Benzopyrimidine compound, and preparation method therefor and use thereof

Abstract

Provided are a benzopyrimidine compound, and a preparation method therefor and a use thereof. Specifically provided is a benzopyrimidine compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which can be used for preparing drugs, especially for preparing drugs for preventing and / or treating EHMT1 and / or EHMT2-mediated diseases or conditions. The groups in formula (I) are as defined in the description.

Description

A benzopyrimidine compound, its preparation method and uses

[0001] This application claims priority to Chinese Patent Application No. 2024115452715, filed on November 1, 2024, and Chinese Patent Application No. 2025100496857, filed on January 13, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application pertains to the pharmaceutical field, specifically relating to a benzopyrimidine compound or its pharmaceutically acceptable salt, its preparation method, and its use. Background Technology

[0003] Histone methylation is a common type of histone modification. Typically, the N-terminal lysine (K) or arginine (R) residues of H3 and H4 histones are methylated, and the methylation site can promote or inhibit transcriptional activation. Histone methylation is mainly catalyzed by histone methyltransferases (HMTs), which can be classified into histone lysine methyltransferases (HKMTs) and histone arginine methyltransferases (PRMTs) based on their substrates.

[0004] Methylation of histone H3 at position 9 (H3K9) is one of the highly conserved epigenetic sites closely related to gene silencing. H3K9 can undergo 1, 2, and 3 methylation. It has been confirmed that H3K9 dimethylation (H3K9me2) mediates transcriptional silencing, H3K9 trimethylation (H3K9me3) mediates transcriptional silencing and heterochromatin formation, while research on H3K9me1 is still insufficient. Some literature has disclosed that H3K9 monomethylation (H3K9me1) is a marker of transcriptional activation, but me1 can be continuously converted to me2 or me3, ultimately exerting a silencing effect.

[0005] EHMT2 (also known as histone methyltransferase G9a) is a major lysine methyltransferase in euchromatin, containing a conserved SET catalytic domain. Belonging to the SUV39 family, it primarily catalyzes the catalytic processes of H3K9me2 and H3K9me. The ankyrin of EHMT2 can recognize and bind to monomethyl and dimethyl H3K9, serving as a scaffold for recruiting other target molecules to chromatin. EHMT1 (G9a-like protein, GLP) is a closely related HKMT to EHMT2, sharing 80% similarity in its SET domain. It also regulates monomethyl and dimethylation at the H3K9 site and forms a heterodimer with G9a.

[0006] EHMT2 plays a crucial role in many biological processes through its complex regulation of gene transcription repression and activation, including embryonic development, DNA damage repair, gene transcription, and tumorigenesis and development. G9a regulates HMGA1 expression levels, maintaining normal insulin receptor levels and the integrity of insulin signaling; G9a knockdown leads to downregulation of insulin receptor, p-AKT, and p-GSK3β. Simultaneously, knockout or inhibition of G9a results in decreased H3K9me1 levels, downregulation of GSTP1 expression, and exacerbation of LPS- or APAP-induced liver injury. G9a can influence inflammatory diseases by regulating the development and differentiation of immune cells; for example, G9a deficiency or inhibition can lead to… T cell differentiation into Th2 cells is suppressed, while differentiation into Treg and TL-17 cells is increased.

[0007] Currently developed EHMT2(G9a) inhibitors generally suffer from low efficacy. There is only one candidate compound that has entered the clinical research stage, but this candidate molecule has poor activity. Therefore, there is an urgent need to develop inhibitors with strong activity and good drug-like properties to solve this problem.

[0008] Currently, the publicly disclosed related patents include WO2022031939A1, WO2023064586A1, and WO2024216164A1. Summary of the Invention

[0009] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] in,

[0011] G is CR 1 Or N;

[0012] Ring A is a 3-12 membered heterocyclic group or C 3-12 cycloalkyl;

[0013] R 1 Selected from H, D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups and 3-8 membered heterocyclic groups;

[0014] R 2 For LR E Or R 8 ;

[0015] L is selected from C 1-12 Alkylene, C 2-12 imide and C 2-12 Idemynyl group, where C 1-12 Alkylene, C 2-12 imide and C 2-12 One, two, or three CH2 groups in the ynethynyl group may be optionally and independently selected from -O-, -S-, and -NR. L1 -、-C(O)-、C 3-6 Substitution of groups in cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-12 Alkylene, C 2-12 imide and C 2-12 The ethynyl group is optionally enclosed by one or more R groups. a replace;

[0016] R L1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups;

[0017] Each R a The same or different, and each independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0018] Or, two Rs a Together with the atoms it is attached to, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0019] R 8 It is a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group is optionally selected from H, D, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 The alkyl group is replaced by one or more substituents in the form of deuterated cycloalkyl groups and 3-8 membered heterocyclic groups;

[0020] R E H, halogen, hydroxyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups and NR g1 R g2 The C mentioned 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0021] R g1 and R g2 The same or different, and each independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0022] Or, R g1 and R g2 Together with the nitrogen atoms to which they are attached, they form 3-8 membered heterocyclic groups, wherein the 3-8 membered heterocyclic groups are optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0023] R 3 Selected from H, halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0024] R 4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0025] R 5 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. v replace;

[0026] R v Selected from H, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR k1 R k2 C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0027] R k1 and R k2 Whether the two are the same or different, each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0028] Or, R 4 and R 5The nitrogen atom bonded to it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0029] R 6 for

[0030] R 6a and R 6b The same or different, and each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0031] Or, R 6a and R 6b Together with the atoms attached to it, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups are optionally selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-8 cycloalkyl, C 3-8 The alkyl group is replaced by one or more substituents in the form of deuterated cycloalkyl groups and 3-8 membered heterocyclic groups;

[0032] Each R 7 They may be the same or different, and each is independently selected from H, halogen, hydroxyl, amino, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups and C 3-8 cycloalkyl;

[0033] n is 0, 1, 2, 3, 4, 5, and 6;

[0034] The heteroatoms in the heterocyclic or heteroaryl groups are selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0035] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and -C 1-6 Alkylene-C 6-10 One or more substituents in the aryl group are substituted; the remaining groups are defined as in general formula (I).

[0036] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0037] G is CR 1 Or N;

[0038] Ring A is a 3-12 membered heterocyclic group;

[0039] R 1 Selected from H, halogens, and cyano groups;

[0040] R 2 For LR E or R 8 ;

[0041] L is selected from C 1-12 Alkylene, C 2-12 imide and C 2-12 Idemynyl group, where C 1-12 Alkylene, C 2-12 imide and C 2-12One, two, or three CH2 groups in the ynethynyl group may optionally and independently be selected from -O-, -S-, and -NR. L1 - group substitution, the C 1-12 Alkylene, C 2-12 imide and C 2-12 The ethynyl group is optionally enclosed by one or more R groups. a replace;

[0042] R L1 Selected from H or C 1-6 alkyl;

[0043] Each R a The same or different, and each independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0044] R 8 It is a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group is optionally selected from H, C 1-6 Alkyl and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0045] R E H, 3-8 membered heterocyclic groups and NR g1 R g2 The 3-8 membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 One or more substituents in the haloalkoxy group are substituted;

[0046] R g1 and R g2 The same or different, and each independently selected from H and C 1-6 Alkyl and C 3-8 cycloalkyl;

[0047] R 3 Selected from H, halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0048] R 4 Selected from H;

[0049] R 5 Selected from C 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups. v replace;

[0050] R v Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR k1 R k2 and C 3-8 cycloalkyl, wherein the C 1-6 Alkyl and C 3-8 Cycloalkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 6-10 One or more substituents in the aryl group are substituted;

[0051] R k1 and R k2 Whether the two are the same or different, each is independently selected from H or C. 1-6 alkyl;

[0052] Or, R 4 and R 5 The nitrogen atom bonded to it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally bonded by one or more C atoms. 1-6 Alkyl groups are substituted;

[0053] R 6 for

[0054] R 6a and R 6b Whether the groups are the same or different, and each is independently selected from H, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 6-10 Aryl;

[0055] Or, R 6a and R 6b Together with the atoms attached to it, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0056] Each R 7 Both are the same or different, and each is independently H;

[0057] n is 0, 1, 2, 3, 4, 5, and 6;

[0058] The heteroatoms in the heterocyclic or heteroaryl groups are selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0059] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0060] (1) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0061] (2) The halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine;

[0062] (3) The C 3-8 Cycloalkyl group is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and again, cyclopropyl or cyclobutyl;

[0063] (4) The 3-8 membered heterocyclic group, 3-12 membered heterocyclic group, or 5-12 membered heterocyclic group is oxoheterobutyl, azaheterobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, or morpholinyl.

[0064] In some embodiments, the 5-12 membered heterocyclic group is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, etc.

[0065] In some embodiments, the 5-12 membered heterocyclic group is a 5-8 membered heterocyclic group, and the heteroatom in the 5-12 membered heterocyclic group is preferably N; preferably, the number of heteroatoms is independently 1 or 2.

[0066] In some embodiments, the heteroatoms in the 3-8 membered heterocyclic group are independently one or both of N and O; preferably, the number of heteroatoms is independently one or two.

[0067] In some embodiments, the heteroatoms in the 3-12 membered heterocyclic group are independently one or both of N and O; preferably, the number of heteroatoms is independently 1, 2 or 3, for example...

[0068] In some embodiments, the 4-8 membered heterocyclic group is a 5-6 membered heterocyclic group; the heteroatoms in the 4-8 membered heterocyclic group are preferably independently one or both of N and O; preferably, the number of heteroatoms is independently 1, 2 or 3; for example

[0069] In some implementations, the C 3-12 Cycloalkyl group is C 3-6Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and again cyclopropyl, cyclobutyl, or cyclohexyl.

[0070] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein for R 6a and R 6b As defined by compound (I).

[0071] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (II).

[0072] Where p is 1 or 2;

[0073] q is 1 or 2;

[0074] G, R 2 R 3 R 4 R 5 R 6a and R 6b As defined by compound (I).

[0075] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0076] Where p is 1 or 2;

[0077] q is 1 or 2;

[0078] G is either CH or N;

[0079] R 2 For LR E L is C 1-6 Alkylene or C 2-4 Idemynyl group, where C 1-6 Alkylene and C 2-4 One, two, or three CH2 groups in the ynynyl group may be optionally and independently replaced by groups selected from -O-;

[0080] R E It is a 3-8 membered heterocyclic group; the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens;

[0081] R 3 C 1-3 Alkoxy;

[0082] R 4 For H;

[0083] R 5 C3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C... 1- 6-alkyl, C 3-8 cycloalkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0084] R 6a and R 6b Each can be independently H or halogen;

[0085] Or, R 6a and R 6b Together with the atoms attached to it, they form C 3-6 Cycloalkyl.

[0086] In some embodiments, in the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, when G is N, for At that time, R 5 C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 It is substituted by one or more substituents in the hydroxyalkyl group.

[0087] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts are used, wherein G is CH.

[0088] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts are used, wherein G is N.

[0089] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 4 For H or C 1-6 alkyl.

[0090] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 4 For H.

[0091] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 6a and R 6b Whether the groups are the same or different, and each is independently selected from H, halogen, cyano, and C. 1-3 Alkyl and phenyl;

[0092] Or, R6a and R 6b Together with the atoms attached to it, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups and 3-8 membered heterocyclic groups.

[0093] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 6a and R 6b All are halogens, with fluorine being the preferred component.

[0094] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 6a and R 6b Different, R 6a For H, R 6b It is a halogen.

[0095] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 6a For H, R 6b It is F.

[0096] In some implementations, R 6a and R 6b Together with the atoms attached to it, they form C 3-6 Cycloalkyl.

[0097] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein for

[0098] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 4 Selected from H and C 1-6 alkyl;

[0099] R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups.v replace;

[0100] R v Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl and -C 1-6 alkylene-phenyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and -C 1-6 Alkylene-phenyl groups are optionally selected from halogen, hydroxyl, amino, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 3-8 It is substituted by one or more substituents in cycloalkyl and 3-8 membered heterocyclic groups.

[0101] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 4 and R 5 The nitrogen atom bonded to it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, hydroxyl groups, and C. 1-6 It is replaced by one or more substituents in the alkyl group.

[0102] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 4 and R 5 The nitrogen atom attached to it forms

[0103] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 2 For LR E L is C 1- 6-alkylene, C 2-6 imide and C 2-4 Idemynyl group, where C 1-6 Alkylene, C 2-6 imide and C 2-4 One, two, or three CH2 groups in the ynethynyl group may optionally and independently be selected from -O- or -NR. L1 - group substitution, the C 1-6 Alkylene, C2-6 imide and C 2-4 The ethynyl group is optionally enclosed by one or more R groups. a replace;

[0104] R L1 For H, C 1-6 Alkyl or C 3-12 cycloalkyl;

[0105] Each R a The same or different, and each independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0106] Or, two Rs a Together with the atoms it is attached to, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0107] R E C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups and NR g1 R g2 The C mentioned above 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3- One or more substituents in the 8-cycloalkyl group are substituted;

[0108] R g1 and R g2 The same or different, and each independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0109] Or, R g1 and R g2 Together with the nitrogen atoms to which they are attached, they form 3-8 membered heterocyclic groups, wherein the 3-8 membered heterocyclic groups are optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 It is substituted by one or more substituents in the cycloalkyl group.

[0110] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 2 For LR E L is C 1- 6-alkylene or C 2-4 Idemynyl group, where C 1-6 Alkylene and C 2-4 One, two, or three CH2 groups in the ynynyl group may be optionally and independently replaced by groups selected from -O-;

[0111] R E It is a 3-8 membered heterocyclic group; the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens.

[0112] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 2 For R 8 ;

[0113] R 8 It is a 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally selected from H, D, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl and C 3-8 It is replaced by one or more substituents of a deuterated cycloalkyl group.

[0114] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 2 for

[0115] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 5 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C3-8 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups. v replace;

[0116] R v Selected from H, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N(C) 1-6 Alkyl)2, C 3-8 cycloalkyl and -C 1-6 alkylene-phenyl, wherein the C 1-6 Alkyl, C 3-8 cycloalkyl and -C 1-6 Alkylene-phenyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 It is substituted by one or more substituents in cycloalkyl and 3-8 membered heterocyclic groups.

