Condensed heteroaryl compound containing alkynyl group

Abstract

The invention belongs to the field of medicinal chemistry, and relates to an alkynyl-containing fused heteroaryl compound which has a structure shown as a formula (I). The invention also relates to a preparation method of the compound, a pharmaceutical composition and application of the compound in treating cancers. # imgabs0 #

Description

Technical Field

[0001] The present application relates to a fused heteroaryl compound containing an alkynyl group, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating cancer. Background Art

[0002] 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.

[0003] In normal cells, p53 levels are typically maintained at low levels because cells promote p53 degradation through the 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. Detailed Description of the Invention

[0004] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in,

[0007] X is selected from S, CH, N, NR a , or O;

[0008] Y is selected from CR b or N;

[0009] R a is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0010] R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R b1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0011] X 1 Selected from CR 1 or N;

[0012] X 2 Selected from CR 2 or N;

[0013] X 3 Selected from CR 3 or N;

[0014] X 4 Selected from CR 4 or N;

[0015] X 5 Selected from C or N;

[0016] X 6 Selected from C or N;

[0017] R 1 、R2 、R 3 and R 4 one selected from optionally one or more R c Substituted -(CH2) n -C 3-12 Cycloalkyl, -(CH2) n -C 3-12 Cycloalkenyl, or -(CH2) n -3-12 membered heterocyclic group, the rest of which is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally substituted by one or more R z Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, or -P(O)(C 1-12 Alkyl)2;

[0018] R c is selected from hydroxy, amino, cyano, halogen, oxo, carboxyl, and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12Alkyl, -OC(O)C 1-12 Alkyl, -P(O)(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0019] R 5 and R 6 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R d Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, or -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group;

[0020] Or, R 5 and R 6 and together with the carbon atoms to which they are attached form =0, and optionally one or more R d Substituted C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group;

[0021] R 7 is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R e Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, or C 3-12 Cycloalkyl;

[0022] R 8 Selected from optionally one or more R f Substituted C 6-12 Aryl, or 5-12 membered heteroaryl;

[0023] R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -C(O)C 1-12Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -S(O)2NH2, -S(O)2-C 3-12 Cycloalkyl, -S(O)2-3-12 membered heterocyclyl, -S(O)2-5-12 membered heteroaryl, -P(O)(C 1-12 Alkyl)2, -OC 3-12 Cycloalkyl, -O-3-12 membered heterocyclic group, -O-5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0024] Or, two adjacent R f and together with the carbon atoms to which they are attached, form a f1 substituted 4-8 membered heterocycle;

[0025] R a1 、R b1 、R z 、R c1 、R d 、R e and R f1 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, carboxyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-8 Cycloalkyl, or 3-8 membered heterocyclic group;

[0026] m is selected from 1, 2 or 3;

[0027] n is selected from 0, 1, 2, 3 or 4.

[0028] In some embodiments, when X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3and R 4 One of the following is selected from -C substituted by one or more substituents 3-12 Cycloalkyl, -C 3-12 cycloalkenyl, or 3-12 membered heterocyclic group.

[0029] In some embodiments, when X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of the following is selected from one or more R g Substituted -C 3-12 Cycloalkyl, -C 3-12 cycloalkenyl, or 3-12 membered heterocyclic group; and R g Selected from optionally substituted C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 In some embodiments, R g Selected from optionally substituted -NHC 1-6 Alkyl, or -N(C 1-6 Alkyl)2.

[0030] In some embodiments, when X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of the following is selected from one or more R g Substituted -C 4-10 Cycloalkyl, -C 4-10 cycloalkenyl, or 4-10 membered heterocyclic group; and R g Selected from optionally substituted -NHC 1-6 Alkyl, or -N(C 1-6 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, or 5-12 membered heteroaryl.

[0031] In some embodiments, when X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of the following is selected from one or more Rg Substituted -C 4-10 cycloalkenyl, or 4-10 membered heterocyclic group; and R g Selected from optionally substituted C 3-12 cycloalkyl, or 3-12 membered heterocyclic group.

[0032] In some embodiments, when X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of the following is selected from one or more R g Substituted -C 5-8 cycloalkenyl, or 5-9 membered heterocyclic group; and R g Selected from optionally substituted -NHC 1-4 Alkyl, or -N(C 1-4 Alkyl)2, C 4-10 cycloalkyl, or 3-10 membered heterocyclic group.

[0033] It should be understood that the structural unit It is a fused bicyclic aromatic system.

[0034] On the other hand, the present application provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof,

[0035]

[0036] in,

[0037] X is selected from NR a , O, or S;

[0038] Y is selected from CR b or N;

[0039] R a is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0040] R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R b1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0041] X 1 Selected from CR 1 or N;

[0042] X 2 Selected from CR 2 or N;

[0043] X 3 Selected from CR 3 or N;

[0044] X 4 Selected from CR 4 or N;

[0045] R 1 、R 2 、R 3 and R 4 one selected from optionally one or more R c Substituted -(CH2) n -C 3-12 Cycloalkyl, -(CH2) n -C 3-12 Cycloalkenyl, or -(CH2) n-3-12 membered heterocyclic group, the rest of which is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally substituted by one or more R z Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, or -P(O)(C 1-12 Alkyl)2;

[0046] R c is selected from hydroxy, amino, cyano, halogen, oxo, carboxyl, and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -P(O)(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl;

[0047] R 5 and R 6are independently selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R d Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, or -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group;

[0048] Or, R 5 and R 6 and together with the carbon atoms to which they are attached form =0, and optionally one or more R d Substituted C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group;

[0049] R 7 is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R e Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, or C 3-12 Cycloalkyl;

[0050] R 8 Selected from optionally one or more R f Substituted C 6-12 Aryl, or 5-12 membered heteroaryl;

[0051] R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -S(O)2NH2, -S(O)2-3-12 membered heterocyclyl, -S(O)2-5-12 membered heteroaryl, or -P(O)(C 1-12 Alkyl)2;

[0052] Or, two adjacent R f and together with the carbon atoms to which they are attached, form a 4-8 membered heterocyclic ring;

[0053] R a1 、R b1 、R z 、R c1 、R d 、R e and R f1 Each independently selected from hydroxy, amino, cyano, halogen, carboxyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-8 Cycloalkyl, or 3-8 membered heterocyclic group;

[0054] m is selected from 1, 2 or 3;

[0055] n is selected from 0, 1, 2, 3 or 4.

[0056] In some embodiments, X is selected from S, CH, N, or NR a .

[0057] In some embodiments, X is selected from S, CH, or N.

[0058] In some embodiments, X is selected from CH or N.

[0059] In some embodiments, X is selected from S or NR a .

[0060] In some embodiments, X is selected from NR a .

[0061] In some embodiments, X is O.

[0062] In some embodiments, X is S.

[0063] In some embodiments, R a Selected from hydrogen, hydroxy, cyano and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, or -OC(O)C 1-12 alkyl.

[0064] In some embodiments, R a Selected from hydrogen, hydroxy, cyano and optionally one or more R a1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -C(O)NHC 1-16 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, or -OC(O)C 1-6 alkyl.

[0065] In some embodiments, R a Selected from hydrogen, hydroxy, cyano and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy.

[0066] In some embodiments, R a Selected from optionally one or more R a1 Substituted -C 1-12 alkyl.

[0067] In some embodiments, R a Selected from optionally one or more R a1 Substituted -C 1-6 alkyl.

[0068] In some embodiments, R a Selected from optionally one or more R a1 Substituted -C 1-3 alkyl.

[0069] In some embodiments, Y is selected from CR b .

[0070] In some embodiments, Y is selected from N.

[0071] In some embodiments, R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R b1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, or -N(C 1-12 In some embodiments, R b Selected from optionally one or more R b1 Substituted-SC 1-12 alkyl.

[0072] In some embodiments, R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R b1 Substituted -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -SC 1-6 alkyl.

[0073] In some embodiments, R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R b1 Substituted -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, or -N(C 1-6 Alkyl)2.

[0074] In some embodiments, R b Selected from optionally one or more R b1 Substituted -C 1-6 Alkyl, or -SC 1-6 alkyl.

[0075] In some embodiments, R b is selected from hydrogen, halogen and optionally one or more R b1 Substituted -C1-12 alkyl.

[0076] In some embodiments, R b Selected from optionally one or more R b1 Substituted -C 1-12 alkyl.

[0077] In some embodiments, R b Selected from optionally one or more R b1 Substituted -C 1-6 In some embodiments, R b Selected from optionally one or more R b1 Substituted-SC 1-6 alkyl.

[0078] In some embodiments, R b Selected from optionally one or more R b1 Substituted -C 1-3 In some embodiments, R b Selected from optionally one or more R b1 Substituted-SC 1-3 alkyl.

[0079] In some embodiments, R b Selected from optionally one or more R b1 In some embodiments, R b Selected from optionally one or more R b1 Substituted -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, -SCH(CH3)CH2CH3, or -SC(CH3)3.

[0080] In some embodiments, R b Selected from optionally one or more R b1 substituted -CH2CH3, or -SCH3.

[0081] In some embodiments, R b1 Selected from halogen.

[0082] In some embodiments, R b1 is selected from fluorine, chlorine, or bromine.

[0083] In some embodiments, R b1 Selected from fluorine.

[0084] In some embodiments, R b Selected from -CH2CF3, -SCHF2 or -SCF3.

[0085] In some embodiments, R b Selected from -CH2CF3.

[0086] In some embodiments, Y is selected from CR b , and R b In some embodiments, Y is selected from CR b , and R b Selected from -SCHF2 or -SCF3.

[0087] In some embodiments, X is selected from CH, N or S, and Y is selected from CR b .

[0088] In some embodiments, X is selected from CH, N, or S, and Y is selected from -CH2CF3, -SCHF2, or -SCF3.

[0089] In some embodiments, X is selected from CH, N, or S, and Y is selected from -CH2CF3.

[0090] In some embodiments, X is selected from CH or N, and Y is selected from -CH2CF3, -SCHF2, or -SCF3.

[0091] In some embodiments, X is selected from S and Y is selected from -CH2CF3.

[0092] In some embodiments, X 1 Selected from CR 1 .

[0093] In some embodiments, X 2 Selected from CR 2 .

[0094] In some embodiments, X 2 Selected from N.

[0095] In some embodiments, X 3 Selected from CR 3 .

[0096] In some embodiments, X 4 Selected from CR 4 .

[0097] In some embodiments, X 5 and X 6 At least one is N.

[0098] In some embodiments, X 5 Selected from N.

[0099] In some embodiments, X 6 Selected from C.

[0100] In some embodiments, X 5 Selected from N, X 6 In some embodiments, X 5 Selected from C, X 6 Selected from N.

[0101] In some embodiments, Selected from In some embodiments, Selected from

[0102] In some embodiments, Selected from

[0103] In some embodiments, Selected from

[0104] In some embodiments, R 1 、R 2 、R 3 and R 4 In the definition, "-(CH2) n -3-12 membered heterocyclic group" is selected from "-(CH2) n -3-12 membered heterocycloalkyl or -(CH2) n -3-12 membered heterocycloalkenyl".

[0105] In some embodiments, R 1 、R 2 、R 3 and R 4 one selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkyl, -(CH2) n -C 5-10 Cycloalkenyl, or -(CH2) n -5-10 membered heterocyclic group, the rest of which is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally substituted by one or more R z Substituted -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -C(O)C1-16 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, or -P(O)(C 1-6 Alkyl)2.

[0106] In some embodiments, R 1 、R 2 、R 3 and R 4 In the definition, "-(CH2) n -5-10 membered heterocyclic group" is selected from "-(CH2) n -5-10 membered heterocycloalkyl or -(CH2) n -5-10 membered heterocycloalkenyl".

[0107] In some embodiments, R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 3-12 Cycloalkyl, -(CH2) n -C 3-12 Cycloalkenyl, or -(CH2) n -3-12 membered heterocyclic group; R 2 、R 3 and R 4 Each independently selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R z Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, or -P(O)(C 1-12 Alkyl)2.

[0108] In some embodiments, R 1 、R2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkyl, -(CH2) n -C 5-10 Cycloalkenyl, or -(CH2) n -5-10 membered heterocyclic group.

[0109] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkyl, or -(CH2) n -5-10 membered heterocyclic group.

[0110] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkyl, -(CH2) n -5-10 membered heterocycloalkyl, or -(CH2) n -5-10 membered heterocycloalkenyl.

[0111] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -5-10 membered heterocyclyl. In some embodiments, R 1 、R 2 、R3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkenyl.

[0112] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted -(CH2) n -5-10 membered heterocycloalkyl, or -(CH2) n -5-10 membered heterocycloalkenyl.

[0113] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted C 5-10 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl.

[0114] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted C 5-10 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl.

[0115] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted C5-8 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl.

[0116] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted C5, C6 or C7 cycloalkenyl, 5-, 6-, 7-, 8- or 9-membered heterocycloalkyl, or 6- or 8-membered heterocycloalkenyl.

[0117] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,

[0118] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Replaced

[0119] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,

[0120] In some embodiments, R 1 、R 2 、R3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,

[0121] In some embodiments, R c is selected from hydroxy, amino, cyano, halogen, oxo, carboxyl and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -P(O)(C 1-12 Alkyl)2, C 3-12 cycloalkyl, or 3-12 membered heterocyclic group.

[0122] In some embodiments, R c is selected from hydroxy, amino, halogen, oxo, and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 cycloalkyl, or 3-12 membered heterocyclic group.

[0123] In some embodiments, R c is selected from hydroxy, amino, halogen, oxo, and optionally one or more R c1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6Alkyl, -N(C 1-6 Alkyl)2, C 3-6 cycloalkyl, or 3-8 membered heterocycloalkyl.

[0124] In some embodiments, R c is selected from hydroxy, amino, halogen, oxo, and optionally one or more R c1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.

[0125] In some embodiments, R c is selected from hydroxy, amino, fluoro, chloro, bromo, oxo, and optionally substituted by one or more R c1 In some embodiments, R c Selected from morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, 2-oxa-6-aza-spiro[3,3]heptane.

[0126] In some embodiments, R c1 is selected from halogen, amino or hydroxy.

[0127] In some embodiments, R c1 In some embodiments, R c1 Selected from hydroxyl groups.

[0128] In some embodiments, R c is selected from hydroxy, amino, fluoro, oxo, methyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2, cyclopropyl, or azetidinyl. In some embodiments, R c Selected from morpholinyl, tetrahydropyrrolyl, or 2-oxa-6-aza-spiro[3,3]heptane.

[0129] In some embodiments, R c Selected from hydroxy, amino, fluoro, oxo, methyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2, cyclopropyl, In some embodiments, R c Selected from

[0130] In some embodiments, when X is selected from CH, or N, X5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from one or more R g Substituted C 5-10 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; and R g Selected from optionally substituted -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-12 cycloalkyl, or 3-12 membered heterocyclic group.

[0131] In some embodiments, when X is selected from CH, or N, X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from one or more R g Substituted C 5-10 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; and R g Selected from optionally substituted C 3-12 cycloalkyl, or 3-12 membered heterocyclic group.

[0132] In some embodiments, when X is selected from CH, or N, X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from one or more R g Substituted C 5-10 cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; and R g is selected from optionally substituted 4-10 membered heterocycloalkyl.

[0133] In some embodiments, when X is selected from CH, or N, X 5 and X 6At least one is N, and R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from one or more R g substituted 6-membered cycloalkenyl, or 5-, 6-, or 9-membered heterocycloalkyl; and R g is selected from optionally substituted 6-8 membered heterocycloalkyl.

[0134] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from

[0135]

[0136] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from

[0137] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from

[0138] In some embodiments, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from

[0139]

[0140] In some embodiments, R 1 、R 2 、R 3 and R 4 Three of them, or R 2 、R 3 and R 4 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R z Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, or -NHC(O)C 1-12 alkyl.

[0141] In some embodiments, R 1 、R 2 、R 3 and R 4 Three of them, or R 2 、R 3 and R 4 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R z Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -NHC(O)C 1-6 alkyl.

[0142] In some embodiments, R z Selected from halogen.

[0143] In some embodiments, R 1 、R 2 、R 3 and R 4 Three of them are hydrogen.

[0144] In some embodiments, R 2 、R 3 and R 4 All are hydrogen.

[0145] In some embodiments, R 1 Selected from optionally one or more R c Substituted -(CH2) n -3-12 membered heterocyclic group; R 2 、R 3 and R 4 All are hydrogen.

[0146] In some embodiments, R 1 Selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkenyl; R 2 、R 3 and R 4 All are hydrogen.

[0147] In some embodiments, R 5 and R 6 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R d Substituted -C 1-12 alkyl.

[0148] In some embodiments, R 5 and R 6 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R d Substituted -C 1-6 alkyl.

[0149] In some embodiments, R 5 and R 6 are each independently selected from hydrogen, or -C 1-6 alkyl.

[0150] In some embodiments, R 5 and R 6 and together with the carbon atoms to which they are attached form =0, and optionally one or more R d Substituted C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.

