Aza-aryl compounds, processes for their preparation and use

Abstract

Disclosed are azaheteroaryl compounds, methods of making and using the same. Specifically, disclosed are azaheteroaryl compounds, pharmaceutically acceptable salts thereof, and solvates thereof, and methods of making the same. In addition, disclosed are compositions containing the compounds and the use of the compounds for the manufacture of medicaments for the treatment of diseases or disorders associated with the mechanism of action of EED protein and / or PRC2 protein complex.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing aryl compound, its preparation method, and its application. Background Technology

[0002] Polycomb Group (PcG) proteins are an important class of chromatin-modifying enzymes. They regulate gene transcription by modifying chromatin, thus playing a crucial role in stem cell growth, differentiation, and long-term cellular memory. In mammalian cells, PcG proteins are mainly divided into two transcriptional repressor complexes: PRC1 (Polycomb Repressive Complex 1) and PRC2 (Polycomb Repressive Complex 2). PRC2 represses the expression of related genes by methylating histone 3 at position 27 (H3K27) in chromatin. The PRC2 protein complex is mainly composed of core proteins such as EZH2 (Enhancer of Zeste Homolog 2) (or its very similar homolog EZH1), EED (Embryonicectoderm Development), and SUZ12 (Suppressor of Zeste 12). EZH2 possesses enzymatic catalytic activity, enabling it to transfer methyl groups from the substrate SAM (S-adenosyl-L-methionine) to H3K27 via the SET (Su(var), E(Z), and Trithorax) protein domain, thereby achieving mono- to trimethylation modification of H3K27. The enzymatic catalytic activity of EZH2 also depends on other components of PRC2, such as the EED protein belonging to the WD40 repeat protein family. The binding of EED to the trimethylated H3K27Me3 significantly promotes the allosteric function of EZH2 and also localizes the PCR2 complex to the chromatin requiring modification. Abnormalities in PRC2 function, such as overexpression or gain-of-function mutations of EZH2, are associated with many clinical cancers, including lung cancer, breast cancer, rectal cancer, prostate cancer, bladder cancer, pancreatic cancer, sarcoma, and lymphoma. PRC2 is also involved in various cellular immune functions. For example, EZH2 participates in regulating lymphocyte activation and can also work with glycolysis to promote T cell responses against tumor cells. Therefore, the development of small molecule inhibitors of PRC2 has significant and broad drug development value.

[0003] The development of PRC2 inhibitors mainly focuses on two strategies: developing EZH2 inhibitors and EED inhibitors. Currently, EZH2 inhibitors in clinical trials include EPZ-6438 (Epizyme, Phase II), GSK2816126 (GSK, Phase I), and CPI-1205 (Constellation, Phase I). Although multiple EZH2 inhibitors have entered clinical research stages, they all share a common 2-pyridone pharmacophore. Furthermore, secondary mutations have begun to appear in clinical treatment with existing EZH2 inhibitors. EED inhibitors have allosteric inhibition of EZH2 enzyme function, achieving the same or similar biological functions as EZH2. Moreover, EED inhibitors effectively overcome the problem of EZH2 resistance, and can be used in combination with EZH2 inhibitors to achieve better synergistic effects. Therefore, the development of new EED inhibitors is of great significance. Summary of the Invention

[0004] The technical problem this invention aims to solve is that existing EED inhibitors have a single, simple structure. Therefore, this invention provides a nitrogen-containing aryl compound, its preparation method, and its applications. The nitrogen-containing aryl compound of this invention exhibits excellent inhibitory activity against tumor cells and has broad prospects for drug development.

[0005] This invention provides a compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate, or isotopically labeled compound:

[0006] (I) in, A is or , X is N or CR 7 ; R 1 H, halogen, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted or unsubstituted amino groups, R 3 C with or without substitution 1-4 Halogenated alkyl, hydroxylated or unsubstituted C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 For H, C 1-4 Alkyl, C 3-6 cycloalkyl or C1-4 Alkyl-substituted or unsubstituted amino groups; R 3 Independently hydroxyl, carbonyl, -CN, halogen, C 3-6 heteroaryl, hydroxyl-substituted or unsubstituted C 1-4 Alkoxy, R 6 Substituted or unsubstituted amino groups, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 Independently carbonyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; R 5 Independently for C 1-4 Alkyl or C 3-6 Heterocyclic alkyl; R 6 Independently for R 6-1 Substituted or unsubstituted C 1-4 alkyl; R 6-1 Independently hydroxyl or C 1-4 Alkyl-substituted or unsubstituted amino groups; R 7 Independently, H, hydroxyl, -CN, halogen, C 1-4 Alkoxy or C 1-4 alkyl; R 3 The number of them is 1, 2, 3 or 4; R 4 The number is 1 or 2; R 5 The number of them is 1, 2, 3 or 4; R 6 The number is 1 or 2; The C 3-6 Heterocyclic alkyl and C 3-6 The heteroatoms in the heteroaryl group are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; The compound shown in formula (I) is not , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0007] In certain preferred embodiments of the present invention, certain groups in the compounds represented by formula (I), their pharmaceutically acceptable salts, stereoisomers, solvates, or their isotopically labeled compounds are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in certain preferred embodiments of the present invention"): When R 1 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.

[0008] In certain preferred embodiments of the present invention: when R 1 C 1-4 When alkoxy is present, the C 1-4 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, with methoxy being preferred.

[0009] In certain preferred embodiments of the present invention: when R 1 For R 3 C with or without substitution 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl or isopentyl, preferably methyl, ethyl, propyl, isopropyl, isobutyl or 3-pentyl.

[0010] In certain preferred embodiments of the present invention: when R 3 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0011] In certain preferred embodiments of the present invention: when R 3 C 3-6When heteroaryl, the C 3-6 The heteroaryl group is imidazole, preferably. .

[0012] In certain preferred embodiments of the present invention: when R 3 C substituted or unsubstituted with hydroxyl group 1-4 When alkoxy is present, the C 1-4 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, preferably isobutoxy, and the number of hydroxyl groups is preferably 1, 2, or 3.

[0013] In certain preferred embodiments of the present invention: when R 3 C substituted with hydroxyl group 1-4 When alkoxy is present, the hydroxyl-substituted C 1-4 alkoxy group is .

[0014] In certain preferred embodiments of the present invention: the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0015] In certain preferred embodiments of the present invention: when R 3 C 1-4 When alkyl haloides are used, the C... 1-4 The alkyl halotypes are trifluoromethyl, trifluoroethyl, difluoromethyl, and difluoroethyl.

[0016] In certain preferred embodiments of the present invention: when R 6 Independently for R 6-1 Replacement C 1-4 When alkyl, the R 6-1 The number of them can be 1, 2 or 3.

[0017] In certain preferred embodiments of the present invention: when R 6 Independently for R 6-1 Substituted or unsubstituted C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably ethyl or isobutyl.

[0018] In certain preferred embodiments of the present invention: when R 6-1 Independently for C 1-4 When the amino group is alkyl-substituted, the C 1-4 The number of alkyl groups is 1 or 2, and the C... 1-4 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, and more preferably methyl.

[0019] In certain preferred embodiments of the present invention: when R 6-1 Independently for C 1-4 When the amino group is alkyl-substituted, the C 1-4 alkyl-substituted amino groups are .

[0020] In certain preferred embodiments of the present invention: when R 6 Independently for R 6-1 Replacement C 1-4 When alkyl, the R 6-1 Replacement C 1-4 Alkyl is or .

[0021] In certain preferred embodiments of the present invention: when R 1 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl.

[0022] In certain preferred embodiments of the present invention: when R 1 For R 3 Replacement C 1-4 When alkyl, the R 3 Replacement C 1-4 Alkyl is , , , , , , , , , , , , , , , CF3 , , , , , or .

[0023] In certain preferred embodiments of the present invention: when R 4 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.

[0024] In certain preferred embodiments of the present invention: when R 1 For R 4When the amino group is substituted, the R 4 The substituted amino group is .

[0025] In certain preferred embodiments of the present invention: when R 1 For R 3 C with or without substitution 1-4 When alkyl halogenated, the halogen in the halogenation is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine, and the C 1-4 The alkyl group in the haloalkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, more preferably methyl, wherein the C 1-4 The alkyl halotype is preferably monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0026] In certain preferred embodiments of the present invention: when R 1 C substituted or unsubstituted with hydroxyl group 3-6 When cycloalkyl, the number of hydroxyl groups is preferably 1, 2, or 3, and the C... 3-6 The alkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, more preferably cyclopropyl or cyclobutyl.

[0027] In certain preferred embodiments of the present invention: when R 1 C substituted with hydroxyl group 3-6 In the case of cycloalkylation, the hydroxyl-substituted C 3-6 cycloalkyl is or .

[0028] In certain preferred embodiments of the present invention: when R 1 For R 5 C with or without substitution 3-6 When heterocyclic alkyl, the C 3-6 The heterocyclic alkyl group is tetrahydropyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or 2-oxa-6-aza-spiro[3,3]heptyl, preferably. , , , or .

[0029] In certain preferred embodiments of the present invention: when R 5 Independently for C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.

[0030] In certain preferred embodiments of the present invention: when R 5 Independently for C 3-6 When heterocyclic alkyl, the C 3-6The heterocyclic alkyl group is tetrahydropyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or 2-oxa-6-aza-spiro[3,3]heptyl, preferably. , , , or More preferably .

[0031] In certain preferred embodiments of the present invention: when R 1 For R 5 Replacement C 3-6 When it is a heterocyclic alkyl group, the R 5 Replacement C 3-6 Heterocyclic alkyl groups , or .

[0032] In certain preferred embodiments of the present invention: when R 1 C 3-6 When heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups , or .

[0033] In certain preferred embodiments of the present invention: R 1 H, methyl, difluoromethyl, trifluoromethyl, methoxy , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Better yet, R 1 for , , , , , , , , , , , , , , , , , , , , or, .

[0034] In certain preferred embodiments of the present invention: when R 2 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.

[0035] In certain preferred embodiments of the present invention: when R 2 C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0036] In certain preferred embodiments of the present invention: when R 2 C 1-4 When the amino group is alkyl-substituted or unsubstituted, the C 1-4 Alkyl groups are preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, more preferably methyl, C 1-4 The number of alkyl groups is preferably 1 or 2, C 1-4 Alkyl-substituted amino groups are preferred .

[0037] In certain preferred embodiments of the present invention: when R 7 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0038] In certain preferred embodiments of the present invention: when R 7 C 1-4 When alkoxy is present, the C 1-4The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, with methoxy being preferred.

[0039] In certain preferred embodiments of the present invention: when R 7 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.

[0040] In certain preferred embodiments of the present invention: A is... .

[0041] In certain preferred embodiments of the present invention: R 1 Preferred H, halogens, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups, more preferably H and C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups, more preferably H, methyl, difluoromethyl, trifluoromethyl, methoxy, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Preferably, R 1 For R 3 Replacement C 1-6 alkyl or hydroxy substituted C 3-6 Cycloalkyl, preferably , , , , , , , , , , , , , , , , , , , , or .

[0042] In certain preferred embodiments of the present invention: R 2 H and C are preferred 1-4 Alkyl, or C 1-4 Alkyl-substituted amino groups, more preferably H, methyl or Preferably, R 2 For H or C 1-4 Alkyl, preferably H or methyl.

[0043] In certain preferred embodiments of the present invention: when R 1 For R 3 C with or without substitution 1-6 When alkyl, R 3 Preferred hydroxyl groups, halogens, and C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups, more preferably hydroxyl, fluorine, , , , , methyl, ethyl, difluoromethyl, trifluoromethyl or Preferably, R 3 Hydroxyl, halogen, C 1-4 Alkyl or C 1-4 The alkyl halogroup is preferably hydroxyl, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0044] In certain preferred embodiments of the present invention: when R 1 For R 4 When the amino group is substituted, R 4 Preferred C 1-4 Alkyl, more preferably methyl.

[0045] In certain preferred embodiments of the present invention: when R 1 For R 5 Replacement C 3-6 When heterocyclic alkyl, R 5 Preferred methyl or .

[0046] In certain preferred embodiments of the present invention: when R 3 For R 6 When the amino group is substituted, R 6 Preferred methyl, or .

[0047] In certain preferred embodiments of the present invention: when R 6 For R 6-1 Replacement C 1-4 When alkyl, R 6-1 Preferably hydroxyl or C 1-4 Alkyl-substituted amino groups, more preferably hydroxyl groups or... .

[0048] In certain preferred embodiments of the present invention: R 7 Preferred elements: H, -CN, halogens, C 1-4 Alkoxy or C 1-4 Alkyl groups, more preferably H, halogens, and C 1-4 Alkoxy or C 1-4 Alkyl groups, more preferably H, fluorine, methoxy, or methyl; preferably, R 7 H, halogen or C 1-4 Alkyl, preferably H, methyl or fluorine.

[0049] In certain preferred embodiments of the present invention: R 1 It can be any of the following structures: , , or Preferred or ; R 3a R 3b H and C independently 1-4 Alkyl (preferably methyl or C) 2-4 Alkyl), C 1-4 Halogenated alkyl groups (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl), C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups, preferably H or C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 3a and R 3b Not both are methyl; when R 3a When it is methyl, R 3b Not H; when R 3a When it is H, R 3b Not methyl; or R 3a R 3b Together with the adjacent atoms, they form C 3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl), C 3-6 Heterocyclic alkyl, preferably C 3-6 cycloalkyl; The C 3-6 The heteroatoms in the heterocyclic alkyl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0050] In certain preferred embodiments of the present invention: R 2 For H.

[0051] In certain preferred embodiments of the present invention: R 7 H, halogen (e.g., fluorine), or C 1-6 Alkyl (e.g., methyl).

[0052] In certain preferred embodiments of the present invention: The compound of formula (I) is selected from the following compounds:

[0053]

[0054] Preferably,

[0055]

[0056]

[0057] In the above compounds, R 1 The definition is as described above.

[0058] In certain preferred embodiments of the present invention: group Preferred , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0059] In certain preferred embodiments of the present invention: the compound of formula (I) is any of the following: Option 1: R 1 H, halogen, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 For H, C 1-4 Alkyl, or C 1-4 Alkyl-substituted amino groups; R 3 Hydroxyl, halogen, C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 C 1-4 alkyl; R 7 H, -CN, halogen, C 1-4 Alkoxy or C 1-4 alkyl; Option 2: R 1 For H, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 For H, C 1-4 Alkyl, or C 1-4 Alkyl-substituted amino groups; R 3 Hydroxyl, halogen, C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 C 1-4 alkyl; R 7 H, halogen, C 1-4 Alkoxy or C1-4 alkyl; Option 3: A is ; R 1 For H, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 H, methyl or ; R 3 Hydroxyl, halogen, C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 C 1-4 alkyl; R 7 It can be H, fluorine, methoxy, or methyl; Option 4: A is ; R 1 For H, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 H, methyl or ; R 3 Hydroxyl, fluorine, , , , methyl, ethyl, difluoromethyl, trifluoromethyl or ; R4 It is methyl; R 5 Methyl or ; R 7 It can be H, fluorine, methoxy, or methyl; Option 5: A is ; R 1 H, methyl, difluoromethyl, trifluoromethyl, methoxy , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 2 H, methyl or ; R 7 It can be H, fluorine, methoxy, or methyl; Option Six: A is ; R 1 For R 3 Replacement C 1-6 alkyl or hydroxy substituted C 3-6 Cycloalkyl, preferably , , , , , , , , , , , , , , , , , , , , or ; R 2 For H or C 1-4 Alkyl, preferably H or methyl; R 3 Hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, preferably hydroxyl, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R 7 H, halogen or C 1-4 Alkyl, preferably H, methyl or fluorine.

[0060] In certain preferred embodiments of the present invention: the compound represented by formula (I) has any of the following structures:

[0061] In certain preferred embodiments of the present invention: the compound represented by formula (I) is any of the following compounds: The retention time is 3.134 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 3.547 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 4.974 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: isocratic elution 45%, flow rate 2.8 mL / min; The retention time is 5.440 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: isocratic elution 45%, flow rate 2.8 mL / min; The retention time is 2.782 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 2.907 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 0.971 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is isopropanol; gradient: isocratic elution of 45% mobile phase B, flow rate 4 mL / min. The retention time is 1.134 min under the following conditions. Chromatographic column: DAIICEL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is isopropanol; gradient: isocratic elution of 45% mobile phase B, flow rate 4 mL / min.

[0062] The present invention also provides isotopically labeled compounds of the compounds represented by formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof, or solvates thereof. The isotopes in the isotopically labeled compounds are selected from... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The atoms in compounds of formula (I) that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, which can be labeled by isotopes. 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc., are used instead.

[0063] In some preferred embodiments of the present invention: the solvate is a hydrate.

[0064] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following steps: The halogenated intermediate B0 was coupled with intermediate E0 to give the compound shown in formula (I);

[0065] Where W represents halogen; R x -B(OH)2 or A, R 1 R 2 The definitions of X are as described above.

[0066] The method for preparing the compound as shown in formula (I) may further include the following steps to prepare intermediate E0;

[0067] Wherein, W represents halogen, preferably Br; R x -B(OH)2 or R 1 X, R 2 All definitions are as defined in this invention.

[0068] This invention also provides a method for preparing intermediate compounds C1-7, C1-a, or C1-b, comprising the following steps: Compound C1-1 reacts with 1,2-dihaloethane (e.g., 1,2-dibromoethane) to give compound C1-2. C1-2 undergoes an elimination reaction to give compound C1-3. C1-3 condenses with p-toluenesulfonylhydrazine to give sulfonylhydrazone C1-4. C1-4 undergoes a furanyl ring-removal reaction to give compound C1-5. The bromine atom of C1-5 is substituted with a cyano group under catalytic conditions to give compound C1-6. The cyano group is reduced to an amino group and protected in situ with Boc anhydride to give C1-7. And / or, further, C1-7 is separated by chiral SFC to obtain C1-7 a and C1-7b, and C1-7 a and C1-7b are deprotected to obtain C1-a and C1-b, respectively.

[0069]

[0070] Z is a halogen (e.g., Cl, Br or I), preferably Br.

[0071] This invention also provides a method for preparing intermediate compound B, comprising the following steps: Compound D-1 reacts with hydrazine hydrate to give compound D-2. Compound D-2 then undergoes cyclization with trimethyl orthoformate in the presence of a catalyst (e.g., trifluoroacetic acid) to give intermediate D. D then reacts with intermediate C to give intermediate B. The reaction equations are as follows:

[0072] The definitions of W and A are as described above.

[0073] This invention also provides intermediate compounds: , , , or ; Among them, X and R 3 The definition is as described above.

[0074] The solvents involved in this invention may be selected from, for example, methanol, ethanol, isopropanol, toluene, xylene, chlorobenzene, water, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or combinations thereof; for example, selected from dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or combinations thereof.

[0075] The alkalis involved in this invention may include organic alkalis and inorganic alkalis.

[0076] The organic bases involved in this invention may be selected from, for example, TEA, DIPEA, or combinations thereof.

