] L is selected from C 1-12 Alkylene, the C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), 3-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, 3-8 membered heterocyclyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace;

[0299] Each R L Each independently selected from oxo, hydroxy, C 1-6 Alkyl, or C 1-6 alkoxy;

[0300] Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-;

[0301] Ring B is selected from 6-10 membered aryl or 5-10 membered heteroaryl;

[0302] n is selected from 1 or 2;

[0303] Each RB Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, or -S(O)2R B1 ;

[0304] R B1 Selected from C 1-6 alkyl;

[0305] Q 3 Selected from -CH2NH-.

[0306] In some embodiments, the compound of formula (I), wherein

[0307] Each are independently selected from a single bond or a double bond;

[0308] R 1 Selected from C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0309] X 1 for CH;

[0310] X 2 for CH;

[0311] X 3 for CH;

[0312] X 4 To connect to Q 1 of carbon atoms;

[0313] X 5 for CH;

[0314] X 6 is N;

[0315] Q 1 Selected from -NH-;

[0316] A is selected from

[0317] Ring Cy is selected from 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;

[0318] m is selected from 1 or 2;

[0319] Each R A are each independently selected from H or halogen;

[0320] L is selected from C 1-12 Alkylene, the C 1-121, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), 3-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, 3-8 membered heterocyclyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R L replace;

[0321] Each R L Each independently selected from oxo, hydroxy, C 1-6 Alkyl, or C 1-6 alkoxy;

[0322] Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-;

[0323] Ring B is selected from phenyl, or 5-6 membered heteroaryl;

[0324] n is selected from 1 or 2;

[0325] Each R B Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, or -S(O)2R B1 ;

[0326] R B1 Selected from C 1-6 alkyl;

[0327] Q 3 Selected from -CH2NH-.

[0328] The present application relates to a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof,

[0329] in, R 1 、R B 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Q 1 , Q 2 , Q 3 , A, L, n, and Ring B are as defined herein.

[0330] The present application relates to a compound of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof,

[0331] in, R 1 、R A 、R B 、X 1 、X 2 、X 3 、X 5 、X 6 , Q 1 , Q 2 , Q 3 , L, m, n, Ring B, and Ring Cy are as defined in this application.

[0332] In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0333] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0334] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0335] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0336] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0337] On the other hand, the present application relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) of the present application, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0338] On the other hand, the present application relates to a method for treating a p53 protein-related disease in a mammal, comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application to a mammal, preferably a human, in need of such treatment.

[0339] On the other hand, the present application relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of a medicament for treating p53 protein-related diseases.

[0340] On the other hand, the present application relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the treatment of p53 protein-related diseases.

[0341] On the other hand, the present application relates to a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application for treating p53 protein-related diseases.

[0342] In some embodiments of the present application, the p53 protein-related disease is preferably a p53 protein mutant (eg, p53 has a mutation at amino acid 220)-related disease.

[0343] In some embodiments of the present application, the p53 protein mutant is selected from p53 Y220C.

[0344] In some embodiments of the present application, the p53 protein-related disease is selected from cancer, such as gastric cancer or liver cancer.

[0345] The compounds of the present application have good p53 DNA binding activity and cell proliferation inhibitory activity (for example, good proliferation inhibitory activity on NUGC-3 cells and Huh-7 cells), as well as good thermodynamic stability of the p53 Y220C protein, and exhibit good drugability in in vitro and in vivo pharmacokinetic, bioavailability and / or pharmacodynamic studies.

[0346] definition

[0347] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0348] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0349] The "substituent" described herein includes all substituents mentioned herein, such as the terms "alkyl", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylsulfonyl", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocyclylalkyl", "aryl", "heteroaryl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano alkyl, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl ... The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)N H2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0350] In some embodiments herein, the substituent is selected from hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1- 12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0351] In some embodiments of the present application, the substituent is selected from oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-6 Alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, carboxyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -C(O)NH2, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-6 Alkyl, -S(O)2N(C 1- 6-membered alkyl) 2, 3-8-membered cycloalkyl, 3-8-membered cycloalkyl C 1-6 Alkylene, 3-8 membered cycloalkyloxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic group C 1-6 Alkylene, 3-8 membered heterocyclyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkylC 1-6 Alkylene, 3-8 membered heterocycloalkyloxy, 5-6 membered heteroaryl, 5-6 membered heteroarylC 1-6 Alkylene, 5-6 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-6 an alkylene group or a 6- to 10-membered aryloxy group.

[0352] In some embodiments of the present application, the substituent is selected from oxo, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or -S(O)2-C 1-6 alkyl.

[0353] The term "substituted" means that a specific atom or group can be replaced by a specified other atom or group. For example, one, two, or three -CH2- in -CH2CH2CH2- can be independently replaced by O, S, or NH to obtain -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -O-CH2-O-, -NH-CH2-O-, -O-, etc.

[0354] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0355] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0356] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0357] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0358] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0359] When the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0360] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0361] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0362] The term "hydroxy" refers to an -OH group.

[0363] The term "cyano" refers to a -CN group.

[0364] The term "mercapto" refers to a -SH group.

[0365] The term "amino" refers to a -NH2 group.

[0366] The term "nitro" refers to a -NO2 group.

[0367] The term "heteroatom" includes atoms of any element except carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. In one embodiment, the heteroatom is selected from N, O and S.

[0368] The term "heteroatom group" refers to a group comprising a heteroatom, which is optionally substituted by a substituent. Non-limiting examples of heteroatom groups include, but are not limited to, -NH-, -O-, -S-, =N-, -S(O)-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, =NO-, -B(OH)-, -P(=O)(OH)-, -P(=O)NH-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, ONHC(O), NHC(O)NH, or -ON=. In some embodiments, the heteroatom group is selected from N, NH, O, or S. In some embodiments, the heteroatom group is selected from N, NH, O, S, C(O), C(O)NH, or NHC(O).

[0369] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched chain divalent hydrocarbon radical typically has 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 2 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6"Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), pentylene, hexylene, heptylene, octylene, nonylene, decylene, and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0370] Term " heteroalkylene " refers to the alkylene group wherein one or more carbon atoms (and the hydrogen atom connected thereto) are each independently replaced by the same or different heteroatom groups.Unless otherwise indicated, the heteroalkylene group comprises 1, 2 or 3 heteroatom groups, and the heteroatom groups non-limiting examples include O, S, N or NH, typically with 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.For example, term " C1-6 heteroalkylene group " refers to the heteroalkylene group containing 1 to 6 carbon atoms and 1-3 heteroatom groups.The heteroatom groups can be placed in any position (for example, inside or end position) of heteroalkylene group, including the position in which alkylene group is connected to the rest of the molecule.Usually, in the presence of more than a heteroatom group, the heteroatoms are not adjacent to each other. Non-limiting examples of heteroalkylene include, but are not limited to, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2OCH2-, -OCH2O-, -OCH2CH2O-, -OCH2OCH2CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -CH2SCH2-, -SCH2S-, -SCH2CH2S-, -SCH2SCH2CH2-, -CH2NH-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -CH2NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -OCH2NH-, -OCH2CH2NH-, -OCH2NHCH2CH2-, -OCH2N(CH3)CH2-, and the like. The heteroalkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0371] The term "alkyl" refers to a group of the formula C n H 2n+1 The saturated hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group can be straight or branched and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C 1-6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0372] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Heteroalkyl" refers to a heteroalkyl group containing from 1 to 6 carbon atoms and from 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal), including the position at which the heteroalkyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0373] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0374] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0375] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, e.g., diC 1-12 Alkylamino refers to -N(C 1-12 alkyl)2, having 1 to 12 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0376] The term "alkylsulfonyl" refers to an -SO2-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0377] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0378] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0379] The term "alkenylene" refers to a divalent form of an alkenyl group. The alkenylene group typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenylene groups include, but are not limited to, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, etc. The alkenylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0380] The term "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and their associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkenyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4"Heteroalkenyl" refers to a heteroalkenyl group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenyl group (e.g., internal or terminal), including the position at which the heteroalkenyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenyl groups include, but are not limited to, CH2=N-, alkenyl-O-, alkenyl-NH-, alkenyl-S-, alkenyl-O-alkylene-, alkyl-O-alkenylene-, alkenyl-NH-alkylene-, alkyl-NH-alkenylene-, alkenyl-S-alkylene-, alkyl-S-alkenylene-, Alkenyl-CH=N-, alkenyl-N=CH-, alkyl-CH=N-alkenylene-, alkenyl-CH=N-alkylene-, or alkyl-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenyl group is a carbon-carbon double bond. The heteroalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0381] The term "heteroalkenylene" refers to the divalent form of heteroalkenyl. Unless otherwise indicated, the heteroalkenylene contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4"Heteroalkenylene" refers to a heteroalkenylene group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenylene group (e.g., internal or terminal), including the position at which the heteroalkenylene group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenylene groups include, but are not limited to, -CH=N-, -alkenylene-O-, -alkenylene-NH-, -alkenylene-S-, -alkenylene-O-alkylene-, -alkylene-O-alkenylene-, -alkenylene-NH-alkylene-, -alkylene-NH-alkenylene-, -alkenylene-S-alkylene-, -alkylene-S- In some embodiments, the double bond in the heteroalkenylene group is a carbon-carbon double bond. The heteroalkenylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0382] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0383] The term "alkynylene" refers to the divalent form of an alkynyl group. The alkynylene group typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-), 1-propynylene (-C≡C-CH2-), 2-propynylene (-CH2-C≡C-), 1,3-butadiynylene (-C≡C≡C-) and the like. The alkynylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0384] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocycle, a bridged ring, or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, 3 to 8 rings, 4 to 8 rings, 5 to 8 rings, 5 to 6 rings, or 6 to 7 rings. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, bicyclo [3.2.0] heptyl, bicyclo [3.3.0] octyl, spiral [3.3] heptyl, spiral [3.4] octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0385] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocycle, bridged ring or spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, 3 to 8 rings, 4 to 8 rings, 5 to 8 rings or 5 to 6 rings. Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl etc. The cycloalkenyl is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl,-C (O) O-alkyl,-OC (O)-alkyl,-C (O) NH ,-C (O) NH-alkyl,-C (O) N (alkyl) ,-NHC (O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0386] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 12-membered, 3 to 10-membered, 3 to 8-membered, 4 to 8-membered, 5 to 8-membered, 5 to 6-membered, 6 to 7-membered, 3 to 7-membered or 4 to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, azetidinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, azaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphaninyl, and the like. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0387] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-12, 3-10, 3-8, 4-8, 5-8, 5-6, 3-7, or 4-6 ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms, preferably sulfur, oxygen, nitrogen, and phosphorus atoms). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Examples of heterocycloalkyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, azetidinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, azaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphaninyl, and the like. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0388] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0389] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or a plurality of fused rings containing 5 to 14, especially 5 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0390] The group Q in this application3 and L are read from left to right, corresponding to Q in the general formula shown 3 Or L connected to the left and right groups connected, for example, when Q 3 When it is -CH2NH-, the structure The corresponding For example, when L is When the structure The corresponding

[0391] The group Q in this application 2 Reading order from left to right corresponds to Q in the general formula shown 2 The upper and left groups of the connection are connected, for example, when Q 2 When it is -C(O)NH-, the structure The corresponding

[0392] The group Q in this application 1 Reading order from left to right, the corresponding upper and lower groups connected to the group in the general formula are connected, for example, when Q 1 When it is -C(O)NH-, the structure The corresponding

[0393] The group A in this application is read from left to right, and the corresponding upper group and right group connected to the group in the general formula are connected. For example, when A is When the structure The corresponding

[0394] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

[0395] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0396] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0397] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0398] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0399] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0400] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0401] The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the disclosure of this application.

[0402] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0403] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0404] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0405] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0406] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0407] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of protection of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0408] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and all such isotopically labeled compounds of the present application are included within the scope of protection of the present application. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P.35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0409] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0410] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0411] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers, and all such stereoisomers are included within the scope of protection of the present application. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0412] Unless otherwise indicated, for compounds having one or more stereoisomers, the bonds to the chiral centers are represented by solid lines. The range indicated encompasses all compounds in single enantiomeric form, in form enriched in one enantiomer, or in racemic form. For example, compound Indicates that the scope covers or a mixture of any two or more thereof (e.g., a racemic form).