[0151] In some embodiments, R 5 and R 6 are all selected from hydrogen.

[0152] In some embodiments, R 7 is selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R e Substituted -C 1-6 alkyl.

[0153] In some embodiments, R e Selected from halogen.

[0154] In some embodiments, R 7 Selected from hydrogen.

[0155] In some embodiments, R 8 Selected from optionally one or more R f substituted phenyl, or 5-10 membered heteroaryl.

[0156] In some embodiments, R 8 Selected from optionally one or more R f Substituted phenyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl, pyridinyl, or pyrimidinyl.

[0157] In some embodiments, R 8 Selected from optionally one or more R f substituted phenyl, or pyridyl.

[0158] In some embodiments, R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2NH2, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-3-6 membered heterocyclyl, -S(O)2-5-6 membered heteroaryl, -P(O)(C 1-6 Alkyl)2, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, -O-5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C6 aryl, or 5-6 membered heteroaryl.

[0159] In some embodiments, R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)N(C1-6 Alkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2NH2, -S(O)2-3-6 membered heterocyclyl, -S(O)2-5-6 membered heteroaryl, or -P(O)(C 1-6 Alkyl)2.

[0160] In some embodiments, R f is selected from halogen, and optionally replaced by one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, or -P(O)(C 1-6 Alkyl)2.

[0161] In some embodiments, R f Selected from optionally one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -P(O)(C 1-6 Alkyl)2, -OC 3-6 cycloalkyl, -O-3-6 membered heterocyclyl, or 5-6 membered heteroaryl.

[0162] In some embodiments, R f Selected from optionally one or more R f1 Substituted -C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2, -OC3-6 In some embodiments, R f Selected from optionally one or more R f1 Substituted-S(O)2C 1-6 alkyl.

[0163] In some embodiments, R f Selected from optionally one or more R f1 Substituted -C 1-4 Alkoxy, -C(O)NHC 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, -OC 3-5 In some embodiments, R f Selected from optionally one or more R f1 Substituted-S(O)2C 1-4 alkyl.

[0164] In some embodiments, R f Selected from optionally one or more R f1 Substituted methoxy, ethoxy, -C(O)NHCH3, -C(O)NHCH2CH3, -P(O)(CH3)2, -P(O)(CH2CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, thienyl, pyrrolyl, or furyl.

[0165] In some embodiments, R f1 is selected from deuterium, hydroxy, amino, cyano, or halogen.

[0166] In some embodiments, R f1 Selected from deuterium, or halogen.

[0167] In some embodiments, R f1 Selected from deuterium.

[0168] In some embodiments, R f1 Selected from halogen.

[0169] In some embodiments, R f1 Selected from hydroxyl groups.

[0170] In some embodiments, R f Selected from -C 1-6 Alkoxy, or -P(O)(C 1-6 In some embodiments, R f Selected from -S(O)2C 1-6 alkyl.

[0171] In some embodiments, R f is selected from methoxy, or -P(O)(CH3)2. In some embodiments, R f Selected from -OCD3, -O-cyclopropyl, -C(O)NHCH3, or In some embodiments, R f Selected from -S(O)2CH3, or -C(O)NHCH2CH(OH)CH3.

[0172] In some embodiments, R f Selected from -P(O)(CH3)2.

[0173] In some embodiments, two adjacent R f Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic ring.

[0174] In some embodiments, two adjacent R f Together with the carbon atoms to which they are attached, they form a 5-membered O-containing heterocyclic ring.

[0175] In some embodiments, two adjacent R f Together with the carbon atoms to which they are attached, they form a dihydrofuran ring.

[0176] In some embodiments, R 8 Selected from In some embodiments, R 8 Selected from In some embodiments, R 8 Selected from

[0177] In some embodiments, R 8 Selected from

[0178] In some embodiments, R 8 Selected from

[0179] In some embodiments, R a1 、R b1 、R c1 、R d 、R e and R f1 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, carboxyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 cycloalkyl, or 3-6 membered heterocyclic group.

[0180] In some embodiments, R a1 、R b1 、R c1 、R d 、R e and R f1 Each is independently selected from hydroxy, amino, cyano, halogen, or carboxyl.

[0181] In some embodiments, R a1 、R b1 、R c1 、R d 、R e and R f1 are each independently selected from halogen.

[0182] In some embodiments, R a1 、R b1 、R c1 、R d 、R e and R f1 are each independently selected from fluorine, chlorine, or bromine.

[0183] In some embodiments, R b1 is selected from fluorine, chlorine, or bromine.

[0184] In some embodiments, R b1 Selected from fluorine.

[0185] In some embodiments, m is selected from 1 or 2.

[0186] In some embodiments, m is selected from 1.

[0187] In some embodiments, n is selected from 0, 1, or 2.

[0188] In some embodiments, n is selected from 0.

[0189] In some embodiments, n is selected from 1.

[0190] In some embodiments, the halogen is selected from fluorine, chlorine, bromine, or iodine.

[0191] 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.

[0192] In some embodiments, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S. In some embodiments, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N or O. In some embodiments, the heteroaryl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heteroaryl group contains 1 N heteroatom.

[0193] In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S. In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 2 heteroatoms selected from N.

[0194] In some embodiments, the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S. In some embodiments, the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms selected from N or O. In some embodiments, the heterocyclyl contains 1, 2, or 3 heteroatoms selected from N. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N.

[0195] In some embodiments, the cycloalkyl group includes monocyclic, spirocyclic, fused, or bridged cycloalkyl groups.

[0196] In some embodiments, the cycloalkenyl group includes monocyclic, spirocyclic, paracyclic, or bridged cycloalkenyl groups.

[0197] In some embodiments, the heterocyclyl is selected from heterocycloalkyl or unsaturated heterocyclyl.

[0198] In some embodiments, the heterocyclyl group is selected from heterocycloalkyl or heterocycloalkenyl.

[0199] In some embodiments, the heterocyclic group includes monocyclic, spirocyclic, fused, or bridged heterocyclic groups.

[0200] In some embodiments, the heterocycloalkyl group includes monocyclic, spirocyclic, fused, or bridged heterocycloalkyl groups.

[0201] In some embodiments, the heterocycloalkenyl group includes monocyclic, spirocyclic, fused, or bridged heterocycloalkenyl groups.

[0202] 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.

[0203] In some embodiments, the heteroaryl, heterocyclyl, heterocycloalkyl or heterocycloalkenyl described herein, wherein the heteroatom is selected from NH, N, O or S; in some specific embodiments, the number of the heteroatoms is selected from 1, 2, 3, 4 or 5; in some specific embodiments, the number of the heteroatoms is selected from 1, 2 or 3.

[0204] In some embodiments, the compound of formula (I) or the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof,

[0205]

[0206] in,

[0207] X, R 1 、R b 、X 2 、X 3 、X 4 、R 8 As defined in this application;

[0208] t is selected from 1, 2, 3 or 4.

[0209] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compounds of formula (VI), formula (VII), formula (VIII), formula (IX) or a pharmaceutically acceptable salt thereof,

[0210]

[0211] in,

[0212] R 1 、R b 、X 2 、X 3 、X 4 、R 8 As defined in this application.

[0213] In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0214] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223] The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] On the other hand, the present application relates to a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (II), formula (III), formula (IV) and formula (V) 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.

[0238] On the other hand, the present application relates to a method for treating or preventing a mammalian disease, comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV) and Formula (V), 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.

[0239] On the other hand, the present application relates to the use of compounds of formula (I), formula (Ia), formula (II), formula (III), formula (IV) and formula (V), or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present application in the preparation of drugs for treating or preventing diseases.

[0240] On the other hand, the present application relates to the use of compounds of formula (I), formula (Ia), formula (II), formula (III), formula (IV) and formula (V), or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present application in treating or preventing diseases.

[0241] On the other hand, the present application relates to compounds of formula (I), formula (Ia), formula (II), formula (III), formula (IV) and formula (V), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present application for treating or preventing diseases.

[0242] In some embodiments of the present application, the disease is selected from cancer.

[0243] In some embodiments of the present application, the disease is selected from p53 protein-related diseases.

[0244] In some embodiments of the present application, the p53 protein-related disease is selected from diseases associated with p53 protein mutants (eg, p53 having a mutation at amino acid 220).

[0245] In some embodiments of the present application, the p53 protein mutant is selected from p53 Y220C.

[0246] In some embodiments of the present application, the p53 protein-related disease is selected from cancer (eg, gastric cancer or liver cancer).

[0247] Technical Effects

[0248] The compounds of the present application have good p53 DNA binding activity and cell proliferation inhibitory activity, as well as good p53Y220C protein thermodynamic stability and liver microsomal stability, and also show good drugability in in vitro and in vivo pharmacokinetics, bioavailability and / or pharmacodynamic studies.

[0249] definition

[0250] 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.

[0251] 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.

[0252] The “substituent” mentioned herein includes all substituents mentioned herein, such as the terms “alkyl”, “alkoxy”, “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 deuterium, tritium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, etc. , carboxyl, aldehyde, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclyl Alkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxo etc., and described substituent is optionally substituted by one or more substituents selected from following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, 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.

[0253] In some embodiments herein, the substituent is selected from deuterium, tritium, 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 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Alkoxy, C1-12 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 1-12 Alkylene, 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 1-12Alkylene, 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0262] The term "hydroxy" refers to an -OH group.

[0263] The term "cyano" refers to a -CN group.

[0264] The term "mercapto" refers to a -SH group.

[0265] The term "amino" refers to a -NH2 group.

[0266] The term "nitro" refers to a -NO2 group.

[0267] The term "carboxy" refers to a -COOH group.

[0268] The term "heteroatom" includes atoms of any element other than 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.

[0269] 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-. In some embodiments, the heteroatom group is selected from N, NH, O, or S.

[0270] 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 1-6 The 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can be present as a monocyclic, bridged, cyclic or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 12 rings, 3 to 10 rings, 4 to 8 rings, 5 to 8 rings or 5 to 6 rings. Non-limiting examples of cycloalkyl include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, bicyclo [3.2.0] heptane, adamantyl etc. The cycloalkyl 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) (O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0275] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring having at least one double bond and which may exist as a monocyclic, bridged, cyclic or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 12-membered ring, a 3 to 10-membered ring, a 4 to 8-membered ring, a 5 to 8-membered ring or a 5 to 6-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, 3a, 4, 7, 7a-tetrahydro-1H-indene, etc. The cycloalkenyl 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) (O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0276] The term "heterocycle" or "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 3 to 12, 3 to 10, 4 to 8, 5 to 8, 5 to 6, 3 to 7 or 4 to 6 rings 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 heterocyclic radicals include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl,

[0277] The heterocyclic group is optionally substituted by 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, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0278] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12-membered, 3 to 10-membered, 4 to 8-membered, 5 to 8-membered, 5 to 6-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. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. 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. Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. Examples of cycloheterocycloalkyl groups include, but are not limited to, Examples of spirocyclic heterocycloalkyl include, but are not limited to, 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, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0279] The term "heterocycloalkenyl" refers to an incompletely saturated cyclic group having at least one double bond and which can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-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. Examples of heterocycloalkenyl groups include, but are not limited to, 3-dihydropyrrolyl, 3,4-dihydrofuranyl, 4H-pyranyl,

[0280] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring with a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 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 hydroxyl, 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, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0281] 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, 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, -P(O)(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0282] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including 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.

[0283] 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 For example, structure fragments Including R configuration S configuration and mixtures; and structural fragments Including R configuration S configuration and mixtures.

[0284] 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.

[0285] 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:

[0286] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0287] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0288] 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.

[0289] 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 disclosures of this application.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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".

[0295] 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 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.

[0296] 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 an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. 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 For example, it should be understood that compounds in which one or more hydrogen atoms in the compounds of formula (I) of the present disclosure are replaced by deuterium atoms are still within the scope of the compounds of formula I of the present disclosure.

[0297] 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 in the Schemes and / or Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0298] 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.

[0299] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0300] 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, the group Including single enantiomeric forms and mixtures thereof in any proportions.

[0301] The compounds of the present application may have one or more atropisomers. Unless otherwise specified, atropisomers refer to optically active isomers resulting from the obstruction of free rotation between single bonds. The compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of a single bond of the compounds of the present application containing a chiral axis is sufficiently high, the atropisomers can be isolated in an optically pure form.

[0302] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients.

[0303] The pharmaceutical composition of the present application can be manufactured using methods well known in the art.

[0304] In all administration methods of the compound of formula (I) of the present application, the daily dosage is 0.001 to 2000 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 replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0305] 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.

[0306] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art with reference to General Route 1, General Route 2, or General Route 3:

[0307] <General Route 1>

[0308]

[0309] <General Route 2>

[0310]

[0311] <General Route 3>

[0312]

[0313] <General Route 4>

[0314]

[0315] <General Route 5>

[0316]

[0317] Among them, X, Y, X 2 、X 3 、X 4 、R b 、R 1 、R 5 、R 6 、R 8 and m are as defined in this application.

[0318] 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.

[0319] This application uses the following abbreviations:

[0320] RuPhos stands for 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; Ruphos G3 Pd stands for (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; Boc stands for tert-butyloxycarbonyl; and DMF stands for N,N-dimethylformamide.

[0321] Commercially available compounds were referred to by their supplier catalog names.

[0322] 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 claimed. 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.

[0323] All reagents used in this application were commercially available and used without further purification. Example

[0324] Example 1: Preparation of Compound 1

[0325]

[0326] Step A: Synthesis of Compound 1-2

[0327] To a 100 mL microwave tube, add compound 1-1 (5 g), palladium acetate (0.553 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.85 g), N,N-dimethylformamide (50 mL), dimethylphosphine oxide (2.88 g), and diisopropylethylamine (9.55 g). After addition, purge with nitrogen for 1 minute and cap the tube. Set the reaction temperature to 120°C and let it react for 2 hours. Remove the solvent by vortexing, and the mixture is purified by reverse-phase column chromatography (0.05% NH4HCO3, acetonitrile / water) to yield the desired product 1-2 (4.8 g).

[0328] MS (ESI, [M+H] + )m / z:201.1

[0329] Step B: Synthesis of Compound 1-3

[0330] To a 100 mL single-necked flask, compound 1-2 (2.2 g), tetrahydrofuran (40 mL), tert-butyl dicarbonate (3.12 g), N,N-dimethylpyridine (1.477 g), and N,N-diisopropylethylamine (2.84 g) were added in sequence. After addition, the temperature was raised to 70°C and the reaction mixture was allowed to react for 2.5 hours. Column chromatography (dichloromethane / methanol = 10:1) yielded a mixture of tert-butyl monocarbonate-protected and tert-butyl dicarbonate-protected compounds, totaling 2.1 g. The mixture was dissolved in methanol, and potassium carbonate (4.56 g) was added. The temperature was raised to 50°C and the reaction was continued for 1 hour. The potassium carbonate was filtered off and the mixture was dried to afford the desired product 1-3 (1.8 g).

[0331] MS (ESI, [M+H] + )m / z:301.2

[0332] Step C: Synthesis of Compound 1-4

[0333] Compound 1-3 (1.6 g), acetonitrile (40 mL), cesium carbonate (3.47 g), and propargyl bromide (0.951 g) were added sequentially to a 100 mL single-necked flask. The mixture was allowed to react at room temperature for 1 hour. Column chromatography (dichloromethane / methanol = 15:1) afforded the desired product 1-4 (1.6 g).

[0334] MS (ESI, [M+H] + )m / z:339.1

[0335] Step D: Synthesis of Compound 1-6

[0336] In a 500 mL three-necked flask, compound 1-5 (25 g) was dissolved in N,N-dimethylformamide (150 mL). Potassium carbonate (27.9 g) was added and stirred at room temperature for 10 minutes. Under nitrogen protection, methyl thioglycolate (15.73 g) was added dropwise in an ice bath. After addition, the temperature was raised to room temperature and the reaction was allowed to proceed overnight. The reaction solution was slowly poured into ice water (500 mL), filtered, and the filter layer was rinsed with water three times. The filter layer was collected and dried to obtain compound 1-6 (30 g). This was used directly in the next step without further purification.

[0337] Step E: Synthesis of Compound 1-7

[0338] Compound 1-6 (30 g) was dispersed in methanol (240 mL) in a 500 mL single-necked flask, and an aqueous solution (80 mL) of sodium hydroxide (15.17 g) was added dropwise. The reaction was continued at room temperature for 3 hours. The methanol was removed by vortexing, and the reaction solution was neutralized by adding dilute hydrochloric acid (2 M) dropwise under an ice bath. The solid was then filtered and dried to obtain compound 1-7 (25 g). This was used in the next step without further purification.

[0339] Step F: Synthesis of Compound 1-8

[0340] Compound 1-7 (12.5 g), copper powder (3.58 g), and N-methylpyrrolidone (60 mL) were added sequentially to a 100 mL microwave reaction vial. The reaction temperature was set to 160°C for 120 minutes. After completion, the reaction solution was poured into ice water (200 mL) to precipitate a solid. Filter the mixture, collect the filter layer, and redissolve it in dichloromethane, mix with silica gel, and column chromatography to obtain the desired product 1-8 (8.35 g).