[0077] The inorganic bases involved in this invention may be selected from, for example, sodium hydride, sodium methoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, LiHMDS, LDA, butyllithium, potassium hydroxide, potassium acetate, lithium aluminum hydride, or combinations thereof; for example, selected from sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, LiHMDS, LDA, butyllithium, or combinations thereof.

[0078] The isotopically labeled compounds of formula (I) of the present invention can be prepared by a synthetic method similar to that of the unlabeled compounds, except that the unlabeled starting materials and / or reagents are replaced with isotopically labeled starting materials and / or reagents.

[0079] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or an isotopically labeled compound thereof, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be one or more of a diluent, absorbent, wetting agent, binder, disintegrant, and lubricant.

[0080] The present invention also provides the use of compounds of formula (I) as described above, pharmaceutically acceptable salts thereof, stereoisomers thereof, solvates thereof, or isotopically labeled compounds thereof, or pharmaceutical compositions as described above, in the preparation of pharmaceuticals. The pharmaceuticals are preferably those for treating cancer.

[0081] The present invention also provides the use of compounds of formula (I) as described above, pharmaceutically acceptable salts thereof, stereoisomers thereof, solvates thereof, or isotopically labeled compounds thereof, or pharmaceutical compositions as described above, in the preparation of medicaments for treating cancers related to the mechanism of action of the EED protein and / or the PRC2 protein complex.

[0082] Preferably, the cancers include, but are not limited to, metastatic large B-cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma and other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, etc.

[0083] Preferably, the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or isotopically labeled compound thereof is used in combination with other drugs; more preferably, the other drugs are selected from anticancer drugs, tumor immunotherapy drugs, anti-allergy drugs, antiemetics, analgesics, or cell-protective drugs.

[0084] This invention also provides a pharmaceutical formulation comprising a compound of formula (I) as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutical composition as described above. The pharmaceutical formulation is preferably in the form of a suspension, syrup, emulsion, or solution, such as tablets, capsules (e.g., sustained-release or time-release capsules), pills, powders, granules (e.g., small particles), elixirs, tinctures, suspensions (e.g., nanosuspensions, microsuspensions), and spray-dried dispersions. Preferred routes of administration for the pharmaceutical formulation include oral administration, sublingual administration, injection including subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, and infusion, nasal administration (e.g., nasal inhalation), topical administration (e.g., creams and ointments), rectal administration (e.g., suppositories), etc. The compounds disclosed in this invention can be taken alone or with a suitable drug carrier.

[0085] This invention also provides that the aforementioned pharmaceutical preparations can be formulated into appropriate drug dosages to facilitate and control the amount of medication taken. The dosage regimens of the compounds disclosed in this invention vary depending on specific factors, such as pharmacodynamics and method of administration, the recipient, gender, age, health status, weight, disease characteristics, other concurrent medications, frequency of administration, liver and kidney function, and desired effects. The compounds disclosed in this invention can be taken as a single daily dose or the total dose can be divided into multiple doses (e.g., two to four times daily).

[0086] The present invention also provides a method for treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as shown in formula (I) as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutical composition as described above. The cancers include, but are not limited to, metastatic large B-cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma and other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, etc.

[0087] The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the aforementioned isotope-labeled compound in combination with other drugs, wherein the other drugs are selected from: anticancer drugs, tumor immunotherapy drugs, anti-allergy drugs, antiemetics, analgesics, cell protection drugs, etc., and the combination has better effects.

[0088] In this invention, the cancer is preferably associated with the EED protein and / or the PRC2 protein complex.

[0089] The present invention also provides a method for inhibiting the activity of EED protein and / or PRC2 protein complex, comprising administering to a subject a therapeutically effective amount of a compound as shown in formula (I) as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof or an isotopically labeled compound thereof, or a pharmaceutical composition as described above.

[0090] The present invention also provides a method for blocking the binding of EED to H3K27 (e.g., H3K27me3), comprising administering to a subject a therapeutically effective amount of a compound as shown in formula (I) as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof or an isotopically labeled compound thereof, or a pharmaceutical composition as described above.

[0091] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0092] Terminology Explanation Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0093] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0094] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0095] Group definition Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0096] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0097] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0098] In this paper, certain chemical groups are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C 1-6Alkyl refers to an alkyl group having a total of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6 carbon atoms) as defined below. The total number of carbon atoms in the simplified symbol does not include carbons that may be present in substituents of the group.

[0099] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0100] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0101] “ When representing a single bond, it means and A mixture of.

[0102] "Hydroxy group" refers to the -OH group.

[0103] "Carbonyl" refers to the -C(=O)- group. When When R is a carbonyl group, for .

[0104] "Cyano" refers to -CN.

[0105] "Amino" refers to -NH2.

[0106] "Substituted amino" refers to an amino group that is substituted by one or two alkyl, alkylcarbonyl, aralkyl, or heteroaralkyl groups as defined below, such as monoalkylamino, dialkylamino, alkylamide, aralkylamino, or heteroaralkylamino.

[0107] The "carboxyl group" refers to -COOH.

[0108] In this application, as a group or part of other groups (e.g., in halogen-substituted alkyl groups), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, even more preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl.

[0109] In this application, as part of a group or other group, the term "haloalkyl" refers to an alkyl group (as defined herein) in which one or more hydrogen atoms are replaced by a halogen (as defined herein), and the number of halogens can be one or more; when there are multiple halogens, the halogens may be the same or different. For example, fluoroalkyl means that an alkyl group is replaced by one or more fluorine atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0110] In this application, preferably, the "heterocyclic alkyl" has 3, 4, 5, or 6 carbon atoms, the heteroatoms are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; more preferably, the number of carbon atoms is 4 or 5, the heteroatoms are selected from N and O, and the number of heteroatoms is 1 or 2; for example , , or .

[0111] In this application, preferably, the "heterospirocycloalkyl" has 4, 5, or 6 carbon atoms, and the heteroatoms are selected from N, O, and S, with 1, 2, 3, or 4 heteroatoms. More preferably, the heteroatoms are selected from N and O, with 1 or 2 heteroatoms. For example... .

[0112] In this application, as part of a group or other group, the term "cyclic hydrocarbon group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused ring systems, bridged ring systems, or spirocyclic systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and may be saturated or unsaturated and may be connected to the rest of the molecule via single bonds through any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the cyclic hydrocarbon group may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 5,6,7,8,9,10-hexahydro-benzocycloheptenyl. Cyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

[0113] In this application, as part of a group or other group, the term "cycloalkyl" means a saturated cycloalkyl group.

[0114] In this application, as a group or part of other groups, the term "cycloalkenyl" means a cyclic hydrocarbon group having at least one double bond (such as a carbon-carbon double bond). A cycloalkenyl group can be connected to the rest of the molecule via the atoms of its double bond.

[0115] In this application, as part of a group or other group, the term "heterocyclic group" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specified in this specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more ring system, which may include fused ring systems, bridged ring systems, or spirocyclic systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be connected to the remainder of the molecule via a carbon atom or heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the connection point with the remainder of the molecule is a non-aromatic ring atom. For the purposes of this invention, the heterocyclic group preferably comprises 1 to 3 stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic groups selected from nitrogen, oxygen, and sulfur heteroatoms, and more preferably comprises 1 to 3 stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic groups selected from nitrogen, oxygen, and sulfur heteroatoms. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aziridine, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazyl, isoxazylalkyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolyl, phthalimide, etc.

[0116] In this application, as a group or part of other groups, the term "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above, provided that the aryl group is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.

[0117] In this application, the term "arylalkyl" refers to an alkyl group as defined above that has been replaced by an aryl group as defined above.

[0118] In this application, as part of a group or other group, the term "heteroaryl" means a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this invention, the heteroaryl group preferably comprises 1 to 5 stable 5- to 12-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms, more preferably 1 to 4 stable 5- to 10-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms, or 1 to 3 5- to 6-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms (e.g., heteroaryl groups of C1-C5, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4). Examples of heteroaryl groups include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolithyl, triazolyl, tetrazolyl, triazinyl, inazinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazolyl, carbazolyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophene, oxadiazolyl, and oxadiazolyl. Azolyl, cyclolinyl, quinazolinyl, phenylthio, indene, o-diazaphenyl, isoxazolyl, phenoxazinyl, phenthiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophene, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0119] In this application, "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups. The substituents used in the claims and specification of this invention are selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclic hydrocarbon, and optionally substituted heterocyclic hydrocarbon.

[0120] In this invention, the term "substitution" or "substituent" refers to the replacement of one or more hydrogen atoms by a specified group. When the number of substituents is not specified, there may be one or more substituents; when the substitution position is not specified, substitution may be at any position, but only the formation of a stable or chemically viable chemical is permitted.

[0121] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the choice of R is independent in each case. For example, in In this context, when n is 2, it means that the benzene ring is substituted by two Rs, and each R has an independent option; that is, the two Rs can be the same or different. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0122] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0123] When the compounds of the present invention contain alkene double bonds, unless otherwise stated, the compounds of the present invention are intended to contain E- and Z-geometric isomers.

[0124] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0125] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention may use racemic, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography. The stereoisomers of the compounds of the present invention may be (R)- or (S)- isomers.

[0126] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0127] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0128] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0129] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0130] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0131] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0132] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0133] The terms “preventive,” “prevention,” and “avoidance” used in this article include reducing the likelihood of a patient developing or worsening a disease or condition.

[0134] The term "treatment" and other similar synonyms used in this article include the following meanings: (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it; (ii) To suppress a disease or symptom, that is, to curb its development; (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or (iv) To alleviate the symptoms caused by the disease or condition.

[0135] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0136] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0137] As used herein, the terms “drug combination,” “drug co-administration,” “combination therapy,” “administration of other treatments,” and “administration of other therapeutic agents” refer to drug therapy obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0138] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0139] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, TW & PGM Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0140] 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.

[0141] The reagents and raw materials used in this invention are all commercially available.

[0142] The positive and progressive effects of this invention are as follows: Compared to the compound N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine) disclosed in US20160176882A1 and WO2017219948A1, the compound of the present invention exhibits approximately 10-fold increased anti-cell proliferation activity. The bicyclic structure outside the binding "pocket" of the compound disclosed in this invention contributes to better metabolic stability when binding to EED proteins. Detailed Implementation

[0143] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0144] The starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidex, and Energie, or can be synthesized by known methods.

[0145] In the following examples, ice bath refers to -5°C to 0°C, room temperature refers to 10°C to 30°C, and reflux temperature generally refers to the solvent reflux temperature at normal pressure. Overnight reaction refers to a time of 8-15 hours. In the following examples, unless a specific operating temperature is specified, all operations are carried out at room temperature.

[0146] In the following examples, the intermediates and final products were separated and purified by normal-phase or reversed-phase chromatographic columns or other suitable methods. Normal-phase rapid chromatographic columns used ethyl acetate and n-hexane or methanol and dichloromethane as the mobile phase. Reversed-phase preparative high-performance liquid chromatography (HPLC) used a C18 column with UV detection at 214 nm and 254 nm, with a mobile phase of A (water and 0.1% formic acid) and B (acetonitrile) or mobile phase A (water and 0.1% ammonium bicarbonate) and B (acetonitrile).

[0147] In each embodiment: LCMS Instrument: Pump Agilent 1260UV; Detector: Agilent 1260 DAD Mass Spectrometer API 3000 Chromatography column: Waters Sunfire C18, 4.6×50mm, 5µm Mobile phase: A-H2O (0.1% HCOOH); B-acetonitrile NMR instrument: Bruker Ascend 400M ( 1 H NMR: 400MHz; 13 C NMR: 100 MHz).

[0148] Example 1: 8-Bromo-5-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (D) Step 1: 5-Bromo-2-chloro-4-hydrazinopyrimidine (D-2):

[0149] D-1 (2 g, 8.78 mmol) and ethanol (20 mL) were added to a 50 mL single-necked flask. Hydrazine hydrate (1.72 g, 53.65 mmol) was slowly added dropwise in an ice bath. The suspension was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and a pale yellow solid precipitated. The solid was collected by filtration, and the filter cake was washed with ethanol (5 mL) and dried to give the pale yellow solid product D-2 (1.8 g, 92% yield).

[0150] 1H NMR (DMSO-d6, 400MHz) δ 8.06 (s, 1H), 7.85 (s, 1H), 4.34 (s, 2H)ppm. Step 2: 8-Bromo-5-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (D):

[0151] D-2 (1.2 g, 5.37 mmol), trimethyl orthoformate (12 mL), and trifluoroacetic acid (1 drop) were added to a 50 mL single-necked flask, and the mixture was heated to 100 °C and reacted for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and trimethyl orthoformate was removed by rotary evaporation. The concentrate was purified by silica gel column chromatography (PE:EA = 20:1) to give a yellow solid product D (960 mg, yield 77%).

[0152] 1 H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.05 (s, 1H) ppm; LCMS: m / z232.9 [M+H] + . Example 2: ((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methylamine (C1-a) Step 1: Intermediate 2-bromo-6-(2-bromoethoxy)-3-fluorobenzaldehyde (C1-2):

[0153] C1-1 (19 g, 86.7 mmol) was added to a 250 mL single-necked flask, followed by the addition of anhydrous DMF (90 mL) and stirring to dissolve. Potassium carbonate (24 g, 173.5 mmol) and 1,2-dibromoethane (24 g, 130.1 mmol) were added sequentially. The mixture was heated to 64 °C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with ethyl acetate (400 mL). The mixture was stirred for 15 minutes, filtered to remove insoluble salts, and the filter cake was washed once with ethyl acetate (100 mL). The filtrate was washed twice with saturated sodium chloride (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was rapidly purified using a short silica gel column (petroleum ether:ethyl acetate = 50:1) to give intermediate C1-2 (25 g, 88% yield) as a yellow solid.

[0154] 1H NMR (400 MHz, CDCl3) δ 10.52-10.27 (m, 1H), 7.40-7.09 (m, 1H), 7.02-6.78 (m, 1H), 4.53-4.05 (m, 2H), 3.68 (t, J = 6.0 Hz, 2H) ppm. Step 2: Intermediate 2-bromo-3-fluoro-6-(ethoxy)benzaldehyde (C1-3):

[0155] C1-2 (10 g, 30.7 mmol) was added to a 1 L single-necked flask, and anhydrous tetrahydrofuran (400 mL) was added and stirred to dissolve. The mixture was cooled to -20 °C, and sodium tert-butoxide (4.4 g, 46.0 mmol) was slowly added in portions. After the addition was complete, the mixture was heated to room temperature and stirred overnight. After the reaction was complete, the mixture was cooled to -10 °C, and water (60 mL) was slowly added dropwise to quench the reaction. Ethyl acetate (100 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:1 to 30:1) to give C1-3 (5 g, 66% yield) as a pale yellow solid.

[0156] 1 H NMR (400 MHz, CDCl3) δ 10.32 (d, J = 9.8 Hz, 1H), 7.29 (dt, J = 16.2,8.3 Hz, 1H), 7.15-6.98 (m, 1H), 6.68-6.46 (m, 1H), 4.89-4.68 (m, 1H), 4.68-4.42 (m, 1H) ppm. Step 3: Intermediate (E)-N'-(2-bromo-3-fluoro-6-(ethoxy)benzyl)-4-methylbenzenesulfonylhydrazine (C1-4):

[0157] C1-3 (5 g, 20.4 mmol) was added to a 250 mL single-necked flask, and dissolved by stirring with 100 mL of anhydrous methanol. p-Toluenesulfonylhydrazine (4.2 g, 22.4 mmol) was slowly added at room temperature, and the mixture was stirred for 18 hours at room temperature. After the reaction was complete, a large amount of white solid precipitated. The mixture was cooled to 0 °C, filtered, and the solid product was collected. The mother liquor was concentrated, and the crude solid was slurried with a mixture of petroleum ether and ethyl acetate (20:1). The solid product was collected and dried under reduced pressure to give C1-4 (7.5 g, 89% yield), a white solid.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.97 (s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 9.0 Hz, 2H), 7.16 (dd, J = 9.1, 4.3 Hz, 1H), 6.67 (dd, J = 13.6, 6.2 Hz, 1H), 4.49 (dd, J = 21.4, 9.8 Hz, 3H), 2.35 (s, 3H) ppm; LCMS: m / z 414.1 [M+H] + . Step 4: Intermediate 6-bromo-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran (C1-5):

[0159] C1-4 (3 g, 7.3 mmol) was added to a 250 mL single-necked flask, followed by the addition of toluene (100 mL) and stirring to dissolve. Lithium tert-butoxide (639 mg, 7.9 mmol) was slowly added at room temperature, along with zinc rhodium dimer (56 mg, 72.6 μmol) under nitrogen protection. The mixture was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to obtain C1-5 (1.67 g, 100% yield), a pale yellow oil, which was directly added to the next reaction without further purification.

[0160] 1 H NMR (400 MHz, CDCl3) δ 7.03-6.81 (m, 2H), 4.97 (t, J = 5.2 Hz, 1H), 2.84 (dt, J = 9.0, 4.4 Hz, 1H), 1.26 (dt, J = 8.0, 6.1 Hz, 1H), 0.55-0.37 (m, 1H)ppm. Step 5: Intermediate 5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-carboxynitrile (C1-6):

[0161] C1-5 (1.9 g, 8.30 mmol), zinc cyanide (1.46 g, 12.4 mmol), tetrakis(triphenylphosphine)palladium (1.44 g, 1.24 mmol), and DMF (12 mL) were added to a 100 mL single-necked flask. Under nitrogen protection, the mixture was heated to 110 °C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), filtered, and the filtrate was washed twice with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to give C1-6 (1.35 g, 92% yield) as a white solid.

[0162] 1 H NMR (400 MHz, CDCl3) δ 7.03-6.84 (m, 2H), 4.97 (t, J = 5.2 Hz, 1H), 2.84 (dt, J = 9.0, 4.5 Hz, 1H), 1.33-1.20 (m, 1H), 0.52-0.40 (m, 1H) ppm. Step Six: Intermediate tert-butyl ((5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)carbamate (C1-7):

[0163] C1-6 (1.2 g, 6.8 mmol) was added to a 100 mL single-necked flask and dissolved in methanol (30 mL). Di-tert-butyl dicarbonate (2.2 g, 10.3 mmol) was added at room temperature, and the mixture was cooled to -5 °C. Nickel chloride hexahydrate (1.95 g, 8.22 mmol) was slowly added, followed by the addition of sodium borohydride solid (778 mg, 20.5 mmol) in portions. The mixture was then allowed to warm naturally to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter cake was washed with methanol (10 mL), and the filtrate was cooled to 0 °C, quenched with water (5 mL), and concentrated under reduced pressure. The crude product was added to ethyl acetate (80 mL), and the organic phase was washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 40:1) to give C1-7 (1.2 g, 63% yield) as a white solid.