[0117] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 5 C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and -C 1-6 It is substituted by one or more substituents in the alkylene-phenyl group.

[0118] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 5 C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 3-8 cycloalkyl and C 1- It is substituted by one or more substituents in the 6-hydroxyalkyl group.

[0119] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 5 -CH3,

[0120] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R3 is H, halogen, hydroxyl, C1-3 alkoxy, or C1-3 haloalkoxy.

[0121] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts are used, wherein R3 is a C1-3 alkoxy group.

[0122] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R3 is H, F, Cl, OH, -OCH3, or -OCHF2.

[0123] In some embodiments, the compound represented by formula (I) or its pharmaceutically acceptable salt, wherein R7 is H, a halogen, or a C1-6 alkyl group; preferably, R7 is H.

[0124] In some embodiments, the compound represented by formula (I) or its pharmaceutically acceptable salt is used, where n is 0 or 1.

[0125] In some embodiments, exemplary specific compounds of formula (I) include, but are not limited to, the structures in Table A below:

[0126] Table A

[0127] In some embodiments, exemplary specific compounds of the compound shown in formula (I) include, but are not limited to, the structures in Table B below:

[0128] Table B

[0129] Another aspect of this application provides isotope labels for compounds shown in formulas (I) and (II), or in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0130] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0131] In another aspect, this application also provides the use of compounds of formula (I) and formula (II), compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for inhibiting EHMT1 and / or EHMT2.

[0132] This application also provides the use of compounds of formulas (I) and (II), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of diseases or conditions mediated by EHMT1 and / or EHMT2.

[0133] This application also provides the use of compounds of formulas (I) and (II), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer; preferably, in the preparation of medicaments for the prevention and / or treatment of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, atopic dermatitis, Kassman's disease, allergic rhinitis, eczema, Kawasaki disease, and psoriatic arthritis.

[0134] This application also provides a method for inhibiting EHMT1 and / or EHMT2, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I) and formula (II), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopic label, or the aforementioned pharmaceutical composition comprising the thereof.

[0135] This application also provides a method for preventing and / or treating EHMT1 and / or EHMT2-mediated diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) and formula (II), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope label, or the aforementioned pharmaceutical composition comprising the thereof.

[0136] This application also provides a method for preventing and / or treating gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) and formula (II), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned.

[0137] This application also provides a method for preventing and / or treating ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, atopic dermatitis, Kassman's disease, allergic rhinitis, eczema, Kawasaki disease, and psoriatic arthritis, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) and (II), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0138] This application also provides a compound of formula (I) and formula (II), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a medicine.

[0139] This application also provides a compound of formula (I) and formula (II), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, as a medicament for use as an EHMT1 and / or EHMT2 inhibitor.

[0140] This application also provides a compound of formula (I) and formula (II), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the prevention and / or treatment of diseases or conditions mediated by EHMT1 and / or EHMT2.

[0141] This application also provides a compound of formula (I) and formula (II), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the prevention and / or treatment of gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer.

[0142] This application also provides a medicament for the prevention and / or treatment of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, atopic dermatitis, Kassman's disease, allergic rhinitis, eczema, Kawasaki disease, and psoriatic arthritis.

[0143] In some embodiments, the diseases mediated by EHMT1 and / or EHMT2 are selected from gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer.

[0144] In some embodiments, the diseases mediated by EHMT1 and / or EHMT2 are selected from ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, diabetes, multiple sclerosis, celiac disease, graft-versus-host disease (GVHD), Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, atopic dermatitis, Kassman disease, allergic rhinitis, eczema, Kawasaki disease, and psoriatic arthritis.

[0145] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0146] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof.

[0147] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0148] When administered as a medicine, the compounds of this application may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powder or aerosol, including via nebulizer; intratracheal, intranasal, oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0149] In preparing the compositions of this application, the active ingredient is typically mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0150] The term "excipients" as used in this application refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0151] On the other hand, pharmaceutically acceptable salts of the compounds described in this application may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0152] On the other hand, the compounds of this application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0153] The term "multiple" in the above-mentioned number of substituents or heteroatoms means 2, 3, 4, or 5.

[0154] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations.

[0155] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0156] Furthermore, the compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds in this application are within the scope of this application. The name of a compound named in a single manner does not exclude any tautomer.

[0157] This application also includes compounds of this application with the same structure as described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0158] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0159] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of a drug or pharmacologically active agent, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0160] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0161] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0162] Terminology Definitions and Explanations

[0163] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0164] In this application This refers to the corresponding group passing through this It can be linked to other fragments or groups in a compound.

[0165] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6. Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers. Alkyl groups may be substituted or unsubstituted.

[0166] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group, which may contain 1-20 carbon atoms, preferably 1-12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1-6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms. The alkylene group may be substituted or unsubstituted. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), -(CH2)5-, -CH(CH3)-(CH2)4-, -(CH2)6-, -CH(CH3)-(CH2)5-, -(CH2)7-, -CH(CH3)-(CH2)6-, -(CH2)8-, or -CH(CH3)-(CH2)7-, etc.

[0167] The term "alkenyl" refers to an alkylene group containing at least one carbon-carbon double bond (alkene bond). Preferably, the number of carbon-carbon double bonds (alkene bonds) can be 1, 2, 3, or 4. The alkylene group, as defined herein, can contain 1-20 carbon atoms, preferably 1-12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1-6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms. The alkenyl group can be substituted or unsubstituted. Non-limiting examples include -CH2-CH=CH-, -(CH2)3-CH=CH-, -(CH2)4-CH=CH-, -(CH2)5-CH=CH-, or -(CH2)6-CH=CH-, etc.

[0168] The term "alkynylene" refers to an alkylene group containing at least one carbon-carbon triple bond (alkynyl group). Preferably, the number of carbon-carbon triple bonds (alkynyl groups) can be 1, 2, 3, or 4. The alkylene group, as defined herein, can contain 1-20 carbon atoms, preferably 1-12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1-6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms. The alkenylene group can be substituted or unsubstituted. Non-limiting examples include -CH2-CH≡CH-, -(CH2)3-CH≡CH-, -(CH2)4-CH≡CH-, -(CH2)5-CH≡CH-, or -(CH2)6-CH≡CH-, etc.

[0169] The term "alkenyl" should be understood to preferably refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group may be substituted or unsubstituted.

[0170] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1- 6. Alkoxy group). Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0171] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0172] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0173] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0174] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0175] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl group as described herein, wherein the ring attached to the parent structure can be a cycloalkyl ring or an aryl ring, and non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0176] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0177] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0178] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0179] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0180] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure may be a heterocyclic group, or an aryl, heteroaryl, or cycloalkyl ring, and non-limiting examples include:

[0181] The heterocyclic group may be substituted or unsubstituted.

[0182] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0183] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes heteroaryl groups as described herein, with non-limiting examples including: Etc. Heteroaryl groups can be substituted or unsubstituted.

[0184] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0185] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", "heterocyclic", and "heteroarylene".

[0186] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0187] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0188] The term “halogenated alkyl” refers to an alkyl group that is substituted with one or more halogens, wherein the alkyl group and the halogen are as defined herein.

[0189] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group and the halogen are as defined herein.

[0190] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium groups, wherein the alkyl group and the deuterium group are as defined herein.

[0191] The term “deuterated haloalkyl” means that a haloalkyl group is substituted with one or more deuterium groups, wherein the haloalkyl group and the deuterium are as defined herein.

[0192] The term “deuterated alkoxy” refers to an alkoxy group that is substituted with one or more deuterium groups, wherein the alkoxy group and the deuterium group are as defined herein.

[0193] The term “deuterated cycloalkyl” refers to a cycloalkyl group that is substituted with one or more deuterium atoms, wherein the cycloalkyl group and the deuterium are as defined herein.

[0194] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group and the hydroxyl group are as defined herein.

[0195] The term "halogen" refers to F, Cl, Br, or I.

[0196] The term "hydroxyl group" refers to -OH.

[0197] The term "amino" refers to -NH2.

[0198] The term "cyano" refers to -CN.

[0199] The term "nitro" refers to -NO2.

[0200] The term "oxo" or "oxo" refers to "=O".

[0201] The term "carbonyl" refers to C=O.

[0202] The term "carboxyl group" refers to -C(O)OH.

[0203] The term “carboxylic acid ester group” refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0204] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0205] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0206] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0207] The reagents and raw materials used in this invention are all commercially available. Beneficial effects:

[0208] This application provides a small molecule compound with a benzopyrimidine structure that can be used as an EHMT1 and / or EHMT2 inhibitor. This type of compound or pharmaceutical composition has a strong inhibitory effect on EHMT1 and / or EHMT2 and has excellent pharmacokinetic activity, and can be used to effectively treat or prevent diseases mediated by EHMT1 and / or EHMT2. Detailed Implementation

[0209] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0210] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0211] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0212] Mass spectrometry (MS) was performed using a Waters 2767HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry system.

[0213] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0214] The silica gel plates used in thin-layer chromatography are GF254 silica gel plates from Cheng Chemical (Shanghai) Co., Ltd. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.2–0.25 mm, while those used for separating and purifying products by thin-layer chromatography have a diameter of 0.4–0.5 mm.

[0215] Column chromatography typically uses 100-200 mesh silica gel as a carrier, as provided by Chenghua Chemical (Shanghai) Co., Ltd.

[0216] High-performance liquid chromatography (HPLC) was performed using Waters HPLC, Gilson HPLC, and Biotage MPLC preparative chromatographs.

[0217] Chiral separation column chromatography was performed using a preparative HPLC model, Gilson GX-281.

[0218] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0219] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 liter.

[0220] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0221] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20℃-30℃.

[0222] Those skilled in the art should understand that chiral compounds can be distinguished by their retention times in a chiral chromatographic column. Therefore, chiral compounds separated according to their retention times are distinguished by corresponding suffixes such as P1, P2, etc. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a compound is listed in the structural formula, it does not imply a one-to-one correspondence with the compounds numbered with suffixes P1 and P2; it merely indicates two possible forms of absolute configuration. The absolute configuration of the compounds numbered with suffixes P1 and P2 is based on the absolute configuration objectively corresponding to a specific retention time.

[0223] Reagent names corresponding to English abbreviations:

[0224] CD3OD: Deuterated methanol; DMSO: Deuterated dimethyl sulfoxide; D2O: Heavy water

[0225] Example 1: Synthesis of Compound 1

[0226] Step 1: Synthesis of compounds 1-3

[0227] Compound 1-2 (1-bromo-3-chloropropane, 77.78 g, 494.04 mmol) and potassium carbonate (34.14 g, 247.02 mmol) were added to a solution of compound 1-1 (methyl 4-hydroxy-3-methoxybenzoate, 30.00 g, 164.68 mmol) in acetonitrile (200 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with aqueous solution (100 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0~5 / 1) to give compound 1-3 (25.00 g). MS m / z (ESI): 259.0 [M+1]+ .

[0228] Step 2: Synthesis of compounds 1-4

[0229] Nitric acid (8.77 g, 139.16 mmol) was added to a solution of compounds 1-3 (24.00 g, 92.77 mmol) in acetic acid and acetic anhydride (100 mL / 100 mL). The reaction mixture was stirred at 25 °C for 6 hours. After the reaction was complete, the reaction solution was quenched with an aqueous sodium bicarbonate solution (200 mL), extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0~5 / 1) to give compounds 1-4 (18.00 g). MS m / z (ESI): 304.0 [M+1] + .

[0230] Step 3: Synthesis of compounds 1-6

[0231] At room temperature, compounds 1-5 (tetrahydropyrrole, 5.97 g, 83.97 mmol), potassium iodide (9.29 g, 55.98 mmol), and potassium carbonate (23.21 g, 167.94 mmol) were added to a solution of compound 1-4 (17.00 g, 55.98 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with an aqueous solution (100 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phases were washed with saturated brine (300 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to give compound 1-6 (12.00 g). MS m / z (ESI): 339.1 [M+1] + .

[0232] Step 4: Synthesis of compounds 1-7

[0233] At room temperature, 18.49 g (97.53 mmol) of stannous chloride was added to a solution of compounds 1-6 (11.00 g, 32.51 mmol) in ethanol and water (50 mL / 50 mL). The reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with an aqueous solution (100 mL), extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude compounds 1-7 (9.00 g). MS m / z (ESI): 309.1 [M+1] +.

[0234] Step 5: Synthesis of compounds 1-8

[0235] Sodium cyanate (1.26 g, 19.46 mmol) was added to a solution of compounds 1-7 (4.00 g, 12.97 mmol) in acetic acid and water (5 mL / 5 mL) at room temperature. The reaction mixture was stirred at 65 °C for 16 hours. Then, sodium hydroxide (10.38 g, 259.40 mmol) was added, and stirring continued at 65 °C for 5 hours. After the reaction was complete, the reaction mixture was quenched with an aqueous solution (50 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to give compounds 1-8 (2.80 g). MS m / z (ESI): 320.1 [M+1] + .

[0236] Step 6: Synthesis of compounds 1-9

[0237] Phosphorus oxychloride (3.31 g, 21.60 mmol) and N,N-diisopropylethylamine (0.93 g, 7.20 mmol) were added to a 10 mL solution of compounds 1-8 (2.30 g, 7.20 mmol) in acetone under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete, the reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude compounds 1-9 (2.00 g). MS m / z (ESI): 356.0 [M+1] + .

[0238] Step 7: Synthesis of compounds 1-11

[0239] At room temperature, compounds 1-10 (4-aminotetrahydropyran, 169.9 mg, 1.68 mmol) and N,N-diisopropylethylamine (542.8 mg, 4.20 mmol) were added to a solution of compounds 1-9 (500.0 mg, 1.40 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 65 °C for 16 hours. The reaction mixture was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0–5 / 1) to give compound 1-11 (450.0 mg). MS m / z (ESI): 421.0 [M+1] + .