[0413] The compounds of the present application may have one or more atropisomers, and all such atropisomers are included in the scope of protection of the present application. Unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The compounds containing chiral axes of the present application can be isolated in racemic form. When the energy barrier for free rotation of single bonds of the compounds containing chiral axes of the present application is high enough, the atropisomers can be isolated in an optically pure form.

[0414] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0415] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0416] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0417] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, and the like for oral administration to a patient.

[0418] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0419] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0420] In all administration methods of the compound of formula (I) of the present application, the daily dosage is 0.01 to 200 mg / kg body weight. The compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0421] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0422] When Q 2 When selected from -C(O)O- or -C(O)NH-, the compound of formula (IV) of the present application can be prepared by a person skilled in the art of organic synthesis through route 1, wherein PG is independently selected from a suitable common protecting group, such as tert-butyloxycarbonyl; Z is O or NH; R 1 、R A 、R B 、X 1 、X 2 、X 3 、X 5 、X 6 , Q 1 , Q 3 , L, m, n, Ring B, and Ring Cy are as defined above.

[0423] Route 1

[0424] Each product obtained by the reaction in the above-mentioned route can be obtained by traditional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this application can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0425] This application uses the following abbreviations:

[0426] Ts represents p-toluenesulfonyl; Boc represents tert-butyloxycarbonyl; Ph represents phenyl; Tf represents trifluoromethanesulfonyl; DIPEA represents N,N-diisopropylethylamine; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; oxone represents potassium peroxymonosulfonate; DMAP represents 4-dimethylaminopyridine; EDCI represents carbodiimide hydrochloride; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCM represents dichloromethane; and TFA represents trifluoroacetic acid.

[0427] Commercially available compounds were referred to by their supplier catalog names.

[0428] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. This application has been described in detail herein and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of this application without departing from the spirit and scope of this application.

[0429] All reagents used in this application were commercially available and used without further purification. Example

[0430] Example 1

[0431] Step A: Preparation of compound 1-2

[0432] Compound 1-1 (5.0 g) and potassium iodide (0.458 g) were placed in a 250 mL round-bottom flask. Anhydrous N,N-dimethylformamide (100 mL) was added to dissolve the mixture. Propyl bromide (6.57 g) and N,N-diisopropylethylamine (10.7 g) were added dropwise with a syringe while stirring. The reaction flask was heated and stirred in a 75°C oil bath overnight. After completion of the reaction, water was added to quench the mixture. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phase was washed twice with saturated sodium chloride solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product, compound 1-2 (4.0 g).

[0433] 1 H NMR (500MHz, DMSO-d6) δ = 7.52 (dd, J = 8.3, 1.7, 1H), 7.31 (d, J = 1.7, 1H), 6.67 (d, J = 8.4, 1H), 6.18(t,J=6.2,1H),3.99(dd,J=6.2,2.3,2H),3.83(s,3H),3.78(s,3H),3.07(t,J=2.3,1H).

[0434] MS (ESI, [M+H] + )m / z:220.2

[0435] Step B: Preparation of Compound 1-4

[0436] In a 50 mL single-necked flask, dissolve the raw material 1-3 (1 g) in dichloromethane (15 ml). Then, add triethylamine (0.690 g), p-toluene cyclopentane (0.780 g), and 4-dimethylaminopyridine (0.042 g) in sequence. After addition, react at room temperature for 3 hours. Directly spin dry and mix with silica gel sand. Purify by silica gel column chromatography to obtain the target product 1-4 (1.3 g). MS (ESI, [M-100+H] + )m / z:348.2

[0437] Step C: Preparation of Compound 1-6

[0438] In a 500mL three-necked flask, compound 1-5 (30g) was first dissolved in N,N-dimethylformamide (300ml). The nitrogen was evacuated three times, and sodium hydride (11.10g) was added in batches under ice bath. Stirred under ice bath for 30 minutes, phenyl cyclohexane chloride (32.7g) was added dropwise. After addition, the temperature was naturally raised to room temperature and the reaction was continued for 2 hours. The reaction solution was slowly poured into stirred ice water (2.5L) to precipitate a solid. Filtered and dried to obtain compound 1-6 (52g). MS (ESI, [M+Na] + )m / z:325.0

[0439] Step D: Preparation of Compound 1-7

[0440] Dissolve compound 1-6 (50g) in tetrahydrofuran (500ml) in a 2L single-necked flask, evacuate nitrogen three times, cool to -78°C, and slowly add lithium diisopropylamide (248ml, 2M). Continue stirring at -78°C for 1 hour, then continue to add a solution of iodine (63.0g) in tetrahydrofuran (250mL) dropwise. After the addition is complete, keep the mixture warm at -78°C for 2 hours. Add saturated sodium thiosulfate solution (200mL) to quench the reaction, and let the reaction solution naturally warm to room temperature. Add 1L of water and separate the layers. The aqueous phase is extracted three times with ethyl acetate (300mL*3), the organic phases are combined and washed with saturated sodium chloride solution (400mL), dried over anhydrous sodium sulfate, filtered, spin-dried, sanded, and purified by column chromatography to obtain compound 1-7 (30g). MS (ESI, [MH] - )m / z:427.1

[0441] Step E: Preparation of Compound 1-8

[0442] Compound 1-7 (17.7 g) was dissolved in tert-butanol (300 ml) and water (30.0 ml) in a 1 L single-necked flask. Potassium tert-butoxide (46.4 g) was added with stirring at room temperature, and the temperature was raised to 70°C for 3 hours. The reaction solution was cooled to room temperature, most of the tert-butanol was removed by vortexing, and ethyl acetate (300 mL) and water (500 mL) were added to separate the liquids. The aqueous phase was extracted with ethyl acetate three times (150 mL * 3), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, dried by vortexing, sanded, and column chromatography to obtain the target product, compound 1-8 (10 g). MS (ESI, [MH] - )m / z:286.9

[0443] Step F: Preparation of Compound 1-9

[0444] Compound 1-8 (10 g) was dissolved in tetrahydrofuran (100 ml) in a 250 mL three-necked flask, nitrogen was purged three times, and sodium hydride (5.55 g) was added in batches under ice bath. After addition, the mixture was stirred under ice bath for 30 minutes, and trifluoroethyl trifluoromethanesulfonate (12.09 g) was added dropwise. After the mixture was added, the mixture was naturally warmed to room temperature and reacted overnight. Water (10 mL) was added dropwise to the reaction solution under ice bath to quench the mixture, and water (150 mL) and ethyl acetate (50 mL) were added to separate the liquids. The aqueous phase was extracted with ethyl acetate (60 mL * 3). The organic phases were combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, sanded, and column chromatography to obtain compound 1-9 (12.1 g).

[0445] Step G: Preparation of Compound 1-10

[0446] In a 250 mL single-necked flask, dissolve intermediate 1-9 (6 g) in acetic acid (70 ml) and heat to 70°C. Add iron powder (5.45 g) in batches and react overnight. Cool the reaction solution to room temperature, remove most of the iron powder with a magnet, and then spin to remove the acetic acid. Add water (5 mL) and ethyl acetate (20 mL) to the crude product, add saturated sodium bicarbonate solution (50 mL) dropwise, and adjust the pH to 8. Separate the liquid, extract the aqueous phase with ethyl acetate three times (20 mL*3), combine the organic phases, wash with saturated sodium chloride (20 mL), dry over anhydrous sodium sulfate, filter, spin dry, sand, and purify by column chromatography to obtain compound 1-10 (3 g).

[0447] 1 H NMR (500MHz, DMSO-d6) δ = 7.00 (s, 1H), 6.82 (t, J = 7.9, 1H), 6.74 (d, J = 8.2, 1H), 6.20 (d, J = 7.5, 1H), 5.36 (s, 2H), 4.97 (q, J = 9.0, 2H).

[0448] MS (ESI, [M+H] + )m / z:340.9

[0449] Step H: Preparation of Compound 1-11

[0450] Compound 1-2 (774 mg), 1-10 (800 mg), cuprous iodide (134 mg), and tetrakistriphenylphosphine palladium (272 mg) were placed in a 100 mL round-bottom flask and dissolved in anhydrous DMSO (15 mL). N,N-diisopropylethylamine (1.8 g) was added dropwise with a syringe while stirring. The reaction flask was placed in a 50°C oil bath and heated with stirring for 2 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (50 mL*3). The organic phase was washed twice with saturated sodium chloride solution (50 mL*2), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, the organic phase was purified by silica gel column chromatography to obtain compound 1-11 (710 mg). MS (ESI, [M+H] + )m / z:432.4

[0451] Step I: Preparation of Compound 1-12

[0452] Compound 1-11 (710 mg) and N-tert-butyloxycarbonyl-4-piperidone (984 mg) were placed in a 100 mL round-bottom flask and dissolved with 1,2-dichloroethane (5 mL) and acetic acid (10 mL). The reaction flask was heated and stirred in a 50°C oil bath for 15 minutes. The first batch of sodium triacetylborohydride (328 mg) was added and allowed to react for 15 minutes. A second batch of NaBH(OAc)3 (328 mg) was added and allowed to react for 15 minutes. A third batch of sodium triacetylborohydride (164 mg) was added and allowed to react for 15 minutes. A fourth batch of sodium triacetylborohydride (164 mg) was added and allowed to react for 30 minutes. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate three times (50 mL x 3). The organic phase was washed twice with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to yield compound 1-12 (1.01 g). MS (ESI, [M+H] + )m / z:615.6

[0453] Step J: Preparation of Compound 1-13

[0454] Compound 1-12 (930 mg) was placed in a 100 mL round-bottom flask, and a solution of hydrogen chloride in 1,4-dioxane (20 mL, 4 M) was added to dissolve the mixture. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was dried to obtain the hydrochloride salt of compound 1-13 (980 mg). MS (ESI, [M+H] + )m / z:515.3

[0455] Step K: Preparation of Compound 1-14

[0456] In a 10 mL microwave tube, the hydrochloride salt of compound 1-13 (200 mg), isopropanol (5 ml), compound 1-2 (226 mg), and N,N-diisopropylethylamine (151 mg) were added in sequence. The tube was capped and microwave reactor was set to 200 W, heated to 120°C, and reacted for 6 h. The product was directly spin-dried and sanded, and column chromatography was performed to obtain compound 1-14 (210 mg). MS (ESI, [M+H] + )m / z:790.4

[0457] Step L: Preparation of Compound 1-15

[0458] In a 25 mL single-necked flask, compound 1-14 (160 mg) was dissolved in methanol (5 mL) and water (0.625 mL), and sodium hydroxide (24.31 mg) was added. The temperature was raised to 50°C and the reaction was allowed to proceed for 6 hours. The methanol was removed by vortexing, and dilute hydrochloric acid (2.3 mL, 2 M) was added dropwise. The pH was adjusted to 5, and ethyl acetate was added and extracted three times (10 mL*3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and dried to obtain compound 1-15 (146 mg). It was used directly in the next step without purification. MS (ESI, [MH] - )m / z:774.5

[0459] Step M: Preparation of Compound 1-16

[0460] Compound 1-15 (150 mg) and a solution of hydrogen chloride in dioxane (5 ml, 4 M) were added sequentially to a 25 mL single-necked bottle and reacted at room temperature for 1 hour. The mixture was spin-dried to obtain the hydrochloride salt of compound 1-16 (130 mg). The product was used directly in the next step without purification. MS (ESI, [M+H] + )m / z:676.5

[0461] Step N: Preparation of compound 1

[0462] In a 25 mL single-necked bottle, the hydrochloride of compound 1-16 (130 mg) was dissolved in pyridine (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.8 mg) was added. The mixture was reacted at room temperature overnight, the pyridine was removed by rotation, and the mixture was dissolved in N,N-dimethylformamide (2 mL). The mixture was purified by reverse phase column chromatography to obtain compound 1 (55 mg).