[0164] 1 H NMR (400 MHz, CDCl3) δ 6.76 (t, J = 9.3 Hz, 1H), 6.64 (dd,J = 8.6, 3.7Hz, 1H), 4.90 (s, 1H), 4.82 (t, J = 5.3 Hz, 1H), 4.48 (d, J = 6.1 Hz, 1H), 4.46-4.33 (m, 1H), 2.85 (d, J = 3.8 Hz, 1H), 1.44 (s, 9H), 1.05 (dd, J = 14.6, 6.0 Hz,1H), 0.32 (s, 1H) ppm; LCMS: m / z 224.1 [M-55] + . Step 7: Intermediates tert-butyl((5-fluoro-1aR,6bR-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)carbamate (C1-7a) and ((5-fluoro-1aS,6bS-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)carbamate (C1-7b):

[0165] C1-7 (1.2 g, 4.3 mmol) was further purified by a chiral SFC as follows: column: AD-H 20x250 mm, 10 μm (Daicel), flow rate: 80 g / min, mobile phase: 13% (0.2% ammonia / methanol) in CO2, detection: 214 nM, yielding C1-7a (0.52 g, 43.3% yield), Rt: 0.99 min; and C1-7b (0.57 g, 47.5% yield), Rt: 0.71 min. C1-7a: 1 H NMR (400 MHz, CDCl3) δ 6.76 (t, J = 9.3 Hz, 1H), 6.64 (dd, J = 8.6, 3.9 Hz, 1H), 4.98-4.73 (m, 2H), 4.45 (ddd, J = 41.3, 14.0, 5.7 Hz, 2H), 2.84 (s, 1H), 1.45 (d, J = 7.7 Hz, 9H), 1.05 (dd, J = 14.8, 6.0 Hz, 1H), 0.31 (d, J = 4.6 Hz, 1H) ppm; LCMS: m / z 224.1 [M-55] + . C1-7b: 1 H NMR (400 MHz, CDCl3) δ 6.76 (t, J = 9.3 Hz, 1H), 6.64 (dd, J = 8.6, 3.9 Hz, 1H), 4.98-4.73 (m, 2H), 4.45 (ddd, J = 41.3, 14.0, 5.7 Hz, 2H), 2.84 (s, 1H), 1.45 (d, J = 7.7 Hz, 9H), 1.05 (dd, J = 14.8, 6.0 Hz, 1H), 0.31 (d, J = 4.6 Hz, 1H) ppm; LCMS: m / z 224.1 [M-55] + . Step 8: Intermediate ((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methylamine (C1-a):

[0166] Compound C1-7a (1.2 g, 4.30 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (20 mL). Trifluoroacetic acid (4 mL, 52 mmol) was added at room temperature and the mixture was stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, yielding 1.26 g of a colorless solid, C1-a, in 100% yield. The product can be used directly in the next step.

[0167] 1 H NMR (400 MHz, MeOD) δ 6.95 (t, J = 9.5 Hz, 1H), 6.84 (dd, J = 8.8, 4.0Hz, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.31 (q, J = 13.7 Hz, 2H), 2.92-2.77 (m, 1H),1.26-1.11 (m, 1H), 0.38-0.21 (m, 1H) ppm; LCMS: m / z 180.1 [M+H] + . Example 3: Intermediate 4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2): Step 1: Intermediate 2-bromo-3,6-difluorobenzaldehyde (C2-2):

[0168] Add C2-1 (22 g, 114 mmol) and dry THF (200 mL) to a 500 mL dry three-necked flask and cool to -70°C. o C. Diisopropylaminolithium (2 M, 68.4 mL) was slowly added dropwise to the reaction solution. After stirring the reaction solution at the same temperature for 45 minutes, DMF (17.8 mL, 228 mmol) was added. After stirring the reaction solution at the same temperature for two hours, the temperature was raised to 0. o C. Saturated ammonium chloride (200 mL) was added to the reaction solution. The reaction solution was extracted with EtOAc (200 mL x 2). The combined organic phases were washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate = 100:1) to give C2-2 (20 g, 79.4% yield) as a pale yellow solid.

[0169] 1 H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 7.34 (ddd, J = 9.2, 7.4, 4.5Hz, 1H), 7.16 (td, J = (9.3, 4.0 Hz, 1H) ppm. Step 2: Intermediate 2-bromo-3-fluoro-6-methoxybenzaldehyde (C2-3):

[0170] Add C2-2 (20 g, 90.5 mmol) to a 2 L three-necked flask and dissolve it with anhydrous THF (1000 ml) and MeOH (200 ml) by stirring. Add sodium methoxide (5.87 g, 108.6 mmol), and heat the reaction mixture at 60 °C. o C. Stir for 18 hours. Concentrate under reduced pressure to remove most of the solvent, then add 500 mL of water. Stir the suspension for 30 minutes, then filter and collect the solid. Pulverize the solid with a mixture of petroleum ether and ethyl acetate (5:1), filter to obtain the solid, and dry under reduced pressure to give C2-3 (18 g, 85% yield) as a yellow solid.

[0171] LC-MS: m / z 233.1 [M+H] + . Step 3: Intermediate 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C2-4):

[0172] C2-3 (16.8 g, 72.1 mmol) and dichloromethane (300 mL) were added to a 1 L single-necked flask. Boron tribromide (21.7 g, 86.5 mmol) was slowly added dropwise at -78 °C. The reaction mixture was brought to room temperature and stirred for 18 hours. The reaction mixture was diluted with dichloromethane (300 mL) and saturated sodium bicarbonate (300 mL) was slowly added. The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether: ethyl acetate = 50:1) to give C2-4 (10 g, 63.3% yield) as a pale yellow solid.

[0173] 1 H NMR (400 MHz, CDCl3) δ 11.77 (s, 1H), 10.34 (s, 1H), 7.29 (dt, J = 12.7, 6.3 Hz, 1H), 6.94 (dd, J = (9.3, 4.1 Hz, 1H) ppm. Step 4: Intermediate 4-bromo-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2-5):

[0174] In a dry three-necked flask, trimethyl sulfoxide (9.73 g, 44.2 mmol) and DMSO (50 ml) were added. Sodium tert-butoxide (4.25 g, 44.2 mmol) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and C2-4 (8.8 g, 40.2 mmol) was added. After stirring at room temperature for 18 hours, ethyl acetate (250 ml) and water (250 ml) were added, and the mixture was extracted with ethyl acetate (250 ml x 2). The organic phase was washed once with water and once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate = 10:1) to give C2-5 (6.2 g, 66.2% yield) as a white solid.

[0175] 1 H NMR (400 MHz, CDCl3) δ 7.03 (t, J = 8.7 Hz, 1H), 6.76 (dd, J = 8.8, 3.5Hz, 1H), 5.51-5.40 (m, 1H), 4.58 (ddd, J =13.4, 10.8, 4.6 Hz, 2H), 2.33 (d, J = 4.9 Hz, 1H) ppm. Step 5: Intermediate 5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carboxynitrile (C2-6):

[0176] In a dry single-necked flask, C2-5 (2.7 g, 11.6 mmol), zinc cyanide (2.04 g, 17.4 mmol), DMF (50 ml), and tetraphenylphosphine palladium (1.34 g, 1.16 mmol) were added sequentially. The reaction mixture was heated to 120°C under nitrogen protection. o C, stirred for 18 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (200 mL x 3) and water (200 mL). The organic phase was washed once with water and once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate = 5:1) to give C2-6 (1.6 g, 77% yield) as a white solid.

[0177] 1 H NMR (400 MHz, CDCl3) δ 7.20-6.99 (m, 2H), 5.63 (dd, J = 6.9, 2.9 Hz, 1H), 4.69 (dd, J = 10.8, 7.1 Hz, 1H), 4.55 (dd, J = 10.8, 3.1 Hz, 1H), 2.74 (s,1H) ppm. Step Six: Intermediate (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (C2):

[0178] In a 100 mL single-necked flask, C2-6 (1.55 g, 8.65 mmol), trifluoroacetic acid (1.09 g, 8.65 mmol), methanol (20 mL), and 10% palladium on carbon (2 g, containing 50% water) were added sequentially. The reaction mixture was puffed with hydrogen for 5 minutes, and the gas was exchanged three times using a hydrogen balloon. The mixture was then placed under the hydrogen balloon at a depth of 60°C. oStirred at C for 48 hours. The mixture was filtered through diatomaceous earth, washed with methanol (50 mL x 2), and the filtrate was concentrated under reduced pressure. Dioxane (10 mL) and 10M sodium hydroxide aqueous solution (1 mL) were added, and the mixture was extracted with dioxane (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound C2 (1.4 g, 90% purity, 87% yield), which was used directly in the next step.

[0179] 1 H NMR (400 MHz, CD3OD) δ 3.27 (t, 2H), 3.77 (s, 2H), 4.56 (t, 2H), 6.59 (dd 1H), 6.81 (dd, 1H) ppm; LC-MS: m / z 168.1 [M+H] + . Example 4: 8-Bromo-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (B1)

[0180] In a 100 mL single-necked flask, trifluoroacetate of compound C1-a (1.0 g, 3.41 mmol), compound D (0.95 g, 4.09 mmol), triethylamine (0.69 g, 6.82 mmol), and acetonitrile (20 mL) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, ethyl acetate (80 mL) was added to dilute and dissolve the organic phase. The organic phase was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: PE:EA = 30:1 to PE:EA = 10:1) to give compound B1 (1.2 g, yield 94%).

[0181] 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 7.85(s, 1H), 6.94 (t, J = 9.5 Hz, 1H), 6.77 (dd, J = 8.7, 3.7 Hz, 1H), 4.92 (t, J = 5.2Hz, 1H), 4.79 (p, J = 9.7 Hz, 1H), 2.88 (dt, J = 8.7, 4.5 Hz, 1H), 0.97 (dd,J = 14.4, 5.7 Hz, 1H), 0.10 (s, 1H) ppm; LCMS: m / z 376.0[M+H] + . Using the method of Example 4, intermediate B2 was obtained by reacting intermediate D and C2:

[0182] LCMS: m / z 364.0 [M+H] + Example 5: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol Step 1: (E)-5-bromo-6-(((dimethylamino)methylene)amino)-pyridine-2-carboxylic acid methyl ester E27-1

[0183] Methyl (E)-5-bromo-6-(((dimethylamino)methylene)amino)-pyridine-2-carboxylate (5.0 g, 21.6 mmol) and 1,1-dimethoxy-N,N-dimethylmethylamine (5.16 g, 43.3 mmol) were dissolved in toluene (100 mL). The reaction solution was heated to 110 °C and reacted for 4 hours. TLC showed no residual starting material. The reaction solution was concentrated to obtain crude product E27-1 (6.00 g).

[0184] LCMS: m / z 285.7 [M+H] + . Step 2: (E)-5-bromo-6-(((hydroxylamine)methylene)amino)-pyridine-2-carboxylic acid methyl ester E27-2

[0185] E27-1 (6.0 g, 20.97 mmol), hydroxylamine hydrochloride (2.91 g, 41.94 mmol), sodium acetate (3.44 g, 41.9 mmol), and ethanol (60 mL) were added sequentially to the reaction flask. The reaction solution was heated to 50 °C under a nitrogen atmosphere and reacted for 4 hours. The reaction was monitored by LCMS until it was complete. The solution was then cooled to room temperature and filtered to obtain E27-2 (5.9 g, 85.0% yield).

[0186] 1H NMR (400MHz, CDCl3) δ 8.41-8.29 (m, 1H), 8.26-8.19 (m, 1H), 7.93(d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 3.97 (s, 3H) ppm; LCMS: m / z 273.7[M+H] + . Step 3: Methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E27-3

[0187] Trifluoroacetic anhydride (23.0 g, 109 mmol) was added dropwise to a tetrahydrofuran (100 mL) solution of E27-2 (10 g, 36.49 mmol) at room temperature. The temperature was then slowly increased to 75 °C and the reaction was stirred for 3 hours. After the reaction was complete, the mixture was quenched at 0 °C with a saturated aqueous solution of sodium bicarbonate (100 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 4:1) to give a white solid E27-3 (5.00 g, yield 53.5%).

[0188] 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 4.08 (s, 3H) ppm; LCMS: m / z 256.0[M+H] + . Step 4: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetone E27-4

[0189] 5.0 g (19.3 mmol) of methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-carboxylate E27-3 was dissolved in tetrahydrofuran (100 mL), cooled to -30 °C, and methyl magnesium bromide (3 M, 32.5 mL) was added dropwise. The reaction was carried out under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS until it ended. The temperature was raised to 0 °C, quenched, extracted, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 0.3 g (6.40% yield) of 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetone E27-4.

[0190] LCMS m / z 240.0 [M+H] + . Step 5: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-butanol E27-5

[0191] 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl) acetone E27-4 (150 mg, 0.6 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -30 °C, and ethyl magnesium bromide (1 M, 3.75 mL) was added dropwise. The reaction was carried out under a nitrogen atmosphere for 6 hours. The reaction was monitored by LCMS until it ended. The temperature was raised to 0 °C, quenched, extracted, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-butanol E27-5 (100 mg, 59.3% yield).

[0192] 1 H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.68 (s, 1H), 2.48-2.41 (m, 1H), 1.97-1.89 (m, 1H), 1.70(s, 3H), 0.59 (t, J = 7.4 Hz, 3H). LCMS m / z 270.0 [M+H] + . Step 6: (5-(2-hydroxybutane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid

[0193] The following ingredients were added: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-butanol E27-5 (100 mg, 0.37 mmol), bis(pinacol)diboron (123 mg, 0.44 mmol), potassium acetate (109 mg, 1.11 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (60.5 mg, 0.07 mmol), and 1,4-dioxane (1.5 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC analysis showed no residual starting material. The reaction solution containing E27-6 was used directly in the next step without further treatment.

[0194] Step 7: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol E27-7

[0195] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo-4,3-c]pyrimidine-5-amine (53.7 mg, 0.15 mmol), sodium carbonate (117 mg, 1.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (30.1 mg, 0.04 mmol), 1,4-dioxane, and (4 mL) water (1 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and then purified by HPLC with an alkali adjustment to obtain 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol E27-7 (43.0 mg, 23.3% yield).

[0196] 1 H NMR (400MHz, DMSO-d6) δ 9.54 (s, 1H), 9.39 (s, 1H), 9.10 (d, J = 8.0Hz, 1H), 8.91 (br s, 1H), 8.62 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.00-6.93(m, 1H), 6.71 (dd, J = 3.9, 8.6 Hz, 1H), 5.67 (s, 1H), 4.78 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.33-3.30 (m, 2H), 2.55-2.51 (m, 1H), 1.99 (dd, J = 7.4, 13.8Hz, 1H), 1.75 (s, 3H), 0.64 (t, J = 7.4 Hz, 3H). LCMS m / z 475.1 [M+H]+ . Step 8: Resolution of 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol E27-7

[0197] 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol E27-7 was separated by chiral SFC (separation method: column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A [0.1%NH3H2O ​​IPA]; B (ethanol: 5%-40% gradient, 4mL / min) to obtain (S)- 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol ((S)-E27-7) or (R)-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)butane-2-ol ((R)-E27-7), one of which has a retention time of 3.134 min (compound a), and the other enantiomer has a retention time of 3.547 min (compound b).

[0198] Compound a: 1H NMR (400MHz, DMSO-d6) δ 9.54 (s, 1H), 9.39 (s, 1H), 9.10 (d, J=8.0 Hz, 1H), 8.91 (br s, 1H), 8.62 (s, 1H), 7.50 (d, J=8.0 Hz, 1H),7.00 - 6.93 (m, 1H), 6.71 (dd, J=3.9, 8.6 Hz, 1H), 5.67 (s, 1H), 4.78 (s,2H), 4.55 (t, J=8.7 Hz, 2H), 3.33 - 3.30 (m, 2H), 2.55 - 2.51 (m, 1H), 1.99(dd, J=7.4, 13.8 Hz, 1H), 1.75 (s, 3H), 0.64 (t, J=7.4 Hz, 3H) ppm. Compound b: ¹H NMR (400MHz, DMSO-d6) δ 9.54 (s, 1H), 9.38 (s, 1H), 9.10 (d, J=8.0 Hz, 1H), 8.91 (br s, 1H), 8.62 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.99 - 6.93 (m, 1H), 6.71 (dd, J=3.9, 8.6 Hz, 1H), 5.67 (s, 1H), 4.78 (s, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.33 - 3.30 (m, 2H), 2.54 - 2.51 (m, 1H), 2.04 -1.94 (m, 1H), 1.75 (s, 3H), 0.64 (t, J=7.4 Hz, 3H) ppm. Example 6: 3-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pentane-3-ol Step 1: 3-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pentan-3-ol E28-1

[0199] 240 mg (0.940 mmol) of methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E27-3 was dissolved in tetrahydrofuran (5.00 mL). The mixture was cooled to -30 °C and ethyl magnesium bromide (1 M, 2.83 mL) was added dropwise. The reaction was carried out under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS until it ended. The mixture was then heated to 0 °C, quenched, extracted, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 3-(8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)pentan-3-ol E28-1 (80.0 mg, 29.8% yield).

[0200] 1 H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 5.37 (s, 1H), 2.60-2.51 (m, 2H), 1.91-1.80 (m, 2H), 0.54(t, J = 7.4 Hz, 6H) ppm; LCMS: m / z 286.0 [M+H] + . Step 2: (5-(3-hydroxypentan-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E28-2

[0201] The following ingredients were added: 3-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pentane-3-ol E28-1 (80.0 mg, 0.280 mmol), bis(pinacol)diboron (79.0 mg, 0.310 mmol), potassium acetate (8.03 mg, 0.840 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (46.0 mg, 0.056 mmol), and 1,4-dioxane (1.00 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC analysis showed no residual starting material. The reaction solution containing E28-2 was used directly in the next step without further treatment.

[0202] Step 3: 3-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pentan-3-ol

[0203] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (41.0 mg, 0.110 mmol), sodium carbonate (89.0 mg, 0.800 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (46.0 mg, 0.056 mmol), 1,4-dioxane, and (1.00 mL) water (0.500 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 3-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)pentan-3-ol (50.0 mg, 35.6% yield).

[0204] 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.40 (s, 1H), 9.11 (d, J =7.9 Hz, 1H), 8.95-8.86 (m, 1H), 8.61 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.00-6.93 (m, 1H), 6.75-6.67 (m, 1H), 5.36 (s, 1H), 4.78 (br d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.33-3.30 (m, 2H), 2.69-2.53 (m, 2H), 1.97-1.84 (m,2H), 0.59 (t, J = 7.4 Hz, 6H). LCMS m / z 489.3 [M+H] + . Example 7: 1,1,1-trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol Step 1: 8-Bromo-5-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propane-2-yl)-[1,2,4]triazolo[1,5-a]pyridine E29-1

[0205] 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetone E27-4 (500 mg, 2.08 mmol) and cesium fluoride (55.0 mg, 0.362 mmol) were dissolved in N,N-dimethylformamide (5 mL). Trifluoromethyltrimethylsilane (326 mg, 2.29 mmol) was added under a nitrogen atmosphere at 0 °C. The reaction was carried out at 20 °C for 1 hour under a nitrogen atmosphere. Then, trifluoromethyltrimethylsilane (296 mg, 2.08 mmol) was added, and the reaction was continued at 20 °C for another hour. TLC and LCMS monitoring showed no residual starting material. The reaction solution containing E29-1 was used directly for the next step without further treatment.