[0240] Step 8: Synthesis of Compound 1

[0241] Compound 1-12 (4-(difluoromethylene)piperidine, 47.9 mg, 0.36 mmol), tris(dibenzylideneacetone)palladium (43.9 mg, 0.048 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (37.78 mg, 0.096 mmol) and cesium carbonate (234.5 mg, 0.72 mmol) were added to a solution of compound 1-11 (100.0 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to give compound 1 (19.2 mg). MS m / z (ESI): 518.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.48(s,1H),7.41(d,J=7.2Hz,1H),6.74(s,1H),4.25–4.22(m,1H),4.09(t,J=6.4Hz,2H),3.94(d,J=8.6Hz, 2H),3.82(s,3H),3.81–3.78(m,4H),3.54–3.41(m,2H),2.33(s,6H),2.14(s,4H),2.01-1.96(m,4H),1.75(s,4H),1.64–1.61(m,2H).

[0242] Example 2: Synthesis of Compound 2

[0243] Step 1: Synthesis of Compounds 2-3

[0244] Compound 2-2 (2-((difluoromethyl)sulfonyl)pyridine, 3.76 g, 19.44 mmol) and potassium tert-butoxide (2.73 g, 24.30 mmol) were added to a solution of compound 2-1 (3-oxopyrrolidine-1-carboxylic acid tert-butyl ester, 3.00 g, 16.20 mmol) in N,N-dimethylformamide (20 mL) under nitrogen atmosphere at -50 °C. The reaction mixture was stirred at -50 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with sodium bicarbonate aqueous solution and 3M hydrochloric acid (10 mL / 3 mL), extracted with ethyl acetate (60 mL × 3), and the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0~2 / 1) to give compound 2-3 (70.0 mg). MS m / z(ESI): 164.0 [M-55] + .

[0245] Step 2: Synthesis of compounds 2-4

[0246] Under nitrogen atmosphere at room temperature, hydrogen chloride / 1,4-dioxane (3 mL, 26.93 mmol) was added to a 1 mL solution of compound 2-3 (130.0 mg, 0.63 mmol) in 1,4-dioxane. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction solution was directly concentrated to give crude compound 2-4 (60.0 mg). MS m / z (ESI): 120.1 [M+1] + .

[0247] Step 3: Synthesis of Compound 2

[0248] Under nitrogen atmosphere at room temperature, compounds 2-4 (60.0 mg, 0.50 mmol), tris(dibenzylacetone)palladium (43.9 mg, 0.048 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (37.78 mg, 0.096 mmol), and cesium carbonate (234.5 mg, 0.72 mmol) were added to a 5 mL solution of N,N-dimethylformamide containing compound 1-11 (100.0 mg, 0.24 mmol, synthesized according to the seventh step of the synthesis of intermediate 1-11 of compound 1). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to obtain the crude product. The crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-70%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2 (4.50 mg). MS m / z (ESI): 504.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.48(s,1H),7.39(d,J=7.1Hz,1H),6.77(s,1H),4.29(d,J=4.2Hz,1H),4.15(s,2H),4.09(t,J=6.3Hz,2H),3. 98–3.91(m,2H),3.83(s,3H),3.68(s,1H),3.43(s,2H),2.81–2.62(m,8H),1.98(d,J=8.3Hz,4H),1.77(s,4H),1.63(d,J=4.0Hz,3H).

[0249] Example 3: Synthesis of Compound 3

[0250] Step 1: Synthesis of Compound 3-2

[0251] Compound 2-2 (2-((difluoromethyl)sulfonyl)pyridine, 2.26 g, 11.68 mmol) and potassium tert-butoxide (1.97 g, 17.52 mmol) were added to a solution of compound 3-1 (2.00 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) under nitrogen atmosphere at -60 °C. The reaction mixture was stirred at -60 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with sodium bicarbonate aqueous solution and 3M hydrochloric acid (15 mL / 5 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to give compound 3-2 (150.0 mg). MS m / z(ESI): 150.0 [M-55] + .

[0252] Step 2: Synthesis of Compound 3-3

[0253] Under nitrogen atmosphere at room temperature, trifluoroacetic acid (2 mL, 26.93 mmol) was added to a solution of compound 3-2 (130.0 mg, 0.63 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was directly concentrated to give crude compound 3-3 (180 mg). MS m / z (ESI): 106.1 [M+1] + .

[0254] Step 3: Synthesis of Compound 3

[0255] At room temperature, compound 3-3 (180.0 mg, 1.71 mmol) and N,N-diisopropylethylamine (663.0 mg, 5.13 mmol) were added to a solution of compound 1-11 (100.0 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 100 °C for 72 hours. The reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0–5 / 1) to obtain the crude product. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20–70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 3 (10.86 mg). MS m / z (ESI): 490.2 [M+1]+ . 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.49(s,1H),7.48(d,J=7.0Hz,1H),6.79(s,1H),4.58(t,J=3.3Hz,4H),4.28–4.24(m,1H),4.08(t,J=6 .3Hz,2H),3.94–3.92(m,2H),3.83(s,3H),3.50–3.39(m,6H),2.59(t,J=7.2Hz,2H),2.01–1.90(m,4H),1.71(s,4H),1.62(d,J=4.6Hz,2H).

[0256] Example 4 Synthesis of Compound 32

[0257] Step 1: Synthesis of Compound 32-2

[0258] At room temperature, compound 32-1 (1-isopropyl-4-aminopiperidine, 179.2 mg, 1.26 mmol) and N,N-diisopropylethylamine (325.6 mg, 2.52 mmol) were added to a solution of N,N-dimethylformamide (10 mL) containing compound 1-9 (300.0 mg, 0.84 mmol, synthesized according to the sixth step of the synthesis of intermediate 1-9 of compound 1). The reaction mixture was stirred at 65 °C for 16 hours. The reaction mixture was quenched with aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to give compound 32-2 (130.0 mg). MS m / z (ESI): 462.0 [M+1] + .

[0259] Step 2: Synthesis of Compound 32

[0260] Compound 1-12 (4-(difluoromethylene)piperidine, 47.93 mg, 0.50 mmol), tris(dibenzylideneacetone)palladium (43.9 mg, 0.048 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (37.7 mg, 0.096 mmol) and cesium carbonate (234.5 mg, 0.72 mmol) were added to a solution of compound 32-2 (110.0 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water / methanol = 100 / 0~1 / 1), followed by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-70%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 32 (29.5 mg). MS m / z (ESI): 559.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 3H), 7.48 (s, 1H), 7.38 (d, J = 6.8Hz, 1H), 6.7 4(s,1H),4.10–4.02(m,2H),3.82(s,3H),3.80–3.63(m,2H),3.01(d,J=11.2 Hz,2H),2.92(d,J=6.3Hz,1H),2.74(d,J=9.3Hz,6H),2.54(s,4H),2.15(s,4 H), 2.06–1.97 (m, 4H), 1.76 (s, 4H), 1.67–1.64 (m, 2H), 1.07 (d, J = 6.5Hz, 6H).

[0261] Example 5: Synthesis of Compound 4

[0262] Step 1: Synthesis of Compound 4-3

[0263] Under nitrogen atmosphere at -78°C, potassium bis(trimethylsilyl)amino (3.86 mL, 3.86 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 4-2 (2-((fluoromethyl)sulfonyl)pyridine) (676.3 mg, 3.86 mmol). The reaction mixture was stirred at -78°C for 1 hour. Then, compound 4-1 (N-tert-butoxycarbonyl-4-piperidinone) (700.0 mg, 3.51 mmol) was added to the reaction mixture. After the reaction was completed, the reaction mixture was quenched with ammonium chloride solution (20 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0~1 / 1) to give compound 4-3 (500.0 mg). MS m / z (ESI): 159.9 [M-55] + .

[0264] Step 2: Synthesis of Compound 4-4

[0265] Compound 4-3 (200.0 mg, 0.93 mmol) was added to a hydrogen chloride / dioxane (5 mL) solution under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction solution was directly concentrated to give compound 4-4 (100 mg, crude product). MS m / z (ESI): 116.2 [M+1] + .

[0266] Step 3: Synthesis of Compound 4

[0267] At room temperature, compound 4-4 (82.9 mg, 0.72 mmol) and N,N-diisopropylethylamine (93.0 mg, 0.72 mmol) were added to a solution of compound 1-11 (100.0 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0–5 / 1). Then, it was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20–70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 4 (17.75 mg). MS m / z (ESI): 500.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.48(s,1H),7.39(d,J=84Hz,1H),6.78(d,J=6.8Hz,1H),6.77(s,1H),4.25–4.20(m,1H),4.17–4.12(m, 2H),4.09–3.98(m,2H),3.96(s,3H),3.83–3.76(m,4H),3.50–3.40(m, 2H),3.12(s,6H),2.24(s,2H),2.12–1.89(m,10H),1.66–1.58(m,2H).

[0268] Example 6 Synthesis of Compound 15

[0269] Step 1: Synthesis of Compound 15-3

[0270] Compound 15-1 (2-methoxy-5-nitrophenol) (3 g, 17.8 mmol) was dissolved in tetrahydrofuran (30 mL), and 15-2 (1-(3-hydroxypropyl)pyrrolidine) (2.52 g, 19.5 mmol) and triphenylphosphine (6.04 g, 23 mmol) were added. After stirring the reaction mixture for 5 minutes, diisopropyl azodicarbonate (4.65 g, 23.01 mmol) was slowly added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 2), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-7%) to give compound 15-3 (3 g). MS m / z (ESI): 281.0 [M+1] + .

[0271] Step 2: Synthesis of Compound 15-4

[0272] Compound 15-3 (3 g, 10.7 mmol) was dissolved in methanol (30 mL), and palladium on carbon (10%, 300 mg) was added. The reaction mixture was stirred at room temperature for 18 hours under hydrogen protection. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 15-4 (3 g, crude product), which was used directly in the next step without purification. MS m / z (ESI): 251.0 [M+1] + .

[0273] Step 3: Synthesis of Compound 15-6

[0274] Compound 15-4 (3.00 g, 12.0 mmol) was dissolved in phosphorus oxychloride (20 mL), and 15-5 (malonic acid) (1.50 g, 14.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then heated to 90 °C and stirred for 12 hours. After the reaction was complete, the reaction mixture was slowly quenched in ice water, the pH was adjusted to 8 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to compound 15-6 (1 g). MS m / z (ESI): 355.0 [M+1] + .

[0275] Step 4: Synthesis of Compounds 15-7

[0276] Under nitrogen protection at room temperature, compound 3-3 (synthesized as described in the second step of compound 3-3 in Example 3) (155.3 mg, 1.44 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (55.5 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (43.9 mg, 0.04 mmol), and sodium tert-butoxide (138.3 mg, 1.44 mmol) were added to a toluene (10 mL) solution of compound 15-6 (170.0 mg, 0.48 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0~5 / 1) to give compound 15-7 (60.0 mg). MS m / z (ESI): 423.9 [M+1] + .

[0277] Step 5: Synthesis of Compound 15

[0278] Under nitrogen protection at room temperature, compounds 1-10 (18.2 mg, 0.18 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (13.8 mg, 0.02 mmol), tris(dibenzylacetone)dipalladium (10.9 mg, 0.01 mmol), and sodium tert-butoxide (34.6 mg, 0.36 mmol) were added to a toluene (3 mL) solution of compound 15-2 (50.0 mg, 0.12 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 0 / 100) to give compound 15 (9.10 mg). MS m / z(ESI): 489.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.48(s,1H),7.07(s,1H),6.65(d,J=6.2Hz,1H),5.64(s,1H),4.66(d,J=3.1Hz,4H),4.13(t,J=6.1Hz,2H),3.98 –3.90(m,2H),3.86(s,3H),3.81–3.73(m,1H),3.62–3.42(m,4H),3.10(s,4H),2.17–2.07(m,2H),1.99–1.85(m,6H),1.65–1.62(m,2H).

[0279] Example 7 Synthesis of Compound 16

[0280] Step 1: Synthesis of Compound 16-1

[0281] Compound 15-6 (synthesized as described in the third step of the synthesis of compound 15-6 in Example 6) (120 mg, 0.34 mmol) was dissolved in toluene (10 mL), and compound 2-4 (synthesized as described in the second step of the synthesis of compound 2-4 in Example 2) (40.5 mg, 0.34 mmol), tris(dibenzylacetone)dipalladium (31.13 mg, 0.034 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (39.35 mg, 0.068 mmol), and sodium tert-butoxide (98.02 mg, 1.02 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–15%) to give compound 16-1 (71 mg). MS m / z (ESI): 438.0 [M+1] +

[0282] Step 2: Synthesis of Compound 16

[0283] Compound 16-1 (66 mg, 0.15 mmol) was dissolved in toluene (10 mL), and compound 1-10 (15.17 mg, 0.15 mmol), tris(dibenzylacetone)dipalladium (13.74 mg, 0.015 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (17.36 mg, 0.030 mmol), and sodium tert-butoxide (43.24 mg, 0.45 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (water / methanol = 0%–10%) to give compound 16 (20.33 mg). MS m / z (ESI): 503.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.38 (s, 1H), 6.86 (s, 1H), 6.23 (d, J = 7.8Hz, 1H), 5.77 ( s,1H),4.13(s,2H),4.06(t,J=6.5Hz,2H),3.93(d,J=9.3Hz,2H),3.84(s,3H),3 .80–3.70(m,1H),3.61(t,J=6.9Hz,2H),3.49(t,J=11.1Hz,2H),2.69(s,2H),2 .54(d,J=7.1Hz,2H),2.44(s,4H),1.99–1.90(m,4H),1.69(s,4H),1.61(m,2H).

[0284] Example 8 Synthesis of Compound 17

[0285] Step 1: Synthesis of Compound 17-1

[0286] Compound 15-6 (200 mg, 0.56 mmol) was dissolved in toluene (10 mL), and compound 1-12 (82.01 mg, 0.62 mmol), tris(dibenzylacetone)dipalladium (51.28 mg, 0.056 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (64.81 mg, 0.11 mmol), and sodium tert-butoxide (161.45 mg, 1.68 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%) to give compound 17-1 (150 mg). MS m / z (ESI): 452.1 [M+1] + .