[0463] 1H NMR (500MHz, DMSO-d6) δ8.22(t,J=5.4Hz,1H),7.51(d,J=8.2Hz,1H),7.38(s,1H),7.00(dd,J=20.9,13.0Hz,2H),6.78(d ,J=8.3Hz,1H),6.69(d,J=8.2Hz,1H),6.17(d,J=7.8Hz,1H),6.07(t,J=6.6Hz,1H),5.32(d,J=8.7Hz,1H),4.99(q,J=9.0H z,2H),4.33(d,J=6.5Hz,2H),3.84(s,3H),3.51(dtd,J=15.4,10.3,5.1Hz,12H),3.39(dd,J=10.1,5.0Hz,2H),2.85–2.7 0(m,2H),2.45(t,J=5.1Hz,2H),2.15(t,J=9.7Hz,2H),1.80(d,J=10.1Hz,2H),1.53(dd,J=18.6,9.1Hz,2H),1.24(s,1H).

[0464] HRMS (ESI, [M+H] + )m / z:658.3217.

[0465] Example 2

[0466] Compound 2-1 was prepared by referring to the preparation method of compound 1-14 in step K of Example 1.

[0467] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 2-2 was prepared using compound 2-1 as a raw material.

[0468] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 2-3 was prepared using compound 2-2 as a raw material.

[0469] Referring to the preparation method of compound 1 in step N of Example 1, compound 2 was prepared using compound 2-3 as raw material.

[0470] 1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.15(s,1H),7.61(d,J=8.3Hz,1H),7 .35(d,J=1.9Hz,1H),6.99(s,1H),6.85–6.74(m,2H),6.26(s,1H),6.01(s, 1H),5.56(s,1H),4.98(q,J=9.1Hz,2H),4.33(d,J=6.6Hz,2H),3.84(s,3H) ,3.35(s,3H),3.00(s,4H),1.91(s,3H),1.58(m,5H),1.24(d,J=6.8Hz,2H).

[0471] HRMS (ESI, [M+H] + )m / z:554.2743.

[0472] Example 3

[0473] Compound 3-1 was prepared by referring to the preparation method of compound 1-14 in step K of Example 1.

[0474] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 3-2 was prepared using compound 3-1 as a raw material.

[0475] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 3-3 was prepared using compound 3-2 as a raw material.

[0476] Referring to the preparation method of compound 1 in step N of Example 1, compound 3 was prepared using compound 3-3 as raw material.

[0477] 1 H NMR (500MHz, DMSO-d6) δ8.10(t,J=5.9Hz,1H),7.52(d,J=8.3Hz,1H),7.33(d,J=1.8Hz,1H),6. 99(t,J=7.9Hz,1H),6.80(q,J=7.7,6.0Hz,3H),6.34(d,J=7.6Hz,1H),6.03(t,J=6.5Hz,1H),5. 12(s,1H),4.99(q,J=9.1Hz,2H),4.32(d,J=6.5Hz,2H),3.83(s,3H),3.78–3.46(m,2H),3.29(s ,1H),2.84–2.57(m,2H),1.79(s,2H),1.62–1.42(m,6H),1.39–1.29(m,3H),1.27–1.20(m,3H).

[0478] HRMS (ESI, [M+H] + )m / z:568.2904.

[0479] Example 4

[0480] Compound 4-1 was prepared by referring to the preparation method of compound 1-14 in step K of Example 1.

[0481] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 4-2 was prepared using compound 4-1 as a raw material.

[0482] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 4-3 was prepared using compound 4-2 as a raw material.

[0483] Referring to the preparation method of compound 1 in step N of Example 1, compound 4 was prepared using compound 4-3 as raw material.

[0484] 1 H NMR(500MHz,DMSO-d6)δ8.11(s,1H),7.55(dd,J=8.3,1.9Hz,1H),7.35(d,J=1.8H z,1H),7.14–6.97(m,2H),6.78(dd,J=15.7,8.3Hz,2H),6.21(d,J=7.8Hz,1H),6. 03(t,J=6.6Hz,1H),5.36(s,1H),5.01(q,J=9.1Hz,2H),4.34(d,J=6.6Hz,2H),3. 84(s,3H),3.83–3.75(m,1H),2.80(s,4H),1.86(m,4H),1.50(s,4H),1.26(m,8H).

[0485] HRMS (ESI, [M+H] + )m / z:582.3070.

[0486] Example 5

[0487] Compound 5-1 was prepared by referring to the preparation method of compound 1-14 in step K of Example 1.

[0488] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 5-2 was prepared using compound 5-1 as a raw material.

[0489] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 5-3 was prepared using compound 5-2 as a raw material.

[0490] Referring to the preparation method of compound 1 in step N of Example 1, compound 5 was prepared using compound 5-3 as raw material.

[0491] 1 H NMR(500MHz,DMSO-d6)δ8.12(t,J=5.7Hz,1H),7.57–7.49(m,1H),7.35(d,J=1.9Hz, 1H),7.02(m,2H),6.78(d,J=8.3Hz,2H),6.25(s,1H),6.05(t,J=6.7Hz,1H),5.21(s ,1H),5.02(q,J=9.1Hz,2H),4.34(d,J=6.6Hz,2H),3.84(s,3H),3.63(s,1H),3.27( d,J=5.9Hz,2H),3.00(d,J=6.9Hz,2H),2.04–1.74(m,3H),1.50(s,6H),1.27(m,9H).

[0492] HRMS (ESI, [M+H] + )m / z:596.3216.

[0493] Example 6

[0494] Step A: Preparation of compound 6-1

[0495] In a 250 mL single-necked flask, intermediate 1-10 (5 g) and N-tert-butyloxycarbonyl-4-piperidone (6 g) were dissolved in 1,2-dichloroethane (25 mL) and acetic acid (50.0 mL). The mixture was heated to 50°C and reacted for 10 minutes. Sodium triacetoxyborohydride (6.23 g) was then added in three portions. After 1.5 hours of reaction, the reaction solution was cooled to room temperature. Under an ice bath, the reaction solution was slowly poured into 15% aqueous NaOH (200 mL) to neutralize the pH to 7. The product was then extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by sand column chromatography to obtain the desired product 6-1 (6.2 g).

[0496] 1H NMR (500MHz, DMSO-d6) δ = 7.14 (s, 1H), 6.91 (t, J = 8.0, 1H), 6.79 (d, J = 8.2, 1H), 6.21 (d, J = 7.8, 1H), 5.44 (d, J = 8.3, 1H), 4.99(q,J=9.0,2H),3.93(d,J=11.8,2H),3.62–3.50(m,1H),2.90(s,2H),1.98-1.87(m,2H),1.41(s,9H),1.32(m,2H).

[0497] MS (ESI, [M+H] + )m / z:524.1

[0498] Step B: Preparation of compound 6-4

[0499] Compound 6-2 (6 g) was dissolved in DMF (50 ml) in a 100 mL single-necked flask, followed by the addition of sodium sulfide (3.28 g). After addition, the mixture was reacted under nitrogen for 4 hours, followed by the addition of compound 6-3 (20.71 g) under an ice bath. The mixture was allowed to warm to room temperature and the reaction continued for 5 hours. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to yield the desired product 6-4 (5.6 g).

[0500] Step C: Preparation of compound 6-5

[0501] In a 100 mL single-necked flask, compound 6-4 (5.6 g) was dissolved in acetone (20 ml) and methanol (2.000 ml). A solution of oxone (17.23 g) in water (20.00 ml) was then added under an ice bath. The mixture was allowed to warm to room temperature and allowed to react for 4 hours. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with 15% sodium sulfite solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to yield the desired product 6-5 (5.8 g).

[0502] Step D: Preparation of compound 6-6

[0503] In a 250 mL single-necked flask, compound 6-5 (3.3 g) was dissolved in ethanol (80 ml) and saturated ammonium chloride (10.00 ml), and iron powder (2.141 g) was added. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the iron powder was filtered off, the ethanol was removed by vortexing, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and sanded. The target product 6-6 (1.8 g) was obtained by column chromatography.

[0504] MS (ESI, [M+H]+) m / z: 288.15.

[0505] Step E: Preparation of Compound 6-7

[0506] Compound 6-6 (500 mg), potassium iodide (28.9 mg), DMF (5 ml), propargyl bromide (0.300 ml), and DIPEA (0.912 ml) were added sequentially to a 10 mL microwave tube. The reaction temperature was set to 75°C and allowed to react for 5 hours. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to yield the desired product 6-7 (380 mg).

[0507] MS (ESI, [M+H] + )m / z:326.1

[0508] Step F: Preparation of Compound 6-8

[0509] Compound 6-7 (337 mg), compound 6-1 (272 mg), tetrakistriphenylphosphine palladium (74.4 mg), cuprous iodide (36.8 mg), dichloromethane (4 ml), and DIPEA (1.125 ml) were added sequentially to a 50 mL single-necked flask. Nitrogen was purged three times, the temperature was raised to 50°C, and the reaction was allowed to proceed for 2 hours. The product was directly sanded and purified by column chromatography to obtain the desired product 6-8 (310 mg).

[0510] MS (ESI, [M+H] + )m / z:721.6

[0511] Step G: Preparation of compound 6-9

[0512] Compound 6-8 (250 mg), dichloromethane (5 ml), p-toluenesulfonyl chloride (264 mg), diisopropylethylamine (0.606 ml), and DMAP (85 mg) were added sequentially to a 50 mL single-necked flask. The mixture was heated to 40°C and reacted for 3 hours. The product was directly sanded and purified by column chromatography to yield the desired product 6-9 (120 mg).

[0513] MS (ESI, [MH]-) m / z: 875.6

[0514] Step H: Preparation of Compound 6-10

[0515] Compound 6-9 (90 mg) was dissolved in hydrogen chloride / dioxane solution (2 ml) in a 25 mL single-necked bottle and reacted for 1 hour. After the reaction was complete, the mixture was directly spin-dried to obtain the hydrochloride salt of the target product 6-10 (90 mg).

[0516] MS (ESI, [M+H] + )m / z:775.5.

[0517] Step I: Preparation of compound 6

[0518] In a 20 mL microwave tube, compound 6-10 (90 mg) was dissolved in isopropanol (15 mL) and diisopropylethylamine (0.081 mL) was added. The reaction temperature was set to 130°C and the reaction was allowed to proceed for 6 hours. After completion of the reaction, the product was directly sanded and purified by column chromatography. The desired product (12 mg) was then purified again by reverse-phase column chromatography.

[0519] 1 H NMR (500MHz, CDCl3) δ7.67-7.50(m,1H),7.25(d,J=1.5Hz,1H),7.22-7.13(m,1H),6.93(d,J=8.3 Hz,1H),6.70(d,J=8.5Hz,2H),6.37(d,J=7.7Hz,1H),5.24(t,J=6.5Hz,1H),4.69(q,J=8.4Hz,2H),4.38(d,J=6.6Hz,2H),3.93(s,3H),3 .72(s,1H),3.14-3.05(m,2H),2.67-2.57(m,4H),2.47-2.38(m,2H),2.08-1.85(m,2H),1.69(dd,J=8.2,3.5Hz,4H),1.46-1.22(m,7H).

[0520] HRMS (ESI, [M+H] + )m / z:603.2623.

[0521] Example 7

[0522] Referring to the preparation method of compound 6-1 in step A of Example 6, compound 1-10 (10 g) and tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (12.8 g) were used as raw materials. After the reaction was completed, column chromatography purification (PE:EA=5:1) was performed to separate and obtain 9.8 g of compound 7-1 (racemate formed by compounds 7-1A and 7-1B).

[0523] Compound 7-4 was prepared by referring to the preparation method of compound 6-4 in step B of Example 6.

[0524] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 7-5 was prepared using compound 7-4 as a raw material.

[0525] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 7-6 was prepared using compound 7-4 as the raw material.

[0526] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 7-7 was prepared using compound 7-6 as raw material.

[0527] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 7-8 (racemate formed by compounds 7-8A and 7-8B) was prepared using compound 7-7 as a raw material.

[0528] Referring to the preparation method of compound 6-9 in step G of Example 6, compound 7-9 (racemate formed by compounds 7-9A and 7-9B) was prepared using compound 7-8 as a raw material.