[0341] 1 H NMR (500 MHz, DMSO-d6) δ = 8.45-8.39 (m, 2H), 8.05-8.04 (m, 1H), 7.72-7.68 (m, 2H). Step G: Synthesis of Compound 1-9

[0342] In a 500mL three-necked flask, compound 1-8 (16.5g) was dissolved in chloroform (200mL). The nitrogen was purged three times, and titanium tetrachloride (69.9g, 40.5ml) and dichlorodimethyl ether (52.9g, 41.6mL) were added dropwise. After addition, the temperature was raised to 60°C and the reaction was allowed to proceed for 30 minutes. TLC confirmed the complete reaction of the starting materials and the reaction was stopped. The reaction mixture was cooled, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the desired product 1-9 (16.8g).

[0343] 1 H NMR (500MHz, DMSO-d6) δ = 10.20 (s, 1H), 9.19 (s, 1H), 8.98 (d, J = 7.5Hz 1H), 8.54 (d, J = 8.0Hz 1H), 7.85 (m, 1H).

[0344] Step H: Synthesis of Compound 1-10

[0345] In a 50 mL single-necked flask, compound 1-9 (8.5 g) was dissolved in N,N-dimethylformamide (10 mL). (Triphenylphosphonium) difluoroacetic acid inner salt (29.2 g) was added. The nitrogen was purged three times and the temperature was raised to 60°C for 80 minutes. A 1 M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (82 mL) was then added and the reaction continued for 45 minutes. Extraction with ethyl acetate and column chromatography (petroleum ether / ethyl acetate = 10:1) afforded the desired product 1-10 (6 g).

[0346] 1 H NMR (500MHz, DMSO-d6)δ=8.49-8.47(m,2H),8.07(s,1H),7.78-7.75(m,1H),4.15-4.08(m,2H).

[0347] Step I: Synthesis of Compound 1-11

[0348] Compound 1-10 (4 g), acetic acid (80 mL), trifluoromethanesulfonic acid (10.00 mL), and N-iodosuccinimide (3.79 g) were added sequentially to a 100 mL single-necked flask. The mixture was allowed to react at room temperature for 4 hours. The solvent was then removed by vortexing, and the product was extracted with ethyl acetate. The product was washed with sodium bicarbonate solution, and the product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the desired product 1-11 (5.6 g).

[0349] Step J: Synthesis of Compound 1-12

[0350] To a 250 mL single-necked flask, compound 1-11 (1.3 g), compound 1-4 (1.140 g), tetrakistriphenylphosphine palladium (0.388 g), cuprous iodide (0.128 g), dichloromethane (80 mL), and N,N-diisopropylethylamine (13.02 g) were added sequentially. After addition, nitrogen was purged three times, the temperature was raised to 50°C, and the reaction was allowed to proceed for 2 hours. Column chromatography (dichloromethane / methanol = 20:1) afforded the desired product 1-12 (1.7 g).

[0351] MS (ESI, [M+H] + )m / z:598.4

[0352] Step K: Synthesis of Compound 1-13

[0353] Compound 1-12 (1.7 g), iron powder (0.797 g), ethanol (20 mL), and saturated ammonium chloride (2.5 mL) were added sequentially to a 100 mL single-necked flask. The temperature was raised to 70°C. The reaction mixture was allowed to react for 2 hours. After completion, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, and purified by column chromatography (dichloromethane / methanol = 20:1) to afford the desired product 1-13 (1.5 g).

[0354] MS (ESI, [M+H] + )m / z:568.4

[0355] Step L: Synthesis of Compound 1-14

[0356] Compound 1-13 (1.5 g), cuprous iodide (1.007 g), and acetonitrile (60 mL) were added sequentially to a 100 mL three-necked flask. After nitrogen was purged three times, tert-butyl nitrite (1.090 g) was added dropwise. The temperature was raised to 35°C and the reaction was allowed to react for 3 hours. Column chromatography (dichloromethane / methanol = 20:1) afforded the desired product 1-14 (680 mg).

[0357] MS (ESI, [M+H] + )m / z:679.4

[0358] Step M: Synthesis of Compound 1-16

[0359] Compound 1-14 (100 mg), cis-3-BOC-3,7-diazabicyclo[4.2.0]octane (6.9 mg), sodium tert-butoxide (28.3 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.76 mg), (2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (24.68 mg), and 1,4-dioxane (15 mL) were added sequentially to a 10 mL microwave tube. After addition, nitrogen was purged for 10 seconds, the tube was sealed, and the reaction was performed in a microwave reactor at 130°C for 1.5 hours. Column chromatography (dichloromethane / methanol = 10:1) was performed to obtain the desired product 1-16 (35 mg).

[0360] MS (ESI, [M+H] + )m / z:763.6

[0361] Step N: Synthesis of Compound 1

[0362] Compound 1-16 (35 mg), dichloromethane (1.5 mL) and trifluoroacetic acid (0.300 mL) were added sequentially to a 50 mL single-necked bottle, reacted at room temperature for 1 hour, dried by rotary evaporation, and purified by reverse phase column chromatography (0.05% NH4HCO3, acetonitrile / water) to obtain the target product 1 (12 mg).

[0363] 1 H NMR (500MHz, CDCl3) δ7.40-7.31(m,3H),7.06-7.05(m,1H),6.61-6.60(m,1H),6 .39-6.38(m,1H),4.34-4.33(m,2H),3.93(s,3H),3.88-3.84(m,2H),3.69-3.67 (m,1H),3.56-3.55(m,1H),3.17-3.13(m,1H),2.86-2.85(m,1H),2.70-2.63(m, 3H),2.05-1.96(m,1H),1.68-1.65(m,2H),1.58-1.55(m,6H),1.53-1.50(m,1H).

[0364] HRMS (ESI) ([M+H] + )m / z:563.1849.

[0365] Example 2: Preparation of Compound 2

[0366]

[0367] Step A: Synthesis of Compound 2-2

[0368] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 2-2 was prepared using compound 1-14 and compound 2-1 as raw materials.

[0369] MS (ESI, [M+H] + )m / z:777.2

[0370] Step B: Synthesis of Compound 2

[0371] Referring to the preparation method of compound 1 in step N of Example 1, compound 2 was prepared using compound 2-2 as the raw material.

[0372] 1 H NMR (500MHz, DMSO-d6) δ7.55(d,J=8.0Hz,1H),7.47-7.34(m,2H),7.11-7.01(m,2H),6.39(t,J=6.3Hz,1H),4.35(d,J=6.3Hz,2H) ,3.93(s,3H),3.85(q,J=11.1Hz,2H),3.61(s,1H),3.12-2.88(m,6H),1.87(d,J=6.4Hz,4H),1.57(d,J=13.3Hz,6H),1.24(s,2H).

[0373] HRMS (ESI) ([M+H] + )m / z:577.2011.

[0374] Example 3: Preparation of Compound 3

[0375]

[0376] Step A: Synthesis of Compound 3-2

[0377] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 3-2 was prepared using compound 1-14 and compound 3-1 as raw materials.

[0378] MS (ESI, [M+H] + )m / z:691.1

[0379] Step B: Synthesis of Compound 3

[0380] Referring to the preparation method of compound 1 in step N of Example 1, compound 3 was prepared using compound 3-2 as the raw material.

[0381] 1 H NMR (500MHz, DMSO-d6) δ7.39(dd,J=7.7,5.7Hz,1H),7.26(t,J=7.8Hz,1H),7.21(d,J=8.0Hz,1H ),7.05(dd,J=7.8,3.1Hz,1H),6.57(d,J=7.7Hz,1H),6.38(t,J=6.3Hz,1H),4.34(d,J=6.3Hz,2 H),3.93(s,3H),3.81(q,J=10.9Hz,2H),3.56(t,J=7.0Hz,2H),3.51(s,1H),3.43(d,J=8.7Hz,2 H),2.61(s,3H),2.32(s,3H),2.04-1.92(m,2H),1.83(d,J=8.7Hz,2H),1.57(d,J=13.3Hz,6H).

[0382] HRMS (ESI) ([M+H] + )m / z:591.2192.

[0383] Example 4: Preparation of Compound 4

[0384]

[0385] Step A: Synthesis of Compound 4-1

[0386] To a 100 mL microwave tube, add compound 1-2 (3 g), potassium iodide (0.5 g), N,N-dimethylformamide (40 mL), and diisopropylethylamine (3.87 g) in sequence. Purge with nitrogen for 1 minute and seal the tube. Set the reaction temperature to 80°C for 5 hours. Cool the reaction mixture, quench with water, extract with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and purify by column chromatography (dichloromethane / methanol = 10:1) to obtain the desired product 4-1 (3 g).

[0387] MS (ESI, [M+H] + )m / z:239.0

[0388] Step B: Synthesis of Compound 4-2

[0389] Referring to the preparation method of compound 1-12 in step J of Example 1, compound 4-2 was prepared using compound 1-11 and compound 4-1 as raw materials.

[0390] Step C: Synthesis of Compound 4-3

[0391] Referring to the preparation method of compound 1-13 in step K of Example 1, compound 4-3 was prepared using compound 4-2 as a raw material.

[0392] Step D: Synthesis of Compound 4-4

[0393] Referring to the preparation method of compound 1-14 in step L of Example 1, compound 4-4 was prepared using compound 4-3 as a raw material.

[0394] Step E: Synthesis of Compound 4

[0395] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 4 was prepared using compound 4-4 as the raw material.

[0396] 1 H NMR (500 MHz, DMSO-d6) δ 7.44 -7.38(m,2H),7.34(t,J=7.9Hz,1H),7.06(dd,J=7.7,3.1Hz,1H),6.85(d,J=7. 7Hz, 1H), 6.38 (t, J=6.3Hz, 1H), 4.35 (d, J=6.3Hz, 2H), 3.93 (s, 3H), 3.85 (q, J= 11.0Hz,2H),3.40-3.37(m,2H),3.16(dd,J=9.4,3.0Hz,2H),2.85(s,2H),2.68 -2.63(m,2H),2.33(dd,J=9.1,3.5Hz,2H),2.23(s,3H),1.57(d,J=13.3Hz,6H).

[0397] HRMS (ESI) ([M+H] + )m / z:577.2040.

[0398] Example 5: Preparation of compounds

[0399]

[0400] Step A: Synthesis of Compound 5

[0401] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 5 was prepared using compound 4-4 and compound 5-1 as raw materials.

[0402] 1H NMR(500MHz,DMSO-d6)δ7.57-7.55(m,1H),7.43-7.38(m,2H),7.09-7.05(m,2H),6.39-6.38(m,1H),4.35-4.34 (m,2H),3.93(s,3H),3.86-3.84(m,2H),3.10-3.08(m,4H),2.25(s,3H),1.58-1.55(m,6H),1.31-1.23(m,4H).

[0403] HRMS (ESI) ([M+H] + )m / z:551.1859.

[0404] Example 6: Preparation of Compound 6

[0405]

[0406] Step A: Synthesis of Compound 6-2

[0407] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 6-2 was prepared using compound 4-4 and compound 6-1 as raw materials.

[0408] MS (ESI, [M+H] + )m / z:677.3

[0409] Step B: Synthesis of Compound 6

[0410] Referring to the preparation method of compound 1 in step N of Example 1, compound 6 was prepared using compound 6-2 as the raw material.

[0411] 1 H NMR (500MHz, DMSO-d6) δ7.39(dd,J=7.7,5.8Hz,1H),7.32-7.22(m,2H),7.05(dd,J=7.8,3.1Hz,1H),6.43(d,J=7.5Hz,1H),6.38(t,J=6.3Hz,1H),4. 34(d,J=6.3Hz,2H),3.93(s,3H),3.86-3.81(m,2H),3.79(m,4H),2.72(t, J=5.5Hz,4H),1.89(s,1H),1.71(t,J=5.5Hz,4H),1.57(d,J=13.3Hz,6H).

[0412] HRMS (ESI) ([M+H] + )m / z:577.2018.

[0413] Example 7: Preparation of Compound 7

[0414]

[0415] Step A: Synthesis of Compound 7

[0416] Referring to the preparation method of compound 1-16 in step M of Example 1, compound 7 was prepared using compound 4-4 and compound 7-1 as raw materials.

[0417] 1 H NMR(500MHz,DMSO-d6)δ7.39(dd,J=7.7,5.8Hz,1H),7.31(d,J=4.8Hz,2H),7.06(dd ,J=7.8,3.1Hz,1H),6.71(s,1H),6.39(t,J=6.3Hz,1H),4.34(d,J=6.3Hz,2H),3.93( s,3H),3.83(dd,J=11.0,4.1Hz,2H),3.66(t,J=8.2Hz,1H),3.59(d,J=8.9Hz,1H),3 .54(q,J=8.4Hz,2H),2.51(m,6H),2.27(s,2H),2.01(s,1H),1.57(d,J=13.3Hz,6H).

[0418] HRMS (ESI) ([M+H] + )m / z:565.2027.

[0419] Example 8: Preparation of Compound 8

[0420]

[0421] Step A: Synthesis of Compound 8-2

[0422] To a 500 mL round-bottom flask, compound 8-1 (20.0 g), palladium acetate (1.6 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.5 g), N,N-dimethylformamide (200 mL), dimethylphosphine oxide (11.6 g), and N,N-diisopropylethylamine (38.4 g) were added in sequence. The atmosphere was replaced with nitrogen and the mixture was reacted in an oil bath at 120°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and the solid was filtered off. The filtrate was collected, the DMF was removed by vortexing, and the target product 8-2 (20.0 g) was purified by silica gel column chromatography.

[0423] MS (ESI, [M+H] + )m / z:200.21

[0424] Step B: Synthesis of Compound 8-3

[0425] Compound 8-2 (20.0 g), N,N-dimethylpyridine (13.5 g), tetrahydrofuran (200 mL), di-tert-butyl dicarbonate (28.5 g), and N,N-diisopropylethylamine (26.0 g) were added sequentially to a 500 mL single-necked flask. The temperature was raised to 50°C and the reaction was allowed to proceed for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed three times with a 10% aqueous citric acid solution, twice with a saturated sodium bicarbonate solution, and twice with a saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The target product 8-3 (8 g) was purified by silica gel column chromatography.

[0426] MS (ESI, [M+H] + )m / z:300.29

[0427] Step C: Synthesis of Compound 8-4

[0428] Compound 8-3 (8 g), acetonitrile (80 mL), cesium carbonate (39.3 g), and propargyl bromide (19.11 g) were added sequentially to a 250 mL single-necked flask. The mixture was allowed to react at room temperature for 8 hours. The solid was removed by filtration, and the filtrate was collected and purified by silica gel column chromatography to obtain the desired product 8-4 (7.1 g).

[0429] MS (ESI, [M+H] + )m / z:338.31

[0430] 1 H NMR(500MHz,DMSO-d6)δ7.42–7.37(m,1H),7.36–7.31(m,2H),3.86(s,3H),3.3 2(s,2H),3.14(t,J=2.5Hz,1H),1.67(d,J=13.4Hz,6H),1.35(d,J=26.7Hz,9H).

[0431] Step D: Synthesis of Compound 8-5

[0432] To a 100 mL single-necked flask, add intermediate 1-11 (5 g), intermediate 8-4 (4.36 g), tetrakis(triphenylphosphine)palladium (1.045 g), cuprous iodide (0.369 g), dichloromethane (40 mL), and NN-diisopropylethylamine (33.8 ml). After addition, heat to 50°C and react for 2 hours. Purify by column chromatography to obtain the desired product 8-5 (7.2 g).

[0433] MS (ESI, [M+H] + )m / z:597.3

[0434] Step E: Synthesis of Compound 8-6

[0435] In a 250 mL single-necked flask, add raw material 8-5 (7.2 g), ethanol (100 mL), saturated ammonium chloride solution (12.50 mL), and iron powder (3.38 g) in sequence. After addition, replace the nitrogen atmosphere three times, raise the temperature to 70°C, and react for 2.5 hours. After the reaction is complete, filter while hot, cool the filtrate, dilute with water, extract with ethyl acetate, and obtain the target product 8-6 (5.3 g) by column chromatography.

[0436] MS (ESI, [M+H] + )m / z:567.2

[0437] Step F: Synthesis of Compound 8-7

[0438] In a 100 mL three-necked flask, the raw material 8-6 ​​(5.3 g) and cuprous iodide (3.56 g) were first dissolved in acetonitrile (150 mL). Then, the nitrogen atmosphere was replaced three times, and tert-butyl nitrite (5.56 mL) was added dropwise. After the addition, the temperature was raised to 35° C. and the reaction was continued for 3 hours. After the reaction was completed, the target product 8-7 (2.5 g) was obtained by column chromatography.

