Diheterocyclic WRN inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a diheterocyclic WRN inhibitor as shown in a formula (I), and a preparation method and application thereof. The invention further relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition to treatment and / or prevention of diseases related to the biological activity of WRN. # imgabs0 #

Description

Bis-heterocyclic WRN inhibitor, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a biheterocyclic WRN inhibitor, a preparation method thereof, and an application thereof. Background Art

[0002] WRN is a member of the RecQ family of DNA helicases and is involved in DNA damage repair, genomic stability maintenance, and telomere maintenance. Defects in the WRN gene can cause Werner syndrome, a recessive genetic disorder characterized by staged premature aging and increased cancer susceptibility (Nat Rev Cancer 2003, 3, 169-178). In 2019, the Cancer Dependency Map (DepMap), a project aimed at identifying new cancer therapeutic targets through genetic screening, drug sensitivity, and drug prediction models, discovered that WRN is essential for the survival of microsatellite instability (MSI) tumors. The results showed that WRN deficiency causes DNA double-strand breaks (DSBs) in MSI cells, cell cycle arrest, and subsequent apoptosis, while having no effect on microsatellite stable (MSS) cells (Nature 2019, 568, 511-516). Further mechanistic studies have shown that the integrity of the WRN exonuclease domain function has no significant effect on the survival of MSI cells, and the integrity of the WRN unwinding domain function is necessary for the survival of MSI cells (Life Sci Alliance 4). In addition, MSI cells contain large-scale expanded and highly unstable TA-dinucleotide repeat sequences. The expanded TA repeat sequences form non-B-shaped cross-shaped DNA secondary structures, which hinder the extension of the replication fork. WRN can unwind this structure to restore normal DNA replication. When WRN is lost, the cross-shaped structure will be cut by the nuclease MUS81, resulting in chromosomal genome damage and cell death. In MSS cells, the TA repeat sequence does not form a cross-shaped structure, so WRN loss will specifically cause MSI cell death (Nature 2020, 586, 292-298). Therefore, inhibitors targeting the WRN unwinding domain may be an effective measure for the treatment of MSI cancers.

[0003] Currently, no drugs related to WRN target inhibition have been found on the market. Based on the potential medical value of WRN target inhibition in the treatment of microsatellite instability (MSI) tumors, the development of compounds related to WRN target inhibition has very important social significance and medical value.

[0004] Summary of the Invention

[0005] Problems to be solved by the invention:

[0006] Although several patent applications for WRN inhibitors have been published, the lack of currently marketed WRN-targeting drugs and the potential medical value of WRN inhibition in the treatment of microsatellite instability (MSI) tumors necessitate further development of new compounds. Through continuous effort, the inventors of this application have designed compounds having the structure represented by general formula (I) and discovered that compounds having such structures exhibit excellent WRN inhibitory effects and potential for the treatment of MSI tumor-related diseases.

[0007] Solutions used to solve the problem:

[0008] In order to solve the above problems, the inventors of the present application have attempted to conduct in-depth research and found that the bicyclic structure compound represented by formula (I) and its derivatives can achieve the desired purpose, resulting in the completion of the present invention.

[0009] The present invention protects the following specific embodiments:

[0010] A compound represented by formula (I), or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof:

[0011] in,

[0012] R1 is selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5-membered or 6-membered cycloalkenyl, 5-10-membered heterocyclyl, 5-membered or 6-membered heteroaryl, phenyl, the heterocyclyl and heteroaryl groups each independently contain 1-2 heteroatoms selected from N, O or S, the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl groups each independently are unsubstituted or replaced by one or more identical or different R g replace;

[0013] Each R g Each independently selected from: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, HOC(O)-(CH2) n -、H3C-C(O)(CH2) n -、C 1-4 Alkyl-OC(O)(CH2) n -, =O, azetidinyl, pyrrolidinyl, R'R"N-, wherein R', R" are each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl group is connected to the R1 main group through the N atom; the C 1-4 Alkyl, C1-4 Alkoxy, azetidinyl, pyrrolidinyl are each independently unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Substitution of alkoxy groups;

[0014] R2 is selected from wherein L is selected from 7-10 membered spiroheterocycloalkyl, The spiroheterocycloalkyl group contains 2-3 N atoms;

[0015] R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 Alkyl, which is unsubstituted or substituted with one or more substituents selected from hydroxy or halogen;

[0016] R4 is selected from H, halogen, hydroxy, cyano, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, wherein the alkyl, cycloalkyl, and alkoxy groups are unsubstituted or substituted with one or more halogens;

[0017] R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

[0018] R6 is selected from H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with one or more halogens;

[0019] R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy; the alkyl, cycloalkyl, alkoxy is unsubstituted or substituted by one or more halogens;

[0020] X is selected from N or CR8, R8 is H or halogen;

[0021] R 2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently replaced by one or more identical or different R c replace;

[0022] R 2bis selected from 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocycloalkyl, 5-14-membered heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl each independently contain 1-4 heteroatoms selected from N, O, or S; the -CH2- on the 5-14-membered heterocycloalkyl and 5-14-membered heterocycloalkenyl rings are each independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocycloalkyl, and 5-14-membered heterocycloalkenyl are each independently replaced by one or more R d replace;

[0023] R 2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R f replace;

[0024] Each R c are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano, amino;

[0025] Each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, hydroxy, halogen, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl each independently contains 1 to 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl, phenyl is unsubstituted or each independently substituted by one or more halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 Substitution of cycloalkyl groups;

[0026] Each R f Each independently selected from hydroxy, cyano, amino, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0027] A compound represented by formula (I), or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof:

[0028] in,

[0029] R1 is selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5-membered or 6-membered cycloalkenyl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heteroaryl, phenyl, wherein the heterocyclyl or heteroaryl group contains 1-2 heteroatoms selected from N, O or S, and the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl is unsubstituted or replaced by one or more identical or different R g replace;

[0030] Each R g Each independently selected from: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, HOC(O)-(CH2) n -、H3C-C(O)(CH2) n -、C 1-4 Alkyl-OC(O)(CH2) n -, =O, azetidinyl, pyrrolidinyl, R'R"N-, wherein R', R" are each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl group is connected to the R1 main group through the N atom; the C 1-4 Alkyl, C 1-4 Alkoxy, azetidinyl, pyrrolidinyl are unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Substitution of alkoxy groups;

[0031] R2 is selected from wherein L is selected from 7-10 membered spiro heterocyclic group,

[0032] R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 Alkyl, which is unsubstituted or substituted with one or more substituents selected from hydroxy or halogen;

[0033] R4 is selected from H, halogen, hydroxy, cyano, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, wherein the alkyl, cycloalkyl, and alkoxy groups are unsubstituted or substituted with one or more halogens;

[0034] R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

[0035] R6 is selected from H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with one or more halogens;

[0036] R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy; the alkyl, cycloalkyl, alkoxy is unsubstituted or substituted by one or more halogens;

[0037] X is selected from N or CR8, R8 is H or halogen;

[0038] R 2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently replaced by one or more identical or different R c replace;

[0039] R 2b is selected from 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocyclic group are each independently replaced by one or more R d replace;

[0040] R 2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R f replace;

[0041] Each R c are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano, amino;

[0042] Each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, 4-7 membered heterocycloalkyl, hydroxyl or halogen; the 4-7 membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S;

[0043] Each R f Each independently selected from hydroxy, cyano, amino, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0044] A compound represented by formula (I), or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof:

[0045] in,

[0046] R1 is selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5-membered or 6-membered cycloalkenyl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heteroaryl, phenyl, wherein the heterocyclyl or heteroaryl group contains 1-2 heteroatoms selected from N, O or S, and the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl is unsubstituted or replaced by one or more identical or different R g replace;

[0047] Each R g Each independently selected from: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, HOC(O)-(CH2) n -、H3C-C(O)(CH2) n -、C 1-4 Alkyl-OC(O)(CH2) n-, =O, azetidinyl, pyrrolidinyl, R'R"N-, wherein R', R" are each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl group is connected to the R1 main group through the N atom; the C 1-4 Alkyl, C 1-4 Alkoxy, azetidinyl, pyrrolidinyl are unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Substitution of alkoxy groups;

[0048] R2 is selected from wherein L is selected from 7-10 membered spiro heterocyclic group,

[0049] R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 Alkyl, which is unsubstituted or substituted with one or more substituents selected from hydroxy or halogen;

[0050] R4 is selected from H, halogen, hydroxy, cyano, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, wherein the alkyl, cycloalkyl, and alkoxy groups are unsubstituted or substituted with one or more halogens;

[0051] R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

[0052] R6 is selected from H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with one or more halogens;

[0053] R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy; the alkyl, cycloalkyl, alkoxy is unsubstituted or substituted by one or more halogens;

[0054] X is selected from N or CR8, R8 is H or halogen;

[0055] R 2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently replaced by one or more identical or different R c replace;

[0056] R 2b is selected from 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocyclic group are each independently replaced by one or more R d replace;

[0057] R 2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R f replace;

[0058] Each R c are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano, amino;

[0059] Each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 halocycloalkyl, hydroxy or halogen;

[0060] Each R f Each independently selected from hydroxy, cyano, amino, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0061] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R2 is selected from

[0062] In one embodiment, R2 is selected from

[0063] In one embodiment, R2 is selected from

[0064] In one embodiment, R2 is selected from

[0065] In one embodiment, R2 is selected from

[0066] In one embodiment, R2 is selected from

[0067] In one embodiment, R2 is selected from

[0068] In one embodiment, R2 is selected from

[0069] In one embodiment, R 2b is selected from 5-membered heteroaryl and 8-14-membered heteroaryl; the 5-membered heteroaryl and 8-14-membered heteroaryl each independently contain 1-4 heteroatoms selected from N, O and S; the 5-membered heteroaryl and 8-14-membered heteroaryl each independently contain one or more R d replace.

[0070] In one embodiment, R 2b is selected from 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl; the 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl each independently contain 1-4 heteroatoms selected from N, O, and S; the 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl are each independently replaced by one or more R d replace.

[0071] In one embodiment, R 2b is selected from 5-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl; the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 heteroatoms selected from N, O and S; the 5-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl are each independently replaced by one or more R d replace.

[0072] In one embodiment, R 2bis selected from 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl; the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 heteroatoms selected from N, O and S; the 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl are each independently replaced by one or more R d replace.

[0073] In one embodiment, R 2b is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrrolyl, pyridofuranyl, pyridothiphenyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridisothiazolyl, pyridoxazolyl, pyridisoxazolyl, benzopyridinyl, and benzopyrimidinyl; the pyrrolyl , furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrrolyl, pyridofuranyl, pyridothiphenyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridisothiazolyl, pyridoxazolyl, pyridisoxazolyl, benzopyridinyl, benzopyrimidinyl are each independently replaced by one or more R d replace.