[0206] LCMS: m / z 383.9 [M+H] + . Step 2: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1,1-trifluoroprop-2-ol E29-2

[0207] Add 5 mL of ethanol to the reaction solution from the previous step, react at 20 °C for 2 hours, and monitor the reaction until completion by TLC. After concentrating the reaction solution, dilute with dichloromethane, wash with saturated sodium chloride solution, dry, filter, and concentrate. The crude product is purified by column chromatography to give a white solid product 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1,1-trifluoroprop-2-ol E29-2 (340 mg, 52.7% yield).

[0208] 1 H NMR (400MHz, CDCl3) δ 8.46 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.70-7.66 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H), 1.93 (s, 3H) ppm. Step 3: (5-(1,1,1-trifluoro-2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E29-3

[0209] In a glove box, 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1,1-trifluoropropane-2-ol E29-2 (150 mg, 0.482 mmol), pinacol diborate (135 mg, 0.530 mmol), potassium acetate (95.0 mg, 0.964 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride•dichloromethane complex (39.4 mg, 0.048 mmol), and dioxane (5 mL) were added sequentially to a sealed flask. The reaction was carried out at 120 °C for 5 hours under a nitrogen atmosphere. LCMS monitoring showed no remaining starting material, and the reaction solution was used directly for the next step without further treatment.

[0210] Step 4: 1,1,1-Trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E29-4

[0211] Add 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (150 mg, 0.412 mmol), potassium carbonate (134 mg, 0.967 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride•dichloromethane complex (39.5 mg, 0.048 mmol), and water (1 mL) to the reaction solution from the previous step. The reaction solution was heated to 100℃ under a nitrogen atmosphere and reacted for 2 hours. The reaction was monitored by LCMS until it ended. The solution was then cooled to room temperature and concentrated. The concentrate was purified by column chromatography to give a grayish-white solid product 1,1,1-trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E29-4 (90.0 mg, 38.9% yield).

[0212] 1 H NMR (400MHz, DMSO- d 6) δ 9.55 (s, 1H), 9.44 (s, 1H), 9.17 (d, J = 8.0Hz, 1H), 9.00 (t, J = 4.8 Hz, 1H), 8.70 (s, 1H), 7.76 (d, J =8.0 Hz, 1H), 7.53(s, 1H), 7.01-6.92 (m, 1H), 6.75-6.68 (m, 1H), 4.78 (d, J = 4.8 Hz, 2H), 4.55(t, J = 8.8 Hz, 2H), 3.36-3.34 (m, 2H), 2.16 (s, 3H) ppm; LCMS: m / z 515.3.0 [M+H] + . Step 5: Resolution of 1,1,1-trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol 1,1,1-Trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E29-4 was separated by chiral SFC (Separation method: column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A [0.1% NH3H2O ​​IPA]; B (ethanol): 45% gradient, 2.8). (mL / min), yielding (S)-1,1,1-trifluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol ((S)-E29-4) or (R)-1,1,1-trifluoro-2-(8-(5-) (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol ((R)-E29-4), one of which has a retention time of 4.974 min (compound c), and the other enantiomer has a retention time of 5.440 min (compound d).

[0213]

[0214] Compound C: 1 H NMR (400MHz, DMSO- d6) δ 9.55 (s, 1H), 9.44 (s, 1H), 9.17(d, J = 8.0 Hz, 1H), 9.00 (t, J = 4.8 Hz, 1H), 8.70 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.53 (s, 1H), 7.01-6.92 (m, 1H), 6.75-6.68 (m, 1H), 4.78 (d, J = 4.8Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.36-3.34 (m, 2H), 2.16 (s, 3H) ppm; LCMS:m / z 515.3.0 [M+H] + . Simultaneously, we obtained Compound d from Example 8: 1 H NMR (400MHz, DMSO- d 6) δ 9.55 (s, 1H), 9.44 (s, 1H), 9.17 (d, J = 8.0Hz, 1H), 9.00 (t, J = 4.8 Hz, 1H), 8.70 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.53(s, 1H), 7.01-6.92 (m, 1H), 6.75-6.68 (m, 1H), 4.78 (d, J = 4.8 Hz, 2H), 4.55(t, J = 8.8 Hz, 2H), 3.36-3.34 (m, 2H), 2.16 (s, 3H) ppm; LCMS: m / z 515.3.0 [M+H] + . Example 9: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methylpropane-2-ol Step 1: (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N,N-dimethylformamidin E30-2

[0215] 3-Bromo-6-methylpyridin-2-amine E30-1 (4.50 g, 24.1 mmol) and N,N-dimethylformamide dimethyl acetal (14.3 g, 120 mmol) were dissolved in toluene (10.0 mL), and then the mixture was heated to 100 °C and reacted under a nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to give (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N,N-dimethylformamidin E30-2 (5.80 g, crude product).

[0216] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 3.14 (s, 3H), 3.10 (s, 3H), 2.40 (s, 3H) ppm; LCMS: m / z242.1 [M+H] + . Step 2: (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N-hydroxymethylamidine E30-3

[0217] (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N,N-dimethylformamidin E30-2 (5.80 g, 24.0 mmol), sodium acetate (4.32 g, 52.7 mmol), and hydroxylamine hydrochloride (3.33 g, 43.9 mmol) were dissolved in ethanol (60.0 mL). The mixture was heated to 50 °C and reacted under a nitrogen atmosphere for 2 hours. The reaction was monitored by TLC until it ended. The mixture was then cooled to room temperature, diluted with water, filtered, and the filter cake was dried to obtain (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N-hydroxyformamidin E30-3 (5.50 g, 98.8% yield).

[0218] 1 H NMR (400 MHz, CDCl3) δ 8.25-8.09 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 2.43 (s, 3H) ppm; LCMS: m / z 230.1 [M+H] + . Step 3: 8-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine E30-4

[0219] (E)-N'-(3-bromo-6-methylpyridin-2-yl)-N-hydroxymethylammonium E30-3 (5.50 g, 23.9 mmol) was dissolved in polyphosphoric acid (5.00 mL), and the mixture was heated to 90 °C and reacted under a nitrogen atmosphere for 2 hours. TLC showed no residual starting material. The mixture was cooled to room temperature, quenched with sodium bicarbonate, extracted, filtered, washed, dried, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 8-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine E30-4 (1.70 g, 33.4% yield).

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 2.72-2.69 (m, 3H) ppm; LCMS: m / z 212.1 [M+H] + . Step 4: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methyl-prop-2-ol E30-5

[0221] 8-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine E30-4 (1.50 g, 7.07 mmol) was dissolved in tetrahydrofuran (40.0 mL), cooled to -78 °C, and diisopropylaminolithium (2.00 M, 7.07 mL) was added dropwise. The reaction was carried out at -78 °C under a nitrogen atmosphere for 2 hours. Acetone (2.47 g, 42.4 mmol, 3.12 mL) was added, and the reaction was carried out at -78 °C under a nitrogen atmosphere for 3 hours. The reaction was monitored by TLC and LCMS until completion. The reaction was quenched, extracted, filtered, washed, and dried. The crude product was purified by rapid silica gel column chromatography and then purified by HPLC to obtain 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methyl-prop-2-ol E30-5 (450 mg, 21.9% yield).

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.06 (d, J =7.8 Hz, 1H), 4.72 (s, 1H), 3.31 (s, 2H), 1.13 (s, 6H) ppm; LCMS:m / z 270.0 [M+H] + . Step 5: (5-(2-hydroxy-2-methyl-propyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E30-6

[0223] The following ingredients were added: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methyl-prop-2-ol E30-5 (150 mg, 0.56 mmol), bis(pinacol)diboron (155 mg, 0.61 mmol), potassium acetate (163 mg, 1.67 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (90.7 mg, 0.110 mmol), and 1,4-dioxane (2.00 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC showed no residual starting material. The reaction solution was used directly for the next step without further treatment.

[0224] Step Six: 1-(-8-(5-(((-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazol[4,3-c]pyrimidin-8-yl)-[1,2,4]triazol[1,5-a]pyridin-5-yl)-2-methyl-prop-2-ol

[0225] Add 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (80.6 mg, 0.220 mmol), sodium carbonate (176 mg, 1.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (45.2 mg, 0.055 mmol), 1,4-dioxane (1.00 mL), and water (0.500 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and then purified by HPLC to obtain 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methylpropane-2-ol (5.00 mg, 1.86% yield).

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.10 (d, J = 7.8 Hz, 1H), 8.94-8.87 (m, 1H), 8.59 (s, 1H), 7.30 (br d, J = 7.8 Hz, 1H), 6.97 (br t, J = 9.5 Hz, 1H), 6.72 (br dd, J = 3.4, 8.5 Hz, 1H), 4.78 (br d, J = 4.4 Hz, 2H), 4.76 (s, 1H), 4.55 (br t, J = 8.6 Hz, 2H), 3.41 (br s, 2H), 3.27-3.18 (m, 2H), 1.17 (s, 6H) ppm; LCMS: m / z 475.3 [M+H] + . Example 10: 1,1,3,3-Tetrafluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol Step 1: 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid E31-1

[0227] Methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid E27-3 (2.50 g, 9.76 mmol), sodium hydroxide (1.17 g, 29.3 mmol), and water (10.0 mL), methanol (20.0 mL), and tetrahydrofuran (20.0 mL) were dissolved in water. The mixture was reacted at 80 °C for 12 hours under a nitrogen atmosphere. The reaction was completed by TLC monitoring. The reaction solution was concentrated under vacuum, diluted with saturated sodium chloride solution, and the pH was adjusted to 5 with 4 M hydrochloric acid. The solid was filtered and collected, washed with saturated sodium chloride solution, to obtain the crude product 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid E31-1 (2.50 g, crude product), which was used directly in the next step.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.11 (d,J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H) ppm. Step 2: 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxyl chloride E31-2

[0229] A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid E31-1 (700 mg, 2.89 mmol), N,N-dimethylformamide (35 mg, 0.479 mmol), and thionyl chloride (10.0 mL) was reacted at 80 °C for 6 hours under a nitrogen atmosphere. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated to give crude product 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic chloride E31-2 (770 mg, crude product).

[0230] Step 3: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1,3,3-tetrafluoroprop-2-ol E31-3

[0231] A solution of 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxyl chloride E31-2 (770 mg, 2.96 mmol), (bromodifluoromethyl)trimethylsilane (1.80 g, 8.87 mmol), triphenylphosphine (1.94 g, 7.39 mmol), and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (1.52 g, 11.8 mmol) in acetonitrile (10.0 mL) was reacted at 20 °C for 12 h, then quenched with water (5.00 mL) and pyridine (0.935 g, 11.8 mmol), and the reaction was carried out at 80 °C for 1.5 h. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, dried over the organic phase, filtered, and concentrated. The crude product was separated by column chromatography to give a white solid product 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1,3,3-tetrafluoroprop-2-ol E31-3 (300 mg, 30.6% yield).

[0232] 1 H NMR (400MHz, CDCl3) δ .44 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.36 (d, J =7.6 Hz, 1H), 6.67-6.36 (m, 3H) ppm; LCMS: m / z 327.9 [M+H] + . Step 4: (5-(1,1,3,3-tetrafluoro-2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E31-4

[0233] In a glove box, 2-(8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol E31-3 (250 mg, 0.762 mmol), pinacol diboronate (232 mg, 0.914 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride•dichloromethane complex (62.2 mg, 0.0762 mmol), potassium acetate (150 mg, 1.52 mmol), and dioxane (5.00 mL) were added sequentially to a sealed flask. The reaction mixture was reacted at 120 °C under a nitrogen atmosphere for 5 hours. The reaction was monitored by TLC until completion. The reaction mixture was used directly for the next step.

[0234] Step 5: 1,1,3,3-Tetrafluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol

[0235] Add 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazol[4,3-c]pyrimidine-5-amine B2 (222 mg, 0.609 mmol), potassium carbonate (211 mg, 1.52 mmol), water (1.00 mL), dioxane (5.00 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride•dichloromethane complex (62.2 mg, 0.0761 mmol) to the reaction solution from step four. The reaction solution was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until completion. The reaction solution was concentrated and purified by column chromatography. The crude product was then slurried with dichloromethane:methyl tert-butyl ether (10:1), followed by acetonitrile, and finally purified by pre-HPLC. The resulting product salt solution was adjusted to pH 8 with saturated sodium bicarbonate solution, concentrated, and the solid was slurried with water, filtered, washed, and lyophilized to obtain the pure product 1,1,3,3-tetrafluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol (95.0 mg, 23.4% yield).

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.23 (d, J = 8.0 Hz, 1H), 9.04 (s, 1H), 8.74 (s, 1H), 7.86 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.17 (br t, J = 53.8 Hz, 2H), 7.00-6.94 (m, 1H), 6.75-6.70 (m, 1H), 4.79(s, 2H), 4.56 (t, J = 8.8 Hz, 2H), 3.34-3.29 (m, 2H)ppm; LCMS m / z 533.3 [M+H] + . Example 11: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-1-ol Step 1: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-one E32-1

[0237] 1.50 g (5.86 mmol) of methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E27-3 was dissolved in tetrahydrofuran (20.0 mL), cooled to -30 °C, and ethyl magnesium bromide was added dropwise. The reaction was maintained at this temperature for 4 hours. The reaction was monitored by LCMS until it ended. The mixture was then quenched, extracted, washed, dried, concentrated, and purified by silica gel column chromatography to obtain 1-(8-bromo-[1,2,4]benztriazolo[1,5-a]pyridine-5-yl)prop-1-one E32-1 (1.00 g, 67.2% yield).

[0238] 1 H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H), 8.14 (d, J =7.9 Hz, 1H), 7.61(d, J =7.9 Hz, 1H), 3.40 - 3.34 (m, 2H), 1.14 (t, J =7.1 Hz, 3H) ppm; LCMS: m / z256.0 [M+3] + . Step 2: 1-(8-bromo-[1,2,4]benztriazole[1,5-a]pyridin-5-yl)prop-1-ol E32-2

[0239] 1-(8-bromo-[1,2,4]benztriazol[1,5-a]pyridin-5-yl)propane-1-one E32-1 (1.00 g, 3.94 mmol) was dissolved in methanol (20.0 mL), cooled to -5 °C, sodium borohydride (447 mg, 11.8 mmol) was added, the temperature was raised to 0 °C, and the reaction was carried out for 2 hours. The reaction was monitored by TLC until it ended. The mixture was quenched, concentrated, extracted, washed, dried, concentrated, and purified by silica gel column chromatography to obtain 1-(8-bromo-[1,2,4]triazol[1,5-a]pyridin-5-yl)propane-1-ol E32-2 (800 mg, 79.0% yield).

[0240] 1 H NMR (400MHz, DMSO-d6) δ 8.60 (s, 1H), 8.05 (d, J =7.8 Hz, 1H), 7.17 -7.15 (m, 1H), 5.88 (d, J=5.1 Hz, 1H), 5.19 - 5.13 (m, 1H), 2.02 - 1.90 (m,1H), 1.74 - 1.62 (m, 1H), 0.92 (t, J =7.4 Hz, 3H) ppm; LCMS: m / z 258.0 [M+3] + . Step 3: (5-(1-hydroxypropyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid

[0241] 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-ol E32-2 (800 mg, 3.12 mmol), pinacol diboronate (872 mg, 3.44 mmol), potassium acetate (919 mg, 9.37 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (510 mg, 0.624 mmol) were dissolved in 1,4-dioxane (8.00 mL). The mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC showed no residual starting material. The reaction solution was used directly in the next step without further treatment.

[0242] LCMS: m / z 222.0 [M+3] + . Step 4: 1-(8-(5-(((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-ol E32-4

[0243] Add 8-bromo-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (512 mg, 1.40 mmol), sodium carbonate (993 mg, 9.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (509 mg, 0.624 mmol), 1,4-dioxane (3.00 mL), and water (1.00 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-1-ol E32-4 (product: 300 mg, 21.0% yield).

[0244] 1 H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.18 (d, J =7.8Hz, 1H), 8.95 - 8.89 (m, 1H), 8.64 (s, 1H), 7.41 (d, J =7.8 Hz, 1H), 7.00 -6.93 (m, 1H), 6.74 - 6.69 (m, 1H), 5.85 (d, J =5.0 Hz, 1H), 5.30 - 5.24 (m,1H), 4.81 - 4.74 (m, 2H), 4.55 (t, J =8.7 Hz, 2H), 3.32 - 3.30 (m, 2H), 2.08 -1.96 (m, 1H), 1.80 - 1.68 (m, 1H), 0.96 (t, J =7.3 Hz, 3H) ppm; LCMS: m / z 461.0[M+H] + . Step 5: Resolution of 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-1-ol E32-4

[0245] 1-(8-(5-(((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-ol E32-4 was separated by chiral SFC (Separation method: column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A [0.1% NH3H2O ​​IPA]; B (ethanol): 5%-40% gradient). (4 mL / min) yielded (S)-1-(8-(5-(((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-ol ((S)-E32-4) or (R)-1-(8-(5-(((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-1-ol ((R)-E32-4), one with a retention time of 2.782 min (compound e), and the other enantiomer with a retention time of 2.907 min. min(compound f).

[0246] Compound e: 1 H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.18 (d, J=7.8 Hz, 1H), 8.95 - 8.89 (m, 1H), 8.63 (s, 1H), 7.41 (d, J=7.9 Hz, 1H),7.01 - 6.93 (m, 1H), 6.75 - 6.69 (m, 1H), 5.84 (d, J=5.0 Hz, 1H), 5.30 - 5.24(m, 1H), 4.78 (br d, J=4.5 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 - 3.30 (m,2H), 2.08 - 1.96 (m, 1H), 1.80 - 1.68 (m, 1H), 0.96 (t, J=7.3 Hz, 3H) ppm. Compound f: 1H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.18 (d, J=7.8 Hz, 1H), 8.95 - 8.89 (m, 1H), 8.64 (s, 1H), 7.41 (d, J=7.8 Hz, 1H),7.00 - 6.93 (m, 1H), 6.74 - 6.69 (m, 1H), 5.85 (d, J=5.0 Hz, 1H), 5.30 - 5.24(m, 1H), 4.81 - 4.74 (m, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 - 3.30 (m, 2H),2.08 - 1.96 (m, 1H), 1.80 - 1.68 (m, 1H), 0.96 (t, J=7.3 Hz, 3H) ppm. Example 12: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol Step 1: Methyl 6-amino-3-methylpyridine-2-carboxylate E33-2

[0247] Methyl 6-amino-3-bromopyridine-2-carboxylate E33-1 (5 g, 21.6 mmol), methylboronic acid (3.24 g, 54.1 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (904 mg, 1.08 mmol), potassium carbonate (4.49 g, 32.4 mmol), and 1,4-dioxane (50 mL) were mixed and purged with nitrogen three times. The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 12 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by rapid silica gel column chromatography to obtain methyl 6-amino-3-methylpyridine-2-carboxylate E33-2 (3.50 g, 21.06 mol, 97.3% yield).