[0529] Referring to the preparation method of compound 6-10 in step H of Example 6, compound 7-9 was used as a raw material to prepare the hydrochloride of compound 7-10 (racemate formed by compounds 7-10A and 7-10B).

[0530] Referring to the preparation method of compound 6 in step I of Example 6, crude compound 7 was prepared using compound 7-10 as raw material, and then purified by HPLC using ammonium acetate as buffer to obtain the acetate salt of compound 7 (racemic compound 7A and 7B).

[0531] 1 H NMR (500MHz, CDCl3) δ7.53(d,J=7.1Hz,1H),7.26(s,1H),7.15(t,J=8.0Hz,1H),6.92(d,J=8 .4Hz,1H),6.79(d,J=8.2Hz,1H),6.65(s,1H),6.46(d,J=7.6Hz,1H),5.24(t,J=6.6Hz,1H),4 .75-4.65(m,3H),4.39(d,J=6.7Hz,2H),3.94(s,3H),3.86(dd,J=11.7,7.1Hz,2H),3.65-3. 52(m,7H),3.46-3.35(m,2H),3.18(s,1H),2.85(d,J=43.7Hz,3H),2.43(s,1H),1.93(s,2H).

[0532] HRMS (ESI, [M+H] + )m / z:653.2444.

[0533] Example 8

[0534] Referring to the preparation method of compound 6-4 in step B of Example 6, compound 8-2 was prepared using compound 6-2 and compound 8-1 as raw materials.

[0535] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 8-3 was prepared using compound 8-2 as a raw material.

[0536] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 8-4 was prepared using compound 8-3 as a raw material.

[0537] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 8-5 was prepared using compound 8-4 as a raw material.

[0538] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 8-6 (racemate formed by compounds 8-6A and 8-6B) was prepared using compound 8-5 as a raw material.

[0539] Referring to the preparation method of compound 6-9 in step G of Example 6, compound 8-7 (racemate formed by compounds 8-7A and 8-7B) was prepared using compound 8-6 as a raw material.

[0540] Referring to the preparation method of compound 6-10 in step H of Example 6, compound 8-7 was used as the starting material to prepare the hydrochloride of compound 8-8 (racemate formed by compounds 8-8A and 8-8B).

[0541] Referring to the preparation method of compound 6 in step I of Example 6, crude compound 8 was prepared using compound 8-8 as raw material, and then purified by HPLC using ammonium acetate as buffer to obtain the acetate salt of compound 8 (racemate formed by compounds 8A and 8B).

[0542] 1H NMR (500MHz, DMSO-d6) δ = 7.41 (dd, J = 8.4, 1.5, 1H), 7.21 (d, J = 1.7, 1H), 7.16 (s, 1H), 7.02 (t, J = 8.0, 1H),6.89(d,J=8.5,1H),6.78(d,J=8.2,1H),6.62(t,J=6.3,1H),6.31(d,J=7.8,1H),5.16(d,J=9.4, 1H),5.04(q,J=8.9,2H),4.69(d,J=48.8,1H),4.36(d,J=6.3,2H),3.89(s,3H),3.72(s,1H),3.63(t, J=7.4,2H),3.53(t,J=6.9,6H),3.48(dd,J=9.5,5.2,6H),3.08(s,1H),2.87(d,J=11.0,1H),2.48(s, 2H),2.35(dd,J=33.3,12.5,1H),2.15(t,J=10.4,1H),1.82(dd,J=21.3,10.5,1H),1.73-1.55(m,1H).

[0543] HRMS (ESI, [M+H] + )m / z:697.2689.

[0544] Example 9

[0545] Step A: Preparation of compound 9-1

[0546] Referring to the preparation method of compound 6-1 in step A of Example 6, compound 9-1 was prepared using compound 1-10 and 1,4-dioxaspiro[4.5]decan-8-one as raw materials.

[0547] Step B: Preparation of compound 9-2

[0548] Compound 9-1 (2.8 g) was dissolved in DCM (10 mL) in a 100 mL single-necked flask and trifluoroacetic acid (20 mL) was added dropwise with stirring. The reaction was allowed to react at room temperature overnight. After completion of the reaction as monitored by TLC, most of the solvent was removed by rotary evaporation. Sodium hydroxide solution was added to neutralize the pH to neutral, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and sanded by rotary evaporation. The target product 9-2 (1.7 g) was obtained by column chromatography.

[0549] MS (ESI, [M+H] + )m / z:436.89.

[0550] Step C: Preparation of compound 9-3

[0551] In a 100 mL single-necked flask, intermediate 9-2 (1.7 g) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.2 g) were dissolved in 1,2-dichloroethane (7.5 ml) and acetic acid (15.0 ml). The temperature was raised to 50°C and the reaction was allowed to react for 10 minutes. Sodium triacetoxyborohydride (1.7 g) was added in three batches. After reacting for 1.5 hours, the reaction solution was cooled to room temperature. 15% sodium hydroxide solution was added to the reaction solution to neutralize the pH to 7. The product was then extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by sand column chromatography to obtain the target product 9-3 (950 mg). MS (ESI, [M+H] + )m / z:619.05.

[0552] 1 H NMR (500MHz, DMSO-d6) δ=7.22(s,1H),6.88(t,J=8.0,1H),6.74(d,J=8.2,1H),6.12(d,J=7.8,1H),5.39(d,J=8.0,1H),4.97(q,J=8.9 ,2H),3.87(s,4H),3.45–3.36(m,1H),3.17(d,J=4.9,4H),2.11(s,1H),1.72–1.47(m,6H),1.40(d,J=10.1,2H),1.35(d,J=14.0,9H).

[0553] Compound 9-4 was prepared by referring to the preparation method of compound 6-4 in step B of Example 6.

[0554] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 9-5 was prepared using compound 9-4 as a raw material.

[0555] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 9-6 was prepared using compound 9-5 as a raw material.

[0556] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 9-7 was prepared using compound 9-6 as a raw material.

[0557] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 9-8 was prepared using compound 9-7 as a raw material.

[0558] Step D: Preparation of compound 9-9

[0559] 9-8 (500 mg), methanol (5 ml), tetrahydrofuran (5 ml), and water (1 ml) were added to a 100 mL single-necked bottle, and sodium hydroxide (30 mg) was added with stirring. The reaction was stirred at 50°C for 1 h. After the reaction was completed, the mixture was cooled to room temperature and neutralized to pH = 7 by adding dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product 9-9 (480 mg).

[0560] MS (ESI, [M+H] + )m / z:788.16.

[0561] Step E: Preparation of Compounds 9-10

[0562] In a 100 mL single-necked bottle, 9-9 (480 mg) and 4 M hydrogen chloride in dioxane solution (10 ml) were added in sequence, reacted at room temperature for 1 hour, and then directly dried to obtain the hydrochloride salt of the target product 9-10 (436 mg).

[0563] MS (ESI, [M+H] + )m / z:688.20.

[0564] Step F: Preparation of compound 9

[0565] In a 100 mL single-necked flask, the hydrochloride salt of compound 9-10 (436 mg) was dissolved in pyridine (50 mL). EDCI (242 mg, 1.262 mmol) was added with stirring. The reaction was stirred at room temperature for 8 hours. The pyridine was removed by vortexing, the mixture was diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and sanded by vortexing. The desired product 9 (20 mg) was obtained by column chromatography.

[0566] 1H NMR (500MHz, DMSO-d6) δ = 7.37 (dd, J = 8.4, 1.8, 1H), 7.28 (s, 1H), 7.19 (d, J = 1.9, 1H), 7.04 (t, J = 8.0, 1H),6.85(d,J=8.4,1H),6.78(d,J=8.2,1H),6.65(t,J=6.2,1H),6.28(d,J=7.7,1H),5.04(q ,J=9.1,2H),4.59(d,J=9.3,1H),4.38(d,J=6.1,2H),4.14(s,2H),3.89(s,3H),3.74(s,2H),3 .54(d,J=3.9,1H),3.46-3.38(m,2H),3.25(d,J=6.8,2H),2.81(d,J=6.7,2H),2.31-2.22(m, 2H),2.18(s,1H),1.71-1.58(m,2H),1.58-1.48(m,2H),1.43-1.34(m,2H),1.32-1.24(m,2H).

[0567] HRMS (ES, [M+H] + )m / z:670.2689.

[0568] Example 10

[0569] Step A: Preparation of compound 10-1

[0570] Compound 1-2 (1 g), methanol (10 ml), water (1.250 ml), and sodium hydroxide (0.730 g) were added sequentially to a 50 mL single-necked flask. The mixture was heated to 50°C and allowed to react for 3 hours. The methanol was then removed by vortexing to neutralize the pH to 5. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and sanded. The desired product 10-1 (860 mg) was obtained by column chromatography.

[0571] 1 H NMR (500MHz, DMSO-d6) δ = 12.19 (s, 1H), 7.50 (dd, J = 8.3, 1.6, 1H), 7.31 (d, J = 1.6, 1H), 6.65 (d ,J=8.3,1H),6.08(t,J=6.2,1H),3.98(dd,J=6.2,2.2,2H),3.83(s,3H),3.06(t,J=2.2,1H).

[0572] MS (ESI, [MH] - )m / z:204.0.

[0573] Step B: Preparation of compound 10-2

[0574] In a 100 mL single-necked flask, add 6-1 (2 g), dichloromethane (10 ml), and trifluoroacetic acid (2.000 ml) in sequence. After addition, react at room temperature for 2 hours. Directly spin dry to obtain the trifluoroacetic acid salt of the target product 10-2 (2.1 g).

[0575] MS (ESI, [M+H] + )m / z:423.9.

[0576] Step C: Preparation of compound 10-3

[0577] 10-2 (1.6 g), azetidine carboxylic acid (0.761 g), DMF (30 ml), HATU (2.156 g), and DIPEA (1.321 ml) were added sequentially to a 100 mL single-necked bottle. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain sand. The target product 10-3 (1.8 g) was obtained by column chromatography.

[0578] MS (ESI, [M-56+H] + )m / z:550.8

[0579] Step D: Preparation of compound 10-4

[0580] 10-3 (1.5 g), dichloromethane (15 ml) and trifluoroacetic acid (3.00 ml) were added to a 100 mL single-necked bottle in sequence. The mixture was allowed to react for 2 hours and then dried to obtain the target product 10-4 as trifluoroacetate (2 g, 160%).

[0581] MS (ESI, [M+H] + )m / z:506.9.

[0582] Step E: Preparation of compound 10-5

[0583] To a 100 mL single-necked flask, compound 10-4 (1.9 g), N-tert-butyloxycarbonyl-3-pyrrolidone (650 mg), 1,2-dichloroethane (20 ml), and acetic acid (40.0 ml) were added in sequence. After addition, the temperature was raised to 50°C and the reaction mixture was reacted for 10 minutes. Sodium triacetoxyborohydride (0.795 g) was then added in four portions. After reacting for 1 hour, the reaction mixture was cooled to room temperature and neutralized with sodium hydroxide to a pH of 7. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, sanded, and purified by column chromatography to yield the desired product 10-5 (2.1 g).

[0584] MS (ESI, [M+H]+ )m / z:675.9.

[0585] Step F: Preparation of compound 10-6

[0586] Compound 10-5 (990 mg), compound 10-1 (301 mg), tetrakistriphenylphosphine palladium (169 mg), cuprous iodide (55.8 mg), dichloromethane (20 ml), and DIPEA (7.68 ml) were added sequentially to a 50 mL single-necked flask. After addition, nitrogen was purged three times, and the temperature was raised to 50°C for 2 hours. The mixture was cooled to room temperature, sanded, and purified by column chromatography to yield the desired product 10-6 (710 mg).

[0587] MS (ESI, [M+H] + )m / z:753.2.

[0588] Step G: Preparation of compound 10-7

[0589] 10-6 (630 mg) and 1 M dioxane solution of hydrogen chloride (40 ml) were added to a 100 mL single-necked bottle in sequence, reacted at room temperature for 1 hour, and then directly dried to obtain the target product 10-7 hydrochloride (708 mg).

[0590] MS (ESI, [M+H] + )m / z:653.2.