[0074] In one embodiment, R 2b is selected from pyrazolyl, benzopyridinyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuryl, pyridopyrrolyl, pyridothiphenyl; the pyrazolyl, benzopyridinyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuryl, pyridopyrrolyl, pyridothiphenyl are each independently replaced by one or more R d replace.

[0075] In one embodiment, R 2b Selected from described Each independently represented by one or more R d replace.

[0076] In one embodiment, R 2b Selected from

[0077] In one embodiment, each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, hydroxyl, halogen, wherein there is only one R d The 4-7 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N, O and S; the 5- or 6-membered heteroaryl group each independently contains 1 to 3 heteroatoms selected from N, O and S.

[0078] In one embodiment, each R d Each independently selected from C 1-4 Alkyl, C 5-6 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, hydroxyl, halogen, wherein there is only one R d The 4-7 membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N, O and S; the 5-membered or 6-membered heteroaryl group each independently contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0079] In one embodiment, each R d Each independently selected from C 1-4 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, 6 membered heteroaryl, phenyl, hydroxyl, halogen, where there is only one R d is a hydroxyl group; the 4-7 membered heterocycloalkyl group contains 1 or 2 O heteroatoms; and the 6 membered heteroaryl group contains 1 or 2 N heteroatoms.

[0080] In one embodiment, each R d Each independently selected from C 1-2 Alkyl, C 3-4 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-2 Fluorinated alkyl, C 3-4 Fluorinated alkyl, C 1-2 Alkoxy, C 3-4Alkoxy, 4-7 membered heterocycloalkyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, hydroxyl, halogen, wherein there is only one R d The 4-7 membered heterocycloalkyl group contains 1 O heteroatom.

[0081] In one embodiment, each R d Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, methoxy, ethoxy, 4-7 membered heterocycloalkyl, pyridyl, hydroxyl, F, Cl, Br, phenyl, wherein there is only one R d The 4-7 membered heterocycloalkyl group contains 1 O heteroatom.

[0082] In one embodiment, each R d Each is independently selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, Cl, phenyl, hydroxyl, where there is only one R d It is a hydroxyl group.

[0083] In one embodiment, the hydroxyl group is substituted in R 2b On the carbon atom in the ortho or meta position to the point of attachment to the main group.

[0084] In one embodiment, the hydroxyl group is substituted in R 2b On the carbon atom adjacent to the site of attachment of the main group.

[0085] In one embodiment, R 2b Selected from

[0086] In one embodiment, each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, halogen; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S; the 5- or 6-membered heteroaryl each independently contains 1 to 3 heteroatoms selected from N, O and S.

[0087] In one embodiment, each R d Each independently selected from C 1-4 Alkyl, C5-6 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, halogen; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S; the 5- or 6-membered heteroaryl each independently contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0088] In one embodiment, each R d Each independently selected from C 1-4 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, 6 membered heteroaryl, phenyl, halogen; the 4-7 membered heterocycloalkyl contains 1 or 2 O heteroatoms; the 6 membered heteroaryl contains 1 or 2 N heteroatoms.

[0089] In one embodiment, each R d Each independently selected from C 1-2 Alkyl, C 3-4 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-2 Fluorinated alkyl, C 3-4 Fluorinated alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy, 4-7 membered heterocycloalkyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, halogen; the 4-7 membered heterocycloalkyl contains 1 O heteroatom.

[0090] In one embodiment, each R d Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, methoxy, ethoxy, 4-7 membered heterocycloalkyl, pyridyl, F, Cl, Br, phenyl; the 4-7 membered heterocycloalkyl contains 1 O heteroatom.

[0091] In one embodiment, each R d Each is independently selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, Cl, phenyl.

[0092] In one embodiment, R 2b Selected from

[0093] In one embodiment, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl each independently contain 1-4 heteroatoms selected from N, O, or S; the -CH2- on the 5-10-membered heterocycloalkyl and 5-10-membered heterocycloalkenyl rings are each independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocycloalkyl, and 5-10-membered heterocycloalkenyl are each independently replaced by one or more R d replace.

[0094] In one embodiment, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently contain 1-4 heteroatoms selected from N, O or S; the -CH2- on the heterocycloalkyl and heterocycloalkenyl rings are each independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl are each independently replaced by one or more R d replace.

[0095] In one embodiment, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently contain 1-4 heteroatoms selected from N, O or S; the -CH2- on the heterocycloalkyl and heterocycloalkenyl rings are each independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl are each independently replaced by one or more R d replace.

[0096] In one embodiment, R 2b is selected from 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 5-membered or 6-membered heterocycloalkyl and 5-membered or 6-membered heterocycloalkenyl; -CH2- on the heterocycloalkyl and heterocycloalkenyl rings are each independently optionally replaced by -C(=O)-; the heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 5-membered or 6-membered heterocycloalkyl and 5-membered or 6-membered heterocycloalkenyl are each independently replaced by 1, 2, 3 or 4 R d replace.

[0097] In one embodiment, R 2b is selected from 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, 1,5-dihydro-2H-pyrrole-2-one, pyridone, 6-membered heterocycloalkyl and pyridone, wherein the heteroaryl and heterocycloalkyl each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, 1,5-dihydro-2H-pyrrole-2-one, pyridone, 6-membered heterocycloalkyl and pyridone are each independently substituted by 1, 2, 3 or 4 R d replace.

[0098] In one embodiment, R 2b is selected from the group consisting of isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridinyl, morpholinopyridinonyl, 1,5-dihydro-2H-pyrrol-2-onyl, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1,5-dihydro-2H-pyrrol-2-one, Each independently by 1, 2, 3 or 4 R d replace.

[0099] In one embodiment, R 2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, The isoxazolyl, pyrazolyl, isothiazolyl, Each independently by 1, 2, 3 or 4 R d replace.

[0100] In one embodiment, R 2b Selected from described Each independently by 1, 2, 3 or 4 R d replace.

[0101] In one embodiment, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, C 1-6 alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, amino or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl each independently contains 1 to 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl, phenyl is unsubstituted or is independently substituted by one or more halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 The cycloalkyl group is substituted with a substituent.

[0102] In one embodiment, each R d are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, cyano or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl each independently contains 1, 2 or 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl, phenyl is unsubstituted or is independently substituted by one or more halogen, cyano, C 1-3 Alkyl, C 1- 3 haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 The cycloalkyl group is substituted with a substituent.

[0103] In one embodiment, each R d are each independently selected from halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C1-4 Alkoxy, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 O heteroatom; the phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl is unsubstituted or substituted with one or more substituents selected from F, Cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoromethoxy.

[0104] In one embodiment, each R d Each is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, fluoro-substituted phenyl, chloro-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxy-substituted phenyl, cyano-substituted pyridyl, fluoro-substituted pyridyl, chloro-substituted pyridyl, methyl-substituted pyridyl, methoxy-substituted pyridyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridyl, trifluoromethoxy-substituted pyridyl, cyano-substituted pyridyl or hydroxy.

[0105] In one embodiment, each R d Each is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl.

[0106] In one embodiment, each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, hydroxyl or halogen, wherein at least one R dThe 4-7 membered heterocycloalkyl group independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group independently contains 1 to 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group and the phenyl group are unsubstituted or independently substituted with one or more heteroatoms selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 The cycloalkyl group is substituted with a substituent.

[0107] In one embodiment, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein at least one R d The 4-7 membered heterocycloalkyl group independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group independently contains 1 to 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group and the phenyl group are unsubstituted or independently substituted with one or more heteroatoms selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 The cycloalkyl group is substituted with a substituent.

[0108] In one embodiment, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein there is only one R d The 4-7 membered heterocycloalkyl group independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group independently contains 1 to 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group and the phenyl group are unsubstituted or independently substituted with one or more heteroatoms selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-5 The cycloalkyl group is substituted with a substituent.

[0109] In one embodiment, each R d are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, 5-membered or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein there is only one R d The 4-7 membered heterocycloalkyl group independently contains 1 or 2 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group independently contains 1, 2 or 3 heteroatoms selected from N, O or S; the 5-membered or 6-membered heteroaryl group and the phenyl group are unsubstituted or independently substituted with one or more heteroatoms selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3- 5. The cycloalkyl group is substituted with a substituent.

[0110] In one embodiment, each R d are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy, wherein there is only one R d is hydroxy; the 4-7 membered heterocycloalkyl group independently contains 1 O heteroatom; the phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl group are unsubstituted or substituted by one or more substituents selected from F, Cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl and fluoromethoxy.

[0111] In one embodiment, each R d Each is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, Fluorine-substituted phenyl, chlorine-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxy-substituted phenyl, cyano-substituted pyridyl, fluorine-substituted pyridyl, chlorine-substituted pyridyl, methyl-substituted pyridyl, methoxy-substituted pyridyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridyl, trifluoromethoxy-substituted pyridyl, cyano-substituted pyridyl or hydroxy, wherein there is one and only one R d It is a hydroxyl group.

[0112] In one embodiment, each R d Each is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl, where there is only one R d It is a hydroxyl group.

[0113] In one embodiment, each R d Each is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl, where there is only one R d is a hydroxyl group, and the hydroxyl group is substituted on R 2b Ortho position to the site of attachment of the main group.

[0114] In one embodiment, R 2b Selected from

[0115] In one embodiment, R 2b Selected from

[0116] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R2 is selected from

[0117] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R2 is selected from

[0118] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R2 is selected from

[0119] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R2 is selected from

[0120] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, or pharmaceutically acceptable salts: R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0121] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0122] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0123] In some specific embodiments, R 2bis selected from 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heterocyclyl and 5-membered or 6-membered heterocyclyl; the heteroaryl and heterocyclyl each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heterocyclyl and 5-membered or 6-membered heterocyclyl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0124] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, 5-membered heterocyclic group, 6-membered heterocyclic group, 6-membered heterocyclic group and pyridinone group, wherein the heteroaryl and heterocyclic group each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl and 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, 5-membered heterocyclic group, 6-membered heterocyclic group, 6-membered heterocyclic group and pyridinone group are each independently substituted by 1, 2, 3 or 4 R d replace.

[0125] In some specific embodiments, R 2b is selected from the group consisting of isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridinyl, morpholinopyridinonyl, 1,5-dihydro-2H-pyrrol-2-onyl, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1,5-dihydro-2H-pyrrol-2-one, Each independently by 1, 2, 3 or 4 R d replace.

[0126] In some specific embodiments, the above-mentioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, amino or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S.

[0127] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C5-6 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S.

[0128] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy; the 4-7 membered heterocycloalkyl each independently contains 1 O heteroatom.

[0129] In some embodiments, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, or hydroxyl groups.

[0130] In some embodiments, each R d Each is independently selected from hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl.

[0131] In some specific embodiments, the above-mentioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, C 1- 6-membered alkoxy, 4-7-membered heterocycloalkyl, hydroxyl or halogen, wherein at least one R d The 4-7 membered heterocycloalkyl groups each independently contain 1 or 2 heteroatoms selected from N, O or S.