[0248] 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.4 Hz, 1H), 6.42 (d, J= 8.4 Hz,1H), 4.54 (br s, 2H), 3.75 (s, 3H), 2.24 (s, 3H). Step 2: Methyl 6-amino-5-bromo-3-methylpyridine-2-carboxylate E33-3

[0249] Methyl 6-amino-3-methylpyridine-2-carboxylate E33-2 (3.5 g, 21.1 mmol) and tetrabutylammonium tribromide (15.2 g, 31.6 mmol) were dissolved in dichloromethane (42.0 mL) and reacted at 25 °C for 12 hours. TLC analysis showed no residual starting material. The reaction mixture was quenched with sodium sulfite, extracted, dried, and concentrated under reduced pressure. The concentrate was purified by rapid silica gel column chromatography to give methyl 6-amino-5-bromo-3-methylpyridine-2-carboxylate E33-3 (2.10 g, 8.57 mmol, 40.7% yield).

[0250] 1 H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 5.05 (br s, 2H), 3.95 (s, 3H), 2.44 (s, 3H) Step 3: Methyl 5-bromo-6-(((dimethylamino)methylethylene)amino)-3-methylpyridine-2-carboxylate E33-4

[0251] Methyl 6-amino-5-bromo-3-methylpyridine-2-carboxylate E33-3 (2.10 g, 8.57 mmol) and N,N-dimethylformamide dimethyl acetal (2.04 g, 17.1 mmol) were dissolved in toluene (20.0 mL). The reaction solution was heated to 110 °C and reacted for 4 hours. TLC showed no residual starting material. The reaction solution was concentrated to obtain crude methyl 5-bromo-6-(((dimethylamino)methylethylene)amino)-3-methylpyridine-2-carboxylate E33-4 (2.30 g, 7.66 mmol, 89.4% yield).

[0252] 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.75 (s, 1H), 3.94 (s, 3H), 3.16 (s, 3H), 3.14 (s, 3H), 2.46 (s, 3H) ppm. Step 4: (5-Bromo-6-(((hydroxyamino)methyl)amino)-3-methylpyridine-2-carboxylic acid methyl ester E33-5

[0253] In a reaction flask, methyl 5-bromo-6-((((dimethylamino)methylethylene)amino)-3-methylpyridine-2-carboxylate E33-4 (2.30 g, 7.66 mmol), hydroxylamine hydrochloride (1.06 g, 15.3 mmol), sodium acetate (1.26 g, 15.3 mmol), and ethanol (23.0 mL) were added sequentially. The reaction solution was heated to 50 °C under a nitrogen atmosphere and reacted for 4 hours. The reaction was monitored by LCMS until it was complete. After cooling to room temperature, the solution was filtered to obtain methyl 5-bromo-6-((((hydroxyamino)methylethylene)amino)-3-methylpyridine-2-carboxylate E33-5 (1.12 g, 50.7% yield).

[0254] 1 H NMR (400 MHz, CDCl3) δ 8.23-8.20 (m, 2H), 7.75 (s, 1H), 3.95 (s, 3H), 2.48 (s, 3H) ppm. Step 5: 8-Bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester E33-6

[0255] Polyphosphoric acid (3.89 mmol, 10.0 mL) was added to methyl 5-bromo-6-(((hydroxylamine)methylethylene)amino)-3-methylpyridine-2-carboxylate E33-5 (1.12 g, 3.89 mmol) at room temperature. The temperature was then slowly increased to 95 °C and the reaction was stirred for 2 hours. After the reaction was completed, the mixture was quenched at 0 °C with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to give a white solid product, methyl 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E33-6 (1.01 g, 3.74 mmol, 96.2% yield). 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.70 (s, 1H), 4.11 (s, 3H), 2.48 (s, 3H) ppm. Step Six: 2-(8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E33-7

[0256] At -30°C, methyl magnesium bromide (3M, 12.4 mL) was added dropwise to a tetrahydrofuran solution of methyl 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-carboxylate E33-6 (1.01 g, 3.74 mmol) and stirred at this temperature for 3 hours. After the reaction was completed, water (30 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate, dried, concentrated, and purified by rapid silica gel column chromatography to give 2-(8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E33-7 (410 mg, 1.52 mmol, 40.6% yield).

[0257] 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.55 (s, 1H), 6.93 (s, 1H), 2.51 (s, 3H), 1.76 (s, 6H) ppm. Step 7: (5-(2-hydroxypropyl-2-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E33-8

[0258] In a glove box, the following compounds were added sequentially to a reaction flask: 2-(8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol E33-7 (310 mg, 1.15 mmol), bis-pinacolborate (320 mg, 1.26 mmol), potassium acetate (225 mg, 2.30 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (187 mg, 0.229 mmol), and 1,4-dioxane (3.00 mL). The reaction was heated to 120 °C and reacted under a nitrogen atmosphere for 7 hours. LC-MS analysis showed no residual starting material, and the reaction solution was used directly for the next step without further treatment.

[0259] Step 8: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-pyrimidin-8-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol

[0260] Add 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (433 mg, 1.19 mmol), potassium carbonate (470 mg, 3.40 mmol), [1,1'-bis(diphenyl)ferrocene]palladium dichloromethane (124 mg, 0.170 mmol), 1,4-dioxane (5 mL), and water (1 mL) to the reaction solution from the previous step. The reaction solution was heated to 100℃ under a nitrogen atmosphere and reacted for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by rapid silica gel column chromatography to obtain a crude product. After separation by HPLC, the crude product was lyophilized to obtain 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol (240 mg, 0.505 mmol, 29.7% yield).

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.36 (s, 1H), 8.92 (s, 2H), 8.55 (s, 1H), 6.96 (t, J = 9.4 Hz, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 5.79(s, 1H), 4.77 (s, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.35-3.35 (m, 2H), 2.77 (s, 3H), 1.86 (s, 6H) ppm. Example 13: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)propane-2-ol Step 1: 4-Amino-5-bromopyrimidine-2-formonitrile E34-2

[0262] At 25 °C, a solution of sodium cyanide (14.1 g, 287 mmol) in water (20 mL) was added to a solution of 5-bromo-2-chloropyrimidin-4-amine E34-1 (50 g, 239 mmol), triethylenediamine (26.9 g, 239 mmol), and dimethyl sulfoxide in a solution of 450 mL. The reaction mixture was heated to 60 °C and stirred at 60 °C for 18 hours. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added to the mixture. The organic phase was dried, concentrated, and the concentrate was purified by rapid silica gel column chromatography to give 4-amino-5-bromopyrimidin-2-carboxynitrile E34-2 (29.0 g, 59.5% yield).

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.35 (br s, 1H), 7.55 (br s,1H) ppm; LCMS: m / z 201.0 [M+3H] + . Step 2: Methyl 4-amino-5-bromopyrimidine-2-carboxylate E34-3

[0264] 4-Amino-5-bromopyrimidine-2-carboxynitrile E34-2 (29.0 g, 145 mmol) was dissolved in methanol (290 mL), and then concentrated sulfuric acid (533 g, 5.33 mol) was added dropwise at 0 °C. The reaction solution was heated to 70 °C and reacted for 12 hours. TLC showed no residual starting material. The pH of the reaction solution was adjusted to 7, and the mixture was extracted. The organic phase was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by rapid silica gel column chromatography to obtain methyl 4-amino-5-bromopyrimidine-2-carboxylate E34-3 (17.0 g, 49.2% yield).

[0265] 1 H NMR (400MHz, DMSO-d6) δ 8.46 (s, 1H), 8.05 (s, 1H), 7.28 (s, 1H), 3.82 (s, 3H) ppm; LCMS: m / z 234.0 [M+3H] + . Step 3: (E)-5-bromo-4-((1-(dimethylamino)ethoxy)amino)pyrimidine-2-carboxylic acid methyl ester

[0266] 4-Amino-5-bromopyrimidine-2-carboxylate methyl ester E34-3 (7.00 g, 30.2 mmol) and N,N-dimethylacetamide dimethyl acetal (12.1 g, 90.5 mmol) were dissolved in toluene (70.0 mL). The mixture was heated to 100 °C and reacted under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, concentrated, and dried to obtain (E)-5-bromo-4-((1-(dimethylamino)ethoxy)amino)pyrimidine-2-carboxylate methyl ester E34-4 (8.00 g, crude product).

[0267] 1 H NMR (400MHz, DMSO-d6) δ 8.67 (s, 1H), 3.85-3.81 (m, 3H), 3.16-3.11(m, 6H), 2.16 (s, 3H) ppm; LCMS: m / z 302.9 [M+3H] + . Step 4: (E)-5-bromo-4-((1-(hydroxyamino)ethenyl)amino)pyrimidine-2-carboxylic acid methyl ester E34-5

[0268] Methyl (E)-5-bromo-4-((1-(dimethylamino)ethylidene)amino)pyrimidine-2-carboxylate E34-4 (8.00 g, 26.6 mmol / L) and hydroxylamine hydrochloride (3.69 g, 53.1 mmol / L) were dissolved in methanol (80.0 mL) and reacted at 20 °C for 3 hours. The reaction was monitored by LCMS until it ended. The reaction solution was concentrated under reduced pressure, slurried, and dried to obtain methyl (E)-5-bromo-4-((1-(hydroxylamine)ethylidene)amino)pyrimidine-2-carboxylate E34-5 (7.10 g, crude product).

[0269] 1 H NMR (400MHz, DMSO-d6) δ 10.93 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 3.87 (s, 3H), 2.40 (s, 3H) ppm; LCMS: m / z 289.0 [M+H] + . Step 5: Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5-carboxylate E34-6

[0270] (E)-5-bromo-4-((1-(hydroxylamine)ethylidene)amino)pyrimidine-2-carboxylate E34-5 (7.10 g, 24.5 mmol) was dissolved in polyphosphoric acid (70.0 mL) and reacted at 85 °C for 2.5 h. The reaction was monitored by LCMS until it ended. The pH was adjusted to 7 with sodium bicarbonate. The reaction solution was extracted and concentrated to obtain methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5-carboxylate E34-6 (2.60 g, 39.0% yield).

[0271] 1 H NMR (400MHz, DMSO-d6) δ 8.63 (s, 1H), 4.02 (s, 3H), 2.57 (s, 3H)ppm; LCMS: m / z 272.9 [M+3H] + . Step Six: 2-(8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)prop-2-ol E34-7

[0272] 1.60 g (5.90 mmol) of methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-carboxylate E34-6 was dissolved in 100 mL of tetrahydrofuran. The solution was cooled to -30 °C, and methyl magnesium bromide (3 M, 9.84 mL) was added dropwise. The reaction was maintained at this temperature for 0.5 hours. The reaction was monitored by TLC until it ended. The reaction solution was quenched, extracted, dried, and concentrated. The crude product was separated by rapid silica gel column chromatography to obtain 2-(8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)prop-2-ol E34-7 (180 mg, 20.2% yield).

[0273] 1 H NMR (400MHz, DMSO-d6) δ 8.53 (s, 1H), 5.58 (s, 1H), 2.57 (s, 3H), 1.70 (s, 6H) ppm; LCMS: m / z 273.0 [M+3H] + . Step 7: (5-(2-hydroxypropyl-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)boronic acid

[0274] 2-(8-bromo-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)propane-2-ol E34-7 (300 mg, 1.11 mmol), pinacol diboronate (309 mg, 1.22 mmol), potassium acetate (325 mg, 3.32 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (180 mg, 0.221 mmol) were dissolved in 1,4-dioxane (3.00 mL). The mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC showed no residual starting material. The reaction solution was used directly in the next step without further treatment.

[0275] Step 8: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)propane-2-ol Add 8-bromo-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine E34-8 (260 mg, 1.10 mmol), sodium carbonate (350 mg, 3.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (179 mg, 0.220 mmol), 1,4-dioxane (3.00 mL), and water (1.00 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to give 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)propane-2-ol (84.0 mg, 15.88% yield).

[0276] 1 H NMR (400MHz, DMSO-d6) δ 9.66 (s, 1H), 9.55 (s, 1H), 9.35 (s, 1H), 9.07-8.99 (m, 1H), 7.01-6.93 (m, 1H), 6.75-6.69 (m, 1H), 5.63 (s, 1H), 4.82-4.76 (m, 2H), 4.55 (t, J =8.7 Hz, 2H), 3.31-3.28 (m, 2H), 2.64 (s, 3H), 1.76(s, 6H) ppm; LCMS: m / z 476.4 [M+H] + . According to the method of Example 12, replacing N,N-dimethylacetamide dimethyl acetal with N,N-dimethylformamide dimethyl acetal in step three, while keeping other conditions unchanged, yields the following compound: Example 14: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)propane-2-ol

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.56 (s, 1H), 9.38 (s, 1H), 9.05 (br s, 1H), 8.84 (s, 1H), 6.97 (t, J = 9.4 Hz, 1H), 6.72 (dd, J = 3.8, 8.7Hz, 1H), 5.66 (s, 1H), 4.79 (s, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.36-3.34 (m,2H), 1.78 (s, 6H) ppm; LCMS: m / z 462.0 [M+H] + . Example 15: 2-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol Step 1: Methyl 6-amino-5-bromo-3-fluoropyridine-2-carboxylate E35-2

[0278] 5.00 g (21.6 mmol) of methyl 6-amino-5-bromopyridine-2-carboxylate E35-1 and 9.97 g (28.1 mmol) of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt were dissolved in acetonitrile (25.0 mL). The mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. The remaining feed was monitored by LCMS. The mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine. The organic phase was dried and concentrated. The crude product was purified by rapid silica gel column chromatography to obtain methyl 6-amino-5-bromo-3-fluoropyridine-2-carboxylate E35-2 (620 mg, 9.20% yield).

[0279] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 9.4 Hz, 1H), 6.55 (s, 2H), 3.82 (s, 3H), LCMS m / z 251.1 [M+H] + . Step 2: Methyl 5-bromo-6-(((dimethylamino)methylethylene)amino)-3-fluoropyridine-2-carboxylate E35-3

[0280] 1.50 g (6.02 mmol) of methyl 6-amino-5-bromo-3-fluoropyridine-2-carboxylate E35-2 and 2.87 g (24.1 mmol) of N,N-dimethylformamide dimethyl acetal were dissolved in toluene (10.0 mL). The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction was stopped by LCMS. The mixture was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to give methyl 5-bromo-6-(((dimethylamino)methylyl)amino)-3-fluoropyridine-2-carboxylate E35-3 (1.40 g, 68.7% yield).

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.19 (d, J = 9.3 Hz, 1H), 3.86 (s, 3H), 3.13 (s, 3H), 3.04 (s, 3H). LCMS m / z 306.1 [M+H] + . Step 3: Methyl 5-bromo-3-fluoro-6-(((hydroxyamino)methylethylene)amino)pyridine-2-carboxylate E35-4

[0282] 5-Bromo-6-(((dimethylamino)methylyl)amino)-3-fluoropyridine-2-carboxylate E35-3 (1.40 g, 4.06 mmol) and hydroxylamine hydrochloride (639 mg, 9.21 mmol) were dissolved in ethanol (6.00 mL). The mixture was stirred at 50 °C for 5 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until it was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 5-bromo-3-fluoro-6-(((hydroxylamino)methylyl)amino)pyridine-2-carboxylate E35-4 (1.30 g, 87.0% yield).

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.44 (d, J = 9.3 Hz, 1H), 8.23 ​​(d, J = 9.8 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 3.89 (s, 3H). LCMS m / z 292.1[M+H] + . Step 4: Methyl 8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E35-5

[0284] 1.30 g (4.45 mmol) of methyl 5-bromo-3-fluoro-6-(((hydroxylamine)methylidene)amino)pyridine-2-carboxylate E35-4 was dissolved in polyphosphoric acid (6.00 mL). The mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until it was complete. The mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated, and the crude product was purified by rapid silica gel column chromatography to obtain methyl 8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate E35-5 (600 mg, 44.2% yield).

[0285] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J = 9.3 Hz, 1H),4.03 (s, 3H) ppm; LCMS m / z 276.1 [M+H] + . Step 5: 2-(8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol E35-6

[0286] Methyl 8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-5-carboxylate E35-5 (550 mg, 2.01 mmol) was dissolved in tetrahydrofuran (8.00 mL), cooled to -50 °C, and methyl magnesium bromide (3 M, 4.5 mL) was added dropwise. The reaction was carried out under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS until it ended. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 2-(8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol E35-6 (370 mg, 63.2% yield).

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.28 (d, J = 11.4 Hz, 1H), 5.96 (s, 1H), 1.77 (s, 3H), 1.75 (s, 3H) ppm; LCMS m / z 274.0 [M+H] + . Step Six: (6-Fluoro-5-(2-hydroxypropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E35-7

[0288] The following ingredients were added: 2-(8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol E35-6 (320 mg, 1.17 mmol), bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (95.3 mg, 0.117 mmol), and 1,4-dioxane (8.00 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 6.5 hours. TLC showed no residual starting material. The reaction solution was used directly for the next step without further treatment.

[0289] Step 7: 2-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol

[0290] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (298 mg, 0.819 mmol), sodium carbonate (372 mg, 3.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (95.5 mg, 0.117 mmol), and then add 1,4-dioxane (1.00 mL) and water (1.50 mL) to the previous reaction solution. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and recrystallized to give 2-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol (183 mg, 32.1% yield).

[0291] 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.57 (s, 1H), 9.24 (d, J = 14.3 Hz, 1H), 9.14-9.06 (m, 1H), 8.77 (s, 1H), 6.97 (t, J = 9.3 Hz, 1H), 6.72 (dd, J = 3.9, 8.5 Hz, 1H), 6.10 (s, 1H), 4.80 (br d, J = 4.3 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.37-3.36 (m, 2H), 1.83 (s, 3H), 1.82 (s, 3H) ppm; LCMS m / z479.4 [M+H] + . Example 16: 1,1-Difluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propane-2-ol Step 1: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1-difluoroprop-2-ol E36-2

[0292] To a solution of 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethyl-1-one E27-4 (670 mg, 2.79 mmol), difluorobromomethyltrimethylsilane (1.42 g, 6.98 mmol), and triphenylphosphine dissolved in acetonitrile (5 mL), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (1.07 g, 8.37 mmol) was added, and the reaction mixture was incubated at 20°C for 12 hours. The reaction proceeds were confirmed to be complete by TLC. Potassium hydroxide solution (400 mg potassium hydroxide dissolved in 3 mL water) was then added to the reaction mixture, and the mixture was stirred at 20°C for 2 hours. Finally, 5 mL of 6M hydrochloric acid was added, and the mixture was stirred for another 2 hours. The product was detected by LCMS. The reaction solution was adjusted to pH 8 with sodium bicarbonate, extracted with ethyl acetate, dried and concentrated, and then purified by prep-HPLC to give the product 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1-difluoroprop-2-ol E36-2 (570 mg, 1.91 mmol, 68.7% yield).

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.92 (t, J = 55.6 Hz, 1H), 6.77 (s, 1H), 1.78 (s, 3H)ppm; LCMS m / z 291.9 / 293.9 [M+H] + Step 2: (5-(1,1-difluoro-2-hydroxypropyl-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E36-3

[0294] The following ingredients were added: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,1-difluoroprop-2-ol E36-2 (500 mg, 1.68 mmol), bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (137 mg, 0.167 mmol), and 1,4-dioxane (10.0 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 6 hours. TLC showed no residual starting material. The reaction solution was used directly for the next step without further treatment.