[0591] Step H: Preparation of compound 10

[0592] In a 250 mL single-necked bottle, the hydrochloride salt of compound 10-7 (708 mg) was dissolved in pyridine (120 ml). EDC (242 mg, 1.262 mmol) was added under ice-cooling. The temperature was naturally raised to room temperature and the reaction was allowed to proceed for 6 hours. The pyridine was removed by spin-drying, the mixture was diluted with water, and the mixture was extracted five times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and sanded by spin-drying. The target product 10 (120 mg) was obtained by column chromatography.

[0593] 1H NMR (500MHz, CDCl3) δ7.23-7.11(m,2H),7.09-7.02(m,1H),6.81(m,2H),6.71-6.55(m,2H),4.9 5-4.81(m,1H),4.74-4.62(m,3H),4.35(dd,J=8.3,5.4Hz,2H),3.87(d,J=12.0Hz,3H),3.80-3. 66(m,3H),3.60(t,J=7.9Hz,2H),3.58-3.42(m,2H),3.26-3.13(m,3H),2.98-2.80(m,3H),2.67 (t,J=11.7Hz,1H),2.32-2.18(m,1H),2.15-2.03(m,2H),1.86-1.74(m,2H),0.89-0.70(m,2H).

[0594] HRMS (ESI, [M+H] + )m / z:635.2964.

[0595] Example 11

[0596] Step A: Preparation of compound 11-2

[0597] To a 100 mL microwave tube, add nitro compound 11-1 (15.12 g), palladium acetate (1.463 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.54 g), DMF (70 ml), diethyl phosphite (13.50 g), and DIPEA (34.1 ml). After addition, purge with nitrogen for one minute and seal the tube. Use a microwave reactor set to 110°C and react for 2 hours. After completion, reverse phase purification yields the desired product 11-2 (10.2 g).

[0598] 1 H NMR (500MHz, DMSO-d6) δ7.97-7.95(m,1H),7.54-7.51(m,1H),7.43-7.39(m,1H),3.98(s,3H),3.96-3.92(m,2H),1.20(t,J=7.0Hz,3H).

[0599] Step B: Preparation of compound 11-3

[0600] In a 250 mL single-necked flask, compound 11-2 (10.2 g) was dissolved in thionyl chloride (120 ml), and DMF (4.54 ml) was added dropwise. The temperature was raised to 75°C and the reaction was allowed to proceed for 10 hours. After completion of the reaction, the desired product 11-3 (10 g) was obtained by direct spin drying and used in the next step without further purification.

[0601] Step C: Preparation of compound 11-4

[0602] Compound 11-3 (10 g) was dissolved in tetrahydrofuran (100 ml) in a 250 mL three-necked flask. The mixture was cooled to -50°C after nitrogen was replaced three times, and vinylmagnesium bromide (85 ml, 1 M) was added dropwise. After the addition was complete, the temperature was slowly raised to -20°C and the reaction was continued for 2 hours. After completion of the reaction, saturated ammonium chloride solution was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried to obtain the desired product 11-4 (10 g). This was used directly in the next step without further purification.

[0603] Step D: Preparation of compound 11-5

[0604] In an 800 mL autoclave, compound 11-4 (10 g) was dissolved in methanol (300 mL), and a 7 M methanolic ammonia solution (100 mL) was added. The reaction temperature was set to 100°C and the reaction was allowed to proceed for 3 hours. After completion of the reaction, the reaction solution was concentrated to 45 mL. The target product 11-5 (6.8 g) was obtained by purification using a reverse-phase column chromatography.

[0605] MS (ESI, [M+H] + )m / z:271.2.

[0606] Step E: Preparation of compound 11-6

[0607] In a 250 mL single-necked flask, compound 11-5 (4.7 g) was dissolved in dichloromethane (50 ml). Di-tert-butyl dicarbonate (4.56 g) and DIPEA (6.08 ml) were added and allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was directly dried and purified by column chromatography to obtain the desired product 11-6 (6.2 g).

[0608] MS (ESI, [M+H] + )m / z:371.3.

[0609] Step F: Preparation of compound 11-7

[0610] In a 250 mL single-necked flask, compound 11-6 (6.2 g) was dissolved in ethanol (60 ml). Iron powder (4.67 g) and saturated ammonium chloride solution (7.50 ml) were then added sequentially. The temperature was raised to 70°C and the reaction was continued for 3 hours. The iron powder was filtered to remove the iron powder, and the filtrate was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the desired product 11-7 (4.2 g).

[0611] MS (ESI, [M+H] + )m / z:341.2.

[0612] Step G: Preparation of compound 11-8

[0613] To a 20 mL microwave tube, compound 11-7 (1.5 g, 4.41 mmol), DMF (16 ml), propargyl bromide (0.570 ml), potassium iodide (0.146 g), and DIPEA (1.539 ml) were added sequentially. After addition, the reaction temperature was set to 70°C and the reaction was allowed to react for 7 hours. Extraction was performed with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to yield the desired product 11-8 (1 g).

[0614] MS (ESI, [M+H] + )m / z:379.1.

[0615] Step H: Preparation of compound 11-10

[0616] Compound 12-1 (580 mg), methyl 3-bromobutyrate (476 mg), potassium carbonate (908 mg), and DMF (10 ml) were added sequentially to a 50 mL single-necked flask. The temperature was raised to 60°C. The mixture was allowed to react for 6 hours, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to yield the desired product 11-10 (the racemate formed by compounds 11-10A and 11-10B) (320 mg).

[0617] MS (ESI, [M+H] + )m / z:542.1

[0618] Step I: Preparation of compound 11-11

[0619] Referring to the preparation method of compound 1-11 in step H of Example 1, compound 11-11 (racemate formed by compounds 11-11A and 11-11B) was prepared.

[0620] Step J: Preparation of Compounds 11-12

[0621] Compound 11-11 (470 mg) and dioxane hydrochloride solution (6 ml, 4 M) were added sequentially to a 50 mL single-necked flask and reacted at room temperature for 2 hours. After completion of the reaction, the mixture was directly spin-dried to obtain the hydrochloride salt (550 mg) of the target product 11-12 (the racemate formed by compounds 11-12A and 11-12B).

[0622] MS (ESI, [M+H] + )m / z:692.5.

[0623] Step K: Preparation of Compounds 11-13

[0624] To a 50 mL single-necked flask, the hydrochloride salt of compound 11-12 (410 mg), methanol (5 ml), water (0.500 ml), and sodium hydroxide (119 mg, 2.96 mmol) were added sequentially. The mixture was heated to 45°C and allowed to react for 2 hours. After completion, the methanol was removed by vortexing, and the mixture was neutralized with dilute hydrochloric acid to pH 6. The mixture was then purified by reverse-phase column chromatography to yield the desired product 11-13 (a racemate formed by compounds 11-13A and 11-13B) (320 mg).

[0625] MS (ESI, [M+H] + )m / z:678.5.

[0626] Step L: Preparation of compound 11

[0627] Compound 11 (racemate formed by compounds 11A and 11B) was prepared by referring to the preparation method of compound 1 in step N of Example 1.

[0628] 1 H NMR(500MHz,DMSO-d6)δ7.26-7.22(m,1H),7.16-7.12(m,2H),6.97-6.96(m,1H),6.85-6.84 (m,1H),6.73-6.72(m,1H),6.22-6.15(m,2H),5.76-5.75(m,2H),5.44-5.42(m,1H),4.94-4 .73(m,3H),4.32-4.28(m,3H),3.85-8.82(m,4H),3.69-3.68(m,1H),3.10-3.08(m,2H),2.8 6-2.85(m,1H),2.42-2.33(m,4H),2.27-2.24(m,4H),1.87-1.69(m,2H),1.48-1.45(m,3H).

[0629] HRMS (ESI, [M+H] + )m / z:660.2694.

[0630] Example 12

[0631] Step A: Preparation of compound 12-1

[0632] Compound 7-1 (2 g) was placed in a 100 mL single-necked flask, dissolved in DCM (50 mL), and TFA (10 mL) was added dropwise with stirring. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to obtain the trifluoroacetate salt (2.5 g) of the target product 12-1 (the racemate formed by compounds 12-1A and 12-1B).

[0633] 1 H NMR (500MHz, DMSO-d6) δ = 7.27 (s, 1H), 6.91 (t, J = 8.0, 1H), 6.82 (d, J = 8.2, 1H), 6.2 5(d,J=7.7,1H),5.39(d,J=8.7,1H),5.00(q,J=9.0,2H),4.71(d,J=50.5,1H),3.74 –3.59(m,1H),3.11(t,J=11.5,1H),2.97(d,J=13.1,1H),2.76(dd,J=39.0,14.3,1H ),2.59(t,J=11.9,1H),1.91(s,1H),1.72(qd,J=12.2,4.1,1H),1.67-1.58(m,1H).

[0634] MS (ESI, [M+H] + )m / z:442.30.

[0635] Step B: Preparation of compound 12-3

[0636] Compound 12-1 (500 mg), compound 12-2 (381 mg), and K2CO3 (783 mg) were placed in a 100 mL single-necked bottle and dissolved in DMF (10 mL). The mixture was heated to 50°C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, dried, and sanded. The target product 12-3 (racemic compound 12-3A and 12-3B) (342 mg) was obtained by column chromatography. MS (ESI, [M+H] + )m / z:585.35.

[0637] Compound 12-5 was prepared by referring to the preparation method of compound 6-4 in step B of Example 6.

[0638] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 12-6 was prepared using compound 12-5 as a raw material.

[0639] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 12-7 was prepared using compound 12-6 as the raw material.

[0640] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 12-8 was prepared using compound 12-7 as a raw material.

[0641] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 12-9 (racemate formed by compounds 12-9A and 12-9B) was prepared using compound 12-8 as a raw material.

[0642] Referring to the preparation method of compound 9-9 in step D of Example 9, compound 12-9 was used as a starting material to prepare compound 12-10 (racemate formed by compounds 12-10A and 12-10B).

[0643] Referring to the preparation method of compound 9-10 in step E of Example 9, the hydrochloride of compound 12-11 (racemate formed by compounds 12-11A and 12-11B) was prepared using compound 12-10 as a raw material.

[0644] Referring to the preparation method of compound 9 in step F of Example 9, compound 12 (racemate formed by compounds 12A and 12B) was prepared using compound 12-11 as the starting material.

[0645] 1 H NMR (500MHz, DMSO-d6) δ=7.79(s,1H),7.34(d,J=8.2,1H),7.17(d,J=13.7,2H),7.01(t,J=7.1,1H),6.89(d,J=8.4, 1H),6.79(d,J=8.2,1H),6.56(t,J=6.1,1H),6.16(d,J=7.8,1H),5.50(d,J=8.4,1H),5.40(s,1H),4.87(d,J=8.5,2H ),4.70(d,J=49.8,1H),4.35(d,J=5.9,2H),3.87(s,3H),3.20–3.16(m,2H),3.08(d,J=6.3,2H),2.95(s,1H),2.74(d ,J=10.2,1H),2.26(d,J=5.5,2H),2.13(t,J=7.3,2H),2.02(t,J=11.0,1H),1.82(d,J=12.0,1H),1.75–1.62(m,4H).

[0646] HRMS (ESI, [M+H] + )m / z:650.2422.

[0647] Example 13

[0648] Referring to the preparation method of compound 6-4 in step B of Example 6, compound 13-1 was prepared using compound 6-2 as the raw material.

[0649] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 13-2 was prepared using compound 13-1 as a raw material.

[0650] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 13-3 was prepared using compound 13-2 as a raw material.

[0651] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 13-4 was prepared using compound 13-3 as a raw material.

[0652] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 13-4 was used as the starting material to prepare compound 13-5 (racemate formed by compounds 13-5A and 13-5B).

[0653] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 13-6 (racemate formed by compounds 13-6A and 13-6B) was prepared using compound 13-5 as a raw material.

[0654] Referring to the preparation method of compound 1-16 in step M of Example 1, the hydrochloride of compound 13-7 (racemate formed by compounds 13-7A and 13-7B) was prepared using compound 13-6 as a raw material.