[0132] In some embodiments, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein at least one R d The 4-7 membered heterocycloalkyl groups each independently contain 1 or 2 heteroatoms selected from N, O or S.

[0133] In some embodiments, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein there is only one R d The 4-7 membered heterocycloalkyl groups each independently contain 1 or 2 heteroatoms selected from N, O or S.

[0134] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein there is only one R d The 4-7 membered heterocycloalkyl groups each independently contain 1 or 2 heteroatoms selected from N, O or S.

[0135] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein there is only one R d The 4-7 membered heterocycloalkyl groups each independently contain 1 O heteroatom.

[0136] In some embodiments, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, or hydroxyl, where there is only one R d It is a hydroxyl group.

[0137] In some embodiments, each R d Each is independently selected from hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl, where there is only one R d It is a hydroxyl group.

[0138] In some embodiments, each R d Each is independently selected from hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy, or Cl, where there is only one R d is a hydroxyl group, and the hydroxyl group is substituted on R 2b Ortho position to the site of attachment of the main group.

[0139] In some specific embodiments, R 2b Selected from

[0140] In some specific embodiments,

[0141] In some specific embodiments, R2 is selected from

[0142] In some specific embodiments, R2 is selected from

[0143] In some specific embodiments, R2 is selected from

[0144] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0145] In some specific embodiments, R 2bis selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0146] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, 5-membered or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently replaced by one or more R d replace.

[0147] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heterocyclyl and 5-membered or 6-membered heterocyclyl; the heteroaryl and heterocyclyl each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heterocyclyl and 5-membered or 6-membered heterocyclyl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0148] In some specific embodiments, R 2b is selected from 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 6-membered heterocyclyl, 6-membered heterocyclyl-pyridone group, wherein the heteroaryl group and the heterocyclyl group each independently contain 1-2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 6-membered heterocyclyl, 6-membered heterocyclyl-pyridone group are each independently substituted by 1, 2, 3 or 4 R d replace.

[0149] In some specific embodiments, R 2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenylpyridinyl, pyridopyrrolyl, morpholinylpyridonyl, pyridonyl; the pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenylpyridinyl, pyridopyrrolyl, morpholinylpyridonyl, pyridonyl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0150] In some embodiments, each Rd are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, cyano, amino or hydroxy.

[0151] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 5-6 a haloalkyl group, a cyano group or a hydroxy group.

[0152] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 a haloalkyl group, a cyano group or a hydroxy group.

[0153] In some embodiments, each R d Each is independently selected from methyl, ethyl, propyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl or hydroxy.

[0154] In some embodiments, each R d Each is independently selected from methyl, Cl, Br, cyclopropyl or hydroxy.

[0155] In some embodiments, each R d Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, amino, hydroxyl or halogen, wherein at least one R d It is a hydroxyl group.

[0156] In some embodiments, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, cyano or hydroxyl, wherein at least one R d It is a hydroxyl group.

[0157] In some embodiments, each R d are each independently selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano or hydroxy, with one and only one R dIt is a hydroxyl group.

[0158] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Halogenated alkyl, C 5-6 Halogenated alkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, cyano or hydroxy, with one and only one R d It is a hydroxyl group.

[0159] In some embodiments, each R d are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano or hydroxy, with one and only one R d It is a hydroxyl group.

[0160] In some embodiments, each R d Each is independently selected from methyl, ethyl, propyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl or hydroxy, wherein there is only one R d It is a hydroxyl group.

[0161] In some embodiments, each R d Each is independently selected from methyl, Cl, Br, cyclopropyl or hydroxy, wherein there is only one R d It is a hydroxyl group.

[0162] In some embodiments, each R d Each is independently selected from methyl, Cl, Br, cyclopropyl or hydroxy, wherein there is only one R d is a hydroxyl group, and the hydroxyl group is substituted on R 2b Ortho position to the site of attachment of the main group.

[0163] In some specific embodiments, R 2b Selected from Each independently may be further substituted by 1, 2 or 3 R d replace.

[0164] In some specific embodiments, R 2b Selected from

[0165] In some specific embodiments, R 2b is selected from 5-membered heteroaryl groups, each of which is independently substituted by 1, 2, 3 or 4 R d replace.

[0166] In some specific embodiments, R 2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, wherein the pyrazolyl, thiazolyl, thienyl, isothiazolyl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0167] In some specific embodiments, R 2b Selected from Can be further divided into 1, 2 or 3 R d replace.

[0168] In some specific embodiments, R 2b Selected from Can be further divided into 1, 2 or 3 R d replace.

[0169] In some specific embodiments, R 2b Selected from:

[0170] In some specific embodiments, R 2b Selected from:

[0171] In some specific embodiments, R 2b is selected from 6-membered heterocyclic groups, 6-membered heterocyclic groups and 6-membered heterocyclic groups, wherein the heterocyclic groups contain 1-2 heteroatoms selected from N, O or S; the 6-membered heterocyclic groups, 6-membered heterocyclic groups and 6-membered heterocyclic groups are each independently substituted by 1, 2, 3 or 4 R d replace.

[0172] In some specific embodiments, R 2b is selected from morpholinyl and pyridone, pyridone; the morpholinyl and pyridone, pyridone are each independently substituted by 1, 2, 3 or 4 R d replace.

[0173] In some specific embodiments, R 2b The pyridone group is selected from pyridone; the pyridone group is 1, 2, 3 or 4 R d replace.

[0174] In some specific embodiments, R 2b Selected from 2-pyridone; said 2-pyridone is 1, 2, 3 or 4 R d replace.

[0175] In some specific embodiments, R 2b Selected from Can be further divided into 1, 2 or 3 Rd replace.

[0176] In some specific embodiments, R 2b Selected from Can be further divided into 1, 2 or 3 R d replace.

[0177] In some specific embodiments, R 2b Selected from

[0178] In some specific embodiments, R 2b Selected from

[0179] In some specific embodiments, R 2b phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl; the heteroaryl contains 1-2 heteroatoms selected from N, O or S; the phenyl and 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heteroaryl and 5-membered or 6-membered heteroaryl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0180] In some specific embodiments, R 2b is selected from phenyl and 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from N, O or S; the phenyl and 6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0181] In some specific embodiments, R 2b is selected from phenyl pyridinyl and pyridopyrrolyl; the phenyl pyridinyl and pyridopyrrolyl are each independently substituted by 1, 2, 3 or 4 R d replace.

[0182] In some specific embodiments, R 2b Selected from Can be further divided into 1, 2 or 3 R d replace.

[0183] In some specific embodiments, R 2b Selected from

[0184] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: R1 is selected from halogen, C 1-6Alkyl, 5-membered or 6-membered cycloalkenyl, 5-10-membered heterocyclyl, 5-membered or 6-membered heteroaryl, phenyl, the heterocyclyl and heteroaryl groups each independently contain 1-2 heteroatoms selected from N, O or S, the alkyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl groups each independently are unsubstituted or replaced by one or more R g replace.

[0185] In one embodiment, R1 is selected from a 5-membered or 6-membered cycloalkenyl, a 5-10-membered heterocyclyl, a 5-membered or 6-membered heteroaryl, or a phenyl group, wherein the heterocyclyl or heteroaryl group independently contains 1-2 heteroatoms selected from N, O, or S, and the cycloalkenyl, heterocyclyl, heteroaryl, or phenyl group is independently unsubstituted or replaced by one or more R g replace.

[0186] In one embodiment, R1 is selected from 5-membered or 6-membered cycloalkenyl, 5-10-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, 5-membered or 6-membered heteroaryl, phenyl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1-2 heteroatoms selected from N, O, or S, and the cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl are each independently unsubstituted or replaced by one or more R g replace.

[0187] In one embodiment, R1 is selected from 6-membered cycloalkenyl, 6-9-membered heterocycloalkyl, 6-membered heterocycloalkenyl, pyridyl, pyrimidinyl, pyridazinyl, the heterocycloalkyl and heterocycloalkenyl groups each independently contain 1-2 heteroatoms selected from N, O or S, and the cycloalkenyl, heterocycloalkyl and heterocycloalkenyl groups are each independently unsubstituted or replaced by one or more R g replace.

[0188] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts: each R g Each independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, =O, R'R"N-; the alkyl and alkoxy groups are each independently unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Alkoxy is substituted by a substituent; wherein R', R" are each independently selected from H, C 1-4 Alkyl, C 1-4 Halogenated alkyl.

[0189] In one embodiment, each R g Each independently selected from hydroxyl, halogen, C 1-2 Alkyl, C 3- 4 alkyl, C 1-2Alkoxy, C 3-4 Alkoxy, =O, R'R"N-; the alkyl and alkoxy groups are each independently unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Alkoxy is substituted by a substituent; wherein R', R" are each independently selected from H, C 1-2 Alkyl, C 3-4 Alkyl, C 1-2 Halogenated alkyl, C 3-4 Halogenated alkyl.

[0190] In one embodiment, each R g Each independently selected from hydroxyl, F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, =O, R'R"N-; the alkyl and alkoxy groups are each independently unsubstituted or substituted by one or more halogen, hydroxyl, C 1-2 Alkoxy is substituted by a substituent; wherein R', R" are each independently selected from H, C 1-2 Alkyl, C 1-2 Halogenated alkyl.

[0191] In one embodiment, each R g Each is independently selected from hydroxy, F, methyl, methoxy, =O, R'R"N-; the methyl group is unsubstituted or substituted by one or more substituents selected from F, Cl, hydroxy, methoxy; wherein R', R" are each independently selected from H, methyl.

[0192] In one embodiment, the above compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, or pharmaceutically acceptable salts: R1 is selected from

[0193] In one embodiment, R1 is selected from

[0194] In one embodiment, R1 is selected from

[0195] In some embodiments, R1 is selected from halogen, C 1-6 Alkyl, 5-membered or 6-membered heterocyclic group, the heterocyclic group contains 1-2 heteroatoms selected from N, O or S, the alkyl, heterocyclic group is unsubstituted or replaced by one or more R g replace.

[0196] In some embodiments, R1 is selected from a 5-membered or 6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O or S, and the heterocyclic group is unsubstituted or replaced by one or more R g replace.

[0197] In some embodiments, R1 is selected from 5-membered or 6-membered heterocycloalkyl, 5-membered or 6-membered heterocycloalkenyl, wherein the heterocycloalkyl or heterocycloalkenyl contains 1-2 heteroatoms selected from N, O or S, and the heterocycloalkyl or heterocycloalkenyl is unsubstituted or replaced by one or more R g replace.

[0198] In some embodiments, R1 is selected from 5-membered or 6-membered heterocycloalkenyl, wherein the heterocycloalkenyl contains 1-2 heteroatoms selected from N or O, and the heterocycloalkenyl is unsubstituted or replaced by one or more R g replace.

[0199] In some embodiments, R1 is selected from is unsubstituted or replaced by one or more R g replace.