[0439] MS (ESI, [M+H] + )m / z:678.3

[0440] Step G: Synthesis of Compound 8-9

[0441] Compound 8-7 (250 mg), compound 8-8 (155 mg), potassium carbonate (153 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (34.4 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (30.9 mg), and 1,4-dioxane (16 mL) were added sequentially to a 20 mL microwave reaction tube. After addition, nitrogen was purged into the reaction flask, which was sealed. The microwave reactor was set to a temperature of 110°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, column chromatography afforded the target product 8-9 (140 mg).

[0442] MS (ESI, [M+H] + )m / z:747.7

[0443] Step H: Synthesis of Compounds 8-10

[0444] In a 50 mL single-necked bottle, raw material 8-9 (140 mg), dichloromethane (3 mL), and trifluoroacetic acid (0.600 mL) were added in sequence. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the mixture was spin-dried, dissolved in water, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain product 8-10 (110 mg). It was used directly in the next step without further purification.

[0445] MS (ESI, [M+H] + )m / z:547.4

[0446] Step I: Synthesis of Compound 8

[0447] Compound 8-10 (120 mg), acetonitrile (15 mL), compound 8-11 (107 mg), and sodium carbonate (186 mg) were added sequentially to a 20 mL microwave tube. The reaction temperature was set to 100°C in a microwave reactor and allowed to react for 13 hours. After completion of the reaction, the crude product was purified by column chromatography and then reverse-phase purified to yield the desired product 8 (15 mg).

[0448] 1 H NMR(500MHz,DMSO-d6)δ7.77-7.75(m,1H),7.45-7.42(m,1H),7.32-7.31(m,1 H),7.23-7.19(m,1H),7.15-7.13(m,1H),6.84-6.82(m,1H),6.06-6.04(m,2H) ,4.61-4.59(m,4H),4.33(d,J=6.5Hz,2H),3.86-3.85(m,5H),3.29-3.27(m,4H ),2.41-2.26(m,4H),1.85-1.70(m,2H),1.59-1.56(m,6H),1.37-1.29(m,1H).

[0449] HRMS (ESI) ([M+H] + )m / z:629.2196.

[0450] Example 9: Preparation of Compound 9

[0451]

[0452] Step A: Synthesis of Compound 9-2

[0453] Compound 8-7 (300 mg), compound 9-1 (160 mg), cesium carbonate (433 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41.3 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (74.2 mg) and 1,4-dioxane (15 mL) were added sequentially to a 20 mL microwave tube. After addition, nitrogen was purged, the tube was sealed, and the temperature was set to 100 ° C using a microwave reactor. The reaction time was 1.5 hours. After completion of the reaction, the product 9-2 (120 mg) was purified by silica gel column chromatography and then reverse phase column chromatography.

[0454] MS (ESI, [M+H] + )m / z:790.6.

[0455] Step B: Synthesis of Compound 9-3

[0456] Compound 9-2 (120 mg), dichloromethane (3 mL), and trifluoroacetic acid (0.600 mL) were added sequentially to a 50 mL single-necked flask. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was directly spin-dried, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate to obtain product 9-3 (90 mg). The product was used directly in the next step without further purification.

[0457] MS (ESI, [M+H] + )m / z:590.5.

[0458] Step C: Synthesis of Compound 9

[0459] Compound 9-3 (90 mg), acetonitrile (15 mL), compound 8-11 (74.5 mg), and sodium carbonate (129 mg) were added sequentially to a 20 mL microwave tube. After addition, the microwave reactor was set to 100°C and microwave-reacted for 14 hours. After completion of the reaction, column chromatography afforded the desired product 9 (25 mg).

[0460] 1H NMR(500MHz,DMSO-d6)δ7.53-7.52(m,1H),7.40-7.38(m,1H),7.22-7.21(m,1H),7 .15-7.13(m,1H),7.05-7.04(m,1H),6.84-6.82(m,1H),6.06-6.04(m,1H),4.61-4. 59(m,4H),4.33(d,J=6.5Hz,2H),3.86-3.81(m,5H),3.29-3.27(m,3H),2.98-2.93( m,4H),2.51-2.50(m,2H),1.87-1.86(m,2H),1.68-1.66(m,4H),1.60-1.54(m,8H).

[0461] HRMS (ESI) ([M+H] + )m / z:672.2618.

[0462] Example 10: Preparation of Compound 10

[0463]

[0464] Step A: Synthesis of Compound 10-2

[0465] In a 100 mL three-necked flask, cyclopropanol (1.526 g) was dissolved in ultra-dry tetrahydrofuran (5.000 mL). The nitrogen atmosphere was replaced three times. Sodium hydride (1.617 g) was added portionwise in an ice bath. After stirring for 30 minutes, a tetrahydrofuran solution of compound 10-1 (4.8 g) was added dropwise. After addition, the reaction was allowed to warm naturally for 1.5 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the desired product 10-2 (3.2 g), which was used directly in the next step without further purification.

[0466] 1 H NMR (500MHz, DMSO-d6) δ8.36 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 8.0 Hz 1H), 4.46-4.44 (m, 1H), 0.86-0.77 (m, 4H).

[0467] Step B: Synthesis of Compound 10-3

[0468] Compound 10-2 (3.1 g), ethanol (30 mL), saturated ammonium chloride solution (3.75 mL), and iron powder (3.35 g) were added sequentially to a 100 mL single-necked flask. After nitrogen was replaced, the temperature was raised to 70°C and the reaction was allowed to proceed for 2.5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was cooled to room temperature, extracted with ethyl acetate, and purified by column chromatography to obtain 10-3 (2.3 g).

[0469] MS (ESI, [M+H] + )m / z:229.1

[0470] Step C: Synthesis of Compound 10-4

[0471] To a 100 mL microwave tube, compound 10-3 (2.3 g), dimethylphosphine (1.019 g), palladium acetate (0.225 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.162 g), DMF (20 mL), and N,N-diisopropylethylamine (5.26 ml) were added sequentially. After addition, nitrogen was purged, the tube was sealed, and the temperature was set to 120°C for 6 hours. After the reaction was complete, the DMF was removed by vortexing, and the product 10-4 (2.2 g) was obtained by column chromatography.

[0472] MS (ESI, [M+H] + )m / z:227.2

[0473] Step D: Synthesis of Compound 10-5

[0474] Compound 10-4 (2.2 g), tetrahydrofuran (30 mL), di-tert-butyl dicarbonate (6.37 g), N,N-dimethylpyridine (1.188 g), and N,N-diisopropylethylamine (5.10 mL) were added sequentially to a 100 mL single-necked flask. The temperature was raised to 65°C and the mixture was reacted for 5 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed twice with 5% citric acid, and column chromatography was performed to obtain 2 g of a mixture of mono- and bis-Boc. This mixture was dissolved in methanol (30 mL) in a 100 mL single-necked flask, and potassium carbonate (1.944 g) was added. The temperature was raised to 50°C and the mixture was reacted for 2 hours. After the reaction was complete, the potassium carbonate was filtered off and column chromatography was performed to obtain 10-5 (1.5 g).

[0475] MS (ESI, [M+H] + )m / z:327.2

[0476] Step E: Synthesis of Compound 10-6

[0477] Referring to the synthesis method of compound 1-4 in step C of Example 1, compound 10-5 and propargyl bromide were used as raw materials to prepare compound 10-6.

[0478] MS (ESI, [M+H]+ )m / z:365.3

[0479] Step F: Synthesis of Compound 10-7

[0480] Referring to the synthesis method of compound 1-12 in step J of Example 1, compound 10-6 and compound 1-11 were used as raw materials to prepare compound 10-7.

[0481] MS (ESI, [M+H] + )m / z:624.5

[0482] Step G: Synthesis of compound 10-8

[0483] Referring to the synthesis method of compound 1-13 in step K of Example 1, compound 10-7 was used as a raw material to prepare compound 10-8.

[0484] MS (ESI, [M+H] + )m / z:594.1

[0485] Step H: Synthesis of Compound 10-9

[0486] Referring to the synthesis method of compound 1-14 in step L of Example 1, compound 10-8 was used as a raw material to prepare compound 10-9.

[0487] MS (ESI, [M+H] + )m / z:705.4

[0488] Step I: Synthesis of Compound 10-10

[0489] Referring to the synthesis method of compound 1-16 in step M of Example 1, compound 10-9 and compound 10-12 were used as raw materials to prepare compound 10-10.

[0490] MS (ESI, [M+H] + )m / z:763.7

[0491] Step J: Synthesis of Compound 10-11

[0492] Referring to the synthesis method of compound 8-3 in Step B of Example 9, compound 10-10 was used as a raw material to prepare compound 10-11.

[0493] MS (ESI, [M+H] + )m / z:563.5

[0494] Step K: Synthesis of Compound 10

[0495] Referring to the synthesis method of compound 8 in step I of Example 8, compound 10-11 and compound 8-11 were used as raw materials to prepare compound 10.

[0496] 1 H NMR(500MHz,DMSO-d6)δ7.42-7.39(m,1H),7.26-7.19(m,2H),7.06-7.04(m,1H) ,6.55-6.54(m,1H),6.24-6.22(m,1H),4.59-4.57(m,4H),4.35-4.31(m,3H),3.8 3-3.78(m,2H),3.56-3.33(m,3H),3.29-3.28(m,4H),3.19-3.16(m,1H),3.96(s, 1H),1.90-1.88(m,1H),1.74-1.69(m,1H),1.61-1.56(m,6H),0.77-0.69(m,4H).

[0497] HRMS (ESI) ([M+H] + )m / z:645.2259.

[0498] Example 11: Preparation of Compound 11

[0499]

[0500] Step A: Synthesis of Compound 11-2

[0501] Compound 11-1 (5 g), acetonitrile (50 mL), and N-bromosuccinimide (6.72 g) were added sequentially to a 100 mL single-necked flask. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was spin-dried, diluted with ethyl acetate, washed with sodium thiosulfate, and purified by column chromatography to obtain the target product 11-2 (6 g).

[0502] 1 H NMR (500MHz, DMSO-d6) δ6.71(d,J=8.5Hz,1H),6.41(d,J=8.0Hz,1H),4.75(s,2H),4.54-4.51(m,2H),3.12-3.09(m,2H).

[0503] Step B: Synthesis of Compound 11-3

[0504] Referring to the synthesis method of compound 10-4 in step C of Example 10, compound 11-2 and dimethylphosphine oxide were used as raw materials to prepare compound 11-3.

[0505] MS (ESI, [M+H] +)m / z:212.2

[0506] Step C: Synthesis of Compound 11-4

[0507] Referring to the synthesis method of compound 10-5 in step D of Example 10, compound 11-3 was used as a raw material to prepare compound 11-4.

[0508] MS (ESI, [M+H] + )m / z:312.2

[0509] Step D: Synthesis of Compound 11-5

[0510] Referring to the synthesis method of compound 1-4 in step C of Example 1, compound 11-4 and propargyl bromide were used as raw materials to prepare compound 11-5.

[0511] MS (ESI, [M+H] + )m / z:350.1

[0512] Step F: Synthesis of Compound 11-6

[0513] Referring to the synthesis method of compound 1-12 in step J of Example 1, compound 11-5 and compound 1-11 were used as raw materials to prepare compound 11-6.

[0514] MS (ESI, [M+H] + )m / z:609.1

[0515] Step G: Synthesis of Compound 11-7

[0516] Referring to the synthesis method of compound 1-13 in step K of Example 1, compound 11-6 was used as a raw material to prepare compound 11-7.

[0517] MS (ESI, [M+H] + )m / z:579.2

[0518] Step H: Synthesis of Compound 11-8

[0519] Referring to the synthesis method of compound 1-14 in step L of Example 1, compound 11-7 was used as a raw material to prepare compound 11-8.

[0520] MS (ESI, [M+H] + )m / z:690.1

[0521] Step I: Synthesis of Compound 11-9

[0522] Referring to the synthesis method of compound 1-16 in step M of Example 1, compound 11-8 and compound 10-12 were used as raw materials to prepare compound 11-9.

[0523] MS (ESI, [M+H] + )m / z:648.2

[0524] Step J: Synthesis of Compound 11-10

[0525] Referring to the synthesis method of compound 9-3 in step B of Example 9, compound 11-9 was used as a raw material to prepare compound 11-10.

[0526] MS (ESI, [M+H] + )m / z:548.2

[0527] Step K: Synthesis of Compound 11

[0528] Referring to the synthesis method of compound 8 in step C of Example 9, compound 11-10 and compound 8-11 were used as raw materials to prepare compound 11.

[0529] 1 H NMR(500MHz,DMSO-d6)δ7.26-7.18(m,2H),7.05-7.01(m,1H),6.71-6.69(m,1H),6 .55-6.53(m,1H),5.95-5.93(m,1H),4.57-4.54(m,6H),4.30(d,J=6Hz,2H),3.80- 3.77(m,2H),3.56-3.44(m,3H),3.38-3.35(m,2H),3.29-3.16(m,4H),3.17-3.16( m,1H),2.96-2.95(m,1H),1.90-1.88(m,1H),1.74-172(m,1H),1.59-1.56(m,6H).

[0530] HRMS (ESI) ([M+H] + )m / z:630.2154.

[0531] Example 12: Preparation of Compound 12

[0532]

[0533] Referring to the synthesis method of compound 9 in step C of Example 9, compound 12 was prepared using compound 9-3 and compound 12-1 as raw materials.

[0534] 1H NMR(500MHz,DMSO-d6)δ7.53(d,J=8.0Hz,1H),7.43-7.35(m,1H),7.26-7.18(m,1H),7.18-7.11(m ,1H),7.06(d,J=7.6Hz,1H),6.87-6.80(m,1H),6.08-5.97(m,1H),4.34(d,J=6.3Hz,2H),3.85(s, 3H),3.84-3.77(m,2H),3.66-3.51(m,4H),3.11-2.99(m,2H),2.98-2.90(m,2H),2.77-2.60(m,1H ),2.32-2.15(m,4H),2.05-1.91(m,2H),1.78-1.70(m,2H),1.69-1.62(m,2H),1.60-1.57(m,8H).

[0535] HRMS (ESI) ([M+H] + )m / z:660.2629.

[0536] Example 13: Preparation of Compound 13

[0537]

[0538] Step A: Synthesis of Compound 13-2

[0539] Compound 8-7 (150 mg), compound 13-1 (97 mg), potassium carbonate (92 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (27 mg), (2-amino-1,1'-biphenyl-2-yl) palladium methanesulfonate (37 mg), 1,4-dioxane (15 mL), and water (1.5 mL) were added sequentially to a 35 mL microwave tube. After addition, nitrogen was purged for 10 seconds. The tube was sealed and microwaved using a reactor set to 130°C for 1.5 hours. The target product 13-2 (100 mg) was obtained by column chromatography.

[0540] MS (ESI, [M+H] + )m / z:717.60

[0541] Step B: Synthesis of Compound 13

[0542] Referring to the preparation method of compound 1 in step N of Example 1, compound 13 was prepared using compound 13-2 as raw material.

[0543] 1H NMR (500MHz, DMSO-d6) δ7.78(d,J=8.1Hz,1H),7.46(d,J=7.7Hz,1H),7.34(dd,J=7.4,1.0Hz,1H),7.22(ddd,J =11.7,7.9,1.6Hz,1H),7.14(dd,J=11.9,1.6Hz,1H),6.83(dd,J=8.1,3.0Hz,1H),6.13(d,J=5.5Hz,1H),6.05 (t,J=6.4Hz,1H),4.34(d,J=6.3Hz,2H),3.86(d,J=10.2Hz,6H),3.60(q,J=4.1Hz,5H),2.62–2.52(m,5H),2.3 6(d,J=4.8Hz,1H),2.24–2.18(m,1H),2.05(d,J=12.3Hz,1H),1.68(d,J=13.4Hz,1H),1.58(d,J=13.2Hz,6H).

[0544] HRMS (ESI) ([M+H] + )m / z:617.2200.

[0545] Example 14: Preparation of Compound 14

[0546]

[0547] Step A: Synthesis of Compound 14-2

[0548] Referring to the preparation method of compound 13-2 in step A of Example 13, compound 14-2 was prepared using compound 8-7 and compound 14-1 as raw materials.

[0549] Step B: Synthesis of Compound 14-3

[0550] Referring to the preparation method of compound 1 in step N of Example 1, compound 14-3 was prepared using compound 14-2 as a raw material.

[0551] Step C: Synthesis of Compound 14

[0552] Compound 14-3 (50 mg), 3,3-bis(bromomethyl)oxetane (56 mg), potassium carbonate (32 mg), and water (10 mL) were added sequentially to a 35 mL microwave tube. The tube was sealed and microwaved at 120°C for 1.5 hours. The reaction was then extracted three times with ethyl acetate, and the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to yield the desired product 14 (8 mg).

[0553] 1 H NMR (500MHz, DMSO-d6) δ7.78(d,J=8.1Hz,1H),7.45(t,J=7.7Hz,1H),7.32(d,J=7.3Hz,1H),7.22(dd d,J=11.7,8.0,1.6Hz,1H),7.14(m,1H),6.83(m,1H),6.11(s,1H),6.04(t,J=6.4Hz,1H),4.59(s,4H ),4.34(d,J=6.4Hz,2H),3.85(s,5H),3.34(s,2H),3.26(d,J=8.5Hz,2H),2.49–2.34(m,2H),2.34–2 .20(m,2H),2.17(d,J=7.5Hz,1H),2.12–2.02(m,1H),1.71(d,J=11.6Hz,1H),1.58(d,J=13.1Hz,6H).