[0287] Step 2: Synthesis of Compound 17

[0288] Compound 17-1 (150 mg, 0.33 mmol) was dissolved in toluene (10 mL), and compound 1-10 (36.72 mg, 0.36 mmol), tris(dibenzylacetone)dipalladium (30.22 mg, 0.033 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (38.19 mg, 0.066 mmol), and sodium tert-butoxide (63.43 mg, 0.66 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–100%) to give compound 17 (17.2 mg). MS m / z (ESI): 517.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.40(s,1H),6.92(s,1H),6.27(d,J=8.0Hz,1 H),6.03(s,1H),4.09(t,J=6.1Hz,2H),3.93(d,J=9.1Hz,2H),3.85(s,3H),3.83–3. 76(m,1H),3.72–3.60(m,4H),3.51(t,J=11.2Hz,2H),2.85–2.81(m,6H),2.20(s,4 H), 2.03 (t, J = 11.2Hz, 2H), 1.94 (d, J = 10.7Hz, 2H), 1.81 (s, 4H), 1.62–1.56 (m, 2H).

[0289] Example 9 Synthesis of Compound 18

[0290] Step 1: Synthesis of Compound 18-1

[0291] Compound 15-6 (90 mg, 0.25 mmol) was dissolved in toluene (10 mL), and compound 4-4 (synthesized as described in the second step of Compound 4 in Example 5) (31.67 mg, 0.28 mmol), tris(dibenzylacetone)dipalladium (22.89 mg, 0.025 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (28.93 mg, 0.050 mmol), and sodium tert-butoxide (72.07 mg, 0.75 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–15%) to give compound 18-1 (83 mg). MS m / z (ESI): 434.0 [M+1] + .

[0292] Step 2: Synthesis of Compound 18

[0293] Compound 18-1 (73 mg, 0.17 mmol) was dissolved in toluene (10 mL), and compound 1-10 (18.92 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (15.57 mg, 0.017 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (19.67 mg, 0.034 mmol), and sodium tert-butoxide (32.67 mg, 0.34 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (water / methanol = 0%–10%) to give compound 18 (35.86 mg). MS m / z (ESI): 499.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H),7.09(s,1H),6.80(d,J=86.7Hz,1H),6.61(brs,1H),6.04(s,1H),4.13(s,2H),3.93(d,J=6.7Hz,2H),3.86( s,3H),3.66(d,J=4.7Hz,4H),3.51(t,J=11.0Hz,2H),3.37–3.30(m,1H) ,3.13(s,6H),2.33(s,2H),2.12(s,4H),1.92(m,6H),1.69–1.60(m,2H).

[0294] Example 10 Synthesis of Compound 49

[0295] Step 1: Synthesis of Compound 49

[0296] Under nitrogen protection at room temperature, compound 49-1 (4-amino-1-methylpiperidine) (9.0 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (7.6 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium (6.0 mg, 0.0066 mmol), and sodium tert-butoxide (19.0 mg, 0.20 mmol) were added to a toluene (3 mL) solution of compound 17-1 (synthesized as described in Example 8, the first step of the synthesis of compound 17-1) (30.0 mg, 0.06 mmol). The reaction mixture was stirred at 130 °C for 16 hours. The reaction solution was quenched with aqueous solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (water (0.1 formic acid) / methanol = 100 / 0~5 / 1) to give compound 49 (2.2 mg). MS m / z (ESI): 530.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.37(s,1H),6.85(s,1H),6.18(d,J=7.7Hz,1H),5.96(s,1H),4.06(t,J=8.0Hz,2H),3.83(s,3H),3.63(s ,4H),3.17(s,3H),2.96–2.75(m,5H),2.55(s,4H),2.25(s,2H),2.19(s,4H),2.02–1.94(m,4H),1.71(s,4H),1.65–1.59(m,2H).

[0297] Example 11 Synthesis of Compound 52

[0298] Step 1: Synthesis of Compound 52

[0299] Compound 17-1 (30 mg, 0.066 mmol) was dissolved in toluene (5 mL), and compound 52-1 (1-ethylpiperidin-4-amine) (9.31 mg, 0.073 mmol), tris(dibenzylacetone)dipalladium (6.04 mg, 0.0066 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (7.64 mg, 0.013 mmol), and sodium tert-butoxide (12.69 mg, 0.13 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (water / methanol = 0%–10%) to give compound 52 (5.73 mg). MS m / z (ESI): 544.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.39 (s, 1H), 6.87 (s, 1H), 6.25 (d, J = 7.7Hz, 1H), 5.97 (s, 1H) ,4.07(t,J=6.2Hz,3H),3.84(s,3H),3.74(s,4H),3.02(d,J=10.5Hz,2H),2.90(s,2H ),2.74(s,2H),2.71(d,J=7.0Hz,1H),2.66(s,4H),2.27(d,J=11.4Hz,2H),2.20(s,4 H), 2.00 (d, J = 7.0Hz, 4H), 1.75 (s, 4H), 1.65 (d, J = 10.8Hz, 2H), 1.07 (t, J = 6.9Hz, 3H).

[0300] Example 12 Synthesis of Compound 55

[0301] Step 1: Synthesis of Compound 55

[0302] Compound 17-1 (30 mg, 0.066 mmol) was dissolved in toluene (5 mL), and compound 32-1 (10.33 mg, 0.073 mmol), tris(dibenzylacetone)dipalladium (6.04 mg, 0.0066 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (7.64 mg, 0.013 mmol), and sodium tert-butoxide (12.69 mg, 0.13 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (water / methanol = 0%–10%) to give compound 55 (15.2 mg). MS m / z (ESI): 558.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.36 (s, 1H), 6.83 (s, 1H), 6.14 (d, J = 8.0Hz, 1H), 5.96 (s, 1H) ),4.05(t,J=6.5Hz,2H),3.83(s,3H),3.67–3.59(m,4H),2.82(d,J=11.2Hz,2H),2. 70(t,J=6.0Hz,2H),2.61–2.50(m,2H),2.44(s,4H),2.30–2.25(m,2H),2.18(d,J=5 .4Hz,4H),1.97–1.93(m,4H),1.69(s,4H),1.67-1.58(m,2H),0.99(d,J=6.5Hz,6H).

[0303] Example 13 Synthesis of Compound 59

[0304] Step 1: Synthesis of Compound 59. Compound 17-1 (50 mg, 0.11 mmol) was dissolved in toluene (5 mL), and compound 59-1 (4-amino-1-cyclopropylpiperidine) (16.97 mg, 0.12 mmol), tris(dibenzylacetone)dipalladium (10.07 mg, 0.011 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (12.73 mg, 0.022 mmol), and sodium tert-butoxide (21.14 mg, 0.22 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (water / methanol = 0%–10%) to obtain compound 59 (5.88 mg). MS m / z (ESI): 556.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.36(s,1H),6.87(s,1H),6.18(d,J=7.8Hz,1H),5.98(s,1H),4.07(t,J=6.2Hz,2H),3.83(s,3H),3.66–3. 63(m,4H),2.98(d,J=11.7Hz,2H),2.72(t,J=7.2Hz,2H),2.65(s,4H),2.41–2.32(m,3H),2.20(s,4H),1.97–1.86(m,5H),1.75(s,

[0305] 4H), 1.65–1.60 (m, 1H), 1.54–1.51 (m, 2H), 0.46–0.41 (m, 2H), 0.31 (d, J = 2.9Hz, 2H).

[0306] Example 14 (Compound 128)

[0307] Step 1: Synthesis of Compound 128-2

[0308] Compound 128-1 (958.7 mg, 8.40 mmol) and benzylamine (600 mg, 5.60 mmol) were dissolved in tetrahydrofuran (5 mL). Acetic acid (100.8 mg, 1.68 mmol) and sodium triacetoxyborohydride (2.37 g, 11.20 mmol) were added sequentially. The reaction mixture was heated to 40 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 128-2 (0.60 g). MS m / z (ESI): 206.2 [M+1] + .

[0309] Step 2: Synthesis of Compound 128-3

[0310] Palladium on carbon (60.0 mg) was added to a methanol (6 mL) solution of compound 128-2 (0.60 g, 8.95 mmol). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 128-3 (80 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 116.1 [M+1] + .

[0311] Step 3: Synthesis of Compound 128

[0312] Under nitrogen protection, sodium tert-butoxide (31.9 mg, 0.33 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (13.8 mg, 0.022 mmol), and tris(dibenzylideneacetone)palladium (10.1 mg, 0.011 mmol) were added sequentially to a toluene (3.0 mL) solution of compound 128-3 (19.1 mg, 0.17 mmol) and compound 17-1 (50.0 mg, 0.11 mmol, synthesized as described in Example 8). The reaction mixture was heated to 120 °C and stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (Gemini 5μm C18 column 150*21.2mm; flow rate 20mL / min; acetonitrile: 0.1% formic acid aqueous solution; gradient: 40-60%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 128 (20.0mg). MS m / z (ESI): 531.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.42(s,1H),6.87(s,1H),6.09(d,J=5.2Hz,1H),5.93( s,1H),4.07(t,J=6.4Hz,2H),4.03–3.97(m,1H),3.95–3.84(m,1H),3.83(s,1H),3.82–3.69( m,2H),3.64(t,J=5.6Hz,4H),2.70–2.60(m,2H),2.59–2.54(m,4H),2.23–2.14(m,4H),2.01– 1.91(m,2H),1.90–1.79(m,2H),1.78–1.67(m,5H),1.62–1.50(m,1H),1.12(d,J=6.4Hz,3H).

[0313] Example 15 (Compound 125)

[0314] Step 1: Synthesis of Compound 125-2

[0315] At room temperature, benzylamine (467.1 mg, 4.39 mmol), glacial acetic acid (238.0 mg, 3.96 mmol), and sodium triacetoxyborohydride (1.68 g, 7.92 mmol) were added sequentially to a tetrahydrofuran (5 mL) solution of compound 125-1 (500 mg, 3.96 mmol). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 125-2 (500 mg). MS m / z (ESI): 218.1 [M+1] + .

[0316] Step 2: Synthesis of Compound 125-3

[0317] At room temperature, 20 mg of palladium on carbon was added to a 2 mL methanol solution of compound 125-2 (200 mg, 0.92 mmol). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 125-3 (100 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 128.1 [M+1] + .

[0318] Step 3: Synthesis of Compound 125

[0319] At room temperature, compound 125-3 (28.1 mg, 0.22 mmol), tris(dibenzylacetone)palladium (10.1 mg, 0.01 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (20.6 mg, 0.03 mmol) and sodium tert-butoxide (31.9 mg, 0.33 mmol) were added sequentially to a toluene (0.5 mL) solution of compound 17-1 (50 mg, 0.11 mmol, synthesis method as described in Example 8). The reaction mixture was heated to 120 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 125 (30.4mg). MS m / z (ESI): 543.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.21 (s, 1H), 7.28 (s, 1H), 6.88 (s, 1H), 6.06 (d, J = 2.0Hz, 1H),5.81(s,1H),4.31(s,2H),4.08(t,J=6.4Hz,2H),3.85(s,4H),3.64(t,J=5.4H z,4H),2.67(t,J=7.0Hz,2H),2.61–2.57(m,4H),2.22–2.14(m,6H),2.13–2.07(m ,2H),2.00–1.94(m,2H),1.92–1.86(m,2H),1.85–1.79(m,2H),1.76–1.70(m,4H).

[0320] Example 16 (Compound 122)

[0321] Step 1: Synthesis of Compound 122-2

[0322] Compound 122-1 (500 mg, 2.36 mmol) was dissolved in dichloromethane (10 mL) under ice bath conditions. Formaldehyde aqueous solution (2.3 g, 30.62 mmol, 40% wt), glacial acetic acid (70.7 mg, 1.18 mmol), and sodium cyanoborohydride (296 mg, 4.71 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) was added to the reaction solution, followed by washing with water (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 122-2 (150 mg). 1 H NMR (400MHz, CDCl3) δ4.56(s,1H),3.90(s,1H),3.18(s,2H),3.09(s,2H),2.50–2.41(m,2H),2.22(s,3H),1.89–1.82(m,2H),1.35(s,9H).

[0323] Step 2: Synthesis of Compound 122-3

[0324] Under ice bath conditions, a 4.0 M, 2 mL solution of 1,4-dioxane chloride was added to a 2 mL solution of 1,4-dioxane in compound 122-2 (150 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 122-3 (100 mg, crude product). The product was used directly in the next step without purification. 1H NMR(400MHz,CD3OD)δ4.41(dd,J=10.8,2.4Hz,1H),4.31(dd,J=10.8,2.0Hz,1H),4.14–4.05(m ,2H),3.81–3.70(m,1H),2.89(s,3H),2.86–2.79(m,1H),2.77–2.68(m,1H),2.56–2.44(m,2H).

[0325] Step 3: Synthesis of Compound 122

[0326] At room temperature, sodium tert-butoxide (36.6 mg, 0.28 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (13.8 mg, 0.022 mmol), and tris(dibenzylideneacetone)palladium (10.1 mg, 0.011 mmol) were added sequentially to a mixed solution of compound 122-3 (27.9 mg, 0.22 mmol) and compound 17-1 (50.0 mg, 0.11 mmol, synthesized according to the method described in Example 8 for the synthesis of compound 17-1). The reaction mixture was heated to 120 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; acetonitrile: 0.1% trifluoroacetic acid aqueous solution); gradient: 40-60%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 122 (10.8mg). MS m / z (ESI): 542.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),10.01(s,1H),9.70(s,1H),8.13(d,J=4.8Hz,1H),7.68 (s,1H),7.39(s,1H),5.73(s,1H),4.42–4.31(m,1H),4.27–4.09(m,6H),4.05–3.94(m,1H),3 .89(s,3H),3.80–3.71(m,2H),3.63(d,J=5.6Hz,2H),3.34–3.29(m,2H),3.11–3.01(m,2H),2 .90–2.76(m,5H),2.46–2.29(m,7H),2.26–2.15(m,2H),2.11–1.98(m,2H),1.96–1.81(m,2H).