[0200] In some embodiments, each R g Each independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1- 4 alkoxy; said C 1-4 Alkyl, C 1-4 Alkoxy is unsubstituted or substituted by one or more halogen, hydroxy, C 1-2 The substituents of the alkoxy group are substituted.

[0201] In some embodiments, each R g Each independently selected from hydroxyl, halogen, C 1-2 Alkyl, C 3- 4 alkyl, C 1-2 Alkoxy, C 3-4 Alkoxy; the alkyl, alkoxy is unsubstituted or substituted by one or more halogen, hydroxy, C 1-2 The substituents of the alkoxy group are substituted.

[0202] In some embodiments, each R g Each independently selected from hydroxyl, F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy; the alkyl, alkoxy is unsubstituted or substituted by one or more halogen, hydroxy, C 1-2 The substituents of the alkoxy group are substituted.

[0203] In some embodiments, each R gEach is independently selected from hydroxy, F, methyl, and ethyl; the methyl and ethyl groups are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, and methoxy.

[0204] In some embodiments, R1 is selected from

[0205] In some embodiments, R1 is selected from

[0206] In some embodiments, R1 is selected from

[0207] In some embodiments, R3 is selected from C 1-4 Alkyl, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from hydroxy or halogen.

[0208] In some embodiments, R3 is selected from C 1-4 An alkyl group, wherein the alkyl group is unsubstituted.

[0209] In some embodiments, R3 is selected from C 1-2 An alkyl group, wherein the alkyl group is unsubstituted.

[0210] In some embodiments, R3 is selected from methyl or ethyl.

[0211] In some embodiments, R3 is selected from ethyl.

[0212] In some embodiments, R4 is selected from H, halogen, C 1-4 Alkyl, which is unsubstituted or substituted with 1, 2 or 3 halogens.

[0213] In some embodiments, R4 is selected from H, halogen, C 1-4 Alkyl, which is unsubstituted or substituted with 1, 2 or 3 F groups.

[0214] In some embodiments, R4 is selected from H, F, Cl, Br, C 1-4 Alkyl, the C 1-4 The alkyl group is unsubstituted.

[0215] In some embodiments, R4 is selected from H, F, Cl, Br, C 1-2 Alkyl, the C 1-2 The alkyl group is unsubstituted or substituted with 1, 2 or 3 F groups.

[0216] In some specific embodiments, R4 is selected from H, F, Cl, Br, methyl, ethyl, and said methyl, ethyl are each independently unsubstituted or substituted with 1, 2 or 3 F.

[0217] In some embodiments, R4 is selected from H, F, Cl, Br, methyl, -CF3.

[0218] In some embodiments, R4 is selected from Cl, methyl, -CF3.

[0219] In some specific embodiments, R4 is selected from H, F, Cl, Br, methyl, ethyl, and the methyl and ethyl groups are unsubstituted.

[0220] In some embodiments, R4 is selected from H, F, Cl, Br or methyl.

[0221] In some embodiments, R4 is selected from Cl or methyl.

[0222] In some embodiments, R5 is selected from H, methyl, and halogen.

[0223] In some embodiments, R5 is selected from H, F, Cl or methyl.

[0224] In some embodiments, R5 is selected from H, Cl or methyl.

[0225] In some specific embodiments, R5 is selected from H.

[0226] In some embodiments, R6 is selected from H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with 1, 2 or 3 halogens.

[0227] In some embodiments, R6 is selected from H, halogen, C 1-4 Alkyl, which is unsubstituted or substituted with 1, 2 or 3 F groups.

[0228] In some embodiments, R6 is selected from H, halogen, C 1-2 Alkyl, which is unsubstituted or substituted with 1, 2 or 3 F groups.

[0229] In some specific embodiments, R6 is selected from H, F, Cl, methyl, ethyl, wherein the methyl, ethyl is unsubstituted or substituted with 1, 2 or 3 F.

[0230] In some embodiments, R6 is selected from H, F, Cl, methyl, or -CF3.

[0231] In some embodiments, R6 is selected from H, F or Cl.

[0232] In some embodiments, R6 is selected from H, halogen, C 1-4 Alkyl, wherein the alkyl is substituted by 1, 2 or 3 F groups.

[0233] In some embodiments, R6 is selected from H, halogen, C 1-2 Alkyl, wherein the alkyl is substituted by 1, 2 or 3 F groups.

[0234] In some specific embodiments, R6 is selected from H, F, Cl, methyl, ethyl, and the methyl, ethyl is substituted with 1, 2 or 3 F.

[0235] In some embodiments, R6 is selected from H, F, Cl or -CF3.

[0236] In some embodiments, R6 is selected from H, F or Cl.

[0237] In some embodiments, R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl; the alkyl or cycloalkyl group is unsubstituted or substituted by one or more halogens.

[0238] In some embodiments, R7 is selected from -SF5, -C(O)H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with 1, 2 or 3 halogens.

[0239] In some embodiments, R7 is selected from -SF5, -C(O)H, halogen, C 1-4 Alkyl; said alkyl is unsubstituted or substituted with 1, 2 or 3 F groups.

[0240] In some embodiments, R7 is selected from -SF5, -C(O)H, halogen, C 1-2 Alkyl; said alkyl is unsubstituted or substituted with 1, 2 or 3 F groups.

[0241] In some specific embodiments, R7 is selected from -SF5, -C(O)H, F, Cl, Br, methyl, ethyl; the methyl, ethyl is unsubstituted or substituted with 1, 2 or 3 F.

[0242] In some embodiments, R7 is selected from -CF3, -CHF2, -CH2CH3, Cl, Br, -SF5 or -C(O)H.

[0243] In some specific embodiments, R7 is selected from -CF3.

[0244] In some specific embodiments, R7 is selected from -OCF3.

[0245] In some embodiments, X is selected from N or CR8, and R8 is selected from H, F, Cl, or Br.

[0246] In some specific embodiments, R8 is selected from H or F.

[0247] In some embodiments, the functional group Selected from

[0248] In some embodiments, the functional group Selected from

[0249] In some embodiments, the functional group Selected from

[0250] In some embodiments, the functional group Selected from

[0251] In some embodiments, the functional group Selected from

[0252] In some specific embodiments, Formula (I) has a general structure selected from Formula (IB):

[0253] Among them, R1, R 2b , R3, and R4 are each defined as described in formula (I).

[0254] In some specific embodiments, formula (I) has the structure shown in formula (IB-1):

[0255] Among them, R1, R 2b , R4 are as defined in formula (I).

[0256] In some specific embodiments, formula (I) has a structure selected from formula (IIA):

[0257] Among them, R1, R 2b , R4, R5, R6, and R7 are as defined in formula (I).

[0258] In some specific embodiments, the formula (IIA) has the structure shown in formula (IIA-1):

[0259] Among them, R1, R d , R4, R5, R6, and R7 are as defined in formula (I).

[0260] In some specific embodiments, the formula (IIA-1) has the structure shown in formula (IIA-1-1):

[0261] Among them, R1, R d Definitions are as described in formula (I).

[0262] In some specific embodiments, the formula (IIA) has the structure shown in formula (IIA-2):

[0263] wherein R1, R4, R5, R6, and R7 are as defined in formula (I).

[0264] In some specific embodiments, the formula (IIA-2) has the structure shown in formula (IIA-2-1):

[0265] wherein R1 is as defined in formula (I).

[0266] In some specific embodiments, the formula (IIA) has the structure shown in formula (IIA-3):

[0267] Among them, R1, R d , R4, R5, R6, and R7 are as defined in formula (I).

[0268] In some specific embodiments, the formula (IIA-3) has the structure shown in formula (IIA-3-1):

[0269] Among them, R1, R d Definitions are as described in formula (I).

[0270] In some specific embodiments, the formula (IIA) has the structure shown in formula (IIA-4):

[0271] wherein Ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O and S; the 5-membered heteroaryl group is unsubstituted or substituted by one or more C 1-4 Alkyl substituted; X, R4, R5, R6, R7 are as defined above.

[0272] In some embodiments, Ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains one heteroatom selected from N, O and S; the 5-membered heteroaryl group is unsubstituted or substituted with one or more C 1-4 Alkyl substituted; X, R4, R5, R6, R7 are as defined above.

[0273] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl; the furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; X, R4, R5, R6, R7 are as defined above.

[0274] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, and thienyl; the furanyl, pyrrolyl, and thienyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0275] In some specific embodiments, ring B is selected from furanyl and pyrrolyl; the furanyl and pyrrolyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0276] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, and thienyl; the pyrrolyl is unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0277] In some specific embodiments, ring B is selected from furanyl and pyrrolyl; the pyrrolyl is unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0278] In some specific embodiments, Ring B is selected from furanyl, pyrrolyl, and thienyl; the pyrrolyl is unsubstituted or substituted with one methyl group; and X, R4, R5, R6, and R7 are as defined above.

[0279] In some specific embodiments, Ring B is selected from furanyl and pyrrolyl; the pyrrolyl is unsubstituted or substituted with 1 methyl group; X, R4, R5, R6, and R7 are as defined above.

[0280] In some specific embodiments, formula (I) has a structure selected from formula (IIB):

[0281] Among them, R1, R 2b , R4, R5, R6, and R7 are as defined in formula (I).

[0282] In some specific embodiments, the formula (IIB) has the structure shown in formula (IIB-1):

[0283] Among them, R1, R d , R4, R5, R6, and R7 are as defined in formula (I).

[0284] In some specific embodiments, the formula (IIB-1) has the structure shown in formula (IIB-1-1):

[0285] Among them, R1, R d Definitions are as described in formula (I).

[0286] In some specific embodiments, the formula (IIB) has the structure shown in formula (IIB-2):

[0287] wherein R1, R4, R5, R6, and R7 are as defined in formula (I).

[0288] In some specific embodiments, the formula (IIB-2) has the structure shown in formula (IIB-2-1):

[0289] wherein R1 is as defined in formula (I).

[0290] In some specific embodiments, the formula (IIB) has the structure shown in formula (IIB-3):

[0291] Among them, R1, R d , R4, R5, R6, and R7 are as defined in formula (I).

[0292] In some specific embodiments, the formula (IIB-3) has the structure shown in formula (IIB-3-1):

[0293] Among them, R1, R d Definitions are as described in formula (I).

[0294] In some specific embodiments, the formula (IIB) has the structure shown in formula (IIB-4):

[0295] wherein Ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O and S; the 5-membered heteroaryl group is unsubstituted or substituted by one or more C 1-4 Alkyl substituted; X, R4, R5, R6, R7 are as defined above.

[0296] In some embodiments, Ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains one heteroatom selected from N, O and S; the 5-membered heteroaryl group is unsubstituted or substituted with one or more C 1-4 Alkyl substituted; X, R4, R5, R6, R7 are as defined above.

[0297] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl; the furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; X, R4, R5, R6, R7 are as defined above.