[0554] HRMS (ESI) ([M+H] + )m / z:629.2237.

[0555] Example 15: Preparation of Compound 15

[0556]

[0557] Step A: Synthesis of Compound 15-1

[0558] Compound 8-7 (300 mg), (R)-3-tert-butyloxycarbonylaminopyrrolidine (165 mg), cesium carbonate (433 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41 mg), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (74 mg), and 1,4-dioxane (10 mL) were added sequentially to a 25 mL microwave tube. After addition, nitrogen was purged for 10 seconds. The tube was sealed and microwaved at 100°C for 1.5 hours. The target product 15-1 (150 mg) was obtained by column chromatography.

[0559] MS (ESI, [M+H] + )m / z:736.60.

[0560] Step B: Synthesis of Compound 15-2

[0561] Referring to the preparation method of compound 1 in step N of Example 1, compound 15-2 was prepared using compound 15-1 as a raw material.

[0562] Step C: Synthesis of Compound 15

[0563] Referring to the preparation method of compound 14 in step C of Example 14, compound 15 was prepared using compound 15-2 as the raw material.

[0564] 1 H NMR (500MHz, DMSO-d6) δ7.27–7.17(m,3H),7.17–7.11(m,J=11.9,1.3Hz,1H),6.86–6.80(m,J=8.0,3.0Hz, 1H),6.55(d,J=7.7Hz,1H),6.07–6.01(m,J=6.4Hz,1H),4.58(s,4H),4.33(d,J=6.4Hz,2H),3.85(s,3H),3 .83–3.72(m,J=11.0,3.5Hz,2H),3.58–3.48(m,2H),3.47–3.40(m,J=8.1,3.7Hz,1H),3.29(s,4H),3.21–3 .11(m,J=9.3,2.2Hz,1H),3.01–2.89(m,1H),1.95–1.84(m,1H),1.78–1.68(m,1H),1.58(d,J=13.2Hz,6H).

[0565] HRMS (ESI) ([M+H] + )m / z:618.2164.

[0566] Example 16: Preparation of Compound 16

[0567]

[0568] Step A: Synthesis of Compound 16-1

[0569] Referring to the preparation method of compound 15-1 in step A of Example 15, compound 16-1 was prepared using compound 8-7 and (S)-3-tert-butoxycarbonylaminopyrrolidine as raw materials.

[0570] Step B: Synthesis of Compound 16-2

[0571] Referring to the preparation method of compound 1 in step N of Example 1, compound 16-2 was prepared using compound 16-1 as a raw material.

[0572] Step C: Synthesis of Compound 16

[0573] Referring to the preparation method of compound 14 in step C of Example 14, compound 16 was prepared using compound 16-2 as the raw material.

[0574] 1 H NMR (500MHz, DMSO-d6) δ7.28–7.17(m,3H),7.17–7.11(m,J=11.9,1.2Hz,1H),6.87–6.80(m,J=8.0,2.9H z,1H),6.55(d,J=7.7Hz,1H),6.08–6.00(m,J=6.4Hz,1H),4.58(s,4H),4.33(d,J=6.3Hz,2H),3.85(s,3 H),3.83–3.72(m,2H),3.58–3.48(m,2H),3.48–3.40(m,J=8.1,3.7Hz,1H),3.31–3.23(m,4H),3.22–3.1 4(m,J=9.3,1.9Hz,1H),3.04–2.92(m,1H),1.94–1.85(m,1H),1.78–1.68(m,1H),1.58(d,J=13.2Hz,6H).

[0575] HRMS (ESI) ([M+H] + )m / z:618.2176.

[0576] Example 17: Preparation of Compound 17

[0577]

[0578] Step A: Synthesis of Compound 17-1

[0579] Referring to the preparation method of compound 15-1 in step A of Example 15, compound 17-1 was prepared using compound 8-7 and tert-butyl (2-azaspiro[3.5]nonan-7-yl)carbamate as raw materials.

[0580] Step B: Synthesis of Compound 17-2

[0581] Referring to the preparation method of compound 1 in step N of Example 1, compound 17-2 was prepared using compound 17-1 as a raw material.

[0582] Step C: Synthesis of Compound 17

[0583] Referring to the preparation method of compound 14 in step C of Example 14, compound 17 was prepared using compound 17-2 as the raw material.

[0584] 1H NMR (500MHz, DMSO-d6) δ7.31–7.26(m,J=7.8Hz,1H),7.25–7.18(m,2H),7.17–7.11(m,J=11.9,1.3Hz,1H),6.86–6.78(m,J=8. 1,3.0Hz,1H),6.41(d,J=7.4Hz,1H),6.07–5.99(m,J=6.4Hz,1H),4.33(d,J=6.4Hz,2H),3.85(s,3H),3.84–3.78(m,2H),3.78– 3.75(m,2H),3.73–3.68(m,2H),3.60–3.50(m,4H),2.48–2.39(m,J=3.7Hz,4H),2.20–2.08(m,J=14.3,6.8Hz,1H),2.01–1.90 (m,J=12.9Hz,2H),1.76–1.67(m,J=10.4Hz,2H),1.58(d,J=13.2Hz,6H),1.53–1.44(m,J=12.8,2.8Hz,2H),1.33–1.22(m,2H).

[0585] HRMS (ESI) ([M+H] + )m / z:660.2635.

[0586] Example 18: Preparation of Compound 18

[0587]

[0588] Step A: Synthesis of Compound 18-1

[0589] Referring to the preparation method of compound 15-1 in step A of Example 15, compound 18-1 was prepared using compound 8-7 and trans-N-Boc-4-fluoropyrrolidin-3-amine as raw materials.

[0590] Step B: Synthesis of Compound 18-2

[0591] Referring to the preparation method of compound 1 in step N of Example 1, compound 18-2 was prepared using compound 18-1 as a raw material.

[0592] Step C: Synthesis of Compound 18

[0593] Compound 18-2 (100 mg), 3,3-bis(bromomethyl)oxetane (132 mg), sodium carbonate (153 mg), and acetonitrile (10 mL) were added sequentially to a 25 mL microwave tube. The tube was sealed and microwaved using a microwave reactor at 110°C for 10 hours. Column chromatography was then performed to obtain the desired product 18 (10 mg).

[0594] 1 H NMR (500MHz, DMSO-d6) δ7.30–7.25(m,2H),7.22(ddd,J=11.7,8.0,1.6Hz,1H),7.14(dd,J=11.9,1.6Hz,1H),6.84(d d,J=8.0,3.0Hz,1H),6.63(dd,J=6.4,2.4Hz,1H),6.04(t,J=6.4Hz,1H),5.00(dd,J=51.6,3.7Hz,1H),4.58(s,3H),4 .34(d,J=6.4Hz,2H),3.85(s,3H),3.81(dt,J=11.6,3.7Hz,2H),3.78–3.70(m,2H),3.64(dd,J=25.1,11.4Hz,1H),3. 39(d,J=1.7Hz,4H),3.23(dd,J=10.0,2.0Hz,1H),3.13(dd,J=15.6,5.2Hz,1H),2.54(s,1H),1.58(d,J=13.2Hz,6H).

[0595] HRMS (ESI) ([M+H] + )m / z:636.2055.

[0596] Example 19: Preparation of Compound 19

[0597]

[0598] Step A: Synthesis of Compound 19-1

[0599] Compound 8-7 (1.0 g) and dichloromethane (10 mL) were added sequentially to a 100 mL three-necked round-bottom flask. The atmosphere was replaced with nitrogen and the temperature was lowered to -10°C. A 2.0 mol / L tetrahydrofuran solution of boron tribromide (1.5 mL) was added dropwise via syringe with stirring. The mixture was allowed to react at -10°C for 3 hours. After completion, the pH was adjusted to 7 with 15% aqueous sodium hydroxide solution. The mixture was extracted three times with dichloromethane and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain the desired product 19-1 (380 mg).

[0600] MS (ESI, [M+H] + )m / z:564.23

[0601] Step B: Synthesis of Compound 19-2

[0602] To a 100 mL round-bottom flask, compound 19-1 (380 mg), potassium carbonate (186 mg), DMF (5 mL), and deuterated iodomethane (98 mg) were added sequentially and stirred at room temperature for 1 hour. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated, and purified by silica gel column chromatography to obtain the desired product 19-2 (270 mg).

[0603] MS (ESI, [M+H] + )m / z:581.17

[0604] Step C: Synthesis of Compound 19-3

[0605] Compound 19-2 (120 mg), tert-butyl N-[2-azaspiro[3.5]nonan-7-yl]carbamate (75 mg), cesium carbonate (202 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (19 mg), (2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (35 mg), and 1,4-dioxane (15 mL) were added sequentially to a 35 mL microwave tube. After addition, nitrogen was purged for 10 seconds. The tube was sealed and microwaved at 130°C for 1 hour. The target product 19-3 (50 mg) was obtained by column chromatography.

[0606] MS (ESI, [M+H] + )m / z:693.65

[0607] Step D: Synthesis of Compound 19-4

[0608] Referring to the preparation method of compound 1 in step N of Example 1, compound 19-4 was prepared using compound 19-3 as a raw material.

[0609] Step E: Synthesis of Compound 19

[0610] Referring to the preparation method of compound 14 in step C of Example 14, compound 19 was prepared using compound 19-4 as the raw material.

[0611] 1H NMR(500MHz,DMSO-d6)δ7.28(t,J=7.8Hz,1H),7.26–7.19(m,2H),7.13(dd,J=11.9,1.6Hz,1H),6.8 3(dd,J=8.1,3.0Hz,1H),6.45–6.38(m,1H),6.04(t,J=6.4Hz,1H),4.33(d,J=6.4Hz,2H),3.84-3.75 (m,4H),3.72(s,2H),3.57(t,J=4.6Hz,4H),3.33(s,2H),2.55(s,2H),2.21(s,1H),1.96(d,J=12.9 Hz,2H),1.76–1.70(m,2H),1.58(d,J=13.2Hz,6H),1.49(td,J=12.9,3.4Hz,2H),1.35–1.26(m,2H).

[0612] HRMS (ESI) ([M+H] + )m / z:663.2829.

[0613] Example 20: Preparation of Compound 20

[0614]

[0615] Step A: Preparation of compound 20-1

[0616] Referring to the method in step G of Example 8, compound 8-7 was reacted with tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)carbamate to obtain compound 20-1.

[0617] MS (ESI, [M+H-Boc] + )m / z:647.55.

[0618] Step B: Preparation of compound 20-2

[0619] Referring to the method of step H in Example 8, compound 20-1 was reacted with trifluoroacetic acid to obtain compound 20-2.

[0620] MS (ESI, [M+H] + )m / z:547.40.

[0621] Step C: Preparation of compound 20

[0622] Referring to the method in step I of Example 8, compound 20-2 was reacted with 3,3-bis(bromomethyl)oxetane to obtain compound 20.

[0623] 1 H NMR(500MHz,DMSO-d6)δ7.82–7.75(m,1H),7.50–7.42(m,1H),7.39–7.29(m,1H),7 .25–7.19(m,1H),7.18–7.12(m,1H),6.88–6.81(m,1H),6.14–6.00(m,2H),4.64–4 .56(m,4H),4.40–4.30(m,2H),3.90–3.81(m,5H),3.40–3.31(m,4H),3.30–3.25(m ,2H),2.89–2.53(m,1H),2.39–2.30(m,2H),1.91–1.63(m,2H),1.60–1.56(m,6H).

[0624] HRMS (ESI, [M+H] + )m / z:629.2240.

[0625] Example 21: Preparation of Compound 21

[0626]

[0627] Step A: Preparation of compound 21-1

[0628] To a 250 mL three-necked flask, tert-butyldimethyl(2-propynyloxy)silane (11 g) and tetrahydrofuran (60 mL) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the mixture was cooled to -78°C with stirring. Then, a 2.5 M solution of n-butyllithium in n-hexane (28.1 mL) was slowly added. After the addition, stirring was continued at low temperature for 1 hour. Iodine (19 g) was then dissolved in tetrahydrofuran (35 mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, ethyl acetate (200 mL) was added to dilute the reaction mixture, followed by washing with saturated sodium thiosulfate solution (100 mL x 3). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography to yield compound 21-1 (17.2 g).

[0629] MS (ESI, [Mt-Bu] - )m / z:239.0.

[0630] Step B: Preparation of compound 21-2

[0631] To a 250 mL three-necked flask, add 2-amino-3-bromopyridine (5.7 g), toluene (50 mL), and copper acetate (1.2 g) in sequence. After the addition, replace the atmosphere with nitrogen and heat to 120°C with stirring. Compound 21-1 (14.7 g) is then added dropwise to the reaction system. After the addition, react at 120°C for 3 h. After the reaction is complete, concentrate and remove the solvent. The remaining oil is purified by silica gel column chromatography to yield compound 21-2 (8.7 g).

[0632] MS (ESI, [M+H] + )m / z:476.20.

[0633] Step C: Preparation of compound 21-3

[0634] Compound 21-2 (8.7 g), tetrahydrofuran (80 mL), and triethylamine trihydrofluoride (9.05 g) were added sequentially to a 250 mL single-necked flask and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was filtered, and the filter cake was washed with a small amount of DCM and dried under vacuum to obtain compound 21-3 (6.1 g).

[0635] MS (ESI, [M+H] + )m / z:352.95.

[0636] Step D: Preparation of compound 21-4

[0637] Compound 21-3 (6 g), acetonitrile (100 mL), and 2-iodoacylbenzoic acid (5.9 g) were added sequentially to a 250 mL single-necked flask. The mixture was heated to 80°C in an oil bath and reacted for 3 h. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 21-4 (5.5 g).

[0638] MS (ESI, [M+H] + )m / z:350.93.

[0639] Step E: Preparation of compound 21-5

[0640] Compound 21-4 (5.5 g), (triphenylphosphonium) difluoroacetic acid inner salt (13.7 g), and N,N-dimethylformamide (80 mL) were added sequentially to a 250 mL three-necked flask. After the addition, the atmosphere was purged with nitrogen and the reaction mixture was heated to 60°C for 1 h. After TLC analysis indicated that the substrate had been consumed, a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (47 mL) was added to the reaction mixture. The reaction mixture was then allowed to react at 60°C for another 1 h. After the reaction was complete, the reaction mixture was diluted with purified water (500 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography to yield compound 21-5 (4.3 g).

[0641] MS (ESI, [M+H] + )m / z:405.01.

[0642] Step F: Preparation of compound 21-6

[0643] Referring to the method of step D of Example 8, compound 21-5 and compound 26-4 should give compound 21-6.

[0644] MS (ESI, [M+H] + )m / z:595.34.

[0645] Step G: Preparation of compound 21-7

[0646] Referring to the method in step G of Example 8, compound 21-6 was reacted with tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate to obtain compound 21-7.

[0647] MS (ESI, [M+H] + )m / z:712.65.

[0648] Step H: Preparation of compound 21-8

[0649] Referring to the method of step H in Example 8, compound 21-7 was reacted with trifluoroacetic acid to give compound 21-8.

[0650] MS (ESI, [M+H] + )m / z:512.07.

[0651] Step I: Preparation of compound 21

[0652] Referring to the method in step I of Example 8, compound 21-8 was reacted with 3,3-bis(bromomethyl)oxetane to obtain compound 21.

[0653] 1H NMR (500MHz, DMSO-d6) δ8.37(d,J=6.6Hz,1H),8.08(d,J=4.3Hz,1H),7.41(d,J=7.9 Hz,1H),7.35(s,1H),7.22(d,J=7.1Hz,1H),7.07–6.94(m,2H),6.76(d,J=8.3Hz,1H ),5.94(t,J=6.1Hz,1H),4.61(s,4H),4.29(d,J=6.1Hz,2H),4.12–4.02(m,2H),3.8 4(s,3H),2.75(d,J=4.3Hz,3H),2.50(s,7H),1.96–1.76(m,2H),1.36–1.19(m,2H).

[0654] HRMS (ESI, [M+H] + )m / z:594.2675.

[0655] Example 22: Preparation of Compound 22

[0656]

[0657] Step A: Preparation of compound 22-1

[0658] Referring to the method in step G of Example 8, compound 21-6 was reacted with tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)carbamate to obtain compound 22-1.

[0659] MS (ESI, [M+H] + )m / z:712.40.

[0660] Step B: Preparation of compound 22-2

[0661] Referring to the method of step H in Example 8, compound 22-1 was reacted with trifluoroacetic acid to obtain compound 22-2.

[0662] MS (ESI, [M+H] + )m / z:512.50.

[0663] Step C: Preparation of compound 22

[0664] Referring to the method in step I of Example 8, compound 22-2 was reacted with 3,3-bis(bromomethyl)oxetane to obtain compound 22.