[0655] Referring to the preparation method of compound 1 in step N of Example 1, compound 13 (racemate formed by compounds 13A and 13B) was prepared using compound 13-7 as raw material.

[0656] 1H NMR(500MHz,DMSO-d6)δ7.46-7.36(m,1H),7.21-7.18(m,1H),7.12-7.03(m,2H),6.90-6.82(m,2H),6.59-6 .54(m,1H),6.43-6.40(m,1H),5.06-4.97(m,3H),4.72-4.51(m,1H),4.39-4.28(m,2H),4.14-4.07(m,1H), 3.88(s,3H),3.28-3.12(m,4H),2.69-2.63(m,1H),2.48-2.42(m,1H),2.08-2.00( m,1H),1.75-1.53(m,3H),1.45-1.43(m,1H),1.41-1.31(m,2H),1.29-1.16(m,5H).

[0657] HRMS (ESI, [M+H] + )m / z:649.2473.

[0658] Example 14

[0659] Referring to the preparation method of compound 6-4 in step B of Example 6, compound 14-1 was prepared using compound 6-2 as the raw material.

[0660] Referring to the preparation method of compound 6-5 in step C of Example 6, compound 14-2 was prepared using compound 14-1 as a raw material.

[0661] Referring to the preparation method of compound 6-6 in step D of Example 6, compound 14-3 was prepared using compound 14-2 as a raw material.

[0662] Referring to the preparation method of compound 6-7 in step E of Example 6, compound 14-4 was prepared using compound 14-3 as a raw material.

[0663] Compound 14-4 was dissolved in dichloromethane (5 ml) in a 50 mL three-necked flask. The nitrogen atmosphere was replaced three times, and the temperature was cooled to -10°C. Boron tribromide tetrahydrofuran solution (2.61 ml, 2 M) was added dropwise. The reaction was allowed to react for 2 hours. Methanol was then added dropwise to quench the reaction, and the mixture was spin-dried and sanded. Column chromatography was performed to obtain the target product 14-5 (420 mg). MS (ESI, [MH]) - )m / z:224.0.

[0664] Referring to the preparation method of compound 11-10 in step H of Example 11, compound 14-6 was prepared using compound 14-5 as a raw material.

[0665] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 14-7 (racemate formed by compounds 14-7A and 14-7B) hydrochloride was prepared using compound 14-6 as a raw material.

[0666] Referring to the preparation method of compound 6-9 in step G of Example 6, compound 14-8 (racemate formed by compounds 14-8A and 14-8B) was prepared using the hydrochloride salt of compound 14-7 as a raw material.

[0667] Referring to the preparation method of compound 6-10 in step H of Example 6, the hydrochloride of compound 14-9 (racemate formed by compounds 14-9A and 14-9B) was prepared using compound 14-8 as a raw material.

[0668] Referring to the preparation method of compound 6 in step 1 of Example 6, the trifluoroacetate of compound 14 (racemate formed by compounds 14A and 14B) was prepared using the hydrochloride of compound 14-9 as a raw material.

[0669] 1 H NMR (500MHz, DMSO-d6) δ7.42–7.34(m,1H),7.27(d,J=1.6Hz,1H),6.99(t,J=8.0Hz,1H),6.88(d,J=8.4Hz,2H),6 .81(d,J=8.2Hz,1H),6.46(d,J=7.7Hz,1H),6.15(t,J=6.1Hz,1H),5.34(s,1H),5.03(dd,J=17.4,8.7Hz,2H),4.7 0(d,J=48.4Hz,1H),4.38(d,J=6.2Hz,2H),4.26(s,2H),3.94–3.81(m,3H),3.64–3.59(m,2H),3.56–3.52(m,2H), 3.09(s,3H),3.06(d,J=7.0Hz,1H),2.80–2.67(m,3H),2.48(s,1H),1.87(s,3H),1.78–1.69(m,1H),1.63(s,1H).

[0670] HRMS (ESI, [M+H] + )m / z:653.2443.

[0671] Example 15

[0672] Referring to the preparation method of compound 19-5 in step E of Example 19, compound 15-1 was prepared using compound 10-2 as the raw material.

[0673] Referring to the preparation method of compound 1-11 in step I of Example 1, compound 15-2 was prepared using compound 15-1 as a raw material.

[0674] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 15-3 was prepared using compound 15-2 as a raw material.

[0675] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 15-4 was prepared using compound 15-3 as a raw material.

[0676] Referring to the preparation method of compound 1-1 in step N of Example 1, compound 15 was prepared using compound 15-4 as the raw material.

[0677] 1 H NMR(500MHz,DMSO-d6)δ7.88(t,J=5.4Hz,1H),7.40(dd,J=8.5,2.1Hz,1H),7.23(d,J=2.1Hz,1H),7.1 0–6.79(m,4H),6.61(t,J=6.3Hz,1H),6.47–6.35(m,2H),5.04(q,J=10.1,9.2Hz,3H),4.66(d,J=48.7 Hz,1H),4.36(d,J=6.4Hz,2H),4.05(d,J=17.1Hz,1H),3.90(s,4H),3.73(d,J=16.0Hz,1H),3.56–3.3 8(m,3H),3.21–2.98(m,6H),2.90(t,J=11.0Hz,1H),2.39(dq,J=11.1,5.2Hz,2H),1.77–1.63(m,1H).

[0678] HRMS (ESI, [M+H] + )m / z:661.2415

[0679] Example 16

[0680] Step A: Preparation of compound 16-1

[0681] Compound 10-2 (1.6 g), 1-tert-butyloxycarbonyl-3-pyrrolidone (0.7 g), 1,2-dichloroethane (10 ml), and acetic acid (20.0 ml) were added to a 100 mL single-necked flask. The mixture was heated to 50°C and reacted for 15 minutes. Sodium triacetoxyborohydride (2.4 g) was then added in four portions. After reacting for 1 hour, the reaction mixture was cooled to room temperature and neutralized with sodium hydroxide to a pH of 7. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, sanded, and purified by column chromatography to obtain the desired product 16-1 (1.17 g).

[0682] MS (ESI, [M+H] + )m / z:593.01.

[0683] Step B: Preparation of compound 16-2

[0684] 16-1 (1.17 g), dichloromethane (10 ml) and trifluoroacetic acid (2.00 ml) were added to a 100 mL single-necked bottle in sequence. The reaction was allowed to proceed for 1 hour, the solvent was dried, and the mixture was extracted and concentrated to obtain the trifluoroacetic acid salt of the target product 16-2 (970 mg).

[0685] MS (ESI, [M+H] + )m / z:492.94.

[0686] Step C: Preparation of compound 16-3

[0687] 16-2 (970 mg), 1-Boc-azetidine-3-carboxylic acid (0.436 g), DMF (10 ml), HATU (1.124 g), and DIPEA (1.721 ml) were added sequentially to a 100 mL single-necked bottle. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain sand. The target product 16-3 (1.3 g) was obtained by column chromatography.

[0688] MS (ESI, [M+H] + )m / z:676.32.

[0689] Referring to the preparation method of compound 10-6 in step F of Example 10, compound 16-4 was prepared using compound 16-3 as a raw material.

[0690] Referring to the preparation method of compound 10-7 in step G of Example 10, compound 16-5 was prepared using compound 16-4 as a raw material.

[0691] Referring to the preparation method of compound 10 in step H of Example 10, compound 16 was prepared using compound 16-5 as raw material.

[0692] 1 H NMR (500MHz, DMSO-d6) δ=7.80(d,J=8.3,1H),7.74(s,1H),7.48–7.42(m,1H),7.35(s,1H),7.23(d,J=8.4,1H),7.19(s,1H),7.10(d ,J=8.4,1H),5.34(d,J=8.5,2H),4.79(t,J=9.1,1H),4.57–4.44(m,2H),4.39(dd,J=9.3,5.9,1H),4.34(s,1H),4.09(dd,J=16.9,7 .7,2H),4.02(s,1H),3.88(s,3H),3.81–3.72(m,1H),3.64(dd,J=14.5,8.2,1H),3.57(d,J=12.3,1H),3.46(s,3H),3.39(d,J=10.7 ,1H),3.28(d,J=11.1,1H),3.18(s,1H),2.95(s,1H),2.68(s,1H),2.55–2.38(m,1H),2.30(d,J=8.4,2H),2.16(s,2H),2.10(s,1H).

[0693] HRMS (ESI, [M+H] + )m / z:635.2968.

[0694] Example 17

[0695] Step A: Preparation of compound 17-1

[0696] Compound 12-1 (815 mg), 1-BOC-pyrrolidine-3-carboxylic acid (437 mg), DMF (10 ml), HATU (1.05 g), and DIPEA (1.6 ml) were added to a 100 mL single-necked bottle. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried to obtain sand. The target product 17-1 (racemate formed by compounds 17-1A and 17-1B) (1.1 g) was obtained by column chromatography.

[0697] MS (ESI, [M-56+H] + )m / z:583.33.

[0698] Step B: Preparation of compound 17-2

[0699] In a 100 mL single-necked bottle, 17-1 (1.1 g), dichloromethane (10 ml), and trifluoroacetic acid (2.00 ml) were added in sequence. The reaction was allowed to proceed for 1 hour, and the solvent was dried by rotary evaporation. The mixture was extracted and concentrated to obtain the trifluoroacetic acid salt (1 g) of the target product 17-2 (racemate formed by compounds 17-2A and 17-2B).

[0700] MS (ESI, [M+H] + )m / z:539.36.

[0701] Step C: Preparation of compound 17-3

[0702] The trifluoroacetic acid salt of compound 17-2 (1 g), N-Boc-bromoethylamine (0.6 g) and potassium carbonate (1.28 g) were placed in a 100 mL single-necked bottle and dissolved in DMF (10 mL). The mixture was heated to 50°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, dried, and sanded. The target product 17-3 (racemic compound 17-3A and 17-3B) (1.07 g) was obtained by column chromatography. MS (ESI, [M+H] + )m / z:682.54.

[0703] Referring to the preparation method of compound 6-8 in step F of Example 6, compound 17-4 (racemate formed by compounds 17-4A and 17-4B) was prepared using compound 17-3 as a raw material.

[0704] Referring to the preparation method of compound 9-9 in step D of Example 9, compound 17-5 (racemate formed by compounds 17-5A and 17-5B) was prepared using compound 17-4 as a raw material.

[0705] Referring to the preparation method of compound 9-10 in step E of Example 9, the hydrochloride of compound 17-6 (racemate formed by compounds 17-6A and 17-6B) was prepared using compound 17-5 as a raw material.

[0706] Referring to the preparation method of compound 9 in step F of Example 9, compound 17 (racemate formed by compounds 17A and 17B) was prepared using compound 17-6 as the starting material.

[0707] 1H NMR (500MHz, DMSO-d6) δ = 8.21 (d, J = 5.7, 1H), 7.51 ( d, J = 7.9, 1H), 7.37 ( s, 1H), 6.97 ( dd, J = 13.3, 6.8, 1H), 6.86-6.80 (m,2H),6.42(d,J=7.8,1H),6.10(t,J=5.5,1H),5.01(dd,J=13.9,9.3,2H),4.74(s,1H),4.30(d,J=5.8,2H),3.83(s ,3H),3.51(dd,J=12.7,6.1,1H),3.39(d,J=18.2,1H),3.30-3.21(m,4H),3.14-3.00(m,2H),2.90(d,J=11.5,2H),2. 68-2.61(m,2H),2.47-2.42(m,1H),2.40-2.33(m,1H),2.25(d,J=7.3,2H),1.74(d,J=8.3,2H),1.56(d,J=11.1,2H).

[0708] HRMS (ESI, [M+H] + )m / z:641.2870.

[0709] Example 18

[0710] Step A: Preparation of compound 18-2

[0711] To a 100 mL single-necked flask, N,N-dimethylformamide (25 mL), ethyl 4-pyrazolecarboxylate (1 g), N-Boc-bromoethylamine (3.2 g), and anhydrous potassium carbonate (2 g) were added in sequence. After the addition, the mixture was reacted at room temperature for 10 h. Dichloromethane (20 mL) and purified water (10 mL) were added to the system, stirred, and the organic phase was separated. The phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was collected by separation. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 450 mg of compound 18-2.