[0298] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, and thienyl; the furanyl, pyrrolyl, and thienyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0299] In some specific embodiments, ring B is selected from furanyl and pyrrolyl; the furanyl and pyrrolyl are each independently unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0300] In some specific embodiments, ring B is selected from furanyl, pyrrolyl, and thienyl; the pyrrolyl is unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0301] In some specific embodiments, ring B is selected from furanyl and pyrrolyl; the pyrrolyl is unsubstituted or substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; X, R4, R5, R6, and R7 are as defined above.

[0302] In some specific embodiments, Ring B is selected from furanyl, pyrrolyl, and thienyl; the pyrrolyl is unsubstituted or substituted with one methyl group; and X, R4, R5, R6, and R7 are as defined above.

[0303] In some specific embodiments, Ring B is selected from furanyl and pyrrolyl; the pyrrolyl is unsubstituted or substituted with 1 methyl group; X, R4, R5, R6, and R7 are as defined above.

[0304] In some specific embodiments, Formula (I) has a structure selected from Formula (IIC):

[0305] Among them, R1, R 2b , R4, R5, R6, and R7 are as defined in formula (I).

[0306] In some specific embodiments, the formula (IIC) has the structure shown in formula (IIC-1):

[0307] Among them, R1, R d , R4, R5, R6, and R7 are as defined in formula (I).

[0308] In some specific embodiments, the formula (IIC-1) has the structure shown in formula (IIC-1-1):

[0309] Among them, R1, R d Definitions are as described in formula (I).

[0310] In some specific embodiments, the formula (IIC) has the structure shown in formula (IIC-2):

[0311] wherein R1, R4, R5, R6, and R7 are as defined in formula (I).

[0312] In some specific embodiments, the formula (IIC-2) has the structure shown in formula (IIC-2-1):

[0313] wherein R1 is as defined in formula (I).

[0314] In some embodiments, Formula (I) is selected from the following compounds:

[0315] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds discovered herein with the specified substituents with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

[0316] The term "prodrug" refers to derivatives of the compound represented by formula (I) with specific substituents discovered in the present invention. They themselves may have weak activity or even no activity, but after administration, they are converted into the compound with specific substituents discovered in the present invention under physiological conditions (for example, by metabolism, solvent decomposition or other means) and produce corresponding biological activity in the body.

[0317] The term "metabolite" refers to a product obtained by in vivo metabolism of a compound of formula (I) having specific substituents discovered by the present invention. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0318] The term "deuterated compound" refers to a compound of the present invention that includes at least one deuterium atom, specifically one or more hydrogen atoms in a compound of the present invention that can be replaced or substituted with a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0319] Preparation method:

[0320] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following illustrative methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0321] The compound of the general formula (I) of the present invention can be synthesized according to the following method:

[0322] Option 1:

[0323] 1) Substitution reaction of A and C to obtain intermediate D;

[0324] 2) removing the protecting group to obtain intermediate E;

[0325] 3) Intermediate E is condensed with the corresponding carboxylic acid to obtain product F or G.

[0326] Wherein W represents halogen, PG is a protecting group, such as -Boc (tert-butyloxycarbonyl), benzyl, PMB, R1, R3, R4, R5, R6, R7, X, R 2a and R 2b As defined in formula (I).

[0327] Option 2:

[0328] 1) H and I undergo substitution reaction to obtain intermediate J;

[0329] 2) Intermediate J undergoes halogenation reaction to produce intermediate K;

[0330] 3) Intermediate K is substituted with the corresponding amine to obtain intermediate L or M;

[0331] 4) After deprotection, the intermediate L or M is condensed with the corresponding carboxylic acid to obtain the product N, O or P.

[0332] Wherein W represents halogen, PG is a protecting group such as Boc (tert-butyloxycarbonyl), benzyl, PMB, R1, R3, L, R4, R5, R6, R7, X, R 2a 、R 2b and R 2e As defined in formula (I).

[0333] Pharmaceutical composition

[0334] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and optional pharmaceutical excipients. Preferably, the pharmaceutical excipients are pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof.

[0335] The present invention also provides a pharmaceutical composition for treating and / or preventing diseases associated with the biological activity of WRN, comprising a therapeutically and / or prophylactically effective amount of the aforementioned compound, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient. Preferably, the pharmaceutical excipient is a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0336] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing diseases associated with the biological activity of WRN.

[0337] In some embodiments, the disease associated with WRN biological activity is a tumor or cancer.

[0338] In some embodiments, the disease associated with WRN biological activity is an MSI tumor or an MSI cancer.

[0339] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0340] The present invention also provides a WRN inhibitor, which comprises a therapeutically and / or prophylactically effective amount of the compound as described above, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, and pharmaceutically acceptable salts.

[0341] Medical uses:

[0342] The present invention also provides the use of the aforementioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions in the preparation of WRN inhibitors.

[0343] The present invention also provides the use of the aforementioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases associated with the biological activity of WRN.

[0344] The present invention also provides the use of the aforementioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions in the treatment and / or prevention of diseases associated with the biological activity of WRN.

[0345] The present invention also provides the compound as described above, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the pharmaceutical composition as described above, for use in treating and / or preventing diseases associated with the biological activity of WRN.

[0346] In some embodiments, the aforementioned disease associated with the biological activity of WRN is a tumor or cancer.

[0347] In some embodiments, the aforementioned disease associated with WRN biological activity is MSI tumor or MSI cancer.

[0348] The present invention also provides a method for treating and / or preventing diseases associated with the biological activity of WRN, comprising administering to an individual in need thereof a therapeutically and / or preventatively effective amount of the compound as described above, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or pharmaceutical compositions as described above.

[0349] In some embodiments, the aforementioned disease associated with the biological activity of WRN is a tumor or cancer.

[0350] In some embodiments, the aforementioned disease associated with WRN biological activity is MSI tumor or MSI cancer.

[0351] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0352] In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0353] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Typically, but not necessarily, a prophylactic dose is used in subjects before the onset of disease or in the early stages of the disease, so the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to a certain extent, preferably stop) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0354] Definition of terms:

[0355] According to the common practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0356] A dash “-” that does not appear between two letters or symbols is used to indicate the point of attachment of a substituent. For example, C 3-6 Cycloalkyl-(C1-6 alkyl) r - means (C1-C6 alkyl) r - connected to the rest of the molecule.

[0357] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced with the selection of a designated group, provided that the normal valence of the designated atom is not exceeded.

[0358] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently, or "C 1-4 Alkyl", or independently disclosed "C 1-3 alkyl".

[0359] The term "alkyl" refers to both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-6 alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. It will be understood by those skilled in the art that C 1-6 Alkyl groups contain a monovalent C 1-6 Alkyl, divalent C 1-6 Alkylene, such as C3-C6 cycloalkyl-(C1-C6 alkyl) r -The C1-C6 alkyl group refers to a C1-C6 alkylene group.

[0360] The term "alkoxy" refers to any of the above alkyl groups (eg, C1-6 alkyl, C1-4 alkyl, C1-3 alkyl, etc.) that is attached to the rest of the molecule through an oxygen atom (-O-).

[0361] The term "C 1-6 Haloalkyl" or "C 1-6 "Haloalkoxy" refers to an alkyl or alkoxy group in which one or more (such as 2 or 3) hydrogen atoms are replaced by halogen atoms, such as fluorine, chlorine, or bromine. The alkyl or alkoxy group is defined as above. In some embodiments, the term "haloalkoxy" refers to an alkyl or alkoxy group in which one or more (such as 2 or 3) hydrogen atoms are replaced by halogen atoms, such as fluorine, chlorine, or bromine. 1-6 "Alkyl" is preferably fluorinated, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "halogenated C 1-6The "alkoxy" is preferably fluorinated, for example, it can be -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0362] The term "hydroxy substituted C 1-6 "C alkyl" means that one of the hydrogen atoms in the alkyl group is replaced by a hydroxyl group, and the definition of the alkyl group is as described above. As an example, the "C alkyl group substituted by a hydroxyl group" 1-6 The "alkyl" may be a hydroxymethyl group.

[0363] The term "alkenyl" refers to a hydrocarbon group including straight or branched configurations and having one or more carbon-carbon double bonds which may be present at any stable point along the chain. For example, "C 2-6 The term "alkenyl" is intended to include C2, C3, C4, C5 and C6. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0364] The term "alkynyl" refers to hydrocarbon groups including straight or branched configurations and having one or more carbon-carbon triple bonds that may be present at any stable point along the chain. For example, "C 2-6 The term "alkynyl" is intended to include C2, C3, C4, C5 and C6 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0365] The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems. When the cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or a carbocyclic ring residue. The two rings of the bicyclic or polycyclic cycloalkyl group can be connected in a manner including bridging, fusion or spiro connection. For example, C 3-10 Cycloalkyl refers to C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0366] The term "cycloalkenyl" refers to a carbocyclic group of a cycloalkyl group as defined above having at least one carbon-carbon double bond, for example

[0367] The term "carbocycle" or "carbocycle residue" refers to any stable 3-, 4-, 5-, 6- or 7-membered monocyclic ring or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic or polycyclic ring, any one of which may be saturated, partially saturated, unsaturated or aromatic. The bicyclic or polycyclic carbocycles may be connected in a manner such as bridging, fusion or spiro. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2,2,2]bicyclooctane, wait.

[0368] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 5 to 14 carbon atoms in the ring portion. When the "aryl" group is bicyclic or tricyclic, each ring is aromatic. The two rings of the bicyclic or tricyclic aryl group can be connected in a manner including bridging, fusion, and spiro connection. Examples include phenyl and naphthyl, each of which can be substituted.

[0369] The terms "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 4-8 membered monocyclic or bicyclic groups, 8-10 membered bicyclic or tricyclic groups, and 10-14 membered tricyclic or polycyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), preferably 1, 2, or 3 heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatoms are exclusively N or O, and the total number does not exceed 3, preferably only 1-2 heteroatoms. The carbon and sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and when valence permits, the ring atoms in the heterocycle may be optionally substituted with =O (oxo). (For example: ). The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated, aromatic or non-aromatic. The heterocyclic group may be attached at any available nitrogen or carbon atom. In some preferred embodiments, the heterocyclic groups herein, the fused rings completing the bicyclic and tricyclic groups are non-aromatic rings. As previously mentioned, heterocyclic groups include "heterocycloalkyl" and "heterocycloalkenyl" as described below. Exemplary heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazacycloheptatrienyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, quinuclidine, wait.

[0370] The term "heterocycloalkyl" refers to a heterocyclic group as defined above wherein all ring atoms are fully saturated, for example When it is bicyclic or tricyclic, "heterocycloalkyl" includes "heterobridged cycloalkyl", "heterospirocycloalkyl" and "heteroparacycloalkyl".

[0371] The term "heterocycloalkenyl" refers to a heterocyclic group having at least one carbon-carbon double bond in the heterocycle as defined above, for example When the heterocycloalkenyl group is bicyclic or tricyclic, the "heterocycloalkenyl group" includes "heterobridged cycloalkenyl group", "heterospirocycloalkenyl group" and "heterocycloalkenyl group". When the heterocycloalkenyl group is bicyclic or tricyclic, the entire ring is unsaturated and cannot form aromaticity.