[0665] 1H NMR(500MHz,DMSO-d6)δ8.39(s,1H),8.09(s,1H),7.53–7.30(m,2H),7.21(s,1H),7.00(s,1H),6.77(s,1H),6.64(s,1H),5.95(s,1H), 4.59(s,4H),4.29(s,2H),4.07(s,2H),3.84(s,3H),3.21(s,4H),2.91–2.65(m,4H),2.37–1.97(m,2H),1.84–1.54(m,2H),1.24(s,2H).

[0666] HRMS (ESI, [M+H] + )m / z:594.2680.

[0667] Example 23: Preparation of Compound 23

[0668]

[0669] Step A: Preparation of compound 23-1

[0670] Referring to the method in step D of Example 8, compound 21-5 was reacted with compound 8-4 to obtain compound 23-1.

[0671] MS (ESI, [M+H] + )m / z:614.37.

[0672] Step B: Preparation of compound 23-2

[0673] Referring to the method in step G of Example 8, compound 23-1 was reacted with tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate to obtain compound 23-2.

[0674] MS (ESI, [M+H] + )m / z:731.66.

[0675] Step C: Preparation of compound 23-3

[0676] Referring to the method of step H in Example 8, compound 23-2 was reacted with trifluoroacetic acid to obtain compound 23-3.

[0677] MS (ESI, [M+H] + )m / z:531.47.

[0678] Step D: Preparation of compound 23

[0679] Referring to the method in step I of Example 8, compound 23-3 was reacted with 3,3-bis(bromomethyl)oxetane to obtain compound 23.

[0680] 1 H NMR(500MHz,DMSO-d6)δ8.37(d,J=6.2Hz,1H),7.30–7.17(m,2H),7.17–7.1 0(m,1H),6.99(s,2H),6.85(d,J=7.3Hz,1H),6.07–5.94(m,1H),4.60(s,4H) ,4.29(d,J=5.3Hz,2H),4.12–3.98(m,2H),3.85(s,3H),3.28(s,3H),2.50(s ,3H),2.34–2.18(m,2H),1.92–1.73(m,2H),1.65–1.52(m,6H),1.33(s,1H).

[0681] HRMS (ESI, [M+H] + )m / z:613.2554.

[0682] Example 24: Preparation of Compound 24

[0683]

[0684] Step A: Preparation of compound 24-1

[0685] To a 25 mL single-necked flask, add 3-(((tert-Butoxycarbonyl)amino)cyclopent-1-en-1-yl trifluoromethanesulfonate (63 mg), pinacol diboron (127 mg), potassium acetate (98 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (27 mg), and 1,4-dioxane (5 mL) in sequence. After the addition, heat to 100°C in an oil bath under nitrogen protection for 4 h. After the reaction was completed as monitored by TLC, no post-treatment or purification was performed, and the reaction solution was used directly in the next reaction.

[0686] Step B: Preparation of compound 24-2

[0687] Referring to the method in step G of Example 8, compound 24-1 was reacted with compound 21-6 to obtain compound 24-2.

[0688] MS (ESI, [M+H] + )m / z:698.69.

[0689] Step C: Preparation of compound 24-3

[0690] Referring to the method of step H in Example 8, compound 24-2 was reacted with trifluoroacetic acid to give compound 24-3.

[0691] MS (ESI, [M+H] + )m / z:498.47.

[0692] Step D: Preparation of compound 24

[0693] Referring to the method in step I of Example 8, compound 24-3 was reacted with 3,3-bis(bromomethyl)oxetane to obtain compound 24.

[0694] 1 H NMR(500MHz,DMSO-d6)δ8.43(s,1H),8.09(s,1H),7.62–7.32(m,2H),7.24(s,2H),7.03(s,1H),6.78(s,1H),5.96(s,1H),4 .59(s,4H),4.30(s,2H),4.08(s,2H),3.84(s,3H),3.59(s,1H),2.75(s,3H),2.63(s,2H),1.97(s,2H),1.74–0.79(m,4H).

[0695] HRMS (ESI, [M+H] + )m / z:580.2521.

[0696] Example 25: Preparation of Compound 25

[0697]

[0698] Step A: Preparation of compound 25-1

[0699] To a 25 mL single-necked flask, compound 1-14 (150 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene)morpholine (72 mg), potassium carbonate (62 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (37 mg), 1,4-dioxane (10 mL), and purified water (3 mL) were added sequentially. After the addition, the mixture was heated to 105°C in an oil bath under nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography to obtain compound 25-1 (144 mg).

[0700] MS (ESI, [M+H] + )m / z:718.38.

[0701] Step B: Preparation of compound 25

[0702] Referring to the method of step H in Example 8, compound 25-1 was reacted with trifluoroacetic acid to give compound 25 (74 mg).

[0703] 1 H NMR(500MHz,DMSO-d6)δ7.81–7.74(m,1H),7.46(t,J=7.7Hz,1H),7.43–7.37(m,1H),7.37–7 .32(m,1H),7.10–7.02(m,1H),6.39(t,J=6.3Hz,1H),6.14(s,1H),4.35(d,J=6.3Hz,2H),3.9 3(s,3H),3.92–3.83(m,2H),3.60(t,J=4.5Hz,4H),3.31(s,3H),2.61–2.53(m,3H),2.41–2.3 4(m,1H),2.25–2.16(m,1H),2.08–2.04(m,2H),1.58(s,3H),1.56(s,3H),1.35–1.18(m,1H).

[0704] HRMS (ESI, [M+H] + )m / z:618.2193.

[0705] Example 26: Preparation of Compound 26

[0706]

[0707] Step A: Synthesis of Compound 26-2

[0708] Referring to the preparation method of compound 8-4 in step C of Example 8, compound 26-1 was used as the raw material to prepare compound 26-2. Step B: Synthesis of compound 26-3

[0709] To a 100 mL round-bottom flask, compound 26-2 (7 g), tetrahydrofuran (25 mL), methanol (25 mL), water (5 mL), and sodium hydroxide (3.5 g) were added sequentially. The atmosphere was replaced with nitrogen and the temperature was raised to 50°C for 2 hours. After completion, the pH was adjusted to 7 with 1 M hydrochloric acid solution, extracted three times with ethyl acetate, and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to yield the desired product 26-3 (6.7 g).

[0710] MS (ESI, [MH] - )m / z:304.23

[0711] Step C: Synthesis of Compound 26-4

[0712] To a 100 mL round-bottom flask, compound 26-3 (6.7 g), methylamine hydrochloride (1.6 g), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12.5 g), N,N-dimethylformamide (100 mL), and N,N-diisopropylethylamine (15 mL) were added sequentially. The atmosphere was replaced with nitrogen and the reaction was stirred at room temperature for 2 h. After completion, water was added and the mixture was extracted three times with ethyl acetate and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate and filtration, the mixture was concentrated and purified by silica gel column chromatography to obtain the desired product 26-4 (7 g).

[0713] Step D: Synthesis of Compound 26-5

[0714] Referring to the preparation method of compound 8-5 in step D of Example 8, compound 26-5 was prepared using compounds 1-11 and 26-4 as raw materials.

[0715] Step E: Synthesis of Compound 26-6

[0716] Referring to the preparation method of compound 8-6 in step E of Example 8, compound 26-5 was used as the raw material to prepare compound 26-6. Step F: Synthesis of compound 26-7

[0717] Referring to the preparation method of compound 8-7 in step F of Example 8, compound 26-7 was prepared using compound 26-6 as the raw material. Step G: Synthesis of compound 26-8

[0718] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 26-7 was used as the raw material to prepare compound 26-8. Step H: Synthesis of compound 26-9

[0719] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 26-9 was prepared using compound 26-8 as a raw material.

[0720] Step I: Synthesis of Compound 26

[0721] Referring to the preparation method of compound 8 in step I of Example 8, compound 26 was prepared using compound 26-9 as raw material.

[0722] 1H NMR(500MHz, DMSO-d6)δ8.10(q,J=4.5Hz,1H),7.42(dd,J=8.3,1.9Hz,1H),7.35(d,J=1.9Hz,1H),7.31–7.20(m, 2H),6.74(d,J=8.3Hz,1H),6.41(d,J=7.5Hz,1H),6.00(t,J=6.3Hz,1H),4.33(d,J=6.3Hz,2H),3.84(s,3H),3.8 1(d,J=10.9Hz,2H),3.77(s,2H),3.71(s,2H),3.56(t,J=4.6Hz,4H),2.75(d,J=4.4Hz,3H),2.45(t,J=4.5Hz,4H ),2.20–2.11(m,1H),1.95(d,J=12.9Hz,2H),1.76–1.68(m,2H),1.49(td,J=12.9,3.4Hz,2H),1.33–1.25(m,2H).

[0723] HRMS (ESI, [M+H] + )m / z:641.2777.

[0724] Example 27: Preparation of Compound 27

[0725]

[0726] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 27-1 was prepared using compound 8-7 as the raw material.

[0727] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 27 was prepared using compound 27-1 as the starting material.

[0728] 1H NMR(500MHz,DMSO-d6)δ7.29–7.19(m,3H),7.14(dd,J=11.9,1.7Hz,1H),6.84(dd,J=8.1,2.9Hz, 1H),6.66–6.59(m,1H),6.04(t,J=6.4Hz,1H),4.33(d,J=6.3Hz,2H),3.85(s,3H),3.79(qd,J=11. 2,6.9Hz,2H),3.61(dd,J=8.7,7.0Hz,1H),3.58–3.50(m,2H),3.36(d,J=8.0Hz,1H),2.86–2.77( m,1H),2.21(s,6H),2.14(ddt,J=9.5,6.3,3.1Hz,1H),1.86–1.77(m,1H),1.58(d,J=13.2Hz,6H).

[0729] HRMS (ESI, [M+H] + )m / z:564.2079.

[0730] Example 28: Preparation of Compound 28

[0731]

[0732] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 28-1 was prepared using compound 8-7 and tert-butyl ((trans)-4-fluoropyrrolidin-3-yl)carbamate as starting materials.

[0733] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 28-2 was prepared using compound 28-1 as a raw material.

[0734] Referring to the preparation method of compound 8 in step I of Example 8, compound 28 was prepared using compound 28-2 as the starting material.

[0735] 1H NMR(500MHz,DMSO-d6)δ7.31–7.25(m,2H),7.22(ddd,J=11.7,7.9,1.5Hz,1H),7.14( dd,J=11.8,1.6Hz,1H),6.84(dd,J=8.1,3.0Hz,1H),6.63(dd,J=6.9,2.0Hz,1H),6.0 4(t,J=6.4Hz,1H),5.00(dd,J=51.3,3.7Hz,1H),4.34(d,J=6.4Hz,2H),3.85(s,3H), 3.83–3.57(m,5H),3.25–3.11(m,6H),1.95(p,J=7.0Hz,2H),1.58(d,J=13.1Hz,6H).

[0736] HRMS (ESI, [M+H] + )m / z:594.1950.

[0737] Example 29: Preparation of Compound 29

[0738]

[0739] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 29-1 was prepared using compound 26-7 as the raw material.

[0740] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 29-2 was prepared using compound 29-1 as a raw material.

[0741] Referring to the preparation method of compound 8 in step I of Example 8, compound 29 was prepared using compound 29-2 as the starting material.

[0742] 1H NMR (500MHz, DMSO-d6) δ8.10(q,J=4.5Hz,1H),7.42(dd,J=8.2,1.8Hz,1H),7.35(d,J=1.8Hz,1H),7.25(t,J=7.8H z,1H),7.19(d,J=7.9Hz,1H),6.74(d,J=8.2Hz,1H),6.55(d,J=7.7Hz,1H),6.00(t,J=6.3Hz,1H),4.58(s,4H),4.3 3(d,J=6.4Hz,2H),3.84(s,3H),3.83–3.75(m,2H),3.58–3.48(m,2H),3.44(td,J=8.2,3.7Hz,2H),3.27(s,2H),3 .18(d,J=9.3Hz,1H),2.96(s,1H),2.75(d,J=4.4Hz,3H),2.49–2.46(m,1H),1.93–1.85(m,1H),1.76–1.68(m,1H).

[0743] HRMS (ESI, [M+H] + )m / z:599.2288.

[0744] Example 30: Preparation of Compound 30

[0745]

[0746] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 30-1 was prepared using compound 8-7 as the raw material.

[0747] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 30-2 was prepared using compound 30-1 as a raw material.

[0748] Referring to the preparation method of compound 8 in step I of Example 8, compound 30 was prepared using compound 30-2 as the raw material.

[0749] 1H NMR(500MHz,DMSO-d6)δ7.30–7.19(m,2H),7.18–7.11(m,2H),6.83(dd,J=8.0,3.0Hz,1H), 6.48(d,J=7.8Hz,1H),6.02(t,J=6.4Hz,1H),4.56(s,4H),4.33(d,J=6.4Hz,2H),3.85(s,3H ),3.83–3.69(m,4H),3.38–3.32(m,5H),3.03(d,J=8.1Hz,1H),2.38(d,J=4.6Hz,1H),1.58( d,J=13.1Hz,6H),0.91(dt,J=7.9,5.4Hz,1H),0.66(q,J=6.4Hz,1H),0.45(t,J=7.8Hz,2H).

[0750] HRMS (ESI, [M+H] + )m / z:644.2354.

[0751] Example 31: Preparation of Compound 31

[0752]

[0753] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 31-1 was prepared using compound 8-7 as the raw material.

[0754] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 31-2 was prepared using compound 31-1 as a raw material.

[0755] Referring to the preparation method of compound 8 in step I of Example 8, compound 31 was prepared using compound 31-2 as the raw material.

[0756] 1H NMR (500MHz, DMSO-d6) δ7.54(d,J=8.0Hz,1H),7.40(t,J=7.8Hz,1H),7.22(ddd,J=11.7,8.0,1.6Hz,1H),7. 15(dd,J=11.9,1.6Hz,1H),7.06(d,J=7.6Hz,1H),6.85(dd,J=8.0,3.0Hz,1H),6.03(t,J=6.4Hz,1H),4.58( q,J=6.6Hz,4H),4.35(d,J=6.4Hz,2H),3.90–3.75(m,5H),3.39–3.33(m,2H),3.28(d,J=4.0Hz,4H),2.72–2 .59(m,1H),2.27(q,J=7.9Hz,2H),1.86–1.72(m,2H),1.58(d,J=13.2Hz,7H),1.00(dd,J=12.8,9.1Hz,1H).

[0757] HRMS (ESI, [M+H] + )m / z:632.2333.

[0758] Example 32: Preparation of Compound 32

[0759]

[0760] Referring to the preparation method of compound 8-9 in step G of Example 8, compound 32-1 was prepared using compound 26-7 as a raw material.

[0761] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 32-2 was prepared using compound 32-1 as a raw material.

[0762] Referring to the preparation method of compound 8 in step I of Example 8, compound 32 was prepared using compound 32-2 as the raw material.

[0763] 1H NMR(500MHz,DMSO-d6)δ8.08(t,J=4.6Hz,1H),7.76(d,J=8.1Hz,1H),7.47–7.39(m,2H),7 .37–7.30(m,2H),6.74(d,J=8.3Hz,1H),6.07(s,1H),5.98(t,J=6.3Hz,1H),4.61(s,4H),4 .33(d,J=6.3Hz,2H),3.92–3.81(m,5H),3.32(s,1H),2.75(d,J=4.5Hz,3H),2.52(d,J=1. 8Hz,2H),2.42–2.33(m,2H),2.28(d,J=18.2Hz,2H),1.87–1.74(m,2H),1.38–1.21(m,2H).

[0764] HRMS (ESI, [M+H] + )m / z:610.2332.

[0765] Example 33: Preparation of Compound 33

[0766]

[0767] Step A: Synthesis of Compound 33-2

[0768] To a 100 mL round-bottom flask, compound 33-1 (500 mg), paraformaldehyde (413 mg), sodium cyanoborohydride (864 mg), methanol (15 mL), and acetic acid (1.3 mL) were added sequentially. The atmosphere was replaced with nitrogen and the temperature was raised to 50°C for 5 h. After completion, the mixture was extracted three times with ethyl acetate and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was filtered, concentrated, and purified by silica gel column chromatography to afford compound 33-2 (200 mg).

[0769] Step B: Synthesis of Compound 33-3

[0770] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 33-2 was used as the raw material to prepare compound 33-3. Step C: Synthesis of compound 33-4

[0771] Referring to the preparation method of compound 9-2 in step A of Example 9, compound 33-4 was prepared using compounds 8-7 and 33-3 as raw materials.

[0772] Step D: Synthesis of Compound 33

[0773] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 33 was prepared using compound 33-4 as the raw material.