[0712] MS (ESI, [M+H]+) m / z: 284.2.

[0713] Step B: Preparation of compound 18-3

[0714] Referring to the preparation method of step L in Example 1, compound 18-3 was prepared using compound 18-2 as the raw material.

[0715] MS (ESI, [MH]-) m / z: 254.2

[0716] Step C: Preparation of Compound 18-4

[0717] Referring to the preparation method of step N of Example 1, compound 18-4 (racemate formed by compounds 18-4A and 18-4B) was prepared using compound 18-3 and compound 12-1 as raw materials.

[0718] MS (ESI, [M+H]+) m / z: 679.1.

[0719] Step D: Preparation of compound 18-5

[0720] Referring to the preparation method of step H in Example 1, compound 18-5 (racemate formed by compounds 18-5A and 18-5B) was prepared using compound 18-4 and compound 1-2 as raw materials.

[0721] MS (ESI, [M+H]+) m / z: 770.6.

[0722] Step E: Preparation of compound 18-6

[0723] Referring to the preparation method of step L in Example 1, compound 18-6 (racemate formed by compounds 18-6A and 18-6B) was prepared using compound 18-5 as a raw material.

[0724] MS (ESI, [M+H]+) m / z: 756.6

[0725] Step F: Preparation of compound 18-7

[0726] Referring to the preparation method of Example 1 Step M, compound 18-6 was used as a raw material to prepare compound 18-7 (racemate formed by compounds 18-7A and 18-7B).

[0727] MS (ESI, [M+H]+) m / z: 656.5

[0728] Step G: Preparation of compound 18

[0729] Referring to the preparation method of Step N in Example 1, the target product Compound 18 (racemate formed by Compounds 18A and 18B) (25 mg) was prepared using Compound 18-7 as the starting material.

[0730] 1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),7.84(s,1H),7.70(s,1H),7.30(s,2H),7.07-6.72(m,4H),6.54(s,1H),6.05(s,1H),5.01(s,2H),4 .91(s,1H),4.47(s,1H),4.30(s,4H),3.82(s,3H),3.66-3.53(m,2H),3.18(s,1H),2.82(s,1H),2.55(s,2H),1.83(s,2H),1.24(s,1H).

[0731] HRMS (ESI, [M+H] + )m / z:638.2502.

[0732] Example 19

[0733] Step A: Preparation of compound 19-1

[0734] Referring to the preparation method of compound 1-12 in step I of Example 1, compound 19-1 was prepared.

[0735] Step B: Preparation of compound 19-2

[0736] Referring to the preparation method of compound 1-13 in step J of Example 1, compound 19-2 was prepared using compound 19-1 as a raw material.

[0737] Step C: Preparation of compound 19-3

[0738] Referring to the preparation method of compound 1-12 in step I of Example 1, compound 19-3 was prepared using compound 19-2 as a raw material.

[0739] Step D: Preparation of compound 19-4

[0740] Referring to the preparation method of compound 1-13 in step J of Example 1, compound 19-4 was prepared using compound 19-3 as a raw material.

[0741] Step E: Preparation of compound 19-5

[0742] Tert-butyl (2-aminoethyl)carbamate (350 mg, 2 mmol), phenyl p-nitrochloroformate (400 mg, 2 mmol), and sodium carbonate (450 mg, 4 mmol) were placed in a 100 mL round-bottom flask and dissolved in THF. After stirring at room temperature for 30 minutes, 19-4 (750 mg, 1.8 mmol) and triethylamine (400 mg, 4 mmol) were added and reacted at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated and sanded, and purified by silica gel column chromatography to obtain the desired product 19-5 (750 mg, 85%) as a light yellow solid. MS (ESI, [M+H] + )m / z:651.09

[0743] Step F: Preparation of compound 19-6

[0744] Referring to the preparation method of compound 1-11 in step H of Example 1, compound 19-6 was prepared using compound 19-5 as a raw material.

[0745] Step G: Preparation of compound 19-7

[0746] Referring to the preparation method of compound 1-15 in step L of Example 1, compound 19-7 was prepared using compound 19-6 as a raw material.

[0747] Step H: Preparation of compound 19-8

[0748] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 19-8 was prepared using compound 19-7 as a raw material.

[0749] Step I: Preparation of compound 19

[0750] Referring to the preparation method of compound 1-17 in step N of Example 1, compound 19 was prepared using compound 19-8 as a raw material.

[0751] 1H NMR (500MHz, DMSO-d6) δ7.66(s,1H),7.51(d,J=8.2Hz,1H),7.30(d,J=2.0Hz,1H),7.01(t,J=7.9Hz,1H),6. 83(d,J=8.4Hz,1H),6.74(d,J=8.9Hz,2H),6.16(d,J=7.8Hz,1H),6.02(t,J=6.8Hz,1H),5.15(d,J=8.1Hz,1H ),4.98(q,J=9.2Hz,2H),4.33(d,J=6.9Hz,2H),4.12-4.04(m,1H),3.83(s,3H),3.27-2.81(m,10H),2.71-2 .58(m,1H),2.22(dd,J=9.3,5.2Hz,1H),2.16-2.06(m,1H),2.04-1.93(m,2H),1.70(dt,J=13.6,7.2Hz,1H).

[0752] HRMS (ESI, [M+H] + )m / z:610.2748

[0753] Example 20

[0754] Step A: Preparation of compound 20-1

[0755] Referring to the preparation method of step I of Example 1, compound 20-1 was prepared using compound 1-10 and 6-Boc-2-oxo-6-azaspiro[3.4]octane as raw materials.

[0756] MS (ESI, [M+H] + )m / z:549.9.

[0757] Step B: Preparation of compound 20-2

[0758] Compound 20-1 (500 mg) was placed in a 100 mL round-bottom flask, and dichloromethane (10 mL) and trifluoroacetic acid (1 mL) were added. The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was dried to obtain compound 20-2 (400 mg).

[0759] MS (ESI, [M+H]+) m / z: 449.9

[0760] Step C: Preparation of Compound 20-3

[0761] Referring to the preparation method of Example 18 Step A, compound 20-3 was prepared using compound 20-2 and N-Boc-bromoethylamine as raw materials.

[0762] MS (ESI, [M+H]+) m / z: 593.04

[0763] Step D: Preparation of compound 20-4

[0764] Referring to the preparation method of step H in Example 1, compound 20-4 was prepared using compound 20-3 and compound 1-2 as raw materials.

[0765] MS (ESI, [M+H]+) m / z: 684.24

[0766] Step E: Preparation of compound 20-5

[0767] Referring to the preparation method of step L in Example 1, compound 20-5 was prepared using compound 20-4 as a raw material.

[0768] MS (ESI, [MH]-) m / z: 668.39

[0769] Step F: Preparation of compound 20-6

[0770] Referring to the preparation method of step M in Example 1, compound 20-6 was prepared using compound 20-5 as a raw material.

[0771] MS (ESI, [M+H] + )m / z:570.14

[0772] Step G: Preparation of compound 20

[0773] Referring to the preparation method of step N of Example 1, the target product compound 20 (20 mg) was prepared using compound 20-6 as the raw material.

[0774] 1 H NMR(500MHz,DMSO-d6)δ8.09(s,1H),7.65-7.64(m,1H),7.43-7.20(m,2H),6.99-6.85(m,2H),6.73 -6.72(m,1H),5.95-5.94(m,1H),5.78(s,1H),5.54-5.53(m,1H),4.93-4.91(m,2H),4.34-4.33(m,2 H),3.84(s,3H),3.04-3.03(m,2H),3.01-2.95(m,1H),2.41-2.37(m,1H),2.18-2.15(m,1H),2.02-1 .90(m,4H),1.73-1.70,1.48-1.45(m,1H),1.11-1.04(m,2H),1.00-0.95(m,1H),0.87-0.84(m,1H).

[0775] HRMS (ESI, [M+H] + )m / z:552.2584.

[0776] Example 21

[0777] Step A: Preparation of compound 21-1

[0778] 10-2 (1 g), 1-(tert-butoxycarbonyl)-3-methoxyazetidine-3-carboxylic acid (0.546 g), pyridine (20 ml), and EDCI (2.156 g) were added to a 100 mL single-necked bottle in sequence. The mixture was reacted at room temperature for 2 hours. The reaction solution was washed with 2N HCl aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain the target product 21-1 (0.8 g).

[0779] Step B: Preparation of compound 21-2

[0780] To a 100 mL single-necked flask, add 21-1 (0.7 g), dichloromethane (20 ml), and trifluoroacetic acid (2.000 ml) in sequence. After addition, react at room temperature for 2 hours. Sodium hydroxide solution is added, the pH is adjusted to approximately 11, and the mixture is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered to yield the desired product 21-2 (0.59 g).

[0781] MS (ESI, [M+H] + )m / z:537.15

[0782] Step C: Preparation of compound 21-3

[0783] To a 100 mL single-necked flask, add compound 21-2 (0.337 g), acetonitrile (20 ml), 1-tert-butoxycarbonyl-3-pyrrolidone (0.14 g), sodium triacetoxyborohydride (0.266 g), and tetraisopropyl titanate (0.372 ml). After addition, heat to 80°C and react for 2 hours. Sanding was performed directly, and column chromatography was performed to obtain the desired product 21-3 (0.44 g).

[0784] MS (ESI, [M+H] + )m / z:706.50.

[0785] Step D: Preparation of compound 21-4

[0786] Referring to the preparation method of Step F in Example 10, compound 21-4 was prepared using compound 21-3 as a raw material.

[0787] MS (ESI, [M+H] + )m / z:797.71

[0788] Step E: Preparation of compound 21-5

[0789] Referring to the preparation method of compound 9-9 in step D of Example 9, compound 21-5 was prepared using compound 21-4 as a raw material.

[0790] MS (ESI, [M+H] + )m / z:783.54

[0791] Step F: Preparation of compound 21-6

[0792] Referring to the preparation method of step G in Example 10, compound 21-6 was prepared using compound 21-5 as a raw material.

[0793] MS (ESI, [M+H] + )m / z:683.56.

[0794] Step G: Preparation of compound 21

[0795] Referring to the preparation method of Step H in Example 10, Compound 21 was prepared using Compound 21-6 as the starting material.

[0796] 1 H NMR (500MHz, DMSO-d6) δ7.23–7.11(m,2H),7.11–6.98(m,2H),6.88(m,1H),6.77(m,1H),6.51(t,J=8.2 Hz,1H),6.12–5.88(m,1H),5.18–4.84(m,2H),4.64(d,J=11.1Hz,1H),4.50–4.26(m,4H),4.11(d,J=7.1 Hz,1H),3.89–3.78(m,3H),3.77–3.64(m,2H),3.61–3.36(m,6H),3.12(dd,J=10.8,3.0Hz,1H),3.03(d, J=53.5Hz,3H),2.96–2.76(m,2H),2.02–1.85(m,2H),1.72(m,2H),1.49(d,J=13.3Hz,1H),1.06(m,1H).

[0797] HRMS (ESI, [M+H] + )m / z:665.3072.

[0798] Test Example 1 In vitro cell proliferation inhibitory activity assay

[0799] NUGC-3 cells (Nanjing Kebai) with good growth status were inoculated into 96-well plates (100 μL / well). After overnight culture in a 37°C cell culture incubator, the compound was added using a pipette, with 2 parallel wells per group, and a control group was set up at the same time. After continuing to culture in a 37°C cell culture incubator for 120 hours, the detection reagent CCK-8 (manufacturer: Japan Tongren Chemical, 10 μL / well) was added. After continuing to culture at 37°C for 1.5 hours, the absorbance value was detected at 450 nM using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed in GraphPad Prism software, and the dose-effect curve was fitted to calculate the IC 50 value.