[0295] Step 3: 1,1-Difluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol

[0296] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (488 mg, 1.68 mmol), sodium carbonate (533 mg, 5.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (137 mg, 0.167 mmol) to the previous reaction solution, and then add 1,4-dioxane (1.00 mL) and water (2.00 mL). The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and preparative chromatography to obtain 1,1-difluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol (475 mg, 57.0% yield).

[0297] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.42 (s, 1H), 9.18 (d, J = 7.9 Hz, 1H), 9.01-8.95 (m, 1H), 8.70 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.17-6.83 (m, 2H), 6.77-6.68 (m, 2H), 4.79 (br d, J = 3.8 Hz, 2H), 4.55 (t, J = 8.8Hz, 2H), 3.36-3.35 (m, 2H), 1.82 (s, 3H) ppm; LCMS m / z 497.3 [M+H] + . Example 17: 1,3-Difluoro-2-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazol[4,3-c]pyrimidin-8-yl)-[1,2,4]triazol[1,5-a]pyridin-5-yl]prop-2-ol Step 1: (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)tert-butyl carbamate E37-1

[0298] 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid E31-1 (4.50 g, 18.5 mmol), 4A molecular sieve (5.00 g), tert-butanol (13.7 g, 185 mmol), and diisopropylethylamine (7.21 g, 55.7 mmol) were added to toluene (25.0 mL), purged with nitrogen three times, and stirred at 25 °C for 30 minutes. Diphenyl azidophosphate (7.68 g, 27.8 mmol) was added to the reaction solution, and the mixture was stirred at 85 °C for 8 hours. The reaction was stopped by TLC, and the mixture was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain (8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)tert-butyl carbamate E37-1 (3.20 g, 54.4% yield). 1 H NMR (400MHz, CDCl3) δ 8.35 (s, 1H), 8.24 (br s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 1.57 (s, 9H) ppm. LCMS m / z 315.0 [M+H] + . Step 2: 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-amine hydrochloride E37-2

[0299] (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)carbamate tert-butyl ester E37-1 (3.20 g, 9.83 mmol) was dissolved in ethanol (10.0 mL), and hydrochloric acid / 1,4-dioxane solution (4 M, 5.00 mL) was added dropwise. The mixture was stirred at 50 °C for 10 hours. The reaction was stopped by TLC. The mixture was then concentrated under reduced pressure to obtain crude 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-amine hydrochloride E37-2 (2.50 g, crude product).

[0300] 1H NMR (400MHz, DMSO- d 6) δ 8.55 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H) ppm; LCMS m / z 213.1 [M+H] + . Step 3: 8-Bromo-5-iodo-[1,2,4]triazolo[1,5-a]pyridine E37-3

[0301] 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-amine hydrochloride E37-2 (450 mg, 1.80 mmol) and p-toluenesulfonic acid (931 mg, 5.41 mmol) were dissolved in acetonitrile (10.0 mL). After stirring at 0 °C for 30 minutes, a solution of potassium iodide (748 mg, 4.51 mmol) and sodium nitrite (248 mg, 3.61 mmol) in water (2.00 mL) was slowly added dropwise. The reaction was then heated to 20 °C and stirred for 2.5 hours. The reaction was stopped by TLC. The solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 8-bromo-5-iodo-[1,2,4]triazolo[1,5-a]pyridine E37-3 (240 mg, 39.8% yield).

[0302] 1 H NMR (400MHz, CDCl3) δ 8.44 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H) ppm. LCMS m / z 325.9 [M+H] + . Step 4: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,3-difluoroprop-2-ol E37-4

[0303] Dissolve 8-bromo-5-iodo-[1,2,4]triazolo[1,5-a]pyridine E37-3 (230 mg, 0.710 mmol) in tetrahydrofuran (5.00 mL), cool to -65 °C, and slowly add a tetrahydrofuran solution of n-butyllithium (2.5 M, 284 μL). After stirring the reaction solution for 3 minutes, slowly add a tetrahydrofuran solution of 1,3-difluoroprop-2-one (66.7 mg, 0.710 mmol) (2.00 mL) to the reaction solution, and continue stirring at -65 °C for 1 hour. The reaction was monitored by LCMS until it ended. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,3-difluoroprop-2-ol E37-4 (170 mg, 60.6% yield).

[0304] 1 H NMR (400 MHz, DMSO- d 6) δ 8.67 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 5.31-5.26 (m, 1H), 5.15 (d, J = 9.6 Hz, 1H), 5.00 (d, J = 9.6 Hz, 1H), 4.88 (d, J = 9.6 Hz, 1H) ppm; LCMS m / z 294.0 [M+H] + . Step 5: (5-(1,3-difluoro-2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E37-5

[0305] The following ingredients were added: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1,3-difluoroprop-2-ol E37-4 (170 mg, 0.582 mmol), bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (47.5 mg, 0.0582 mmol), and 1,4-dioxane (6.00 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 6.5 hours. LC-MS analysis showed no residual starting material. The reaction solution was used directly in the next step without further treatment.

[0306] Step Six: 1,3-Difluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol

[0307] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (121 mg, 0.332 mmol), sodium carbonate (184 mg, 1.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (47.3 mg, 0.0579 mmol), and then add 1,4-dioxane (1.00 mL) and water (1.50 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and preparative chromatography to obtain 1,3-difluoro-2-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazol[4,3-c]pyrimidin-8-yl)-[1,2,4]triazol[1,5-a]pyridin-5-yl]prop-2-ol (50.0 mg, 17.2% yield).

[0308] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.53 (br s, 1H), 9.43 (s, 1H), 9.17 (d, J = 8.0 Hz, 1H), 8.98 (br s, 1H), 8.70 (s, 1H), 7.64 (br d, J = 7.4 Hz, 1H), 7.12-6.87 (m, 2H), 6.72 (dd, J = 3.4, 8.4 Hz, 1H), 5.34 (br d, J = 9.5 Hz, 1H), 5.22 (br d, J = 9.6 Hz, 1H), 5.07 (d, J = 9.5 Hz, 1H), 4.96 (d, J = 9.4 Hz, 1H), 4.78(s, 2H), 4.56(t, J =8.8 Hz, 2H), 3.42-3.41 (m, 2H) ppm; LCMS m / z 497.4 [M+H] + . Example 18: 1-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazol[1,5-a]pyridin-5-yl]cycloprop-1-ol Step 1: 8-Bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-[1,2,4]triazolo[1,5-a]pyridine E38-1

[0309] At -78°C, sodium bis(dimethylsilyl)amino (1M, 8.12mL) was added dropwise to a tetrahydrofuran solution (20mL) of 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)acetone E27-4 (1.30g, 5.42mmol), and the reaction mixture was stirred at 25°C for 1 hour. Then, tert-butyldimethylchlorosilane (1.63g, 10.8mmol, 1.33mL) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction was monitored by LCMS until it ended. The mixture was quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried and concentrated. The concentrate was purified by rapid silica gel column chromatography to give a white solid 8-bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-[1,2,4]triazolo[1,5-a]pyridine E38-1 (1.20 g, 3.39 mmol, 62.5% yield).

[0310] 1 H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 5.18 (d, J = 1.8 Hz, 1H), 0.98 (s,9H), 0.24 (s, 6H). Step 2: 8-Bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridine E38-2

[0311] At 0 °C, trimethylaluminum (2 M, 10.1 mL) was added dropwise to a dichloromethane solution of 8-bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-[1,2,4]triazolo[1,5-a]pyridine E38-1 (1.20 g, 3.39 mmol) (150 mL), followed by a dichloromethane solution of diiodomethane (7.26 g, 27.0 mmol, 2.19 mL) (10 mL). The reaction mixture was stirred at 40 °C for 48 hours. After the reaction was complete, it was quenched with hydrochloric acid (1M), extracted with dichloromethane, dried the organic phase, concentrated, and purified by rapid silica gel column chromatography to obtain a yellow oil: 8-bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridine E38-2 (412 mg, 27.6% yield).

[0312] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 1.28-1.16 (m, 4H), 0.67 (s, 9H), -0.17 (s, 6H) ppm; LCMS m / z 368.1 [M+H] + . Step 3: (5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E38-3

[0313] 8-Bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridine E38-2 (412 mg, 1.12 mmol), pinacol diboronate (312 mg, 1.23 mmol), potassium acetate (329 mg, 3.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (182 mg, 223 μmol) were dissolved in 1,4-dioxane (6.00 mL). The mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC showed no residual starting material. The reaction solution was used directly in the next step without further treatment. LCMS: m / z 334.2 [M+H] + Step 4: 8-(5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine E38-4

[0314] Add 8-bromo-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (244 mg, 0.671 mmol), sodium carbonate (355 mg, 3.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (182 mg, 0.223 mmol), 1,4-dioxane (5.00 mL), and water (1.00 mL) to the reaction solution from the previous step. The reaction was carried out under a nitrogen atmosphere at 100 °C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to give 8-(5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine E38-4 (430 mg, 0.707 mmol, 63.2% yield) as a brown solid.

[0315] 1 H NMR (400MHz, DMSO-d6) δ 9.54 (d, J = 1.4 Hz, 2H), 9.17 (d, J = 7.8 Hz, 1H), 8.97 (t, J = 5.1 Hz, 1H), 8.66 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.02-6.92(m, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 4.79 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.8Hz, 2H), 3.38-3.35 (m, 2H), 1.32-1.19 (m, 4H), 0.68 (s, 9H), -0.17 (s, 6H)ppm; LCMS: m / z .573.4[M+H] + Step 5: 1-(8-(5-(((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclopropanol

[0316] A mixture of 8-(5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-benzodihydrofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine E38-4 (430 mg, 0.707 mmol, 94.2% purity) and tetrabutylamine fluoride (1 M in THF, 2.83 mL) was stirred at 25°C for 2 hours. The reaction was monitored by LCMS until it ended. The reaction solution was cooled to room temperature, and water and ethyl acetate were added to the mixture. The organic phase was dried and concentrated. The concentrate was purified by rapid silica gel column chromatography to give 1-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]cycloprop-1-ol (159 mg, 0.344 mmol, 48.6% yield).

[0317] 1 H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 9.47 (s, 1H), 9.14 (d, J = 7.9Hz, 1H), 8.94 (br s, 1H), 8.64 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.01-6.93 (m,1H), 6.75-6.70 (m, J = 3.9 Hz, 1H), 6.39 (s, 1H), 4.79 (br d, J = 3.3 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 3.39-3.36 (m, 2H), 1.56-1.51 (m, 2H), 1.21-1.17 (m,2H) ppm; LCMS: m / z 459.4[M+1H] + . Example 19: 1-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]cyclobut-1-ol Step 1: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclobutanol E39-1

[0318] 8-Bromo-5-iodo-[1,2,4]triazolo[1,5-a]pyridine E37-3 (800 mg, 2.47 mmol) was dissolved in tetrahydrofuran (15.0 mL), cooled to -70 °C, and n-butyllithium (2.5 M, 988 μL) was added dropwise. The reaction was carried out under a nitrogen atmosphere for 5 min, followed by the addition of a tetrahydrofuran solution of n-butanone (173 mg, 2.47 mmol) at the same temperature. The reaction was then carried out at -70 °C for 1 h. The reaction was monitored by TLC and LCMS until completion. The reaction solution was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclobutanol E39-1 (500 mg, 61.0% yield).

[0319] 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 6.99(d, J = 7.8 Hz, 1H), 2.71-2.56 (m, 4H), 2.27-2.13 (m, 1H), 1.91-1.74 (m, 1H)ppm; LCMS: m / z 270.0 [M+H]+. Step 2: (5-(1-hydroxycyclobutyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E39-2

[0320] 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclobutanol E39-1 (500 mg, 1.86 mmol), bis-pinacol borate (568 mg, 2.24 mmol), potassium acetate (549 mg, 5.59 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (304 mg, 0.372 mmol) were dissolved in 1,4-dioxane (15.0 mL). The reaction solution was heated to 120 °C and reacted under a nitrogen atmosphere for 5 hours. TLC showed no residual starting material. The reaction solution was used directly in the next step without further treatment.

[0321] Step 3: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)cyclobutanol

[0322] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine B2 (203 mg, 0.558 mmol), sodium carbonate (592 mg, 5.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (304 mg, 0.372 mmol), 1,4-dioxane, and (10.0 mL) water (2.0 mL) to the reaction solution from the previous step. The reaction solution was heated to 100℃ under a nitrogen atmosphere and reacted for 1 hour. The reaction was monitored by LCMS until it ended. The solution was cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain 1-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]cyclobut-1-ol (90.0 mg, 0.189 mmol, 10.2% yield).

[0323] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.47 (s, 1H), 9.15 (d, J =7.8 Hz, 1H), 8.94 (br s, 1H), 8.65 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 9.4 Hz, 1H), 6.72 (dd,J = 3.9, 8.6 Hz, 1H), 5.92 (s, 1H), 4.78 (s, 2H), 4.56 (t, J = 8.6 Hz, 2H), 3.37-3.35 (m, 2H), 2.96-2.80 (m, 2H), 2.38 (ddd, J =6.9, 9.1, 12.1 Hz, 2H), 2.18-2.02 (m, 1H), 1.87-1.71 (m, 1H) ppm. Example 20: 1-Fluoro-2-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]propane-2-ol Step 1: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1-fluoropropane-2-ol E40-1

[0324] 8-Bromo-5-iodo-[1,2,4]triazolo[1,5-a]pyridine E37-3 (1.50 g, 4.63 mmol) was dissolved in tetrahydrofuran (10.0 mL), and the mixture was cooled to -65 °C. A tetrahydrofuran solution of n-butyllithium (2.5 M, 1.85 mL) was slowly added dropwise. After stirring the reaction mixture for 1 minute, a tetrahydrofuran solution of 1-fluoroprop-2-one (352 mg, 4.63 mmol) in tetrahydrofuran (1.00 mL) was slowly added dropwise. The mixture was stirred at -65 °C for 0.5 hours. The reaction was monitored by LCMS until it was complete. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to give 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1-fluoropropane-2-ol E40-1 (920 mg, 66.3% yield).

[0325] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 5.32-5.13 (m, 1H), 4.82-4.62 (m, 1H),1.66 (d, J= 2.4 Hz, 3H) ppm; LCMS m / z 275.9 [M+H] + . Step 2: (5-(1-fluoro-2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)boronic acid E40-2

[0326] The following ingredients were added: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1-fluoropropane-2-ol E40-1 (920 mg, 3.36 mmol), bis(pinacol)diboron (1.02 g, 4.03 mmol), potassium acetate (1.15 g, 11.75 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (548 mg, 0.631 mmol), and 1,4-dioxane (8.00 mL). The reaction mixture was heated to 120 °C and reacted under a nitrogen atmosphere for 6.5 hours. LCMS analysis showed no residual starting material. The reaction solution was used directly for the next step without further treatment.

[0327] Step 3: 1-Fluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol E40-3

[0328] Add 8-bromo-N-((-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidine-5-amine (855 mg, 2.35 mmol), sodium carbonate (1.07 g, 10.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (411 mg, 0.503 mmol) to the previous reaction solution, and then add 1,4-dioxane (1.00 mL) and water (2.00 mL). The reaction was carried out under a nitrogen atmosphere at 100°C for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was then cooled to room temperature, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography and preparative chromatography to obtain 1-fluoro-2-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]propane-2-ol E40-3 (816 mg, 50.7% yield).

[0329] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.40 (s, 1H), 9.15 (d, J =7.9 Hz, 1H), 8.94 (t, J = 4.9 Hz, 1H), 8.67 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H),7.01-6.92 (m, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 6.33 (s, 1H), 5.41-5.15 (m,1H), 4.92-4.68 (m, 3H), 4.56 (t, J = 8.8 Hz, 2H), 3.35-3.34 (m, 2H), 1.73 (d, J = 2.1 Hz, 3H) ppm; LCMS m / z 479.4 [M+H] + . Step 4: Resolution of 1-fluoro-2-[8-(5-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]propane-2-ol E40-3

[0330] 1-Fluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol (627 mg, 1.29 mmol) was separated by chiral SFC (Separation method: column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); mobile phase: A [0.1% NH3H2O ​​IPA]; B (isopropanol): 45% gradient). (4 mL / min), to obtain (S)-1-fluoro-2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amine)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-ol ((S)-E40-3) or (R)-1-fluoro-2-[8-(5-{[ (5-Fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]propane-2-ol ((R)-E40-3), one of which had a retention time of 0.971 min (compound g) (210 mg, 34.1% yield, 98.6 ee%); the other enantiomer had a retention time of 1.134 min (compound h) (206 mg, 33.1% yield, 98.4 ee%).