[0372] The term "heteroaryl" refers to substituted and unsubstituted aryl groups described above having at least one heteroatom (O, N, or S) in at least one ring, including aromatic 5-8 membered monocyclic groups, 8-10 membered bicyclic groups, and 10-14 membered tricyclic groups, wherein the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, N, or S. Each heteroatom-containing ring of the heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. Each ring of a bicyclic or tricyclic heteroaryl group is aromatic.

[0373] The term "spirocyclyl" refers to a bicyclic structure having one common ring atom, wherein each monocyclic ring is a saturated or unsaturated, aromatic or non-aromatic carbocyclic ring having 3-7 carbon atoms. Exemplary spirocyclyls include, but are not limited to, spiro[4.5]decane, spiro[3.4]octane, spiro[2.3]hexane, Herein, the spirocyclic group does not include the aryl group defined above.

[0374] The term "spiroheterocyclyl" refers to a bicyclic structure having one common ring atom, wherein each monocyclic ring is a saturated or unsaturated monocyclic group having 3 to 8 ring atoms, wherein at least one ring has 1 or 2 ring atoms selected from N, O or S(O) n wherein n is an integer from 0 to 2 and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group. Exemplary spiroheterocyclyls include, but are not limited to, 5-azaspiro[2.3]hexane and 6-oxaspiro[3.4]-7-octanone. As used herein, the spiroheterocyclyl group does not include heteroaryl groups as defined above.

[0375] The term "heteroatom" shall include oxygen, sulfur and nitrogen.

[0376] The term "halogen" shall include "F, Cl, Br, I".

[0377] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0378] When the term "saturated" is used herein to refer to a ring or group, unless otherwise specified, the ring or group shall be fully saturated.

[0379] From all the above descriptions, it is obvious to those skilled in the art that any group whose name is a compound name, such as "pyridothiphenyl", is constructed from a pyridyl or thienyl group, preferably from a thienyl group; other similar compound names can be understood with reference to the foregoing content.

[0380] The term "optionally" means that it can be selected or not. For example, "optionally 1 to 3 R d Substituted C 1- 6 alkyl", which means that the C 1-6 The alkyl group may be substituted with 1 to 3 R d It may be replaced by 1 to 3 R d Other similar definitions can be understood with reference to the above content.

[0381] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds and compounds useful as pharmaceutically acceptable compounds and / or intermediate compounds useful in preparing pharmaceutically acceptable compounds.

[0382] Herein, unless otherwise expressly stated, the description “…are independently selected from” used throughout this document may mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, or that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0383] The term "XXX is substituted with one or more substituents selected from YYY" means that XXX can be substituted with one or more substituents at any substitutable position, and the substituents are selected from YYY. When XXX is substituted with multiple substituents selected from YYY at any substitutable position, the multiple substituents can be the same or different. The multiple substituents are 2 or more, preferably 2, 3 or 4, and more preferably 2 or 3. For example, C 1-6 The alkyl group is substituted at any substitutable position by one or more substituents selected from cyano and hydroxy groups, which means that C 1-6The alkyl group may be substituted by one or more cyano groups at any substitutable position, may be substituted by one or more hydroxyl groups at any substitutable position, or may be substituted by one or more cyano groups and hydroxyl groups (e.g., one cyano group and one hydroxyl group, or two cyano groups and one hydroxyl group, or two cyano groups and two hydroxyl groups, etc.) at any substitutable position.

[0384] When it is mentioned that "one or more H atoms in XXX may be further replaced by one or more identical or different YYY", it means that the H atoms in XXX may be replaced by YYY or not; the H atoms in XXX may be replaced by one or more identical YYY or one or more different YYY, and each substituent should not have the same sign and interfere with each other.

[0385] Effects of the invention:

[0386] The compound represented by formula (I) of the present invention has a good WRN inhibitory effect and can be used as a drug for the treatment and / or prevention of diseases related to this effect, and can be particularly used for the treatment and / or prevention of MSI tumor-related diseases. DETAILED DESCRIPTION

[0387] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[0388] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCENA-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were calculated based on a 10 - 6 The units are given in ppm.

[0389] Reaction monitoring and MS measurements were performed using a Thermofisher ESQ (ESI) mass spectrometer.

[0390] HPLC determination was performed using a Thermo Fisher U3000DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3 μm 3.0*100 mm column).

[0391] Qingdao Ocean GF254 silica gel plates were used for thin-layer chromatography (TLC). Silica gel plates with a size of 0.15-0.2 mm were used for thin-layer chromatography (TLC). High-performance thin-layer chromatography (HPLC) preparative plates with a size of 0.9-1.0 mm were used for TLC separation and purification. Column chromatography used Qingdao Ocean 200-300 mesh silica gel as the carrier. The developing solvents used were A: dichloromethane and methanol; B: petroleum ether and ethyl acetate. The solvent volume ratio was adjusted according to the polarity of the compound. A Biotage Isera One preparative liquid phase was used for medium-pressure preparative liquid chromatography (HPLC). An Agilent 1290 Infinity II preparative liquid chromatograph was used.

[0392] In the following examples, unless otherwise specified, all reaction raw materials can be purchased from manufacturers such as San Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0393] Abbreviated description

[0394] Preparation of intermediate int-1: tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0395] Step 1: Dissolve methyl 3-oxopentanoate (int-1a, 70 g, 538.05 mmol) in DCM (500 mL), add NBS (100.6 g, 564.95 mmol), then add TSOH.H2O (20.4 g, 107.61 mmol), and stir at room temperature for 3 hours. Filter and concentrate the filtrate under reduced pressure to obtain crude methyl 2-bromo-3-oxopentanoate (int-1b, 126.5 g, 602.87 mmol). MS Calcd: 207.97; MS Found: 206.98 ([MH] - ).

[0396] Step 2: Dissolve methyl 2-bromo-3-oxopentanoate (int-1b, 10 g, 47.85 mmol), tert-butyl piperazine-1-carboxylate (int-1c, 49.0 g, 263.16 mmol), and potassium carbonate (39.7 g, 287.08 mmol) in MeCN (100 mL) and stir at room temperature for 30 minutes. Filter, neutralize with dilute hydrochloric acid, wash with water, extract with DCM, and concentrate the organic phase. The residue is purified by column chromatography to afford tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (int-1d, 10.97 g, 34.89 mmol, 72.9%). MS Calcd: 314.18; MS Found: 315.23 ([M+H] + ).

[0397] Step 3: At room temperature, H3PO4 (4.5 g, 46.01 mmol) was added to a solution of 5-bromo-2H-1,2,4-triazole-3-amine (int-1e, 5 g, 30.67 mmol) and tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (int-1d, 10.6 g, 33.74 mmol) in anhydrous ethanol (50 mL) and heated to 80°C with stirring for two days. Saturated sodium bicarbonate was added to quench the reaction and the pH was adjusted to 6-7. The reaction solution was concentrated and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by flash column chromatography (DCM = 95%, MeOH = 5%) to give tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 2.09 g, 4.89 mmol, 15.9%). MS Calcd: 426.10; MS Found: 427.07 ([M+H] + ).

[0398] Preparation of intermediate int-2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0399] Step 1: To a 50 mL eggplant flask, tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 400 mg, 0.94 mmol) and solvent 1,4-dioxane (5 mL) were added. Then, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (374 mg, 1.03 mmol) and DIPEA (383 mg, 2.81 mmol) were added thereto, and the mixture was stirred at room temperature at 85°C for 5 hours. Water (20 mL) was added thereto, and the mixture was extracted with EA (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE:EA=1:2) to give tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 430 mg, 0.65 mmol, 69.3% yield). MS Calcd:662.89; MS Found:564.15([M+H-100] + ).

[0400] Step 2: To a 50 mL eggplant flask was added tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 350 mg, 0.53 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (166 mg, 0.79 mmol) and solvent 1,4-dioxane (3 mL), H2O (1.5 mL). Then, Pd(dppf)Cl2 (39 mg, 0.053 mmol) and potassium phosphate (365 mg, 1.58 mmol) were added thereto, and the mixture was stirred at 80°C overnight under nitrogen protection. Water (20 mL) was added thereto, and the mixture was extracted with EA (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA=1:2) The reaction mixture was quenched to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2b, 220 mg, 0.33 mmol, 61.8% yield) MS Calcd: 666.10; MS Found: 610.19 ([M-56] + ).

[0401] Step 3: To a 50 mL eggplant flask was added tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2b, 220 mg, 0.33 mmol) and solvent DCM (5 mL). Then, trifluoroacetic acid (1 mL) was added and stirred at room temperature overnight. LCMS confirmed the completion of the reaction. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with EA (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 140 mg, 0.25 mmol, 75.7% yield). MS Calcd: 565.18; MS Found: 566.26 ([M+H] + ).

[0402] Preparation of intermediate int-3: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0403] Step 1: 5-Bromo-2H-1,2,4-triazole-3-amine (int-1e, 2.0 g, 12.3 mmol) and methyl 3-oxopentanoate (int-1a, 2.2 g, 15.3 mmol) were added to a 25 mL round-bottom flask. AcOH (7 mL) was added and the mixture was heated to 80°C and stirred overnight. After cooling to room temperature, the mixture was stirred at 0°C for 1 h, filtered, and the filter cake was washed with a small amount of EtOH (10 mL) and oven-dried. The filtrate was concentrated to dryness, washed with a small amount of EtOH (10 mL), and the solid was oven-dried to obtain the second portion of product. This was combined to give 2-bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 1.63 g, 6.71 mmol, 54.5% yield). MS Calcd:241.98, 243.98; MS Found:242.98, 244.98([M+H] + ).

[0404] Step 2: Add 2-bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 1.63 g, 6.71 mmol) and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (2.67 g, 7.35 mmol) to a 25 mL round-bottom flask, add 1,4-dioxane (7 mL), and stir at 80 ° C for 4 h under nitrogen protection. The mixture was cooled to room temperature, and a white precipitate was precipitated. The mixture was filtered and the filtrate was concentrated. After adding EA, a white solid was precipitated again. The mixture was filtered and washed with EA (10 mL). The solids were combined and the solvent was removed under reduced pressure to obtain 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (int-3b, 3.02 g, 6.31 mmol, 94.0% yield). MS Calcd: 476.98, 478.98; MS Found: 477.94, 479.95 ([M+H] + ).

[0405] Step 3: 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (int-3b, 3.0 g, 6.27 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.71 g, 8.14 mmol) were added to a 100 mL two-necked flask, and potassium phosphate (3.99 g, 18.80 mmol), Pd(dppf)Cl2 (458 mg, 0.63 mmol), 1,4-dioxane (40 mL) and purified water (20 ml) were added in sequence. The system became a brown suspension and was stirred at 80 ° C for 2 h under nitrogen protection. The mixture was cooled to room temperature, and the excess solvent was removed by vortexing. DCM (100 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with DCM (50 mL*3). The organic phases were combined and washed with saturated brine (100 mL). The solvent was removed under reduced pressure, and EA / PE (2:1) was added to produce a brown precipitate. Column chromatography (DCM:MeOH=10:1) gave N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-3c, 1.58 g, 3.28 mmol, 52.3% yield). MS Calcd: 481.11; MS Found: 479.94 ([MH] - ).