[0774] 1 H NMR (500MHz, DMSO-d6) δ7.57(d,J=8.1Hz,1H),7.42(t,J=7.9Hz,1H),7.22(ddd,J=11.6,8.0,1.5Hz,1H) ,7.18–7.11(m,2H),6.84(dd,J=8.0,3.0Hz,1H),6.03(t,J=6.4Hz,1H),5.17(d,J=50.4Hz,1H),4.34(d, J=6.4Hz,2H),3.85(s,5H),3.49–3.43(m,1H),3.21(dd,J=12.1,4.5Hz,1H),3.01–2.88(m,2H),2.60–2. 52(m,1H),2.31(s,6H),2.10–2.01(m,1H),1.91(dtd,J=44.3,13.7,5.1Hz,1H),1.58(d,J=13.1Hz,6H).

[0775] HRMS (ESI, [M+H] + )m / z:596.2131.

[0776] Example 34: Preparation of Compound 34

[0777]

[0778] Referring to the preparation method of compound 8 in step I of Example 8, compound 34 was prepared using compound 8-10 as the starting material.

[0779] 1H NMR (500MHz, DMSO-d6) δ7.77(d,J=8.1Hz,1H),7.45(t,J=7.8Hz,1H),7.33(dd,J=7.4,1.0Hz,1H),7.22(ddd,J=11.7,7.9, 1.6Hz,1H),7.14(dd,J=11.9,1.6Hz,1H),6.83(dd,J=8.0,3.0Hz,1H),6.06(dt,J=12.7,4.0Hz,2H),5.26(d,J=6.6Hz,1H), 4.34(d,J=6.4Hz,2H),4.17(q,J=6.3Hz,1H),3.85(s,5H),3.53(dtd,J=19.4,6.3,2.4Hz,2H),2.72(q,J=6.0Hz,2H),2.43 –2.34(m,2H),2.31(dt,J=12.5,4.3Hz,2H),1.91–1.77(m,2H),1.58(d,J=13.2Hz,6H),1.37(dtd,J=12.5,9.2,5.7Hz,1H).

[0780] HRMS (ESI, [M+H] + )m / z:603.2053.

[0781] Example 35: Preparation of Compound 35

[0782]

[0783] Referring to the preparation method of compound 33-2 in step A of Example 33, compound 35 was prepared using compound 8-10 as the raw material.

[0784] 1H NMR (500MHz, DMSO-d6) δ7.77(d,J=8.1Hz,1H),7.45(t,J=7.7Hz,1H),7.34(d,J=7.4Hz,1H),7.22(ddd,J=11.6,8 .0,1.6Hz,1H),7.14(dd,J=11.9,1.5Hz,1H),6.83(dd,J=8.0,3.0Hz,1H),6.13(dd,J=5.2,2.6Hz,1H),6.05(t,J =6.3Hz,1H),4.34(d,J=6.3Hz,2H),3.85(s,5H),3.33(s,1H),2.49–2.43(m,2H),2.35(d,J=16.8Hz,1H),2.23(s ,6H),2.17(dd,J=12.7,4.4Hz,1H),2.02(d,J=11.7Hz,1H),1.58(d,J=13.2Hz,6H),1.51(dt,J=11.2,5.2Hz,1H).

[0785] HRMS (ESI, [M+H] + )m / z:575.2095.

[0786] Example 36: Preparation of Compound 36

[0787]

[0788] Referring to the preparation method of compound 8-9 in step G of Example 8, compound 36-2 was prepared using compound 36-1 as a raw material.

[0789] Referring to the preparation method of compound 8-10 in step H of Example 8, compound 36-3 was prepared using compound 36-2 as the raw material.

[0790] Referring to the preparation method of compound 8 in step I of Example 8, compound 36 was prepared using compound 36-3 as the raw material.

[0791] 1H NMR(500MHz,DMSO-d6)δ8.47–8.36(m,1H),8.08(d,J=5.0Hz,1H),7.40(dd,J=8.2,1.9 Hz,1H),7.34(d,J=1.8Hz,1H),6.92(d,J=5.6Hz,2H),6.75(d,J=7.1Hz,2H),6.06–5.87 (m,2H),4.61(s,4H),4.27(d,J=6.1Hz,2H),3.84(s,3H),2.75(d,J=4.4Hz,3H),2.33( d,J=24.8Hz,4H),1.80(dd,J=34.3,14.2Hz,2H),1.39–1.21(m,4H),0.93–0.67(m,1H).

[0792] HRMS (ESI, [M+H] + )m / z:611.2289.

[0793] Example 37: Preparation of Compound 37

[0794]

[0795] Step A: Synthesis of Compound 37-1

[0796] Compound 8-7 (100 mg), 3-(dimethylamino)azetidine dihydrochloride (38.3 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.8 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (24.7 mg), cesium carbonate (240 mg), and 1,4-dioxane (15 mL) were added sequentially to a 20 mL microwave reaction tube and microwave-dried at 100°C for 1.5 h under nitrogen protection. After completion of the reaction, the reaction solution was dried and purified by column chromatography to obtain compound 37-1 (70 mg).

[0797] MS (ESI, [M+H] + )m / z:650.57

[0798] Step B: Synthesis of Compound 37

[0799] Compound 37-1 (70 mg) and dichloromethane (5 mL) were added sequentially to a 50 mL single-necked bottle, followed by the dropwise addition of trifluoromethanesulfonic acid (1.5 mL). After the reaction was complete, dichloromethane (20 mL) was added to dilute the reaction solution, which was then dried at room temperature and purified by reverse-phase column chromatography to obtain product 37 (42 mg).

[0800] 1H NMR (500MHz, DMSO-d6) δ7.36-7.28(m,2H),7.26-7.18(m,1H),7.14(d,J=11.7Hz,1H),6.83(d,J=5.5Hz,1H),6.50(d,J=6.5Hz,1H),6.0 3(t,J=6.0Hz,1H),4.34(d,J=6.1Hz,2H),4.18(s,2H),3.91–3.76(m,7H),3.28–3.25(m,1H),2.46–2.21(m,6H),1.58(d,J=13.2Hz,6H).

[0801] HRMS (ESI, [M+H] + )m / z:550.1899

[0802] Example 38: Preparation of Compound 38

[0803]

[0804] Step A: Synthesis of Compound 38-1

[0805] Referring to the synthesis method of compound 9-2 in step A of Example 9, compound 38-1 was prepared using compound 8-7 and 1-(3-acridinyl)pyrrolidine dihydrochloride as raw materials.

[0806] MS (ESI, [M+H] + )m / z:676.61

[0807] Step B: Synthesis of Compound 38

[0808] Referring to the synthesis method of compound 9-3 in step B of Example 9, compound 38 (28 mg) was prepared using compound 38-1 as the starting material.

[0809] 1 H NMR (500MHz, DMSO-d6) δ7.32–7.18(m,3H),7.14(d,J=11.8Hz,1H),6.83(dd,J=8.0,2.9Hz,1H),6.46(d,J=7.2Hz,1H),6.03(t,J=6.3Hz,1 H),4.34(d,J=6.3Hz,2H),4.13(t,J=7.0Hz,2H),3.88–3.76(m,7H),3.43(s,1H),2.49–2.45(m,4H),1.71(s,4H),1.57(d,J=13.2Hz,6H).

[0810] HRMS (ESI, [M+H] +)m / z:576.2051.

[0811] Example 39: Preparation of Compound 39

[0812]

[0813] Step A: Synthesis of Compound 39-1

[0814] Referring to the synthesis method of compound 9-2 in step A of Example 9, compound 39-1 was prepared using compound 8-7 and 3-(Boc-amino)pyrrolidine as raw materials.

[0815] MS (ESI, [M+H] + )m / z:736.64

[0816] Step B: Synthesis of Compound 39-2

[0817] Referring to the synthesis method of compound 9-3 in step B of Example 9, compound 39-2 was prepared using compound 39-1 as the raw material.

[0818] MS (ESI, [M+H] + )m / z:536.26.

[0819] Step C: Synthesis of Compound 39

[0820] To a 10 mL microwave tube, add starting material 39-2 (68 mg), 1,3-dibromo-2-propanol (83 mg), sodium carbonate (108 mg), and acetonitrile (3 mL) in sequence. Under nitrogen protection, microwave the reaction at 110°C for 5 h. After completion of the reaction, column chromatography and preparative purification were performed to obtain the product, compound 39 (6 mg).

[0821] 1H NMR (500MHz, DMSO-d6) δ7.27–7.18(m,3H),7.14(d,J=11.8Hz,1H),6.83(dd,J=8.0,2.8Hz,1H),6.55(d ,J=7.3Hz,1H),6.04(t,J=6.3Hz,1H),5.34–5.25(m,1H),4.33(d,J=6.3Hz,2H),4.13(s,1H),3.85(s,3 H),3.84–3.73(m,2H),3.60–3.55(m,1H),3.54–3.50(m,1H),3.48–3.45(m,1H),3.03–2.98(m,1H),2.7 6–2.70(m,2H),2.01(s,1H),1.92(s,1H),1.79–1.72(m,1H),1.58(d,J=13.2Hz,6H),1.40–1.33(m,2H).

[0822] HRMS (ESI, [M+H] + )m / z::592.2005

[0823] Example 40: Preparation of Compound 40

[0824]

[0825] Step A: Synthesis of Compound 40-2

[0826] Compound 40-1 (4.8 g), acetonitrile (50 mL), iodosuccinimide (5.22 g), and trifluoroacetic acid (1.017 g) were added sequentially to a 100 mL single-necked flask. The mixture was allowed to react at room temperature for 2 h. After completion, the reaction was quenched by the addition of 15% (w / w) aqueous sodium thiosulfate solution. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and purified by column chromatography to afford compound 40-2 (6 g).

[0827] MS (ESI, [M+H] + )m / z:395.1.

[0828] Step B: Synthesis of Compound 40-3

[0829] Compound 40-2 (3.6 g), 1,10-phenanthroline (0.164 g), trifluoromethylthione (1.962 g), and N,N-dimethylformamide (20 mL) were added sequentially to a 100 mL microwave tube. Nitrogen was purged for 1 minute. The mixture was allowed to react at 60°C for 7 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and purified by column chromatography to yield compound 40-3 (2.2 g).

[0830] MS (ESI, [M+H]+ )m / z:369.1.

[0831] Step C: Synthesis of Compound 40-4

[0832] Compound 40-3 (2.2 g), tetrahydrofuran (15 mL), water (15.00 mL), and lithium hydroxide (0.367 g) were added sequentially to a 100 mL single-necked flask. The mixture was allowed to react at room temperature for 2 h until the reaction was complete. The pH was adjusted to 7 with 2 M dilute hydrochloric acid to precipitate a white solid, which was filtered and dried to obtain compound 40-4 (1.6 g).

[0833] MS (ESI, [MH] - )m / z:339.1.

[0834] Step D: Synthesis of Compound 40-5

[0835] Compound 40-4 (1.5 g), iodine (4.46 g), potassium phosphate (1.120 g), and dimethyl sulfoxide (20 mL) were added sequentially to a 50 mL single-necked flask. Nitrogen was purged three times after addition, and the temperature was raised to 120°C. The reaction was allowed to react for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature, extracted with ethyl acetate, and purified by column chromatography to afford compound 40-5 (1.1 g).

[0836] MS (ESI, [MH] - )m / z:423.0.

[0837] Step E: Synthesis of Compound 40-6

[0838] Referring to the synthesis method of compound 8-5 in step D of Example 8, compound 40-6 was prepared using compounds 40-5 and 8-4 as raw materials.

[0839] MS (ESI, [M+H] + )m / z:632.34.

[0840] Step F: Synthesis of Compound 40-8

[0841] To a 20 mL microwave tube were added compound 40-6 (250 mg), compound 8-8 (255 mg), potassium carbonate (169 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (38 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl tris(trichloro-palladium) (68 mg), water (1.7 mg), and 1,4-dioxane (10 mL). The mixture was microwaved at 100°C under nitrogen for 2 h. After completion of the reaction, the product 40-8 (100 mg) was purified by column chromatography.

[0842] MS (ESI, [M+H] +)m / z:749.64.

[0843] Step G: Synthesis of Compound 40-9

[0844] Referring to the synthesis method of compound 8-10 in step H of Example 8, compound 40-9 was prepared using compound 40-8 as a raw material.

[0845] MS (ESI, [M+H] + )m / z:549.30.

[0846] Step H: Synthesis of Compound 40

[0847] Referring to the synthesis method of compound 8 in step I of Example 8, compound 40 was prepared using compound 40-9 as raw material.

[0848] 1 H NMR(500MHz,DMSO-d6)δ8.48(d,J=6.7Hz,1H),7.43(d,J=7.1Hz,1H),7.24–7.10(m,3H),6.91(s, 1H),6.85(dd,J=8.1,2.9Hz,1H),6.04(t,J=6.4Hz,1H),5.25(d,J=6.6Hz,1H),4.33(d,J=6.2Hz, 2H),4.20–4.11(m,1H),3.86(s,3H),3.56–3.46(m,2H),2.73–2.68(m,2H),2.38–2.34(m,1H),2. 34–2.24(m,2H),1.95–1.87(m,2H),1.83–1.75(m,1H),1.57(d,J=13.2Hz,6H),1.41–1.32(m,1H).

[0849] HRMS (ESI) ([M+H] + )m / z:605.2013.

[0850] Example 41: Preparation of Compound 41

[0851]

[0852] Step A: Synthesis of Compound 41-3

[0853] Compound 1-14 (100 mg), intermediate 41-2 (48.7 mg), potassium carbonate (40.7 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (6.88 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl tris(trichlorotriphenylphosphino) (6.17 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a 20 mL microwave tube. After addition, nitrogen was purged, the tube was sealed, and the temperature was raised to 130°C for 2 h. After completion of the reaction, compound 41-3 (65 mg) was obtained by column chromatography.

[0854] MS (ESI, [M+H] + )m / z:665.54

[0855] Step B: Synthesis of Compound 41

[0856] Compound 41-3 (55 mg), dichloromethane (3 mL) and trifluoroacetic acid (0.6 mL) were added to a 50 mL single-necked bottle in sequence and reacted at room temperature for 1 h. After the reaction was complete, the mixture was dried by rotary evaporation and purified by reverse phase column chromatography to obtain compound 41 (16 mg).

[0857] 1 H NMR(500MHz,DMSO-d6)δ7.79-7.78(m,1H),7.42-7.38(m,2H),7.33-7.32(m,1H),7.08-7.06(m,1H),6.38-6.36(m,1H),4.36-4 .34(m,3H),3.96-3.93(m,2H),3.89-3.83(m,2H),3.73-3.72(m,2H),2.50-2.46(m,3H),32.46-2.31(m,8H),1.58-1.55(m,6H).

[0858] HRMS (ESI) ([M+H] + )m / z:565.1936.

[0859] Example 42: Preparation of Compound 42

[0860]

[0861] Step A: Synthesis of Compound 42-2

[0862] Compound 8-7 (150 mg), cesium carbonate (216 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (20.66 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl tris(trichloro-palladium) (37.1 mg), 1,4-dioxane (16 mL), and (R)-pyrrol-3-ol (25.08 mg) were added sequentially to a 20 mL microwave tube. After addition, nitrogen was purged, the tube was sealed, and the microwave temperature was set to 100°C for 1.5 h. Upon completion of the reaction, compound 42-2 (60 mg) was obtained by column chromatography.

[0863] MS (ESI, [M+H] + )m / z:637.4

[0864] Step B: Synthesis of Compound 42

[0865] Compound 42-2 (60 mg), dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) were added sequentially to a 50 mL single-necked flask. The mixture was allowed to react at room temperature for 1 h until the reaction was complete. The solvent was removed by vortexing, the mixture was redissolved in acetonitrile, and the mixture was purified by reverse phase purification to obtain compound 42 (25 mg).

[0866] 1 H NMR(500MHz,DMSO-d6)δ7.25-7.12(m,4H),6.84-6.82(m,1H),6.57-6.56(m ,1H),6.05-6.02(m,1H),5.00-4.99(m,1H),4.39(s,1H),4.33(d,J=6.0Hz, 2H),3.85(s,3H),3.83-3.70(m,3H),3.62-3.59(m,1H),3.50-3.48(m,1H), 3.36-3.35(m,1H),2.05-2.02(m,1H),1.90-1.88(m,1H),1.59-1.54(m,6H).

[0867] HRMS (ESI) ([M+H] + )m / z:537.1510.

[0868] Example 43: Preparation of Compound 43

[0869]

[0870] Step A: Synthesis of Compound 43-2

[0871] Compound 43-1 (25 g), ethyl acrylate (88 mL), and 1,4-diazabicyclo[2.2.2]octane (9.61 mL) were added sequentially to a 100 mL microwave tube. The mixture was allowed to react overnight at room temperature. After completion, the solvent was removed by vortexing, the mixture was diluted with water, extracted with ethyl acetate, and purified by column chromatography to afford compound 43-2 (38 g).

[0872] MS (ESI, [M+H] + )m / z:286.0

[0873] Step B: Synthesis of Compound 43-3

[0874] Compound 43-2 (38.5 g) and acetic anhydride (300 mL) were added sequentially to a 500 mL single-necked flask. After addition, the nitrogen atmosphere was replaced three times. The temperature was raised to 120°C and the reaction was continued for 18 hours. After the reaction was complete, the acetic anhydride was removed by vortexing and the mixture was purified by column chromatography to obtain compound 43-3 (35 g).