[0331] Compound g: 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.40 (s, 1H), 9.14(d, J = 8.0 Hz, 1H), 8.95 (br s, 1H), 8.67 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H),7.02-6.92 (m, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 6.35 (s, 1H), 5.44-5.15 (m,1H), 4.90-4.68 (m, 3H), 4.55 (t, J = 8.8 Hz, 2H), 3.39-3.38 (m, 2H), 1.72 (d, J = 2.1 Hz, 3H) ppm; LCMS m / z 479.4 [M+H]+ . Compound h from Example 21 was also obtained during chiral separation: 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.40 (s, 1H), 9.15 (d, J =7.9 Hz, 1H), 8.94 (br t, J = 4.9 Hz, 1H), 8.67 (s, 1H), 7.59 (d, J = 8.0 Hz,1H), 7.03-6.91 (m, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 6.33 (s, 1H), 5.46-5.14 (m, 1H), 4.89-4.69 (m, 3H), 4.55 (t, J = 8.8 Hz, 2H), 3.36-3.35 (m, 2H), 1.73 (d, J = 2.3 Hz, 3H) ppm; LCMS m / z 479.4 [M+H] + . Example 21 Using the above method, the following compounds were synthesized by replacing the raw materials: N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.45 (s, 1H), 9.11 (d, J =7.7 Hz, 1H), 9.04 (s, 1H), 8.63 (s, 1H), 7.29 (dd, J = 7.7, 1.1 Hz, 1H), 6.96(dd, J = 10.3, 8.7 Hz, 1H), 6.78 (dd, J = 8.7, 3.9 Hz, 1H), 5.00–4.85 (m, 3H), 2.97 (dt, J= 9.1, 4.5 Hz, 1H), 2.79 (s, 3H), 1.02 (dt, J = 9.0, 5.9 Hz, 1H), 0.14 (ddd, J = 6.1, 4.0, 1.9 Hz, 1H) ppm; LCMS: m / z 429.0 [M+H] + . Example 22 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0333] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.45 (s, 1H), 9.11 (d, J =7.7 Hz, 1H), 8.90 (t, J = 5.0 Hz, 1H), 8.64 (d, J = 9.7 Hz, 1H), 7.28 (d, J = 7.8Hz, 1H), 7.02–6.92 (m, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.78 (d, J = 4.9Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.35 (s, 2H), 2.79 (s, 3H) ppm; LCMS: m / z417.0 [M+H] + . Example 23 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0334] 1H NMR (400 MHz, MeOD) δ 9.40-9.30 (m, 1H), 9.25-9.19 (m, 1H), 8.88(dd, J = 9.3, 7.4 Hz, 1H), 8.53-8.47 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.84(dd, J = 17.3, 7.3 Hz, 1H), 6.70-6.64 (m, 1H), 4.82 (d, J = 18.0 Hz, 1H), 4.63(dd, J = 20.5, 11.7 Hz, 1H), 3.45 (d, J = 17.4 Hz, 2H) ppm; LCMS: m / z 437.0 [M+H] + . Example 24 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (d, J = 2.6 Hz, 1H), 9.58 (s, 1H), 9.36 (d, J = 7.9 Hz, 1H), 9.18 (t, J = 4.9 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 9.4 Hz, 1H), 6.72 (dd, J = 8.6, 3.8 Hz, 1H), 4.81 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.32 (s, 2H) ppm; LCMS: m / z 471.1 [M+H] + . Example 25 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluorodihydrobenzofuran-4-yl)methyl)-8-(5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.33 (s, 1H), 9.17 (d, J =8.4 Hz, 1H), 8.83 (s, 1H), 8.59 (s, 1H), 6.99-6.93 (m, 1H), 6.91 (d, J = 8.5Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 4.20 (s,3H), 3.30 (t, J = 6.4 Hz, 2H) ppm; LCMS: m / z 433.1 [M+H] + . Example 26 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-morpholino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.32 (s, 1H), 9.10 (d, J =8.3 Hz, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 6.99-6.94 (m, 1H), 6.81 (d, J = 8.3Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (t, J= 8.7 Hz,2H), 3.92-3.81 (m, 4H), 3.56-3.46 (m, 4H), 3.35 (s, 2H) ppm; LCMS: m / z 488.1[M+H] + . Example 27 Using the above method, by replacing the raw materials, the following compounds were synthesized: 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0338] 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.63 (s, 1H), 8.31 (d, J = 8.4Hz, 2H), 6.85-6.72 (m, 1H), 6.61 (dd, J = 8.6, 3.9 Hz, 1H), 6.48 (d, J = 8.1Hz, 1H), 4.77 (s, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.24(s, 6H) ppm; LCMS: m / z 446.1 [M+H] + . Example 28 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0339] 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.31 (s, 1H), 9.08 (d, J =8.3 Hz, 1H), 8.80 (d, J= 4.7 Hz, 1H), 8.58 (s, 1H), 6.99-6.92 (m, 1H), 6.78(d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 4.77 (d, J = 4.3 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.51 (s, 4H), 3.34 (d, J = 7.4 Hz, 2H), 2.58 (s, 4H), 2.28 (s, 3H) ppm; LCMS: m / z 501.2 [M+H] + . Example 29 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.44 (s, 1H), 9.05 (d, J =7.7 Hz, 1H), 8.88 (t, J = 5.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.03-6.92 (m,1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.79 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.7Hz, 2H), 3.30 (d, J = 8.8 Hz, 2H), 2.74 (s, 3H), 2.58 (s, 3H) ppm; LCMS: m / z431.1 [M+H] + . Example 30 Using the above method, by replacing the raw materials, the following compounds were synthesized: 1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methoxy)-2-methylpropane-2-ol

[0341] 1 H NMR (400 MHz, MeOD) δ 9.35 (d, J = 2.7 Hz, 1H), 9.08 (d, J = 3.4 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.40 (d, J = 7.8 Hz,1H), 6.89-6.81 (m, 1H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 5.35 (t, J = 4.6 Hz,1H), 5.13 (s, 2H), 4.84 (s, 2H), 4.64 (t, J = 8.7 Hz, 2H), 3.93 (s, 2H), 3.22(s, 2H), 1.28 (s, 6H) ppm; LCMS: m / z 460.2 [M+H] + . Example 31 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(5-((dimethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.46 (s, 1H), 9.18 (d, J =7.7 Hz, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.97 (dd, J= 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.78 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.01 (s, 2H), 3.36 (t, 2H), 2.35 (s, 6H) ppm; LCMS:m / z 460.2 [M+H] + . Example 32 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-((4-methylpiperazin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0343] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.16 (d, J =7.7 Hz, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.02-6.92(m, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.78 (d, J = 4.7 Hz, 2H), 4.56 (t, J =8.7 Hz, 2H), 4.07 (s, 2H), 3.30 (s, 2H), 2.61 (s, 4H), 2.40 (s, 4H), 2.19 (s,3H) ppm; LCMS: m / z 515.2 [M+H] + . Example 33 Using the above method, the following compounds were synthesized by replacing the raw materials: 1-(((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)amino)-2-methylpropane-2-ol

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.16 (d, J =7.7 Hz, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.96 (d, J =10.1 Hz, 1H), 6.72 (dd, J = 8.6, 4.0 Hz, 1H), 4.79 (d, J = 4.9 Hz, 2H), 4.56(s, 2H), 4.28 (s, 3H), 3.37 (s, 1H), 3.30 (s, 2H), 2.07 (s, 2H), 1.12 (s, 6H)ppm; LCMS: m / z 504.1 [M+H] + . Example 34 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(morpholinomethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.17 (d, J =7.7 Hz, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 6.97 (t, J =9.4 Hz, 1H), 6.72 (dd, J = 8.4, 3.6 Hz, 1H), 4.79 (s, 2H), 4.56 (t, J= 8.7 Hz,2H), 4.08 (s, 2H), 3.65 (s, 4H), 3.33 (s, 2H), 2.60 (s, 4H) ppm; LCMS: m / z502.1 [M+H] + . Example 35 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(pyrrolidone-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.24 (s, 1H), 9.02 (d, J =8.4 Hz, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.00-6.91 (m, 1H), 6.71 (dd, J = 8.6, 3.8 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.75 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.82 (s, 4H), 3.31 (s, 2H), 2.00 (s, 4H) ppm; LCMS: m / z 472.1 [M+H] + . Example 36 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-morpholinopiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.31 (s, 1H), 9.07 (d, J=8.3 Hz, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 7.01-6.92 (m, 1H), 6.78 (d, J = 8.3Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.12 (d, J = 11.9 Hz, 2H), 3.72-3.50 (m, 4H), 3.32-3.28 (m, 2H), 2.91 (t, J = 11.1 Hz, 2H), 2.58-2.51 (m, 4H), 2.43 (d, J = 9.8 Hz, 1H), 1.96 (d, J =12.3 Hz, 2H), 1.66 (dd, J = 20.5, 11.4 Hz, 2H) ppm; LCMS: m / z 571.2 [M+H] + . Example 37 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.25 (s, 1H), 9.05 (d, J =8.3 Hz, 1H), 8.70 (s, 1H), 8.50 (s, 1H), 7.02-6.91 (m, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 11.0 Hz, 6H), 4.62-4.44 (m,6H), 3.31 (d, J= 8.8 Hz, 2H) ppm; LCMS: m / z 500.2 [M+H] + . Example 38 Using the above method, by replacing the raw materials, the following compound was synthesized: N1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)-N1,N2,N2-trimethylethane-1,2-diamine

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.43 (s, 1H), 9.14 (d, J =7.7 Hz, 1H), 8.94 (s, 1H), 8.62 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 6.97 (t, J =9.5 Hz, 1H), 6.72 (dd, J = 8.5, 3.7 Hz, 1H), 4.78 (s, 2H), 4.56 (s, 2H), 4.11(s, 2H), 3.35 (d, J = 8.6 Hz, 2H), 2.64 (d, J = 7.0 Hz, 2H), 2.46 (d, J = 6.9Hz, 2H), 2.36 (s, 3H), 2.15 (s, 6H) ppm; LCMS: m / z 517.2 [M+H] + . Example 39 Using the above method, by replacing the raw materials, the following compounds were synthesized: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-methylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.32 (s, 1H), 9.09 (d,J =8.2 Hz, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 6.97 (s, 1H), 6.80 (d, J = 8.3 Hz,1H), 6.76-6.67 (m, 1H), 4.77 (d, J = 4.0 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.99 (d, J = 11.3 Hz, 3H), 3.82 (dd, J = 19.0, 9.7 Hz, 2H), 3.31 (s, 2H), 2.96(dd, J = 11.6, 8.7 Hz, 1H), 2.70 (d, J = 10.6 Hz, 1H), 1.19 (d, J = 6.2 Hz, 3H)ppm; LCMS: m / z 502.2 [M+H] + . Example 40 Using the above method, the following compounds were synthesized by replacing the raw materials: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0351] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.57 (s, 1H), 9.32 (d, J =11.5Hz, 1H), 9.09 - 9.04 (m, 1H), 8.70 (s, 1H), 6.98 (t, J =9.5 Hz, 1H), 6.73 (dd, J =3.9, 8.6 Hz, 1H), 4.80 (d, J =3.4 Hz, 2H), 4.56 (t, J =8.7 Hz, 2H), 3.64 - 3.58(m, 1H), 3.32 - 3.30 (m, 2H), 2.76 (d, J=2.5 Hz, 3H) ppm; LCMS: m / z 435.1 [M+H] + . Example 41 Using the above method, by replacing the raw materials, the following compounds were synthesized: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.55 (s, 1H), 9.05 (d, J =2.3 Hz, 1H), 9.01 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 7.00-6.94(m, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J = 8.7 Hz,2H), 3.93 (s, 3H), 3.31 (s, 2H) ppm; LCMS: m / z 433.1 [M+H] + . Example 42 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(2-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0353] 1 H NMR (400MHz, DMSO-d6) δ 9.62 (s, 1H), 9.55 (s, 1H), 9.18 (dd, J =2.3, 11.3 Hz, 1H), 8.98-8.90 (m, 2H), 6.98 (t, J = 9.5 Hz, 1H), 6.73 (dd, J =3.9, 8.6 Hz, 1H), 4.80 (d, J= 4.8 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.31-3.28(m, 2H), 3.10 (s, 6H) ppm; LCMS: m / z 464.3 [M+H] + . Example 43 Using the above method, the following compounds were synthesized by replacing the raw materials: 8-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.50 (s, 1H), 9.07 (dd, J =7.7, 1.2 Hz, 1H), 8.82 (s, 1H), 8.61 (dd, J = 6.6, 1.2 Hz, 1H), 7.10 (dd, J =7.7, 6.6 Hz, 1H), 6.98 (dd, J = 10.3, 8.7 Hz, 1H), 6.73 (dd, J = 8.7, 3.9 Hz,1H), 4.79 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.30 (d, J = 8.8 Hz, 2H), 3.10 (s,6H) ppm; LCMS: m / z 446.1 [M+H] + . Example 44: Using the above method, but replacing the raw materials, the following compounds were synthesized: 8-(5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0355] 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.57 (s, 1H), 9.33 (br d, J =7.6 Hz, 1H), 9.09 (br s, 1H), 8.77 (s, 1H), 7.78 (br s, 1H), 7.65 (t, J =52.8Hz, 1H), 6.98 (br t, J =9.5 Hz, 1H), 6.73 (br dd, J =3.4, 8.5 Hz, 1H), 4.81 (brd, J =3.4 Hz, 2H), 4.56 (t, J =8.5 Hz, 2H), 3.31 - 3.23 (m, 2H) ppm; LCMS: m / z453.3 [M+H] + . Example 45: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0356] 1 H NMR (400MHz, DMSO-d6) δ 9.46 (br s, 1H), 9.35 (s, 1H), 9.07 (s, 1H), 8.59 (s, 1H), 6.93 (t, J = 9.2 Hz, 1H), 6.68 (dd, J = 4.0, 8.8 Hz, 1H), 4.73(s, 2H), 4.53 (t, J = 8.8 Hz, 2H), 3.44 (s, 6H), 3.32 - 3.28 (m, 2H) ppm; LCMS:m / z 447.3 [M+H] + . Example 46: Using the above method, but replacing the raw materials, the following compound was synthesized: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethane-1-ol

[0357] 1 H NMR (400 MHz, DMSO- d 6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.19-9.17 (d, J = 8.0 Hz, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.44-7.42 (d, J = 8.0 Hz, 1H),6.99-6.94 (m, 1H), 6.73-6.70 (m, 1H), 5.90-5.89 (d, J = 4.0 Hz, 1H), 5.43-5.40(m, 1H), 4.78 (s, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.34-3.27 (m, 2H), 1.56-1.54(d, J = 8.0 Hz, 3H) ppm; LCMS: 447.3 m / z [M+H] + . Example 47: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-(5-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0358] 1 H NMR (400MHz, DMSO- d 6) δ 9.54 (s, 1H), 9.49 (s, 1H), 9.25 (d, J = 14.4Hz, 1H), 8.95-8.90 (m, 1H), 8.62 (s, 1H), 6.97 (t, J =9.5 Hz, 1H), 6.72 (dd, J=4.1, 8.7 Hz, 1H), 4.77 (br d, J = 4.0 Hz, 2H), 4.55 (t, J =8.7 Hz, 2H), 3.27 (brd, J =5.1 Hz, 2H), 3.15 (d, J =2.8 Hz, 6H) ppm; LCMS m / z 464.1 [M+H] + . Example 48: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-(5-(dimethylamino)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0359] 1 H NMR (400MHz, DMSO- d 6) δ 9.50 (s, 1H), 9.28 (s, 1H), 9.00 (d, J = 8.4Hz, 1H), 8.74 (d, J =1.2 Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 6.71 (dd, J = 3.9, 8.8Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.31-3.27 (m, 2H), 3.13 (s, 6H), 2.55 (s, 3H) ppm; LCMS: m / z 460.3 [M+H] + . Example 49: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylonitrile

[0360] 1H NMR (400MHz, DMSO- d 6) δ 9.81 (s, 1H), 9.59 (s, 1H), 9.57 (br s,1H), 9.40 (s, 1H), 9.14 (br d, J =1.1 Hz, 1H), 8.86 (s, 1H), 6.97 (t, J =9.6 Hz, 1H), 6.72 (dd, J =3.9, 8.6 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J =8.7 Hz, 2H), 3.25-3.22 (m, 2H) ppm; LCMS: m / z 428.0 [M+H] + . Example 49: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0361] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.51 (s, 1H), 9.19 (dd, J = 7.6, 0.9 Hz, 1H), 8.98 (s, 1H), 8.93 (dd, J = 6.7, 1.0 Hz, 1H), 8.63 (s, 1H), 7.43–7.38 (m, 1H), 7.01–6.95 (m, 1H), 6.73 (dd, J = 8.6, 3.9 Hz, 1H), 4.79 (s,2H), 4.56 (t, J = 8.7 Hz, 2H), 3.33 (d, J = 8.8 Hz, 2H) ppm; LCMS: m / z 403.1 [M+H] + . Example 50: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropenzo[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.51 (s, 1H), 9.19 (dd, J = 7.6, 0.9 Hz, 1H), 8.98 (s, 1H), 8.93 (dd, J = 6.7, 1.0 Hz, 1H), 8.63 (s, 1H), 7.43–7.38 (m, 1H), 7.01–6.95 (m, 1H), 6.73 (dd, J = 8.6, 3.9 Hz, 1H), 4.79 (s,2H), 4.56 (t, J = 8.7 Hz, 2H), 3.33 (d, J = 8.8 Hz, 2H) ppm; LCMS: m / z 403.1 [M+H] + . Example 51: Using the above method, but replacing the raw materials, the following compound was synthesized: 8-(5-((1H-imidazol-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0363] 1 H NMR (400 MHz, DMSO-d6) δ 9.54-9.51 (m, 1H), 9.44 (s, 1H), 9.12 (d, J = 7.8 Hz, 1H), 8.72 (s, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 7.07 (d, J= 7.9 Hz,1H), 6.96 (s, 1H), 6.72 (s, 1H), 5.81 (s, 2H), 4.78 (s, 2H), 4.55 (s, 2H),3.17-3.15 (m, 2H) ppm; LCMS: m / z 483.1 [M+H] + . Example 52: Using the above method, but replacing the raw materials, the following compound was synthesized: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

[0364] 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.55 (s, 1H), 9.38 (s, 1H), 9.02 (br t, J =5.1 Hz, 1H), 8.78 (s, 1H), 7.00 - 6.93 (m, 1H), 6.72 (dd, J = 3.9, 8.6 Hz, 1H), 4.78 (d, J = 4.9 Hz, 2H), 4.55 (t, J =8.8 Hz, 2H), 3.32- 3.30 (m,2H), 2.96 (s, 3H) ppm; LCMS: m / z 418.0 [M+H] + . Pharmacology and Applications While EED, a major component of the PRC2 protein complex, does not possess enzymatic catalytic activity, it plays a crucial role in the overall function of PRC2. EED's effect on PRC2 manifests in two ways: 1) EED directly binds to trimethylated H3K27Me3, thus localizing the PCR2 complex to the desired chromatin; 2) EED significantly promotes the allosteric catalytic function of EZH2. Therefore, developing compounds targeting the allosteric protein EED provides a new strategy for inhibiting EZH2 enzyme activity. Moreover, such inhibitors offer advantages that are better or complementary to EZH2 enzyme catalytic site inhibitors; for example, when patients develop resistance to EZH2 enzyme inhibitors, EED inhibitors can still inhibit EZH2 enzyme activity. This invention discloses compounds that can act as EED target inhibitors and have therapeutic effects on diseases related to the mechanisms of action of EED and / or PRC2.

[0365] The biological functions of the compounds disclosed in this invention have been demonstrated in biochemical and cellular tests. For example, in biochemical tests, the compounds disclosed in this invention exhibit strong competitive binding activity (IC50) with the H3K27Me3 peptide, which binds to the EED protein. 50 The concentration can reach <1 nM. At the cellular level, the compounds disclosed in this invention can not only inhibit the methylation level of histone H3K27, but also inhibit the proliferation of cancer cells through this action (IC50). 50 The molecular weight can reach <5 nM. When the compound disclosed in this invention binds to EED protein, the bicyclic structure on the outside of the binding "pocket" enables the compound to have better metabolic stability.

[0366] Example 53: Evaluation of the effect of compounds in blocking the binding of EED and H3K27me3 by AlphaScreen (a-screening) method First, prepare compound solutions with different concentration gradients. Dissolve the compound powder in DMSO to prepare a stock solution. Take 1.5 μl of the stock solution and mix it with 198.5 μl of reaction buffer (25 mM HEPES (pH 8.0), 50 mM NaCl, 0.015% Tween 20, 0.5% BSA). Then, perform a 3-fold serial dilution with the above buffer containing 0.75% DMSO. Set up 9 different test concentrations for the same compound. Take 5 μL of each concentration gradient of the compound into a ProxiPlate-384 Plus White assay plate (PerkinElmer, 6008280), and set up 2 replicates for each concentration gradient.

[0367] Next, the binding blocking reaction was performed. The full-length EED protein (441 amino acids) tagged with His6 was diluted to 60 nM with the above buffer, and the biotinylated peptide fragment H3K27me3 (amino acids 19-33) was diluted to 75 nM. 5 μl of the 75 nM peptide fragment and 5 μl of the 60 nM protein were transferred to the detection wells containing the compound, respectively. The detection plate was sealed with a membrane and incubated at room temperature for 30 minutes.