[0327] Example 17 (Compound 121)

[0328] Step 1: Synthesis of Compound 121

[0329] At room temperature, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (8.3 mg, 0.013 mmol), tris(dibenzylacetone)palladium (4.1 mg, 0.004 mmol) and sodium tert-butoxide (12.7 mg, 0.13 mmol) were added sequentially to a mixed solution of compound 17-1 (20.0 mg, 0.044 mmol, synthesized according to the method described in Example 8 for the synthesis of compound 17-1) and compound 121-1 (7.5 mg, 0.066 mmol) in toluene (2 mL). The reaction mixture was heated to 120 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 121 (3.6mg). MS m / z (ESI): 529.30 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.34(s,1H),6.85(s,1H),6.57(d,J=5.6Hz,1H),5.77( s,1H),4.70(s,2H),4.54(s,2H),4.06(t,J=6.2Hz,2H),3.93–3.89(m,1H),3.83 (s,3H),3.67–3.62(m,4H),2.82–2.75(m,2H),2.62(t,J=7.0Hz,2H),2.57–2.5 3(m,4H),2.27–2.21(m,2H),2.21–2.15(m,4H),2.00–1.91(m,2H),1.72(s,4H).

[0330] Example 18 (Compound 145-P1)

[0331] Step 1: Synthesis of compound 145-P1-2

[0332] Under nitrogen protection, iodoethane (142.9 mg, 0.92 mmol) and potassium carbonate (189.9 mg, 1.37 mmol) were added to a solution of compound 145-P1-1 (100 mg, 0.46 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 50 °C for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: 100%) to give compound 145-P1-2 (99.0 mg). MS m / z (ESI): 247.25 [M+1] + .

[0333] Step 2: Synthesis of compound 145-P1-3

[0334] Compound 145-P1-2 (120.0 mg, 0.34 mmol) was added to a solution of 1,4-dioxane-2-hydrochloride (2.0 M, 4 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 145-P1-3 (42.0 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 147.1 [M+1] + .

[0335] Step 2: Synthesis of compound 145-P1

[0336] At room temperature, compound 145-P1-3 (14.5 mg, 0.10 mmol) and compound 17-1 (30 mg, 0.066 mmol, synthesis method referred to in Example 8, Synthesis of Compound 17-1) were dissolved in toluene (2 mL) solution, and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (8.2 mg, 0.013 mmol), tris(dibenzylideneacetone)palladium (6.1 mg, 0.007 mmol) and sodium tert-butoxide (19.1 mg, 0.20 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 145-P1 (7.5mg). MS m / z (ESI): 562.5 [M+1] + . 1H NMR (400MHz, DMSO-d6 / D2O) δ7.48(s,1H),6.93(s,1H),6.03(s,1H),4.90(d,J=50.0H z,1H),4.11(t,J=6.0Hz,2H),3.92–3.81(m,4H),3.69–3.63(m,4H),3.23–3.14(m,1H ),3.11–3.03(m,6H),3.01–2.94(m,1H),2.49–2.32(m,4H),2.24–2.14(m,6H),2.11( d, J=6.7Hz, 1H), 1.89 (d, J=6.2Hz, 4H), 1.76 (d, J=12.0Hz, 1H), 1.03 (t, J=7.2Hz, 3H).

[0337] Example 19 (Compound 145-P2)

[0338] Step 1: Synthesis of compound 145-P2-2

[0339] Under nitrogen protection, iodoethane (142.9 mg, 0.92 mmol) and potassium carbonate (189.9 mg, 1.37 mmol) were added to a solution of compound 145-P2-1 (100 mg, 0.46 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 50 °C for 8 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: 100%) to give compound 145-P2-2 (79.0 mg). MS m / z (ESI): 247.1 [M+1] + .

[0340] Step 2: Synthesis of compound 145-P2-3

[0341] Compound 145-P2-2 (79.0 mg, 0.32 mmol) was added to a solution of 1,4-dioxane (2.0 M, 4 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 145-P2-3 (61.0 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 147.2 [M+1] + .

[0342] Step 3: Synthesis of compound 145-P2

[0343] Under nitrogen protection, compound 145-P2-3 (9.7 mg, 0.066 mmol) and compound 17-1 (20 mg, 0.044 mmol) were dissolved in toluene (1.0 mL) solution, and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (5.5 mg, 0.009 mmol), tris(dibenzylacetone)palladium (4.1 mg, 0.004 mmol) and sodium tert-butoxide (12.7 mg, 0.13 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 4 hours under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 145-P2 (7.5mg). MS m / z (ESI): 562.5 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.46 (s, 1H), 6.88 (s, 1H), 6.23 (d, J = 8.4Hz, 1H), 6.03 (s, 1H),4.88(d,J=50.0Hz,1H),4.08(t,J=6.4Hz,2H),3.91–3.80(m,4H),3.69–3.61( m,4H),3.20–3.11(m,1H),2.99–2.92(m,1H),2.86–2.70(m,6H),2.45–2.29(m,3H ),2.25–2.09(m,6H),2.05–1.97(m,2H),1.83–1.70(m,5H),1.02(t,J=7.2Hz,3H).

[0344] Example 20 (Compound 144)

[0345] Step 1: Synthesis of Compound 144

[0346] Under nitrogen protection, compound 17-1 (30.0 mg, 0.066 mmol, synthesis method referred to in Example 8 for the synthesis of compound 17-1) and compound 144-1 (6.7 mg, 0.066 mmol) were dissolved in toluene (1.0 mL) solution, and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (3.8 mg, 0.007 mmol), tris(dibenzylideneacetone)dipalladium (6.1 mg, 0.007 mmol) and sodium tert-butoxide (19.1 mg, 0.19 mmol) were added sequentially. The mixture was heated to 120 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 144 (6.0mg). MS m / z (ESI): 517.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.40(s,1H),6.86(s,1H),6.64(d,J=5.2Hz,1H),5.75(brs,1H),5.01(s,1H),4.07(t,J=6.4Hz,2H),3.83(s,3H ),3.67–3.61(m,5H),2.70–2.66(m,2H),2.62–2.58(m,4H),2.23–2.17(m, 4H),2.15–2.03(m,2H),2.01–1.92(m,4H),1.75–1.70(m,4H),1.34(s,3H).

[0347] Example 21 (Compound 160)

[0348] Step 1: Synthesis of Compound 160-2

[0349] Compound 160-1 (200.0 mg, 0.99 mmol) and cyclobutanone (84 mg, 1.2 mmol) were dissolved in ethanol (5 mL), and palladium on carbon (40.0 mg) was added. The reaction mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 160-2 (120.0 mg). MS m / z (ESI): 199.1 [M-55] + .

[0350] Step 2: Synthesis of Compound 160-3

[0351] Compound 160-2 (120 mg, 0.47 mmol) was added to a solution of 1,4-dioxane (1.6 mL, 4 M) of hydrogen chloride. The reaction mixture was stirred at room temperature for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was freeze-dried to give compound 160-3 (70.0 mg). MS m / z (ESI): 155.3 [M+1] + .

[0352] Step 3: Synthesis of Compound 160

[0353] Under nitrogen protection, compound 160-3 (17.1 mg, 0.11 mmol) and compound 17-1 (50.0 mg, 0.11 mmol, synthetic method as described in Example 8, Synthesis of Compound 17-1) were dissolved in toluene (2 mL), and sodium tert-butoxide (26.6 mg, 0.28 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (13.8 mg, 0.022 mmol), and tris(dibenzylacetone)palladium (10.13 mg, 0.011 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; acetonitrile: 0.1% trifluoroacetic acid aqueous solution); gradient: 15-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 160 (11.5mg). MS m / z (ESI): 570.55 [M+1] + . 1 H NMR (400MHz, DMSO-d6)11.66(s,1H),9.77(s,1H),9.62(s,1H),7.80(d,J=6.8Hz,1H),7 .73(s,1H),7.40(s,1H),5.97(s,1H),4.15(t,J=5.6Hz,2H),4.11–3.99(m,1H),3.90(s, 3H),3.80–3.72(m,4H),3.68–3.59(m,3H),3.56–3.48(m,3H),3.11–3.03(m,2H),3.01–2 .90(m,2H),2.40–2.34(m,4H),2.28–2.16(m,8H),2.12–1.98(m,3H),1.94–1.72(m,6H).

[0354] Example 22 (Compound 158)

[0355] Step 1: Synthesis of Compound 158-2

[0356] At room temperature, 1-methylcyclopropylamine hydrochloride (71.1 mg, 31.64 mmol) and sodium bicarbonate (53.2 mg, 0.63 mmol) were added sequentially to a mixed solution of compound 158-1 (900 mg, 6.3 mmol) in toluene and water (20 mL / 1.3 mL). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 158-2 (300 mg). 1 H NMR (400MHz, CDCl3) δ2.85 (t, J = 6.0 Hz, 4H), 2.32 (t, J = 6.0 Hz, 4H), 0.99 (s, 3H), 0.60–0.53 (m, 2H), 0.35–0.31 (m, 2H).

[0357] Step 2: Synthesis of Compound 158-3

[0358] Under nitrogen protection, benzylamine (0.28 mL, 2.54 mmol), acetic acid (0.11 mL, 1.96 mmol), and sodium triacetoxyborohydride (829.9 mg, 3.92 mmol) were added sequentially to a tetrahydrofuran (10 mL) solution of compound 158-2 (300 mg, 1.96 mmol). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 158-3 (110 mg). MS m / z (ESI): 245.1 [M+1] + .

[0359] Step 3: Synthesis of Compound 158-4

[0360] At room temperature, palladium on carbon (13.1 mg, 0.12 mmol) was added to a methanol (2 mL) solution of compound 158-3 (95 mg, 0.62 mmol). The reaction mixture was heated to 40 °C and stirred for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 158-4 (80 mg crude product). The product was used directly in the next reaction without purification. 1H NMR (400MHz, DMSO-d6) δ3.41–3.25(m,5H),2.15–2.05(m,3H),1.42–1.33(m,3H),1.30(s,3H),0.75–0.66(m,2H).

[0361] Step 4: Synthesis of Compound 158

[0362] Under nitrogen protection, compound 158-4 (40.9 mg, 0.27 mmol) and compound 17-1 (60.0 mg, 0.13 mmol, synthesis method referred to in Example 8, Synthesis of Compound 17-1) were dissolved in toluene (3.0 mL), and sodium tert-butoxide (31.9 mg, 0.33 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (16.5 mg, 0.027 mmol) and tris(dibenzylideneacetone)palladium (12.2 mg, 0.013 mmol) were added sequentially. The reaction mixture was stirred at 120 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; acetonitrile: 0.1% trifluoroacetic acid aqueous solution); gradient: 40-60%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 158 (12.3mg). MS m / z (ESI): 570.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.69(s,1H),9.28(s,1H),7.80(d,J=7.2Hz,1H),7.74 (s,1H),7.41(s,1H),5.97(s,1H),4.18–4.07(m,2H),3.88(s,3H),3.80–3.76(m,3H),3.66–3 .61(m,3H),3.51–3.46(m,4H),3.35–3.30(m,2H),3.10–3.02(m,2H),2.41–2.35(m,4H),2.2 6–2.18(m,4H),2.08–2.02(m,2H),1.94–1.83(m,4H),1.40(s,3H),1.20(s,2H),0.81(s,2H).

[0363] Example 23 (Compound 154-P2)

[0364] Step 1: Synthesis of compound 154-P2-2

[0365] Under nitrogen protection, compound 154-P2-1 (104.5 mg, 0.44 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (55.1 mg, 0.089 mmol), tris(dibenzylacetone)dipalladium (40.5 mg, 0.044 mmol), and sodium tert-butoxide (63.8 mg, 0.66 mmol) were added sequentially to a toluene (2 mL) solution of compound 17-1 (100 mg, 0.221 mmol, synthesis method as described in Example 8). The reaction mixture was stirred at 120 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-30%) to give compound 154-P2-2 (35 mg). MS m / z (ESI): 652.35 [M+1] + .

[0366] Step 2: Synthesis of compound 154-P2-3

[0367] Under ice bath conditions, a solution of 1,4-dioxane (4.0 M, 0.09 mL, 3.68 mmol) was added to a solution of compound 154-P2-2 (24 mg, 0.037 mmol) in dichloromethane (0.2 mL). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, triethylamine was slowly added dropwise to adjust the pH to 8. The solution was then concentrated under reduced pressure to obtain compound 154-P2-3 (24 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 552.37 [M+1] + .

[0368] Step 3: Synthesis of compound 154-P2

[0369] Compound 154-P2-4 (15.2 mg, 0.087 mmol) and sodium triacetoxyborohydride (9.2 mg, 0.044 mmol) were added to a solution of compound 154-P2-3 (24 mg, 0.044 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18, 19 × 150 mm, 5 μm; mobile phase: acetonitrile:water (0.1% trifluoroacetic acid); gradient: 22-55%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 154-P2 (2.7 mg). MS m / z (ESI): 592.45 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),9.63(s,1H),7.80(s,1H),7.62(d,J=8.8Hz,1H),7.42(s ,1H),6.24(s,1H),4.78–4.58(m,1H),4.16(t,J=5.6Hz,2H),3.90(s,3H),3.82–3.73(m,4H),3 .66–3.61(m,2H),3.25–3.16(m,2H),3.13–2.98(m,4H),2.91–2.79(m,1H),2.38–2.32(m,4H), 2.26–2.19(m,2H),2.14–1.99(m,4H),1.94–1.83(m,4H),0.59–0.44(m,2H),0.44–0.27(m,2H).

[0370] Example 24 (Compound 153-P1)

[0371] Step 1: Synthesis of compound 153-P1-1

[0372] At room temperature, compound 154-P2-4 (998.3 mg, 5.73 mmol) and acetic acid (137.6 mg, 2.29 mmol) were added sequentially to a mixed solution of compound 145-P1-1 (250.0 mg, 1.15 mmol) in methanol and tetrahydrofuran (5 mL / 5 mL). The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of sodium cyanoborohydride (215.9 mg, 3.44 mmol). The reaction mixture was stirred at 60 °C for 4 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (40 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give compound 153-P1-1 (200 mg). MS m / z (ESI): 259.25 [M+1] + .

[0373] Step 2: Synthesis of compound 153-P1-2

[0374] Compound 153-P1-1 (200 mg, 0.77 mmol) was dissolved in 1,4-dioxane hydrochloride (4.0 M, 5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 153-P1-2 (100 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 159.20 [M+1]+ .