[0406] Step 4: Add N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-3c, 1.35 g, 2.80 mmol) to a 50 mL flask, and add NBS (548 mg) and acetonitrile (50 mL) in sequence. Heat to 80 °C and continue the reaction for 6 h. After cooling, a solid precipitated, which was filtered and the filter cake was purified by column chromatography (MeOH:DCM=1:10) to give the title compound: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (int-3, 0.51 g, 0.91 mmol, 32.5% yield). MS Calcd: 559.02, 561.02; MS Found: 559.8, 562.0 ([M+H] + ).

[0407] Preparation of intermediate int-4: N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[0408] Step 1: To a 250 mL eggplant-shaped flask, add 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (int-4a, 9.5 g, 39.09 mmol) and THF (20 mL) and cool to -78°C. Under nitrogen, slowly add LDA (4.6 g, 43.00 mmol) dropwise. Stir at -78°C for 2 hours, then add iodomethane (4.76 g, 76 mL, 58.64 mmol). Warm to room temperature and react overnight. Quench with saturated ammonium chloride in an ice bath, extract with dichloromethane (50 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product: 1-bromo-3-fluoro-2-methyl-4-(trifluoromethyl)benzene (int-4b, 9.0 g, 35.02 mmol, 89.6% yield). 1 H NMR (400MHz, DMSO-d6) δ7.70 (d, J = 8.4Hz, 1H), 7.58 (t, J = 8.4Hz, 1H), 2.35 (d, J = 2.8Hz, 3H).

[0409] Step 2: Add 1-bromo-3-fluoro-2-methyl-4-(trifluoromethyl)benzene (int-4b, 9.0 g, 35.02 mmol), tert-butyl carbamate (4.5 g, 38.52 mmol) and solvent 1,4-dioxane (20 mL) to a 250 mL eggplant-shaped flask, add Xantphos (1.4 g, 2.45 mmol), Pd2(dba)3 (1.6 g, 1.75 mmol), Cs2CO3 (17.1 g, 52.53 mmol), and heat to 85 ° C under nitrogen protection for 3 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane. The organic phase was dried under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (PE:EA=20:1) to give: tert-butyl 3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)carbamate (int-4c, 7.3 g, 24.89 mmol, 71.1% yield). MS Calcd: 293.10; MS Found: 292.1 ([MH] - ).

[0410] Step 3: To a 250 mL eggplant-shaped flask, tert-butyl 3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)carbamate (int-4c, 7.26 g, 24.75 mmol) and methanolic hydrochloric acid (20 mL) were added and reacted at room temperature for two hours. Sodium hydroxide was added to the reaction solution to adjust the pH to neutral. Insoluble matter was removed by filtration, and the organic phase was washed with 2*30 mL of water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product: 3-fluoro-2-methyl-4-trifluoromethylaniline (int-4d, 4.3 g, 22.27 mmol, 89.6% yield). MS Calcd: 193.05; MS Found: 192.11 ([MH] - ).

[0411] Step 4: 3-Fluoro-2-methyl-4-trifluoromethylaniline (int-4d, 4.3 g, 22.27 mmol), dichloromethane (30 mL), and triethylamine (6.17 mL, 44.54 mmol) were added to a 100 mL eggplant-shaped flask. A dichloromethane solution (10 mL) of chloroacetyl chloride (2.65 mL, 26.72 mmol) was added dropwise under an ice bath. The mixture was then allowed to react overnight at room temperature. The reaction mixture was dried under reduced pressure to give a crude product, which was purified by flash column chromatography (PE:EA=3:1) to give 2-chloro-N-[3-fluoro-2-methyl-4-trifluoromethylphenyl]acetamide (int-4e, 5.5 g, 18.77 mmol, 84.3% yield). MS Calcd: 269.02; MS Found: 268.07 ([MH] - ).

[0412] Step 5: 2-Chloro-N-[3-fluoro-2-methyl-4-trifluoromethylphenyl]acetamide (int-4e, 5.5 g, 18.77 mmol), potassium iodide (6.8 g, 40.80 mmol) and acetone (30 mL) were added to a 250 mL eggplant flask and reacted at 50°C for 3 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was purified by flash column chromatography (PE:EA=5:1) to obtain: N-[3-fluoro-2-methyl-4-trifluoromethylphenyl]-2-iodoacetamide (int-4, 6.12 g, 16.95 mmol, 82.7% yield). MS Calcd: 360.96; MS Found: 359.99 ([MH] - ).

[0413] Preparation of intermediate int-5: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0414] Step 1: tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1,14 g, 32.8 mmol) was placed in a 250 mL three-necked flask containing dioxane (150 mL) and water (50 mL). 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (10.3 g, 49.1 mmol), K2CO3 (9.1 g, 65.6 mmol), and Pd(dppf)Cl2 (1.2 g, 1.64 mmol) were then added in sequence. The mixture was replaced with trifluoroacetic acid in a nitrogen atmosphere. The mixture was heated to 100°C for 14 hours, cooled to room temperature, and 300 mL of water was added. The mixture was extracted three times with 300 mL of dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spun down to dryness. The mixture was purified by column chromatography (DCM / MeOH = 100 / 0-95 / 5) to obtain a crude product. The crude product was slurried with methyl tert-butyl ether to obtain pure tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-5, 9.2 g, 65% yield). MS Calcd.: 430.2; MS Found: 431.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.00(s,br,1H),6.81(br,1H),4.28-4.27(m,2H),3.93-3.90(m,2H),3.83-3.80(m,2H),3.37-3. 33(m,2H),2.90-2.89(m,2H),2.79-2.73(m,2H),2.64-2.60(m,2H),2.51-2.50(m,2H),1.42(s,9H),1.19(t,J=7.2Hz,3H).

[0415] Preparation of intermediate int-6: (R)-tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylate

[0416] Step 1: In a 2-L three-necked flask, dissolve ethyl 3-oxopentanoate (int-6a, 100.00 g, 693.63 mmol) in dichloromethane (1 L). Add NBS (129.62 g, 728.31 mmol) and TsOH*H2O (26.39 g, 138.73 mmol) sequentially. Stir the resulting reaction mixture at room temperature overnight. After completion, pour the reaction mixture into saturated brine (1 L) and extract twice with dichloromethane (1 L x 2). The combined organic phases are backwashed twice with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified on a flash silica gel column (petroleum ether / ethyl acetate = 10:1) to afford ethyl 2-bromo-3-oxopentanoate (int-6b, 120.0 g, 77.6% yield). MS Calcd.:221.99; MS Found:229.2[M+H] + .

[0417] Step 2: In a 1 L single-necked flask, dissolve ethyl 2-bromo-3-oxopentanoate (int-6b, 60.00 g, 268.98 mmol) in acetonitrile (300 mL). Add KCO (74.36 g, 537.96 mmol) and (R)-1-N-Boc-2-methylpiperazine (56.56 g, 282.43 mmol) sequentially. Stir the resulting reaction mixture at room temperature overnight. Remove undissolved inorganic salts by filtration, and concentrate the filtrate to dryness. The resulting residue is purified on a flash silica gel column (petroleum ether / ethyl acetate = 5:1) to afford tert-butyl (2R)-4-(1-ethoxy-1,3-dioxopentan-2-yl)-2-methylpiperazine-1-carboxylate (int-6c, 64.0 g, 69.5% yield). MS Calcd.:342.22; MS Found:343.22[M+H]+ .

[0418] Step 3: Weigh tert-butyl (2R)-4-(1-ethoxy-1,3-dioxopentan-2-yl)-2-methylpiperazine-1-carboxylate (int-6c, 91.32 g, 266.68 mmol) into a 1 L single-necked flask and dissolve in ethanol (150 mL). Then, add 5-bromo-2H-1,2,4-triazole-3-amine (int-1e, 47.81 g, 293.35 mmol) and phosphoric acid (27.44 g, 280.01 mmol) sequentially. Switch the reaction system to nitrogen three times. Stir the reaction at 90°C for 44 hours and then cool to room temperature. Add DIPEA (103.40 g, 800.04 mmol) and Boc2O (29.10 g, 133.34 mmol) to the single-necked flask and react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into saturated brine (500 mL) and extracted three times with ethyl acetate (1 L x 3). The combined organic phases were backwashed twice with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a residue. The residue was purified on a flash silica gel column (dichloromethane / methanol = 17:3) to obtain the title compound: (R)-tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylate (int-6, 50.0 g, 38.6% yield). MS Calcd.: 442.12; MS Found: 443.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ4.16 (d, J = 23.6Hz, 1H), 3.81-3.69 (m, 1H), 3.58-3.49 (m, 1H), 3.41-3.31 (m, 1H), 3.19-3.09 (m ,1H), 3.09-2.89(m,1H), 2.88-2.77(m,1H), 2.66-2.54(m,2H), 1.42(s,9H), 1.29-1.26(m,3H), 1.18(t,J=7.6Hz,3H).

[0419] Preparation of intermediate int-7: 4-hydroxyisoxazole-3-carboxylic acid

[0420] Step 1: Dissolve ethyl 4-chloro-3-oxobutanoate (int-7a, 10 g, 60.75 mmol) in AcOH (48 mL). Slowly add a solution of NaNO2 (5.2 g, 75.94 mmol) in H2O (40 mL) at 0°C. The reaction mixture turns red and is then warmed to room temperature and stirred overnight. Add 100 mL of H2O to the reaction mixture, extract with 100 mL of ethyl acetate three times, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (PE:EA = 3:1) to obtain ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate (int-7b, 11 g, 56.82 mmol, 93.5% yield).

[0421] Step 2: Ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate (int-7b, 12 g, 61.98 mmol) and urea (29.8 g, 495.87 mmol) were added sequentially to a DMF (50 mL) solution, heated to 100°C, and stirred for 20 min. 150 mL of water was added to the reaction solution, and the mixture was extracted with DCM (100 mL x 3). The mixture was washed four times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain ethyl 4-hydroxyisoxazole-3-carboxylate (int-7c, 8 g, 50.92 mmol, 82.2% yield). MS Calcd: 157.04; MS Found: 158.08 ([M+H] + ).

[0422] Step 3: Dissolve ethyl 4-hydroxyisoxazole-3-carboxylate (int-7c, 2000 mg, 12.73 mmol) in THF (20 mL). Add NaOH (2546 mg, 63.65 mmol) under ice-cooling and react at room temperature for 2.0 h. The solvent was evaporated to dryness and separated by column chromatography (DCM:MeOH = 1:1) to obtain the title compound: 4-hydroxyisoxazole-3-carboxylic acid (int-7, 1000 mg, 7.75 mmol, 60.8% yield). MS Calcd: 129.01; MS Found: 128.0 ([M+H] + ).