[0368] Finally, the AlphaScreen method was used for detection. Shortly before use, nickel chelate acceptor beads and streptoantibiotic donor beads were mixed in a 1:1 ratio (Perkin Elmer, product number 6760619M) into the above reaction buffer. Then, 5 μl of the premixed detection solution was added to each well, resulting in a final concentration of 5 μg / mL for both the donor and acceptor beads. The detection plate was sealed with aluminum foil and placed at room temperature in the dark for 1 hour. The signal was read using the AlphaScreen detector on a Spectra max i3. The AlphaScreen signal was standardized based on the readings obtained from the positive control (maximum signal control) and negative control (minimum signal control) to provide the inhibition rate of different compound concentrations. Nonlinear regression analysis was then performed using a GraphPad Prism 5, and inhibition curves were plotted using the dose-response equation Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) to obtain the IC50 of each compound. 50 value.

[0369] To eliminate false positives caused by compound interference with the AlphaScreen detection system, the compound was diluted using the same method, and the EED and peptide H3K27me3 in the detection system were replaced with biotinylated-(His)6 labeled with biotinylated-(His)6. After incubation for the same time, the signal values ​​were read on Spectra max i3. The data were processed in the same manner.

[0370] Table 1 below shows the IC50 values ​​of some compounds. 50 value.

[0371] Table 1

[0372] Example 54: ELISA (H3K27 trimethylation) analysis Representative compounds of this disclosure were serially diluted 3-fold with DMSO, with 10 concentration gradients detected for each compound, up to a maximum concentration of 10 μM. The compounds were then diluted 200-fold into G401 cells cultured in 96-well plates (final DMSO concentration 0.5%). After 72 hours of cell culture, histone H3K27 trimethylation levels were detected by ELISA.

[0373] Histone extraction: Cells treated with the compound in 96-well plates were washed three times with 1x PBS (10x PBS buffer (80g NaCl (Sigma, product number S3014), 2g KCl (Sigma, product number 60128), 14.4g Na2HPO4 (Sigma, product number S5136), 2.4g KH2PO4 (Sigma, product number P9791) to 1L of water, pH adjusted to 7.4). 100μL of 0.4N HCl was added to each well, and the plates were incubated at 4°C with gentle shaking for 2 hours to lyse the cells. The cell lysate was then neutralized with 80μL of neutralization buffer (0.5M disodium hydrogen phosphate, pH 12.5, 2.5mM DTT; 1% cocktail (Sigma, product number P8340)) (the cell lysate and neutralization buffer were thoroughly mixed).

[0374] ELISA assay: Cell lysates were transferred in parallel to two 384-well assay plates (PerkinElmer, OptiPlate-384HB, product number 6007290). One plate was used to detect H3K27 trimethylation levels, and the other plate was used to determine H3 levels. PBS was adjusted to a final volume of 50 μL / well, and the plates were incubated overnight at 4°C. The next day, the solutions in the wells were discarded, and the cells were washed five times with TBST buffer (1 x TBS (10 x TBS: 24.2 g Tris (Sigma, product number T6066), 80 g NaCl (Sigma, product number S3014) dissolved in 1 L of water, pH adjusted to 7.6 with HCl), 0.1% Tween-20). The cells were then blotted dry on absorbent paper. 70 μL of blocking buffer (TBST, 5% BSA) was added to the coated reaction wells, and the cells were incubated at room temperature for 1 hour. Discard the blocking buffer and add primary antibody (30 μL / well). All required primary antibodies should be diluted with blocking buffer at the following dilution ratios: anti-H3K27me3 antibody (Cell Signaling Technology, product number 9733), 1:2000; anti-H3 antibody (Cell Signaling Technology, product number 4499), 1:10000. After adding the primary antibody, incubate at room temperature for 1 hour. Wash 5 times with TBST, drain, and add secondary antibody (30 μL / well) to each reaction well, incubating at room temperature for 1 hour. The secondary antibody (anti-rabbit antibody (Jackson ImmunoResearch, product number 111-035-003)) should be diluted 2000-fold with blocking buffer before use. After 1 hour, wash with TBST and drain. Add 30 μL of ECL substrate (Pierce, product number 34080) to each well and centrifuge at 2000 rpm for 30 seconds. Signals for each sample were detected using Molecular Devices and SpectraMax. Data processing: H3K27 methylation readings were first normalized using the H3 signal. Samples treated with 0.5% DMSO were used as controls to calculate the inhibition percentage of the compounds. The data were then fitted to dose-response curves using GraphPad Prisim5 to obtain the IC50 of the tested compounds. 50 value.

[0375] Table 2 below shows the IC50 values ​​of some compounds. 50 value.

[0376] Table 2

[0377] Example 55: Cell proliferation analysis Human B-cell non-Hodgkin lymphoma cells (KARPAS-422 S) were cultured in culture flasks under standard cell culture conditions. The culture medium consisted of 15% fetal bovine serum (FBS, Invitrogen, product number 10099-141), 1% penicillin / streptomycin solution (P / S), and RPMI-1640 (Invitrogen, product number 11875). The culture flasks were incubated in a sterile incubator at 37°C, 95% relative humidity, and 5% CO2. To investigate the effect of PRC2 inhibitors on cell proliferation, cells in the exponential growth phase were cultured at a concentration of 1 x 10⁻⁶ cells / year. 4 Cells were seeded at a density of 100 μL of culture medium into each well of a 96-well plate (Corning, product number 3904). Subsequently, different concentrations of the compounds disclosed herein were added to the cell-seedled wells (nine concentration gradients for each compound, with a maximum detection concentration of 10 μM and 3-fold serial dilutions), with two replicates for each treatment concentration. The final DMSO concentration was 0.5%. Cell viability was then measured every 3–4 days using a Vi-CELL (Beckman Coulter) scanner. Cells counted at each assay were then stored at the same density (1 x 10⁻⁶ cells / well). 4 Cells (1 cell / well) were seeded into new 96-well plates, and fresh culture medium was added to a final volume of 100 μL, along with different concentrations of the compound. On day 13, 100 μL of CellTiter-Glo (CellTiter-GloCellTiter-GloCellTiter-GloCTG) (Promega, product number G7573) was added to each well. The plates were incubated at room temperature in the dark for 10–20 minutes, and the luminescence signal was read using a Molecular Devices, SpectraMax i3X. The data were fitted to a dose-response curve using GraphPadprisim5 to obtain the IC50 of the tested compound. 50 value.

[0378] Table 3 below shows the IC50 values ​​of some compounds. 50 value.

[0379] Table 3

[0380] The compounds disclosed in this invention can be used to treat cancers related to the mechanism of action of EED protein and / or PRC2 protein complex, including but not limited to metastatic large B-cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma and other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas, etc.

Claims

1. A compound of formula (I), its pharmaceutically acceptable salt or stereoisomer: （I） in, A is or , X is N or CR 7 ; R 1 H, halogen, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted or unsubstituted amino groups, R 3 C with or without substitution 1-4 Halogenated alkyl, hydroxylated or unsubstituted C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 For H, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-4 Alkyl-substituted or unsubstituted amino groups; R 3 Independently hydroxyl, -CN, halogen, C 3-6 heteroaryl, hydroxyl-substituted or unsubstituted C 1-4 Alkoxy, R 6 Substituted or unsubstituted amino groups, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; R 5 Independently for C 1-4 Alkyl or C 3-6 Heterocyclic alkyl groups; R 6 Independently for R 6-1 Substituted or unsubstituted C 1-4 alkyl; R 6-1 Independently hydroxyl or C 1-4 Alkyl-substituted or unsubstituted amino groups; R 7 Independently, H, hydroxyl, -CN, halogen, C 1-4 Alkoxy or C 1-4 alkyl; R 3 The number of them is 1, 2, 3 or 4; R 4 The number is 1 or 2; R 5 The number of them is 1, 2, 3 or 4; R 6 The number is 1 or 2; The C 3-6 Heterocyclic alkyl and C 3-6 The heteroatoms in the heteroaryl group are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; The compound shown in formula (I) is not , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that: When R 1 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R 1 C 1-4 When alkoxy is present, the C 1-4 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl or isopentyl; And / or, when R 3 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R 3 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 3 C 1-4 When alkyl haloides are used, the C... 1-4 The alkyl halotypes are trifluoromethyl, trifluoroethyl, difluoromethyl, and difluoroethyl. And / or, when R 3 C 3-6 When heteroaryl, the C 3-6 The heteroaryl group is an imidazolyl group; And / or, when R 3 C substituted or unsubstituted with hydroxyl group 1-4 When alkoxy is present, the C 1-4 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy; And / or, when R 3 C substituted with hydroxyl group 1-4 When alkoxy is used, the number of hydroxyl groups is 1, 2, or 3; And / or, when R 6 Independently for R 6-1 Replacement C 1-4 When alkyl, R 6-1 The number can be 1, 2, or 3; And / or, when R 6 Independently for R 6-1 Substituted or unsubstituted C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 6-1 Independently for C 1-4 When an alkyl-substituted amino group is present, C 1-4 The number of alkyl groups is 1 or 2; And / or, when R 6-1 Independently for C 1-4 When the amino group is alkyl-substituted or unsubstituted, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 4 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 1 For R 3 C with or without substitution 1-4 When the alkyl group is haloalkaned, the halogen in the halo group is fluorine, chlorine, bromine or iodine; And / or, when R 1 For R 3 C with or without substitution 1-4 When alkyl haloides are used, the C... 1-4 The alkyl group in the haloalkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 1 C substituted with hydroxyl group 3-6 When cycloalkyl, the number of hydroxyl groups is 1, 2, or 3; And / or, when R 1 C substituted or unsubstituted with hydroxyl group 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; And / or, when R 1 For R 5 C with or without substitution 3-6 When heterocyclic alkyl, the C 3-6 The heterocyclic alkyl group is tetrahydropyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or 2-oxa-6-aza-spiro[3,3]heptyl; And / or, when R 5 Independently for C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 5 Independently for C 3-6 When heterocyclic alkyl, the C 3-6 The heterocyclic alkyl group is tetrahydropyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or 2-oxa-6-aza-spiro[3,3]heptyl; And / or, when R 2 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 2 C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; And / or, when R 2 C 1-4 When the amino group is alkyl-substituted or unsubstituted, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 2 C 1-4 When an alkyl-substituted amino group is present, C 1-4 The number of alkyl groups is 1 or 2; And / or, when R 7 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R 7 C 1-4 When alkoxy is present, the C 1-4 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy; And / or, when R 7 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

3. The compound of formula (I) as described in claim 2, its pharmaceutically acceptable salt or stereoisomer, characterized in that: When R 1 When the halogen is halogen, the halogen is chlorine; And / or, when R 1 C 1-4 When alkoxy is present, the C 1-4 The alkoxy group is a methoxy group; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, isobutyl, or 3-pentyl; And / or, when R 3 When the halogen is halogen, the halogen is fluorine; And / or, when R 3 C 3-6 When heteroaryl, the C 3-6 heteroaryl is ; And / or, when R 3 C substituted or unsubstituted with hydroxyl group 1-4 When alkoxy is present, the C 1-4 The alkoxy group is isobutoxy; And / or, when R 6 Independently for R 6-1 Substituted or unsubstituted C 1-4 When alkyl, the C 1-4 The alkyl group is methyl; And / or, when R 6-1 Independently for C 1-4 When the amino group is alkyl-substituted or unsubstituted, the C 1-4 The alkyl group is methyl; And / or, when R 4 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl; And / or, when R 1 For R 3 C with or without substitution 1-4 When alkyl haloides are used, the halogen in the halo group is fluorine; And / or, when R 1 For R 3 C with or without substitution 1-4 When alkyl haloides are used, the C... 1-4 The alkyl group in haloalkyl is methyl; And / or, when R 1 C substituted or unsubstituted with hydroxyl group 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl or cyclobutyl; And / or, when R 1 For R 5 C with or without substitution 3-6 When heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups , , , or ; And / or, when R 5 Independently for C 1-4 When alkyl, the C 1-4 The alkyl group is methyl; And / or, when R 5 Independently for C 3-6 When heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups , , , or ; And / or, when R 2 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl; And / or, when R 2 C 1-4 When the amino group is alkyl-substituted or unsubstituted, the C 1-4 The alkyl group is methyl; And / or, when R 7 When the halogen is halogen, the halogen is fluorine; And / or, when R 7 C 1-4 When alkoxy is present, the C 1-4 The alkoxy group is a methoxy group; And / or, when R 7 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl.

4. The compound of formula (I) as claimed in claim 2, its pharmaceutically acceptable salt or stereoisomer, characterized in that: When R 5 Independently for C 3-6 When heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups .

5. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that: A is ; And / or, R 1 H, halogen, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; And / or, R 2 For H, C 1-4 Alkyl or C 1-4 Alkyl-substituted amino groups; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, R 3 Hydroxyl, halogen, C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; And / or, when R 1 For R 4 When the amino group is substituted, R 4 C 1-4 alkyl; And / or, when R 1 For R 5 Replacement C 3-6 When heterocyclic alkyl, R 5 Methyl or ; And / or, when R 3 For R 6 When the amino group is substituted, R 6 Methyl, or ; And / or, when R 6 For R 6-1 Replacement C 1-4 When alkyl, R 6-1 Hydroxyl or C 1-4 Alkyl-substituted amino groups; And / or, R 7 H, -CN, halogen, C 1-4 Alkoxy or C 1-4 alkyl.

6. The compound of formula (I) as claimed in claim 5, its pharmaceutically acceptable salt or stereoisomer, characterized in that: R 1 For H, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; And / or, R 2 For H or C 1-4 alkyl; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, R 3 Hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; And / or, R 7 H, halogen, C 1-4 Alkoxy or C 1-4 alkyl.

7. The compound of formula (I) as claimed in claim 5, its pharmaceutically acceptable salt or stereoisomer, characterized in that: R 1 For R 3 Replacement C 1-6 alkyl or hydroxy substituted C 3-6 cycloalkyl; And / or, R 7 H, halogen or C 1-4 alkyl.

8. The compound of formula (I) as claimed in claim 5, its pharmaceutically acceptable salt or stereoisomer, characterized in that: R 1 H, methyl, difluoromethyl, trifluoromethyl, methoxy , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; And / or, R 2 H, methyl or ; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, R 3 Hydroxyl, fluorine, , , , , methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl or ; And / or, when R 1 For R 4 When the amino group is substituted, R 4 It is methyl; And / or, when R 6 For R 6-1 Replacement C 1-4 When alkyl, R 6-1 hydroxyl or ; And / or, R 7 It can be H, fluorine, methoxy, or methyl.

9. The compound of formula (I) as claimed in claim 5, its pharmaceutically acceptable salt or stereoisomer, characterized in that: R 1 for , , , , , , , , , , , , , , , , , or ; And / or, R 2 It is H or methyl; And / or, when R 1 For R 3 C with or without substitution 1-6 When alkyl, R 3 It can be hydroxyl, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; And / or, R 7 It can be H, methyl, or fluorine.

10. A compound of formula (I), its pharmaceutically acceptable salt or stereoisomer, characterized in that: The compound of formula (I) is selected from the following compounds: In the above compounds, R 1 The definition is as described in any one of claims 1 to 9.

11. The compound of formula (I) as claimed in claim 10, its pharmaceutically acceptable salt or stereoisomer, characterized in that: The compound of formula (I) is selected from the following compounds: 。 12. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that, The compound of formula (I) is as follows: Option 1: R 1 H, halogen, C 1-4 Alkoxy, R 3 C with or without substitution 1-6 Alkyl, R 4 Substituted amino groups, C 1-4 Halogenated alkyl, hydroxylated C 3-6 cycloalkyl, or R 5 C with or without substitution 3-6 Heterocyclic alkyl groups; R 2 For H, C 1-4 Alkyl or C 1-4 Alkyl-substituted amino groups; R 3 Hydroxyl, halogen, C 3-6 heteroaryl and hydroxyl substituted C 1-4 Alkoxy, R 6 Substituted amino groups, C 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 1-4 Alkyl-substituted or unsubstituted C 3-6 Heterocyclic alkyl groups; R 4 C 1-4 alkyl; R 7 H, -CN, halogen, C 1-4 Alkoxy or C 1-4 alkyl.

13. The compound of formula (I) as claimed in claim 12, its pharmaceutically acceptable salt or stereoisomer, characterized in that: In the first scheme, R 1 for , , , , , , , , , , , , , , , , , or ; And / or, in Scheme 1, R 2 It is H or methyl; And / or, in Scheme 1, R 3 It can be hydroxyl, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl, or trifluoromethyl; And / or, in Scheme 1, R 7 It can be H, methyl, or fluorine.

14. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that, The compound of formula (I) is any one of the following compounds: , , , , , , , , , , , , , , , , , , , , , or .

15. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that, The compound represented by formula (I) is any one of the following compounds: The retention time is 3.134 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 3.547 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 4.974 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: isocratic elution 45%, flow rate 2.8 mL / min; The retention time is 5.440 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: isocratic elution 45%, flow rate 2.8 mL / min; The retention time is 2.782 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 2.907 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is ethanol; gradient: gradient elution 5% mobile phase B → 40% mobile phase B, flow rate is 4 mL / min. The retention time is 0.971 min under the following conditions. Chromatographic column: DAICL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is isopropanol; gradient: isocratic elution of 45% mobile phase B, flow rate 4 mL / min. The retention time is 1.134 min under the following conditions. Chromatographic column: DAIICEL CHIRALPAK IG, column length 250 mm, column inner diameter 30 mm, packing particle diameter 10 μm; mobile phase A is IPA containing 0.1% NH3H2O, mobile phase B is isopropanol; gradient: isocratic elution of 45% mobile phase B, flow rate 4 mL / min.

16. A method for preparing a compound of formula (I) as described in any one of claims 1-15, comprising the following steps: The halogenated intermediate B0 was coupled with intermediate E0 to give the compound shown in formula (I); in, W represents halogen; R x -B(OH)2 or .

17. Use of a compound of formula (I) as claimed in any one of claims 1-15, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament; wherein the medicament is a medicament for treating cancer; and wherein the cancer is selected from lymphoma and prostate cancer.

18. The use as described in claim 17, wherein, The lymphoma is a metastatic large B-cell lymphoma, follicular lymphoma, or non-Hodgkin's lymphoma. And / or, the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, may be used alone or in combination with other drugs.

19. The use as described in claim 18, wherein, The other drugs mentioned are anticancer drugs, tumor immunotherapy drugs, anti-allergy drugs, antiemetics, analgesics, or cell-protective drugs.

20. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-15, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

21. A pharmaceutical formulation comprising a compound of formula (I) as described in any one of claims 1-15, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as described in claim 20.

22. The pharmaceutical formulation according to claim 21, characterized in that, The pharmaceutical preparation is a tablet, capsule, pill, powder, granule, elixir, tincture, suspension, syrup, emulsion or solution; And / or, the drug formulation may be administered orally, sublingually, subcutaneously, intravenously, intramuscularly, intrasternally, nasally, topically, or rectally.

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