[0875] MS (ESI, [M+H] + )m / z:268.2

[0876] Step C: Synthesis of Compound 43-5

[0877] To a 20 mL microwave tube, 43-3 (10 g), compound 43-4 (9.76 g), dichloroethane (65 mL), and trimethylsilyl chloride (6.81 g) were added sequentially. After nitrogen purge, the temperature was set to 100°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, compound 43-5 (10.3 g) was obtained by column chromatography.

[0878] MS (ESI, [M+H] + )m / z:368.1

[0879] Step D: Synthesis of Compound 43-6

[0880] To a 250 mL single-necked flask, add 43-5 (10 g), ethanol (50 mL), tetrahydrofuran (50.0 mL), water (25.00 mL), and potassium hydroxide (4.57 g) in sequence. After addition, heat to 80°C and react for 2 h. Cool to room temperature, remove the organic solvent, dilute with water, and neutralize with dilute hydrochloric acid until neutral, resulting in the precipitation of a solid. Collect the solid by filtration and dry to afford compound 43-6 (9.2 g).

[0881] MS (ESI, [MH] - )m / z:338.1

[0882] Step E: Synthesis of Compound 43-7

[0883] Compound 43-6 (9.8 g), dichloromethane (100 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (16.43 g), N,O-dimethylhydroxylamine hydrochloride (8.43 g), and N,N-diisopropylethylamine (18.62 g) were added sequentially to a 250 mL single-necked flask. The mixture was allowed to react overnight. After completion of the reaction, column chromatography afforded compound 43-7 (11 g).

[0884] MS (ESI, [M+H] + )m / z:383.1

[0885] Step F: Synthesis of Compound 43-8

[0886] Compound 43-7 (11 g) was dissolved in tetrahydrofuran (110 mL) in a 100 mL three-necked flask, the atmosphere was purged with nitrogen three times, and the temperature was lowered to 0°C. 1 M diisobutylaluminum hydride (34.4 mL) was added dropwise, and the reaction was continued for 1 h. After completion, the reaction was quenched by dropwise addition of water, followed by the addition of 15% (w / w) potassium sodium tartrate solution and stirred for 2 h. The reaction solution became clear, extracted with ethyl acetate, and purified by column chromatography to afford compound 43-8 (8.5 g).

[0887] Step G: Synthesis of compound 43-9

[0888] Compound 43-8 (7.5 g), methanol (10 mL), potassium carbonate (9.59 g), and dimethyl (1-diazo-2-oxopropyl)phosphonate (5.21 mL) were added sequentially to a 250 mL single-necked flask. Nitrogen was purged three times and the mixture was allowed to react at room temperature for 3 h. Upon completion of the reaction, the mixture was directly purified by silica gel column chromatography to yield compound 43-9 (7.2 g).

[0889] Step H: Synthesis of Compound 43-10

[0890] To a 250 mL single-necked flask, zinc trifluoromethanesulfonate (13.74 g), toluene (100 mL), N,N,N',N'-tetramethylethylenediamine (5.70 mL), and triethylamine (5.27 mL) were added sequentially. The nitrogen was purged three times and the mixture was allowed to react at room temperature for 2 h. Compound 43-9 (5.5 g) was dissolved in toluene, added to the reaction mixture, and the temperature was raised to 60°C for 1 h. After cooling to room temperature, paraformaldehyde (3.10 g) was added and the reaction was continued at 60°C for 8 h. After the reaction was complete, the silica gel was directly spin-dried and column chromatography was performed to obtain the desired product 43-10 (5 g).

[0891] MS (ESI, [M+H] + )m / z:350.0

[0892] Step I: Synthesis of Compound 43-11

[0893] To a 100 mL single-necked flask, compound 43-10 (3 g), acetonitrile (50 mL), and 2-iodoacylbenzoic acid (6.00 g) were added sequentially. The nitrogen was purged three times, and the temperature was raised to 60°C for 2 h. After the reaction was complete, the mixture was filtered, the filtrate was dried, and column chromatography was performed to obtain the desired product 43-11 (2.8 g).

[0894] Step J: Synthesis of Compound 43-13

[0895] Compound 43-11 (1.5 g), compound 8-2 (1.20 g), dichloromethane (30 mL), acetic acid (2.46 mL), and sodium triacetoxyborohydride (1.37 g) were added sequentially to a 25 mL single-necked flask. The mixture was allowed to react at room temperature for 1 h. Upon completion of the reaction, the mixture was directly subjected to silica gel column chromatography to obtain the desired product 43-13 (2 g).

[0896] MS (ESI, [M+H] + )m / z:531.2

[0897] Step K: Synthesis of Compound 43-15

[0898] Compound 43-13 (900 mg), compound 8-8 (821 mg), potassium carbonate (585 mg), tetrakistriphenylphosphine palladium (391 mg), water (1.875 mL), and dioxane (15 mL) were added sequentially to a 20 mL microwave tube. After nitrogen was purged, the tube was sealed and microwaved at 100°C for 2 h. The reaction was monitored for success and column chromatography yielded compound 43-15 (880 mg).

[0899] MS (ESI, [M+H] + )m / z:648.4

[0900] Step L: Synthesis of Compound 43-16

[0901] Compound 43-15 (900 mg), dichloromethane (8 mL), and trifluoroacetic acid (1 mL) were added sequentially to a 50 mL single-necked flask. The mixture was allowed to react at room temperature for 1.5 hours. After the reaction was complete, the mixture was dried by rotary evaporation at room temperature and purified by reverse-phase column chromatography to yield the desired product 43-16 (560 mg).

[0902] MS (ESI, [M+H] + )m / z:548.3

[0903] Step M: Synthesis of Compound 43

[0904] Compound 43-16 (150 mg), acetonitrile (16 mL), compound 8-11 (134 mg), and sodium carbonate (232 mg) were added sequentially to a 20 mL microwave tube. The temperature was raised to 110°C and the reaction was continued for 14 h. After the reaction was complete, the mixture was purified by column chromatography and lyophilized to obtain compound 43 (58 mg).

[0905] 1 H NMR(500MHz,DMSO-d6)δ8.41-8.40(m,1H),7.21-7.17(m,1H),7.13-7.11( m,1H),6.93-6.89(m,2H),6.85-6.83(m,1H),6.76(s,1H),5.99-5.95(m,2H ),4.62-4.60(m,4H),4.28-4.27(m,2H),3.84(s,3H),3.32-3.30(m,3H),2 .34-2.26(m,4H),1.84-1.74(m,2H),1.57-1.55(m,6H),1.35-1.22(m,2H).

[0906] HRMS (ESI, [M+H] + )m / z:630.2201.

[0907] Test Example 1 In vitro cell proliferation inhibitory activity assay

[0908] 1.1 Antiproliferative activity of compounds on NUGC-3 cells

[0909] 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 GraphPadPrism software, and the dose-effect curve was fitted to calculate the IC 50 value.

[0910] 1.2 Antiproliferation activity of compounds on Huh-7 cells

[0911] 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. 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 GraphPadPrism software, and the dose-effect curve was fitted to calculate the IC 50 value.

[0912] The compounds of the present application showed good inhibitory activity against NUGC-3 cells and Huh-7 cells. The experimental results of some compounds are shown in Table 1.

[0913] Table 1 In vitro cell proliferation inhibitory activity of compounds

[0914]

[0915]

[0916] Experimental Example 2 In vitro DNA binding activity experiment

[0917] 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 comprising the p53 DNA binding domain (amino acids 94-312, SSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPCEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNT) (SEQ ID No. 2) 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.

[0918] 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.

[0919] The HTRF ratio (Ratio, R) signal is calculated using the following formula:

[0920] R=F 665 / F 620 *10 4 ;

[0921] 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.

[0922] Test Example 3P53 Y220C protein thermodynamic stability test

[0923] 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 Thermocycler (heating rate 0.03°C / s, excitation / emission filters = 465 / 580 nm). Tm measurements were performed using 50 ng / μL p53Y220C protein and 4x SYPRO Orange in PBS buffer in a 20 μL reaction volume. Each sample was analyzed in triplicate.

[0924] The ΔTm value was calculated as ΔTm=Tm(protein+compound)-Tm(protein). The experimental results of some compounds are shown in Table 2.

[0925] Table 2 Thermodynamic stability of compound P53 Y220C protein

[0926]

[0927]

[0928] Test Example 4 In vitro liver microsome stability test

[0929] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis.

[0930] The results showed that the residual amount of the compound of the present application after 60 minutes was higher than 50% in the stability tests in mouse and human liver microsomes, respectively.

[0931] Experimental Example 5: Pharmacokinetic Study in Mice

[0932] ICR mice weighing 20-25g were randomly divided into groups of 9 after acclimation for 3-5 days and orally administered with a 10 mg / kg dose of the test compound solution. Blood was collected from the eye sockets at 0 min, 5 min, 0.25 min, 0.5 h, 2 h, 6 h, 10 h, and 24 h for plasma preparation.

[0933] 20 μL of the plasma sample to be tested and the standard sample were aspirated and added to an acetonitrile solution containing the internal standard for protein precipitation. The resulting supernatant was diluted and used for LC / MS / MS analysis. The experimental results are shown in Table 3.

[0934] Table 3

[0935]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X is selected from S, CH, N, NR a , or O; Y is selected from CR b or N; R a is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl; R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R b1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl; X 1 Selected from CR 1 or N; X 2 Selected from CR 2 or N; X 3 Selected from CR 3 or N; X 4 Selected from CR 4 or N; X 5 Selected from C or N; X 6 Selected from C or N; R 1 、R 2 、R 3 and R 4 one selected from optionally one or more R c Substituted -(CH2) n -C 3-12 Cycloalkyl, -(CH2) n -C 3-12 Cycloalkenyl, or -(CH2) n -3-12 membered heterocyclic group, the rest of which is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally substituted by one or more R z Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, or -P(O)(C 1-12 Alkyl)2; R c is selected from hydroxy, amino, cyano, halogen, oxo, carboxyl, and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 2-12 Alkenyl, -C 2-12 Alkynyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -C(O)C 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -P(O)(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl; R 5 and R 6 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl, and optionally one or more R d Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, or -N(C 1-12 Alkyl)2, -C(O)C 1-12 Alkyl, -NHC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group; Or, R 5 and R 6 and together with the carbon atoms to which they are attached form =0, and optionally one or more R d Substituted C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group; R 7 is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R e Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, or C 3-12 Cycloalkyl; R 8 Selected from optionally one or more R f Substituted C 6-12 Aryl, or 5-12 membered heteroaryl; R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -C(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)NHC 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, -NHC(O)C 1-12 Alkyl, -NHC(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, -S(O)C 1-12 Alkyl, -S(O)2C 1-12 Alkyl, -S(O)2NH2, -S(O)2-C 3-12 Cycloalkyl, -S(O)2-3-12 membered heterocyclyl, -S(O)2-5-12 membered heteroaryl, -P(O)(C 1-12 Alkyl)2, -OC 3-12 Cycloalkyl, -O-3-12 membered heterocyclic group, -O-5-12 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl; Or, two adjacent R f and together with the carbon atoms to which they are attached, form a f1 substituted 4-8 membered heterocycle; R a1 、R b1 、R z 、R c1 、R d 、R e and R f1 are each independently selected from deuterium, hydroxyl, amino, cyano, halogen, oxo, carboxyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-8 Cycloalkyl, or 3-8 membered heterocyclic group; m is selected from 1, 2 or 3; n is selected from 0, 1, 2, 3 or 4.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein When X is selected from CH, N or NR a When X 5 and X 6 At least one is N, and R 1 、R 2 、R 3 and R 4 One of the following is selected from one or more R g Substituted -C 3-12 Cycloalkyl, -C 3-12 cycloalkenyl, or 3-12 membered heterocyclic group; and R g Selected from optionally substituted C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -NHC 1-6 Alkyl, or -N(C 1-6 Alkyl)2; Optionally, X is selected from S, CH, or N; or, X is selected from S or NR a ; Alternatively, X is selected from CH or N; Alternatively, X is S; Optionally, Y is selected from CR b ; or, Y is selected from CR b , and R b is selected from -CH2CF3; or, Y is selected from N; Optionally, R a Selected from hydrogen, hydroxy, cyano and optionally one or more R a1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy; or, R a Selected from optionally one or more R a1 Substituted -C 1-6 alkyl; Optionally, R b is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally one or more R b1 Substituted -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -SC 1-6 Alkyl; or, R b Selected from optionally one or more R b1 Substituted -C 1-6 Alkyl, or -SC 1-6 Alkyl; or, R b Selected from -CH2CF3, -SCHF2 or -SCF3; Optionally, R b1 is selected from halogen; or, R b1 is selected from fluorine, chlorine, or bromine; Optionally, X 1 Selected from CR 1 ; Optionally, X 2 Selected from CR 2 ; or, X 2 Selected from N; Optionally, X 3 Selected from CR 3 ; Optionally, X 4 Selected from CR 4 ; Optionally, X 5 and X 6 At least one is N; or, X 5 Selected from N, X 6 Selected from C.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 、R 2 、R 3 and R 4 one selected from optionally one or more R c Substituted -(CH2) n -C 5-10 Cycloalkyl, -(CH2) n -C 5-10 Cycloalkenyl, or -(CH2) n -5-10 membered heterocyclic group, the rest of which is selected from hydrogen, hydroxy, amino, cyano, halogen, carboxyl and optionally substituted by one or more R z Substituted -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -C(O)C 1-16 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, or -P(O)(C 1-6 Alkyl)2; Or, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from optionally one or more R c Substituted C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; Or, R 1 、R 2 、R 3 and R 4 One of, or R 1 and R 4 One of, or R 1 Selected from Optionally, R c is selected from hydroxy, amino, halogen, oxo, and optionally one or more R c1 Substituted -C 1-12 Alkyl, -C 1-12 Alkoxy, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, or 3-12 membered heterocyclic group; or, R c is selected from hydroxy, amino, halogen, oxo, and optionally one or more R c1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, or 3-8 membered heterocycloalkyl; or, R c Selected from hydroxy, amino, fluoro, oxo, methyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2, cyclopropyl, Optionally, R c1 is selected from halogen, amino or hydroxy; Optionally, R 1 、R 2 、R 3 and R 4 Three of them, or R 2 、R 3 and R 4 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R z Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -NHC(O)C 1-6 alkyl; Or, R 2 、R 3 and R 4 All are hydrogen.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 5 and R 6 are independently selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R d Substituted -C 1-6 alkyl; Or, R 5 and R 6 are each independently selected from hydrogen, or -C 1-6 alkyl; Or, R 5 and R 6 and together with the carbon atoms to which they are attached form =0, and optionally one or more R d Substituted C 3-6 Cycloalkyl, or 3-6 membered heterocycloalkyl; Or, R 5 and R 6 are all selected from hydrogen.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 7 is selected from hydrogen, hydroxy, amino, cyano, halogen, and optionally one or more R e Substituted -C 1-6 alkyl; Or, R 7 selected from hydrogen; Optionally, R 8 Selected from optionally one or more R f substituted phenyl, or 5-10 membered heteroaryl; or, R 8 Selected from optionally one or more R f substituted phenyl, or pyridyl; or, R 8 Selected from Optionally, R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2NH2, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-3-6 membered heterocyclyl, -S(O)2-5-6 membered heteroaryl, -P(O)(C 1-6 Alkyl)2, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, -O-5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C6 aryl, or 5-6 membered heteroaryl; or, R f is selected from hydroxy, amino, halogen, carboxyl, and optionally one or more R f1 Substituted -C 1-6 Alkyl, -C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2NH2, -S(O)2-3-6 membered heterocyclyl, -S(O)2-5-6 membered heteroaryl, or -P(O)(C 1-6 Alkyl)2; Or, R f Selected from optionally one or more R f1 Substituted -C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2, -S(O)2C 1-6 Alkyl, -OC 3-6 Cycloalkyl, or 5-6 membered heteroaryl; Or, R f Selected from methoxy, or -P(O)(CH3)2, -OCD3, -O-cyclopropyl, -C(O)NHCH3, -S(O)2CH3, or -C(O)NHCH2CH(OH)CH3; Or, two adjacent R f and together with the carbon atoms to which they are attached, form a 5-6 membered heterocyclic ring; Or, two adjacent R f Together with the carbon atoms to which they are attached, they form a dihydrofuran ring.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: n is selected from 0; optionally, m is selected from 1.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is selected from a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), or formula (IX), or a pharmaceutically acceptable salt thereof, in, X, R 1 、R b 、X 2 、X 3 、X 4 、R 8 As defined in any one of claims 1 to 6; t is selected from 1, 2, 3 or 4.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is selected from:

9. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8; further comprising a pharmaceutically acceptable excipient.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating or preventing a disease; Optionally, the disease is selected from cancer; optionally, the cancer is selected from gastric cancer or liver cancer.

Images