[0375] Step 3: Synthesis of compound 153-P1

[0376] Under nitrogen protection, compound 153-P1-2 (40 mg, 0.25 mmol), tris(dibenzylacetone)palladium (46.3 mg, 0.05 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (63.0 mg, 0.10 mmol) and sodium tert-butoxide (72.9 mg, 0.76 mmol) were added sequentially to a toluene (3 mL) solution of compound 17-1 (114.3 mg, 0.25 mmol, synthesis method referred to in Example 8 for the synthesis of compound 17-1). The reaction mixture was stirred at 110 °C for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 153-P1 (9.9mg). MS m / z (ESI): 574.45 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1.59H),7.43(s,1H),6.87(s,1H),6.16(d,J=7.8Hz,1H) ,6.04(s,1H),4.86(d,J=49.6Hz,1H),4.07(t,J=6.4Hz,2H),3.83–3.81(m,4H),3.67–3.6 4(m,4H),3.22–3.18(m,1H),3.02(d,J=9.8Hz,1H),2.71–2.59(m,7H),2.45–2.43(m,1H), 2.19(s,4H),2.07–1.94(m,3H),1.77–1.69(m,6H),0.46–0.44(m,2H),0.35–0.25(m,2H).

[0377] Example 25 (Compound 153-P2)

[0378] Step 1: Synthesis of compound 153-P2-1

[0379] Sodium cyanoborohydride (57.6 mg, 0.92 mmol) and glacial acetic acid (137.6 mg, 2.29 mmol) were added sequentially to a mixed solution of compound 145-P2-1 (100 mg, 0.46 mmol) and compound 154-P2-5 (399.3 mg, 2.29 mmol) in methanol and tetrahydrofuran (2 mL / 2 mL). The reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 153-P2-1 (100 mg). MS m / z (ESI): 259.25 [M+1] + .

[0380] Step 2: Synthesis of compound 153-P2-2

[0381] Under ice bath conditions, a 4.0 M, 2 mL solution of 1,4-dioxane-1,4-hydrochloride was added to a 2 mL solution of 1,4-dioxane (100 mg, 0.39 mmol) of compound 153-P2-1. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 153-P2-2 (80 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 159.2 [M+1] + .

[0382] Step 3: Synthesis of compound 153-P2

[0383] Under nitrogen protection, sodium tert-butoxide (38.3 mg, 0.39 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (16.5 mg, 0.027 mmol) and tris(dibenzylideneacetone)palladium (12.2 mg, 0.013 mmol) were added sequentially to a toluene (3 mL) solution of compound 153-P2-2 (31.5 mg, 0.19 mmol) and compound 17-1 (60.0 mg, 0.13 mmol). The reaction mixture was stirred at 120 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; acetonitrile: 0.1% trifluoroacetic acid aqueous solution); gradient: 40-60%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 153-P2 (5.1mg). MS m / z (ESI): 574.4 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.89(s,1H),7.95–7.62(m,2H),7.47(s,1H),6 .04(s,1H),5.17(d,J=43.7Hz,1H),4.57–4.29(m,1H),4.16(t,J=5.4Hz,2H),3.90(s, 3H),3.72(s,4H),3.70–3.55(m,5H),3.36–3.29(m,2H),3.12–3.01(m,2H),2.44–2.3 0(m,6H),2.28–2.17(m,2H),2.13–1.98(m,4H),1.95–1.82(m,2H),1.14–0.50(m,4H).

[0384] Example 26 (Compound 163)

[0385] Step 1: Synthesis of Compound 163-2

[0386] At room temperature, compound 163-1 (440.1 mg, 4.94 mmol), potassium carbonate (2.05 g, 14.82 mmol), and potassium iodide (1.64 g, 9.88 mmol) were added sequentially to a solution of compound 1-4 (1.50 g, 4.94 mmol, synthesized as described in Example 1, Synthesis of Compound 1-4) in 60 mL of acetonitrile. The reaction mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give compound 163-2 (1.20 g). MS m / z (ESI): 357.10 [M+1] + .

[0387] Step 2: Synthesis of Compound 163-3

[0388] At room temperature, palladium on carbon (300 mg) was added to a 20 mL ethanol solution of compound 163-2 (1.20 g, 3.37 mmol), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 163-3 (1.00 g, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 327.10 [M+1] + .

[0389] Step 3: Synthesis of Compound 163-4

[0390] Potassium cyanate (671.1 mg, 8.27 mmol) was added to a mixed solution of compound 163-3 (900 mg, 2.76 mmol) in acetic acid and water (10 mL / 0.5 mL). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was then cooled to room temperature, and potassium hydroxide (773.7 mg, 13.79 mmol) was added. The reaction mixture was stirred at 80 °C for another 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with diethyl ether to give compound 163-4 (550 mg). MS m / z (ESI): 338.05 [M+1] + .

[0391] Step 4: Synthesis of Compound 163-5

[0392] Compound 163-4 (550 mg, 1.63 mmol) was dissolved in phosphorus oxychloride (10 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was quenched with ice water (50 mL). The pH was adjusted to 9 with saturated potassium hydroxide aqueous solution (20 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1:0–9:1) to give compound 163-5 (400 mg). MS m / z (ESI): 374.05 [M+1] + .

[0393] Step 5: Synthesis of compound 163-6

[0394] At room temperature, compound 59-1 (149.9 mg, 1.07 mmol) and N,N-diisopropylethylamine (414.4 mg, 3.21 mmol) were added sequentially to a solution of compound 163-5 (400.0 mg, 1.07 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1:0–9:1) to give compound 163-6 (180.0 mg). MS m / z (ESI): 478.30 [M+1] + .

[0395] Step 6: Synthesis of Compound 163

[0396] At room temperature, compounds 1-12 (30.6 mg, 0.23 mmol) and N,N-diisopropylethylamine (89.2 mg, 0.69 mmol) were added sequentially to N,N-dimethylformamide (4 mL) of compound 163-6 (110 mg, 0.23 mmol), and the reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were then washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-80%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 70 bar) to obtain compound 163 (40.6 mg). MS m / z (ESI): 575.55 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),10.49(s,1H),9.85–9.66(m,1H),9.12(s,1H) ),7.81(s,1H),7.30(s,1H),5.51(d,J=51.6Hz,1H),4.39(s,1H),4.17(t,J=5.6Hz ,2H),4.04–3.73(m,9H),3.67–3.65(m,2H),3.36–3.21(m,6H),2.81(s,1H),2.34( s,4H),2.28–2.07(m,6H),1.89–1.86(m,2H),1.02–1.01(m,2H),0.85–0.83(m,2H).

[0397] Example 27 (Compound 144-P1)

[0398] Step 1: Synthesis of compound 144-P1

[0399] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.7 mg, 0.004 mmol), tris(dibenzylideneacetone)dipalladium (4.0 mg, 0.004 mmol) and sodium tert-butoxide (12.7 mg, 0.133 mmol) were added sequentially to a toluene (1.5 mL) solution of compound 17-1 (20 mg, 0.044 mmol, synthesized as described in Example 8) and compound 144-P1-1 (6.7 mg, 0.066 mmol). The reaction mixture was stirred at 120 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-70%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 144-P1 (5.8mg). MS m / z (ESI): 517.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.25(s,2H),7.40(s,1H),6.90(s,1H),5.68(s,1H),4.14–4.04(m,3H),3.84(s,3H),3.63(t,J= 5.4Hz,4H),2.92–2.79(m,6H),2.49–2.43(m,2H),2.26–2.14(m,4H),2.10–1.98(m,5H),1.84–1.77(m,4H),1.32(s,3H).

[0400] Example 28 (Compound 118)

[0401] Step 1: Synthesis of Compound 118

[0402] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (13.8 mg, 0.022 mmol), tris(dibenzylacetone)dipalladium (10.1 mg, 0.011 mmol) and sodium tert-butoxide (31.9 mg, 0.33 mmol) were added sequentially to a toluene (2.0 mL) solution of compound 17-1 (50 mg, 0.11 mmol) and compound 118-1 (27.9 mg, 0.221 mmol). The reaction mixture was stirred at 120 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 118 (6.3mg). MS m / z (ESI): 542.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6 / D2O) δ7.64(s,1H),7.34(s,1H),6.01(s,1H),4.16(t,J=5.6Hz,2H),3.91(s,3H),3.69–3.59(m,3H),3.55– 3.45(m,6H),3.39–3.25(m,3H),3.10–3.02(m,2H),2.43–2.32(m,10H),2.28–2.15(m,3H),2.13–1.99(m,3H),1.94–1.85(m,2H).

[0403] Example 29 (Compound 23)

[0404] Step 1: Synthesis of Compound 23-2

[0405] Under nitrogen protection, potassium tert-butoxide (3.38 g, 30.11 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 23-1 (6.99 g, 15.06 mmol). The reaction mixture was stirred at 70 °C for 2 hours, followed by the addition of compound 4-1 (2 g, 10.04 mmol). The reaction mixture was then stirred at 70 °C for another 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with petroleum ether (400 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-5%) to give compound 23-2 (1.70 g). 1H NMR (400MHz, CDCl3) δ3.43 (t, J = 5.8 Hz, 4H), 2.31 (t, J = 5.6 Hz, 4H), 1.48 (s, 9H), 1.03 (s, 4H).

[0406] Step 2: Synthesis of Compound 23-3

[0407] Trifluoroacetic acid (2 mL) was added to a solution of compound 23-2 (0.45 g, 2.02 mmol) in dichloromethane (6 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and then adjusted to pH 7 with saturated sodium bicarbonate solution (10 mL). The reaction solution was extracted with ethyl acetate (10 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 23-3 (180 mg), which was used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ3.16–3.01(m,4H),2.49–2.44(m,4H),1.06(s,4H).

[0408] Step 3: Synthesis of Compound 23-4

[0409] Under a nitrogen atmosphere, compound 15-6 (150 mg, 0.42 mmol, synthesized according to step 3 of Example 6), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (48.8 mg, 0.08 mmol), tris(dibenzylacetone)dipalladium (38.6 mg, 0.04 mmol), and sodium tert-butoxide (81.1 mg, 0.84 mmol) were added sequentially to a toluene (3 mL) solution of compound 23-3 (156.6 mg, 0.63 mmol). The reaction mixture was stirred at 90 °C for 1.5 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-20%) to obtain compound 23-4 (120 mg). MS m / z(ESI): 442.20 [M+1] + .

[0410] Step 4: Synthesis of Compound 23

[0411] Under nitrogen protection, compounds 23-4 (100 mg, 0.23 mmol) and 1-10 (34.3 mg, 0.34 mmol) were dissolved in toluene (5 mL), and sodium tert-butoxide (43.48 mg, 0.45 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (28.2 mg, 0.045 mmol) and tris(dibenzylacetone)palladium (20.7 mg, 0.023 mmol) were added sequentially. The reaction mixture was stirred at 120 °C for 1.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; acetonitrile: 0.1% trifluoroacetic acid aqueous solution); gradient: 25-65%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 23 (7.2mg). MS m / z (ESI): 507.35 [M+1] + . 1 H NMR (400MHz, DMSO-d6 / D2O) δ7.70(s,1H),7.38(s,1H),6.06(s,1H),4.16(t,J=5.4Hz, 2H),4.13–4.04(m,1H),3.98–3.93(m,2H),3.90(s,3H),3.80–3.71(m,4H),3.67–3.61( m,2H),3.58–3.53(m,2H),3.38–3.29(m,2H),3.12–3.03(m,2H),2.50–2.43(m,4H),2. 26–2.18(m,2H),2.12–2.03(m,2H),1.96–1.86(m,4H),1.78–1.66(m,2H),1.10(s,4H).

[0412] Example 30 (Compound 154-P1)

[0413] Step 1: Synthesis of compound 154-P1-2

[0414] Under nitrogen protection, compounds 154-P1-1 (261.4 mg, 1.11 mmol), tris(dibenzylacetone)palladium (50.7 mg, 0.06 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (68.9 mg, 0.11 mmol), and sodium tert-butoxide (212.6 mg, 2.21 mmol) were added sequentially to a toluene (40 mL) solution of compound 17-1 (500 mg, 1.11 mmol, synthesis method as described in Example 8). The reaction mixture was stirred at 110 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (150 mL), extracted with ethyl acetate (120 mL × 2), and the combined organic phases were washed with saturated brine (200 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-80%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 70 bar. The compound 154-P1-2 (30 mg) was purified. MS m / z (ESI): 652.45 [M+1] + .

[0415] Step 2: Synthesis of compound 154-P1-3

[0416] Compound 154-P1-2 (30.0 mg, 0.05 mmol) was dissolved in a mixed solution of 1,4-dioxane hydrochloride (4.0 M, 0.2 mL) and acetonitrile (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 154-P1-3 (15 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 552.4 [M+1] + .

[0417] Step 3: Synthesis of compound 154-P1

[0418] At room temperature, compound 154-P2-4 (23.7 mg, 0.14 mmol) and acetic acid (3.3 mg, 0.05 mmol) were added sequentially to a mixture of compound 154-P1-3 (15.0 mg, 0.03 mmol) in methanol and tetrahydrofuran (1:1, 4 mL). The reaction mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (3.4 mg, 0.05 mmol) was then added, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with water (4 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was 150*21.2 mm thick; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar. The compound 154-P1 (0.95 mg) was purified. MS m / z (ESI): 592.35 [M+1] + .

[0419] Example 31 (Compound 162)

[0420] Step 1: Synthesis of Compound 162-1

[0421] Compounds 1-9 (140 mg, 0.39 mmol, synthesized according to step 6 of Example 1, intermediate 1-9) were dissolved in N,N-dimethylformamide (20 mL), and compound 59-1 (55.1 mg, 0.39 mmol) and N,N-diisopropylethylamine (152.4 mg, 1.18 mmol) were added. The reaction mixture was stirred at 60 °C for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol:ammonia-methanol solution = 7:3:0.1) to give compound 162-1 (21 mg). MS m / z (ESI): 460.30 [M+1] + .