[0800] Huh-7 cells (Nanjing Kebai) with good growth status were inoculated into 96-well plates (100 μL / well). After overnight culture in a 37°C cell culture incubator, the compound was added using a pipette, with 2 parallel wells per group, and a control group was set up at the same time. After continuing to culture in a 37°C cell culture incubator for 120 hours, the detection reagent CCK-8 (manufacturer: Japan Tongren Chemical, 10 μL / well) was added, and after continuing to culture at 37°C for 1.5 hours, the absorbance value was detected at 450 nM using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed in GraphPad Prism software, and the dose-effect curve was fitted to calculate the IC 50 value.

[0801] The compounds disclosed herein exhibited inhibitory activity against NUGC-3 cells and Huh-7 cells. The experimental results of some compounds are shown in Table 1.

[0802] Experimental Example 2 In vitro DNA binding activity assay

[0803] The activity of compounds in enhancing the DNA binding ability of p53 Y220C was determined by a homogeneous time-resolved fluorescence (HTRF) assay. The assay used a recombinant His-tagged p53 Y220C truncated mutant protein (amino acids 94-312) comprising the p53 DNA binding domain (SEQ ID No. 2: SSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPCEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNT) and a consensus DNA sequence (a biotin-labeled DNA duplex having a 5′-ATTAGGCATGTCTAGGCATGTCTAGG-3′ sequence (SEQ ID No. 1)). In the HTRF assay, the binding ability of the p53 Y220C mutant protein to the consensus DNA sequence was detected by measuring the fluorescence shift of the interaction between an anti-His antibody conjugated with the small molecule fluorescent probe d2 and europium (Eu)-conjugated streptavidin.

[0804] The test compound was mixed with 10 μL of a recombinant His-tagged p53 Y220C protein solution and an anti-His tag antibody conjugated to the small molecule fluorescent probe d2 in ice-cold assay buffer 1 (50 mM Tris-HCl, pH 7.4; 75 mM KCl; 0.75 mM DTT; and 0.2 mg / mL bovine serum albumin (BSA)). The mixture was added to each well of a 384-well polypropylene black plate. An equal amount of buffer without protein was added to the control sample. The test and control samples were rotated at 1200 rpm for 1 minute and incubated at room temperature for 75 minutes. 10 microliters of biotin-labeled consensus DNA and europium-conjugated streptavidin in assay buffer 2 (50 mM Tris-HCl, pH 7.4; 75 mM KCl; and 0.2 mg / mL BSA) were added to each well of the test and control samples. The plate was rotated at 1200 rpm for 1 minute and incubated at room temperature for 20 minutes. The assay signal was monitored by reading the fluorescence at excitation at 340 nm and emission at 620 nm and 665 nm on a plate reader.

[0805] The HTRF ratio (Ratio, R) signal is calculated by the following formula: R = F 665 / F 620 *10 4 ;

[0806] Among them F 665 is the fluorescence intensity of the sample at 665 nm after background subtraction; F 620 is the fluorescence intensity of the sample at 620 nm after background subtraction.

[0807] Test Example 3 P53 Y220C protein thermodynamic stability test

[0808] The thermal stability of p53 mutants was determined by differential scanning fluorimetry (DSF) using the fluorescent dye SYPRO Orange (Invitrogen). Detection was performed in a 96-well plate using a LightCycler 480 Real-Time qPCR Thermal Cycler (heating rate 0.03°C / s, excitation / emission filters = 465 / 580 nm). Tm measurements were performed using 50 ng / μL p53 Y220C protein and 4x SYPRO Orange in PBS buffer in a 20 μL reaction volume. Each sample was assayed in triplicate. ΔTm values ​​were calculated as ΔTm = Tm(protein + compound) - Tm(protein).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Each are independently selected from a single bond or a double bond; R 1 Selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1- 12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; X 1 Selected from CR 2 , CR 2 R 3 、N、NR 2 , O, S, C(O), or connected to Q 1 of carbon atoms; X 2 Selected from CR 4 , CR 4 R 5 、N、NR 4 , O, S, C(O), or connected to Q 1 of carbon atoms; X 3 Selected from CR 6 , CR 6 R 7 、N、NR 6 , O, S, C(O), or connected to Q 1 of carbon atoms; X 4 Selected from CR 8 , CR 8 R 9 、N、NR 8 , O, S, C(O), or connected to Q 1 of carbon atoms; The premise is that X 1 、X 2 、X 3 and X 4 There is only one connection to Q 1 of carbon atoms; X 5 Selected from CR 10 , N, or NR 10 ; X 6 selected from CH, or N; R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; Q 1 is selected from a single bond, -CH2-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -O-, -S-, -S(O)-, -S(O)NH-, -NHS(O)-, -S(O)2-, -NHS(O)2-, or -S(O)2NH-; A is selected from a single bond, or Ring Cy is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; m is selected from 1, 2, 3, or 4; Each R A Each independently selected from H, oxo, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1- 12 Alkylamino, halogenated di-C 1-12 Alkylamino, -C(O)R A1 、-C(O)NR A1 R A2 、-NR A1 C(O)R A2 、-OC(O)R A1 、-C(O)OR A1 、-S(O)R A1 、-S(O)2R A1 、-NR A1 S(O)2R A2 、-S(O)2NR A1 R A2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; R A1 、R A2 Each independently selected from H or C 1-12 alkyl; L is selected from a single bond or C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are independently optionally replaced by the following atoms or groups: heteroatom groups, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered Heteroaryl, the C 1-20 Alkylene, heteroatom group, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl are each independently optionally substituted by one or more R L replace; Each R L Each independently selected from oxo, halogen, cyano, hydroxy, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -S(O)-, -S(O)NH-, -NHS(O)-, -S(O)2-, -NHS(O)2-, or -S(O)2NH-; Ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; n is selected from 1, 2, 3, or 4; Each R B Each independently selected from H, oxo, halogen, cyano, hydroxyl, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1- 12 Alkylamino, halogenated di-C 1-12 Alkylamino, -C(O)R B1 、-C(O)NR B1 R B2 、-NR B1 C(O)R B2 、-OC(O)R B1 、-C(O)OR B1 、-S(O)R B1 、-S(O)2R B1 、-NR B1 S(O)2R B2 、-S(O)2NR B1 R B2 , 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; R B1 、R B2 Each independently selected from H or C 1-12 alkyl; Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-12 Alkylene, C 1-12 Heteroalkylene, C 2-12 Alkenylene, or C 1-12 heteroalkenylene; Each R Q3 Each independently selected from oxo, halogen, cyano, hydroxy, amino, alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1- 12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 1-12 Alkylthio, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; Each R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R A 、R A1 、R A2 、R L 、R B 、R B1 、R B2 , or R Q3 Each is independently optionally substituted with one or more substituents.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1- 6-alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, R 1 Selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1- 4-alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Or, R 1 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1- 4 alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; Or, R 1 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino; Or, R 1 Selected from H, methyl, ethyl, trifluoromethyl, or -CH2CF3.

3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxy Group, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, halogenated di-C 1-6 Alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Each independently selected from H, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Or, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 are each independently selected from H, fluorine, chlorine, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, haloethyl, halomethoxy, halomethylamino, or halodimethylamino; Or, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 are each independently selected from H, fluoro, chloro, cyano, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy; Or, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , or R 10 Selected from H.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Q 1 is selected from a single bond, -CH2-, -C(O)-, -NH-, or -O-; Or, Q 1 is a single bond; Or, Q 1 is selected from -CH2-, -NH-, or -O-; Or, Q 1 It is -NH-.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein A is a single bond; Alternatively, A is selected from Alternatively, A is selected from Alternatively, A is selected from Alternatively, A is selected from Alternatively, A is selected from Alternatively, A is selected from 6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Ring Cy is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, ring Cy is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, ring Cy is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Alternatively, ring Cy is selected from 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl; Alternatively, ring Cy is selected from cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl; Alternatively, ring Cy is selected from cyclohexyl, spiro[3.3]heptyl, piperidinyl, or azaspiro[3.3]heptyl; Alternatively, ring Cy is selected from cyclohexyl, spiro[3.3]heptyl, pyrrolidinyl, piperidinyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: L is selected from a single bond; Alternatively, L is selected from C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-20 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-16 Alkylene, the C 1-16 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-16 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-14 Alkylene, the C 1-14 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-14 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-12 Alkylene, the C 1-12 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-12 Alkylene, the C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted with one or more R L replace; Alternatively, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -CH=CH-, -C≡C-, cyclobutane, cyclobutyl, cyclopentane ... pentyl, cyclohexyl, cycloheptyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, or azaspiro[3.4]octyl, wherein C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, spiro[3.3]heptane, spiro[3.4]octane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptane, azabicyclo[3.3.0]octane, azaspiro[3.3]heptane, or azaspiro[3.4]octane, each independently optionally substituted with one or more R L replace; Alternatively, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C (O), azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl; Alternatively, L is selected from Alternatively, L is selected from C 1-20 Alkylene, the C 1-20 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-20 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-16 Alkylene, the C 1-16 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-16 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-14 Alkylene, the C 1-14 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl, wherein the C 1-14 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-12 Alkylene, the C 1-12 One or more CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)NH, NHC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from C 1-12 Alkylene, the C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, =N-, -N=, C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -ON=, =NO-, -CH=CH-, -C≡C-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-12 Alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2, 3, 4, 5 or 6 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, S, C(O), C(O)O, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O), S(O)2, S(O)2NH, NHS(O)2, -CH=CH-, -C≡C-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl, spiro[3.4]octyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[3.3.0]octyl, azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.3]heptyl, oxidized azaphosphorinyl, or pyrazolyl, said C 1-12 alkylene, NH, C(O)NH, NHC(O), NHC(O)O, OC(O)NH, NHC(O)NH, S(O)2NH, NHS(O)2, -CH=CH-, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, spiro[3.3]heptane, spiro[3.4]octane, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azabicyclo[3.2.0]heptane, azabicyclo[3.3.0]octane, azaspiro[3.3]heptane, azaspiro[3.4]octane, diazaspiro[3.3]heptane, oxidized azaphosphorinyl, or pyrazolyl are each independently optionally substituted with one or more R L replace; Alternatively, L is selected from a linear C 1-12 Alkylene, the straight chain C 1-12 1, 2 or 3 CH2 on the alkylene group are each independently optionally replaced by the following atoms or groups: NH, O, C(O), C(O)NH, NHC(O), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl, wherein the C 1-12 Alkylene, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,6-diazaspiro[3.3]heptyl, 4-oxo-1,4-azaphosphorinyl, or pyrazolyl are each independently optionally substituted by one or more R L replace; Alternatively, L is selected from 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, or -S(O)2-; Or, Q 2 is selected from a single bond, -C(O)-, -C(O)O-, -C(O)NH-, or -S(O)2-.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Ring B is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, Ring B is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, Ring B is selected from a 6-10 membered aryl group or a 5-10 membered heteroaryl group; Alternatively, ring B is selected from phenyl or 5-6 membered heteroaryl; Alternatively, Ring B is selected from phenyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; Alternatively, Ring B is selected from phenyl, thienyl, or pyridyl; Alternatively, Ring B is selected from Alternatively, Ring B is selected from Alternatively, Ring B is selected from Alternatively, Ring B is selected from 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-6 Alkylene, C 1-5 Heteroalkylene, C 2-6 Alkenylene, or C 1-5 heteroalkenylene; Or, Q 3 Selected from -O-, -S-, or optionally one or more R Q3 Substituted groups: -NH-, C 1-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 heteroalkenylene; Or, Q 3 Selected from optionally one or more R Q3 Substituted with the following groups: C 1-4 Alkylene or C 1-3 heteroalkylene; Or, Q 3 Selected from optionally one or more R Q3 Substituted as follows: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-; Or, Q 3 Selected from -CH2NH-.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from a compound of formula (II) or formula (III) or formula (IV) or formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof, in, R 1 、R A 、R B 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Q 1 , Q 2 , Q 3 , A, L, m, n, ring B, and ring Cy are as defined in any one of claims 1-10.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is selected from:

13. The compound of formula (I) according to any one of claims 1 to 12, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, which is selected from:

14. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13; further comprising a pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating p53 protein-related diseases; Optionally, the p53 protein-related disease is a p53 protein mutant-related disease; Optionally, the p53 protein mutant is selected from p53 Y220C; Optionally, the p53 protein-related disease is selected from cancer.

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