[0422] Step 2: Synthesis of Compound 162

[0423] At room temperature, compounds 1-12 (8.7 mg, 0.065 mmol) and N,N-diisopropylethylamine (21.1 mg, 0.16 mmol) were added sequentially to N,N-dimethylformamide (3 mL) of compound 162-1 (15 mg, 0.033 mmol), and the reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-80%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 70 bar) to obtain compound 162 (5.1 mg). MS m / z (ESI): 557.45 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.68(s,2H),9.06(s,1H),7.79(s,1H),7.24(s,1H),4.36(s,1H),4.16(t,J=5.5Hz,2H),3.87(s,8H),3.64( s,4H),3.35–3.27(m,4H),3.07(d,J=8.0Hz,2H),2.81(s,1H),2.33(s,4H ),2.21(s,4H),2.05(s,2H),1.91–1.86(m,2H),1.00(s,2H),0.86(s,2H).

[0424] Example 32 (Compound 164)

[0425] Step 1: Synthesis of Compound 164-2

[0426] At room temperature, malonic acid (4.63 g, 44.54 mmol) was added to a phosphorus oxychloride solution (60 mL) containing compound 164-1 (6 g, 29.69 mmol). The reaction mixture was heated to 90 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with dichloromethane (60 mL). Water (60 mL) was slowly added to the mixture under ice bath conditions, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was then extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 15%–25%) to give compound 164-2 (2.10 g). MS m / z (ESI): 305.85, 307.85 [M+1, M+3] + .

[0427] Step 2: Synthesis of Compound 164-3

[0428] At room temperature, compounds 1-12 (173.5 mg, 1.03 mmol), tris(dibenzylacetone)dipalladium (119.3 mg, 0.13 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (75.4 mg, 0.13 mmol), and sodium tert-butoxide (250.5 mg, 2.61 mmol) were added to a 1,4-dioxane solution (1.5 mL) of compound 164-2 (400 mg, 1.303 mmol). The reaction mixture was heated to 90 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water, and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–20%) to give compound 164-3 (100 mg). MS m / z (ESI): 402.95, 404.95 [M+1, M+3] + .

[0429] Step 3: Synthesis of Compound 164-5

[0430] At room temperature, 164-4 (24.3 mg, 0.22 mmol), palladium dichloride bis(triphenylphosphine) (10.4 mg, 0.015 mmol), and cesium carbonate (121.1 mg, 0.37 mmol) were added to a DMF (0.5 mL) solution of compound 164-3 (60 mg, 0.15 mmol). The reaction mixture was heated to 100 °C and stirred for 5 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (1 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%–60%) to give compound 164-5 (30 mg). MS m / z (ESI): 432.10 [M+1] +

[0431] Step 4: Synthesis of Compound 164

[0432] At room temperature, compound 59-1 (6.3 mg, 0.045 mmol), tris(dibenzylacetone)palladium (2.7 mg, 0.003 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.8 mg, 0.003 mmol) and sodium tert-butoxide (7.2 mg, 0.075 mmol) were added to a toluene (1 mL) solution of compound 164-5 (13.0 mg, 0.030 mmol). The reaction mixture was heated to 120 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18; 150×21.2mm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 15-45%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm; column pressure: 80bar) to obtain compound 164 (2.2mg). MS m / z (ESI): 536.2 [M+1] +

[0433] Example 33 (Compound 119)

[0434] Step 1: Synthesis of Compound 119-2

[0435] At room temperature, 0.07 mL (0.1 mmol) of compound 2-bromoethanol and 414 mg (3.0 mmol) of potassium carbonate were added sequentially to a 5 mL solution of compound 119-1 (200 mg, 0.1 mmol). The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give compound 119-2 (200 mg).

[0436] Step 2: Synthesis of Compound 119-3

[0437] Compound 119-2 (150 mg, 0.614 mmol) was dissolved in 1,4-dioxane hydrochloride (2 mL, 4 M), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 119-3 (100 mg). MS m / z (ESI): 144.97 [M+1] + .

[0438] Step 3: Synthesis of compound 119-4

[0439] At room temperature, tert-butyldimethylchlorosilane (83.4 mg, 0.55 mmol) and triethylamine (0.23 mL, 1.66 mmol) were added sequentially to a 2 mL solution of compound 119-3 (100 mg, 0.55 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give compound 119-4 (30 mg). MS m / z (ESI): 259.1 [M+1] + .

[0440] Step 4: Synthesis of compound 119-5

[0441] At room temperature, compound 119-4 (28.6 mg, 0.11 mmol), xantphos (12.8 mg, 0.022 mmol), Pd2(dba)3 (10.1 mg, 0.011 mmol) and sodium tert-butoxide (31.9 mg, 0.33 mmol) were added sequentially to a 2 mL toluene solution of compound 17-1 (50 mg, 0.11 mmol, synthesized as described in Example 8). The reaction mixture was heated to 120 °C and stirred overnight under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic phases were then washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using a Combi-Flash rapid reagent system (C18 reversed-phase column; mobile phase: methanol-water; gradient: 25-100%) to obtain compound 119-5 (40 mg). MS m / z (ESI): 674.0 [M+1] + .

[0442] Step 5: Synthesis of Compound 119

[0443] At room temperature, cesium fluoride (27.1 mg, 0.18 mmol) was added to a solution of compound 119-5 (40 mg, 0.059 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18, 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-30%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 119 (1.99 mg). MS m / z (ESI): 560.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6)8.19(s,2H),7.38(s,1H),6.86(s,1H),6.19(d,J=7.6Hz ,1H),5.96(s,1H),4.07(t,J=5.8Hz,2H),3.84(s,3H),3.64(t,J=5.6Hz,4H),3. 55(t,J=6.4Hz,2H),2.96(d,J=11.8Hz,2H),2.70–2.59(m,6H),2.49–2.20(m,2 H),2.23–2.16(m,5H),2.02–1.92(m,6H),1.76–1.67(m,4H),1.66–1.54(m,2H).

[0444] Example 34 (Compound 141)

[0445] Step 1: Synthesis of Compound 141-2

[0446] Compound 141-1 (1.0 g, 4.07 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 163-1 (399 mg, 4.48 mmol), potassium carbonate (1.69 g, 12.21 mmol), and potassium iodide (1.10 g, 6.11 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 141-2 (670 mg). MS m / z (ESI): 299.0 [M+1] + .

[0447] Step 2: Synthesis of Compound 141-3

[0448] Compound 141-2 (710 mg, 2.38 mmol) was dissolved in methanol (5 mL) at room temperature, and palladium on carbon (71 mg, 0.067 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, diatomaceous earth was added to the reaction solution and stirred for 5 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 141-3 (680 mg). MS m / z (ESI): 269.0 [M+1] + .

[0449] Step 3: Synthesis of Compound 141-4

[0450] Compound 141-3 (630 mg, 2.35 mmol) and malonic acid (0.23 mL, 3.52 mmol) were added to phosphorus oxychloride (25 mL), and the reaction mixture was stirred at 90 °C for 1.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and phosphorus oxychloride was removed by concentration under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 0–20%) to obtain a crude product containing salt. The crude product was redissolved in ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0–20%) to obtain compound 141-4 (440 mg). MS m / z (ESI): 373.0, 374.9 [M+1, M+3] + .

[0451] Step 4: Synthesis of compound 141-5

[0452] Compound 141-4 (440 mg, 1.18 mmol) was dissolved in toluene (5 mL) at room temperature, followed by the sequential addition of compound 1-12 (240 mg, 1.42 mmol), tris(dibenzylacetone)dipalladium (108 mg, 0.12 mmol), sodium tert-butoxide (340 mg, 3.537 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (136.4 mg, 0.24 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1–5:1) to give compound 141-5 (160 mg). MS m / z (ESI): 470.0 [M+1] + .

[0453] Step 5: Synthesis of Compound 141

[0454] Compound 141-5 (130 mg, 0.28 mmol) was dissolved in toluene (3 mL), and compound 32-1 (59 mg, 0.33 mmol), sodium tert-butoxide (80 mg, 0.83 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (32 mg, 0.055 mmol), and tris(dibenzylacetone)dipalladium (23 mg, 0.028 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to C18 reversed-phase column chromatography (0.1% formic acid / acetic acid = 0–30%) to obtain a crude product, which was then subjected to preparative high-performance liquid chromatography (HPLC) (column: Agilent ZORBAX SB-C18). The column was purified using a 21.2*250 mm, 5 μm column; flow rate: 20 mL / min; acetonitrile: 90%–10% water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm. Compound 141 (35.13 mg) was obtained. MS m / z (ESI): 576.1 [M+1] + .

[0455] 1H NMR (400MHz, DMSO-d6) δ8.25 (s, 3H), 7.42 (s, 1H), 6.90 (s, 1H), 6.36 (d, J = 7.1Hz, 1H), 5.9 9(s,1H),5.20(dt,J=56.1,5.8Hz,1H),4.07(t,J=6.4Hz,2H),3.85(s,3H),3.73–3.57(m, 5H),3.17–3.00(m,3H),2.93–2.78(m,2H),2.73–2.56(m,5H),2.42–2.27(m,1H),2.25–2. 03(m,7H),1.98–1.92(m,2H),1.90–1.81(m,1H),1.79–1.65(m,2H),1.13(d,J=6.5Hz,6H).

[0456] Example 35 (Compound 138)

[0457] Step 1: Synthesis of Compound 138-2

[0458] Compound 138-1 (1 g, 4.581 mmol) was dissolved in a mixed solution of 1,4-dioxane (21 mL) and saturated sodium carbonate (7 mL). The reaction mixture was cooled to 0 °C, and benzyl chloromethane (0.97 mL, 6.87 mmol) was added dropwise. The reaction mixture was stirred in an ice bath for 20 min. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 138-2 (800 mg). MS m / z (ESI): 253.1 [M-99] + .

[0459] Step 2: Synthesis of Compound 138-3

[0460] Under ice bath conditions, 1.74 mL of trifluoroacetic acid was added to a mixture of compound 138-2 (800 mg, 2.27 mmol) and 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated to give compound 138-3 (900 mg). MS m / z (ESI): 253.0 [M+1] + .

[0461] Step 3: Synthesis of Compound 138-4

[0462] At room temperature, 2-bromopropane (0.22 mL, 2.39 mmol) and potassium carbonate (822 mg, 5.95 mmol) were added sequentially to a solution of compound 138-3 (300 mg, 1.19 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-15%) to give compound 138-4 (120 mg). MS m / z (ESI): 295.1 [M+1] + .

[0463] Step 4: Synthesis of compound 138-5

[0464] At room temperature, palladium on carbon (12 mg, 0.011 mmol) was added to a 5 mL ethanol solution of compound 138-4 (120 mg, 0.41 mmol). The reaction mixture was heated to 40 °C and stirred for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give compound 138-5 (40 mg). MS m / z (ESI): 161.1 [M+1] + .

[0465] Step 5: Synthesis of Compound 138

[0466] At room temperature, compound 17-1 (35 mg, 0.077 mmol, synthesis method as described in Example 8, Synthesis of Compound 17-1) was dissolved in toluene (3 mL), and compound 138-5 (12.4 mg, 0.077 mmol), sodium tert-butoxide (22.3 mg, 0.23 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (9 mg, 0.015 mmol), and tris(dibenzylideneacetone)dipalladium (6 mg, 0.008 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (0.1% formic acid / methanol: 0–30%) to obtain the crude product. The crude product was then subjected to preparative high-performance liquid chromatography (Agilent ZORBAX SB-C18 column). The column was purified using a 21.2*250 mm, 5 μm column; flow rate: 20 mL / min; elution gradient: 90% acetonitrile - 10% H₂O (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm. Compound 138 (3.3 mg) was obtained. MS m / z (ESI): 576.1 [M+1]+ . 1 H NMR(400MHz,DMSO-d6)δ8.22(s,2H),7.45(s,0.5H),7.38(s,0.5H),6.89(s,1H),6 .37(d,J=8.4Hz,0.5H),6.20(d,J=8.4Hz,0.5H),6.07(d,J=22.3Hz,1H),4.08(t,J= 6.3Hz,2H),3.85(s,3H),3.65–3.60(m,5H),3.20–3.00(m,2H),2.85–2.65(m,6H), 2.40–2.31(m,2H),2.20(s,4H),2.04–1.92(m,4H),1.77(s,6H),1.07–0.94(m,6H).

[0467] Example 36 (Compound 142)

[0468] Step 1: Synthesis of Compound 142-1

[0469] Compound 138-3 (150 mg, 0.595 mmol, synthesis method as described in Step 2 of Example 35, Synthesis of Compound 138-3) was dissolved in a mixed solution of acetic acid (0.05 mL) and methanol (5 mL) at room temperature. Sodium cyanoborohydride (112.1 mg, 1.78 mmol) and formaldehyde (0.36 mL, 1.78 mmol, 37% w / w aqueous solution, containing 7-8% methanol as a stabilizer) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-20%) to give compound 142-1 (45 mg). MS m / z (ESI): 267.0 [M+1] + .

[0470] Step 2: Synthesis of Compound 142-2

[0471] Compound 142-1 (40 mg, 0.15 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, followed by the sequential addition of palladium on carbon (20 mg) and palladium hydroxide (20 mg). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 142-2 (10 mg). MS m / z (ESI): 133.1 [M+1] + .

[0472] Step 3: Synthesis of Compound 142

[0473] Compound 17-1 (15 mg, 0.033 mmol, synthesis method as described in Example 8, Synthesis of Compound 17-1) was dissolved in toluene (3 mL), and compound 142-2 (4.4 mg, 0.033 mmol), sodium tert-butoxide (9.6 mg, 0.1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (3.8 mg, 0.007 mmol), and tris(dibenzylacetone)dipalladium (2.7 mg, 0.003 mmol) were added sequentially. The reaction mixture was heated to 120 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (water (0.1% formic acid) / methanol = 0–30%) to obtain the crude product. The crude product was then subjected to preparative high-performance liquid chromatography (Agilent ZORBAX SB-C18 column). The column was purified using a 21.2*250mm, 5μm column; flow rate: 20mL / min; gradient: 90% acetonitrile-10% water (0.1% formic acid); column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm. Compound 142 (6.2mg) was obtained. MS m / z (ESI): 548.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.23(s,3H),7.48(s,0.66H),7.38(s,0.34H),6.87(s,1H),6. 38(d,J=8.4Hz,0.33H),6.21(d,J=8.4Hz,0.67H),6.08(s,0.34H),7.02(s,0.66H),4.1 1–4.03(m,2H),3.84–3.79(m,4H),3.78–3.65(m,4H),3.17–3.02(m,1H),2.71(t,J=7. 1Hz,2H),2.68–2.60(m,4H),2.24–2.10(m,10H),2.03–1.94(m,3H),1.80–1.66(m,6H).

[0474] Example 37 (Compound 65)

[0475] Step 1: Synthesis of Compound 65-1

[0476] Compound 164-2 (395.4 mg, 3.91 mmol, synthesis method as described in Step 1 of Example 32) and N,N-diisopropylethylamine (757.9 mg, 5.86 mmol) were added to a solution of compound 1-10 (600 mg, 1.95 mmol) in 12 mL of N-methylpyrrolidone. The reaction mixture was microwaved at 150 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (60 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give compound 65-1 (250 mg). MS m / z (ESI): 370.9, 372.9 [M+1, M+3] + .

[0477] Step 2: Synthesis of Compound 65-2

[0478] Compounds 1-12 (228.2 mg, 1.35 mmol) and trifluoroacetic acid (383.5 mg, 3.36 mmol) were added to a 2-pentanol (10 mL) solution of compound 65-1 (250 mg, 0.67 mmol). The reaction mixture was microwaved at 170 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (60 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give compound 65-2 (90 mg). MS m / z (ESI): 468.2, 470.2 [M+1, M+3] + .

[0479] Step 3: Synthesis of Compound 65

[0480] At room temperature, compound 164-4 (10.5 mg, 0.096 mmol), bis(triphenylphosphine)palladium dichloride (4.5 mg, 0.0064 mmol), and cesium carbonate (62.7 mg, 0.19 mmol) were added to a solution of compound 65-2 (30 mg, 0.064 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (instrument model: SHIMAZU LCMS-2020-2; column: Gemini 5 μm C18 150*21.2 mm; acetonitrile / water (0.05% ammonia)) to obtain compound 65 (6.6 mg). MS m / z (ESI): 497.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.41(s,1H),7.40(s,1H),6.32(d,J=8.0Hz,1H),6.14(s,1H),4.01–3.90(m,2H),3.88(s,3H),3.86–3.78(m,1H),3.66( t,J=5.6Hz,4H),3.63(s,2H),3.56–3.47(m,2H),2.64–2.58(m,4H),2.2 4–2.14(m,4H),2.00–1.90(m,2H),1.78–1.70(m,4H),1.67–1.56(m,2H).

[0481] Example 38 (Compound 150-P1)

[0482] Step 1: Synthesis of Compound 150-2

[0483] Potassium carbonate (3.36 g, 24.3 mmol), potassium iodide (2.69 g, 16.2 mmol), and compound 150-1 (2.03 g, 16.2 mmol) were added to a solution of compound 141-1 (2 g, 8.1 mmol) in acetonitrile (40 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0–4:1) to give compound 150-2 (2.40 g). MS m / z (ESI): 299.1 [M+1] + .

[0484] Step 2: Synthesis of Compound 150-3

[0485] Compound 150-2 (2 g, 6.7 mmol) and palladium on carbon (0.5 g) were added to a methanol (20 mL) solution. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 150-3 (1.80 g, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 268.7 [M+1] +

[0486] Step 3: Synthesis of Compound 150-4

[0487] Compound 150-3 (1.80 g, 6.7 mmol) and malonic acid (1.05 g, 10 mmol) were dissolved in phosphorus oxychloride (20 mL). The reaction mixture was stirred at 90 °C for 5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, quenched with ice water (50 mL), and then adjusted to pH > 8 with saturated potassium hydroxide solution (50 mL). The mixture was extracted with ethyl acetate (80 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1:0–9:1) to give compound 150-4 (1.10 g). MS m / z (ESI): 372.8 [M+1] + .

[0488] Step 4: Synthesis of Compound 150-5

[0489] Under nitrogen protection, compounds 1-12 (142.7 mg, 1.07 mmol), tris(dibenzylacetone)palladium (49.1 mg, 0.054 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (62.0 mg, 0.107 mmol), and sodium tert-butoxide (154.5 mg, 1.61 mmol) were added sequentially to a toluene (5 mL) solution of compound 150-4 (200 mg, 0.54 mmol). The reaction mixture was stirred at 90 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was diluted with water (100 mL). The filtrate was extracted with ethyl acetate (250 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give compound 150-5 (160 mg). MS m / z(ESI): 470.2 [M+1] + .

[0490] Step 5: Synthesis of compound 150-P1

[0491] Under nitrogen protection, compound 150-5 (66.0 mg, 0.14 mmol) and compound 59-1 (29.5 mg, 0.21 mmol) were dissolved in toluene (1 mL), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (17.5 mg, 0.028 mmol), tris(dibenzylacetone)palladium (12.8 mg, 0.014 mmol) and sodium tert-butoxide (33.7 mg, 0.35 mmol) were added sequentially. The reaction mixture was stirred at 120 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm; flow rate: 20mL / min; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 150-P1 (2.8mg). MS m / z (ESI): 574.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6 / D2O)δ7.71(s,1H),7.37(s,1H),5.99(s,1H),5.51( d,J=54.0Hz,1H),4.16(t,J=5.4Hz,2H),4.13–3.95(m,2H),3.90(s,3H),3. 83–3.71(m,5H),3.66(d,J=10.5Hz,2H),3.45–3.25(m,6H),2.81(s,1H),2 .41–2.34(m,4H),2.29–2.16(m,5H),2.05–1.81(m,3H),1.04–0.86(m,4H).

[0492] The following compounds can be synthesized and prepared using methods similar to those described in the examples.

[0493] Biological Examples

[0494] Test Example 1. EHMT2 Enzyme Activity Assay

[0495] Prepare 1× test buffer (50 mM Tris-HCl (pH 7.5) (Sigma, Cat. No. T2319), 1 mM DTT (Sigma, Cat. No. D0632-10G), 0.01% Tween-20 (Sigma, Cat. No. P2287-100 mL)). Dissolve the test compound in DMSO to prepare a 10 mM stock solution, and dilute it to a final concentration of 100-fold with DMSO. Add 100 nmol of the compound to each well of the drug administration group, and add 100 nmol of DMSO solution to each negative control and positive control well. Then, add 5 μL of EHMT2 (G9a, final concentration 1 nM; BPS, Cat. No. 51001) to each well of the drug administration group and positive control, and add 5 μL of 1× test buffer to each well of the negative control. Incubate at room temperature for 15 minutes. Add 5 μL of a mixture of Biotinylated-H3(1-21) (final concentration 0.1 μM; GL Biochem, customized) and SAM (final concentration 50 μM; Cayman, Cat. No. 13956) to each well and incubate at room temperature for 50 minutes.

[0496] Prepare 1×Epigenetics buffer (PerkinElmer, Cat.No. AL008F) to dilute the receptor and donor microbeads. Add 15 μL of receptor microbeads (final concentration 10 μg / mL; Revvity, Cat.No. AL117M) and donor microbeads (final concentration 10 μg / mL; Revvity, Cat.No. AS106M), incubate at room temperature in the dark for 1 hour, and then detect the results using the Alpha module of an Enspire microplate reader. Calculate the inhibition rate in Excel: Inhibition rate (%) = (maximum value) 阴性对照 -Detected signal value) / (Maximum value) 阳性对照 -Minimum value 阴性对照 )*100, using XL-Fit to fit IC 50 Value, fitting formula: Y=Bottom+(Top-Bottom) / (1+(IC) 50 / X)^HillSlope). The results are shown in Table 1. Where A represents: IC 50 Value ≤ 100nM; B represents: 100nM <IC 50 Value ≤ 500nM; C represents: IC 50 Value > 500nM.

[0497] Table 1

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, G is CR 1 Or N; Ring A is a 3-12 membered heterocyclic group or C 3-12 cycloalkyl; R 1 Selected from H, D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups and 3-8 membered heterocyclic groups; R 2 For LR E Or R 8 ; L is selected from C 1-12 Alkylene, C 2-12 imide and C 2-12 Idemynyl group, where C 1-12 Alkylene, C 2-12 imide and C 2-12 One, two, or three CH2 groups in the ynethynyl group may be optionally and independently selected from -O-, -S-, and -NR. L1 -、-C(O)-、C 3-6 Substitution of groups in cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-12 Alkylene, C 2-12 imide and C 2-12 The ethynyl group is optionally enclosed by one or more R groups. a replace; R L1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups; Each R a The same or different, and each independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; Or, two Rs a Together with the atoms it is attached to, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted; R 8 It is a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group is optionally selected from H, D, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 The alkyl group is replaced by one or more substituents in the form of deuterated cycloalkyl groups and 3-8 membered heterocyclic groups; R E H, halogen, hydroxyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups and NR g1 R g2 The C mentioned 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy and C 3-8 One or more substituents in the cycloalkyl group are substituted; R g1 and R g2 The same or different, and each independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; Or, R g1 and R g2 Together with the nitrogen atoms to which they are attached, they form 3-8 membered heterocyclic groups, wherein the 3-8 membered heterocyclic groups are optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted; R 3 Selected from H, halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R 4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. v replace; R v Selected from H, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR k1 R k2 C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 cycloalkyl, 3-8 membered heteroaryl, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; R k1 and R k2 Whether the two are the same or different, they are each independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; Or, R 4 and R 5 The nitrogen atom bonded to it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted; R 6 for R 6a and R 6b The same or different, and each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted; Or, R 6a and R 6b Together with the atoms attached to it, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups are optionally selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-8 cycloalkyl, C 3-8 The alkyl group is replaced by one or more substituents in the form of deuterated cycloalkyl groups and 3-8 membered heterocyclic groups; Each R 7 They may be the same or different, and each is independently selected from H, halogen, hydroxyl, amino, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 cycloalkyl; n is 0, 1, 2, 3, 4, 5, and 6; The heteroatoms in the heterocyclic or heteroaryl groups are selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein for According to claim 1, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (II), in, p is 1 or 2; q is 1 or 2. According to claim 3, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (II), p is 1 or 2; q is 1 or 2; G is either CH or N; R 2 For LR E L is C 1-6 Alkylene or C 2-4 Idemynyl group, where C 1-6 Alkylene and C 2-4 One, two, or three CH2 groups in the ynynyl group may be optionally and independently replaced by groups selected from -O-; R E It is a 3-8 membered heterocyclic group; the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens; R 3 C 1-3 Alkoxy; R 4 For H; R 5 C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C... 1- 6-alkyl, C 3-8 cycloalkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; R 6a and R 6b Each can be independently H or halogen; Or, R 6a and R 6b Together with the atoms attached to it, they form C 3-6 Cycloalkyl. The compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein G is CH or N. The compound of formula (I) according to any one of claims 1-5, wherein for The compound of formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, It satisfies one or more of the following conditions: (1)R 4 For H or C 1-6 alkyl; (2)R 5 C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic groups are optionally surrounded by one or more R groups. v replace; R v Selected from H, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N(C) 1-6 Alkyl)2, C 3-8 cycloalkyl and -C 1-6 alkylene-phenyl, wherein the C 1-6 Alkyl, C 3-8 cycloalkyl and -C 1-6 Alkylene-phenyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 The alkyl group is replaced by one or more substituents in the cycloalkyl and 3-8 membered heterocyclic groups; (3)R 4 and R 5 The nitrogen atom bonded to it forms a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted; (4)R 2 For LR E L is C 1-6 Alkylene, C 2-6 imide and C 2-4 Idemynyl group, where C 1-6 Alkylene, C 2-6 imide and C 2-4 One, two, or three CH2 groups in the ynethynyl group may optionally and independently be selected from -O- or -NR. L1 - group substitution, the C 1-6 Alkylene, C 2-6 imide and C 2-4 The ethynyl group is optionally enclosed by one or more R groups. a replace; R L1 For H, C 1-6 Alkyl or C 3-12 cycloalkyl; Each R a The same or different, and each independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; Or, two Rs a Together with the atoms it is attached to, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted; R E C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups and NR g1 R g2 The C mentioned above 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3- One or more substituents in the 8-cycloalkyl group are substituted; R g1 and R g2 The same or different, and each independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; Or, R g1 and R g2 Together with the nitrogen atoms to which they are attached, they form 3-8 membered heterocyclic groups, wherein the 3-8 membered heterocyclic groups are optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 One or more substituents in the cycloalkyl group are substituted; (5)R 2 For R 8 ; R 8 It is a 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally selected from H, D, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl and C 3-8 The deuterated cycloalkyl group is substituted with one or more substituents; (6)R 3 H, halogen, hydroxyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxyloxyl. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, It satisfies one or more of the following conditions: (1)R 4 For H; (2)R 5 C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; (3)R 2 For LR E L is C 1-6 Alkylene or C 2-4 Idemynyl group, where C 1-6 Alkylene and C 2-4 One, two, or three CH2 groups in the ynynyl group may be optionally and independently replaced by groups selected from -O-; R E It is a 3-8 membered heterocyclic group; the 3-8 membered heterocyclic group may optionally be replaced by one or more halogens; (4)R 3 It can be H, F, Cl, OH, -OCH3 or -OCHF2. The compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, It satisfies one or more of the following conditions: (1)R 2 for (2)R 5 -CH3, (3)R 4 and R 5 The nitrogen atom attached to it forms The compound of formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure: The compound of formula (I) according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure: A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of formula (I) as claimed in any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Use of a compound or a pharmaceutical composition according to claim 12 in the preparation of a medicament, wherein the compound is a compound of formula (I) according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof; The drug is a drug that inhibits EHMT1 and / or EHMT2, a drug for the prevention and / or treatment of EHMT1 and / or EHMT2-mediated diseases, or a drug for the prevention and / or treatment of gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer. As described in claim 13, the medicament for the prevention and / or treatment of gastrointestinal diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer is a medicament for the prevention and / or treatment of ulcerative colitis, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, diabetes, multiple sclerosis, celiac disease, graft-versus-host disease, Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, autoimmune hepatitis, atopic dermatitis, Kassman's disease, allergic rhinitis, eczema, Kawasaki disease, or psoriatic arthritis.

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