[0423] Preparation of intermediate int-8: 2-(4-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0424] Step 1: Add 4-methoxycyclohexan-1-one (int-8a, 1 g, 7.8 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide (2.8 g, 7.8 mmol) to dry THF (20 mL), reduce the temperature to -78°C, and then add LiHMDS THF solution (1N, 7.8 mL) dropwise. Stir at this temperature for 2 hours, then slowly return to room temperature and stir overnight. Quench with saturated aqueous ammonium chloride solution and extract with EA (20 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography (EA:PE = 1:5) to give crude 4-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate (int-8b, 1.3 g, 5 mmol, 64%).

[0425] Step 2: 4-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate (int-8b, 1.3 g, 5 mmol), 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.9 g, 7.5 mmol), potassium acetate (1.5 g, 15 mmol), 1,1-bis(diphenylphosphine)dichloroferric palladium (366 mg, 0.5 mmol) were added to dioxane (15 mL) ), replaced with nitrogen for 3 minutes, the temperature was raised to 85°C, stirred for 3 hours, and concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:20) to give the title compound: 2-(4-methoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (int-8, 910 mg, 3.82 mmol, 76%). MS Calcd: 238.17; MS Found: 239.21 ([M+H] + ).

[0426] Preparation of intermediate 1-c: 2-(2-(3,6-dihydropyran-4-yl)-5-ethyl-7-oxo-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)yl)-N-(2-methyl-4-trifluoromethylphenyl)acetamide

[0427] Step 1: In a 100 mL single-necked bottle, tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 1000 mg, 2.34 mmol), 2-iodo-N-(2-methyl-4-trifluoromethylphenyl)acetamide (880 mg, 2.57 mmol), DIPEA (907 mg, 7.02 mmol) and solvent DMF (5 mL) were added in sequence and stirred at room temperature overnight. The reaction was completed under LCMS monitoring. The reaction solution was added with 100 mL of DCM and washed with 3*30 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was purified by flash column chromatography (MeOH:DCM = 0:100% to 10%:90% in 30 min) to give tert-butyl 4-(2-bromo-5-ethyl-4-(2-(2-methyl-4-(trifluoromethylphenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (1-a, 1200 mg, 1.87 mmol, 79% yield). MS Calcd: 641.16; MS Found: 640.05 ([MH] - ).

[0428] Step 2: In a 30 mL microwave tube, reactants 4-(2-bromo-5-ethyl-4-(2-(2-methyl-4-(trifluoromethylphenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (1-a, 900 mg, 1.40 mmol), 2-(3,6-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (441 mg, 2.10 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), anhydrous potassium phosphate (967 mg, 4.20 mmol) and solvent 1,4-dioxane (10 mL) and water (2 mL) were added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred in a microwave at 90 ° C for 2 hr. The reaction was complete as monitored by LCMS. The reaction mixture was filtered through celite, and the filter cake was washed with 3*10 mL of methanol. The filtrates were combined and dried under reduced pressure. The crude product was purified by flash column chromatography (MeOH:DCM = 0:100% to 10%:90% in 30 min) to give tert-butyl 4-(2-(3,6-dihydropyran-4-yl)-5-ethyl-4-(2-(2-methyl-4-trifluoromethylphenylamino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (1-b, 820 mg, 1.27 mmol, 90% yield). MS Calcd: 645.29; MS Found: 644.23 ([MH] - ).

[0429] Step 3: In a 100 mL single-necked bottle, tert-butyl 4-(2-(3,6-dihydropyran-4-yl)-5-ethyl-4-(2-(2-methyl-4-trifluoromethylphenylamino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (1-b, 500 mg, 0.77 mmol), dioxane hydrochloride solution (4 M, 5 mL) and solvent DCM (10 mL) were added. The mixture was stirred at room temperature for 2 hr until the solution became turbid. The reaction solution was dried under reduced pressure to give crude 2-(2-(3,6-dihydropyran-4-yl)-5-ethyl-7-oxo-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)yl)-N-(2-methyl-4-trifluoromethylphenyl)acetamide (1-c, 380 mg, 0.7 mmol, 89% yield). MS Calcd: 545.24; MS Found: 546.21 ([M+H] + ).

[0430] Example 1 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 3)

[0431] Step 1: Add diethyl ethoxymethylenemalonate (3-a, 1.5 g, 6.94 mmol) and methylhydrazine sulfate (1.0 g, 6.94 mmol) to 10 mL of aqueous solution and stir at 100°C for 6 hours. The reaction solution was cooled to room temperature, and a solid precipitated. The crude product, ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (3-b, 350 mg, 2.06 mmol, 29.6% yield), was obtained by filtration. MS Calcd: 170.17; MS Found: 171.11 ([M+H] + ).

[0432] Step 2: Dissolve 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3-b, 250 mg, 1.47 mmol) in 6 mL of a methanol / water (5:1) mixture, add potassium hydroxide (824 mg, 14.7 mmol), raise the temperature to room temperature, reflux and stir overnight. TLC monitors the completion of the reaction. The reaction solution is completely concentrated, and 5N HCl solution is slowly added to the residue until a solid precipitates. Filter and obtain 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 150 mg, 1.06 mmol, 71.9% yield). MS Calcd: 142.11; MS Found: 143.05 ([M+H] + ).

[0433] Step 3: 5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 78 mg, 0.55 mmol) and 1-chloro-N,N,2-trimethylpropenamine (80 mg, 0.60 mmol) were added to 5 mL of dichloromethane solution, stirred at room temperature for 3 hours, and then 2-(2-(3,6-dihydropyran-4-yl)-5-ethyl-7-oxo-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)yl)-N-(2-methyl-4-trifluoromethylphenyl)acetamide (1-c, 150 mg, 0.27 mmol) and DIPEA (178 mg, 1.37 mmol) were added, and the temperature was continued to rise to 40°C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (3,8 mg, 0.01 mmol, 4% yield). MS Calcd: 669.26; MS Found: 670.27 ([M+H] + ). 1 H NMR (400MHz, DMSO) δ10.42(brs,1H),10.02(s,1H),7.88(s,1H),7.72(d,J=8.4H z,1H),7.63(s,1H),7.54(d,J=8.4Hz,1H),6.83(s,1H),5.25(s,2H),4.30-4.16 (m,4H),3.81(t,J=5.2Hz,2H),3.66(s,3H),3.51-3.45(m,2H),3.17-3.01(m,4H ),2.72(d,J=10.8Hz,2H),2.54-2.52(m,2H),2.36(s,3H),1.21(t,J=7.6Hz,3H).

[0434] Example 2 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 8)

[0435] Step 1: 5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 45 mg, 0.32 mmol) and 1-chloro-N,N,2-trimethylpropenamine (46 mg, 0.35 mmol) were added to 5 mL of dichloromethane solution, stirred at room temperature for 3 hours, and then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 90 mg, 0.16 mmol) and DIPEA (102 mg, 0.8 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (8, 10 mg, 0.01 mmol, 9.1% yield). MS Calcd: 689.21; MS Found: 690.32 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.08(d,J=8.4Hz,1H),7.99(d,J=2.0Hz,1 H),7.90(s,1H),7.74(dd,J=8.4,2.0Hz,1H),6.85(t,J=2.0Hz,1H),5.34(s,2H) ,4.28-4.20(m,4H),3.82(t,J=5.6Hz,2H),3.68(s,3H),3.50–3.44(m,2H),3.11 –2.99(m,4H),2.74(d,J=10.8Hz,2H),2.54-2.52(m,2H),1.22(t,J=7.6Hz,3H).

[0436] Example 3 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 14)

[0437] Step 1: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (int-3, 100 mg, 0.18 mmol), (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.9 mmol), silver tetrafluoroborate (35 mg, 0.18 mmol) were added to dry DMSO (2 mL), and then under nitrogen protection, the temperature was raised to 120 ° C, stirred for 4 hours, and the raw materials were reacted. The mixture was cooled to room temperature. The mixture was stirred for 2 h at room temperature, saturated aqueous sodium bicarbonate solution was added, and then extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 1:1) to give (R)-4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (14-a, 74 mg, 0.11 mmol, 60%). MS Calcd: 679.25; MS Found: 680.33 ([M+H] + ).

[0438] Step 2: (R)-4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (14-a, 74 mg, 0.11 mmol) was added to DCM (5 mL), followed by trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 4 hours. The reaction was complete and the reaction mixture was reduced to 400 mL. The mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with DCM (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 51 mg, 0.09 mmol, 80%). MS Calcd: 579.20; MS Found: 580.31 ([M+H] + ).

[0439] Step 3: 5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 17 mg, 0.11 mmol) was added to DCM (1 mL), followed by the addition of 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (16 mg, 0.11 mmol), stirred at room temperature for 2 hours, and then added to a solution of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 51 mg, 0.09 mmol) and DIPEA (70 mg, 0.54 mmol) in dichloromethane and stirred at room temperature overnight. Water (3 mL) was then added, and the mixture was extracted with DCM (3 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14.8 mg, 0.011 mmol, 12.6% yield). MS Calcd: 703.22; MS Found: 704.31 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),10.55(s,1H),8.09(d,J=8.8Hz,1H),7.97(d,J=2.0Hz ,1H),7.90(s,1H),7.73(dd,J=8.8,2.0Hz,1H),6.85(t,J=2.0Hz,1H),5.33(s,2H),4.35-4. 30(m,1H),4.35-4.26(m,3H),3.82(t,J=5.6Hz,2H),3.68(s,3H),3.52-3.50(m,2H),3.17-3 .12(m,2H),2.98-2.93(m,1H),2.75-2.62(m,4H),1.45-1.35(m,3H),1.24(t,J=7.2Hz,3H).

[0440] Example 4 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 15)

[0441] Step 1: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 60 mg, 0.10 mmol), DIPEA (13 mg, 0.10 mmol), 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 60 mg, 0.3 mmol) were added to 2-methyl-2-butanol and the mixture was stirred for 2 h. The bath was heated to 180°C and stirred for 30 minutes. The reaction system was dissolved in methanol and directly purified by prep-HPLC to obtain the title compound: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (15,15 mg, 0.020 mmol, 21% yield). MS Calcd: 729.24; MS Found: 730.31 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.09(dd,J=8.8,6.0Hz,1H),7.99(d,J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz, 1H),7.60(s,1H),6.97–6.73(m,1H),5.35(d,J=2.8Hz,2H),4.70-4.50(m,1H),4.28-4.26(m,2H),3.82(t,J=5.6Hz ,2H),3.70(d,J=11.2Hz,1H),3.54–3.26(m,3H),3.19-3.14(m,1H),2.98-2.93(m,1H),2.79(d,J=10.0Hz,1H),2.7 1-2.69(m,1H),2.56-2.46(m,2H),2.36-2.34(m,1H),1.45-1.41(m,2H),1.24(t,J=7.2Hz,3H),1.02-0.95(m,5H).

[0442] Example 5 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 16)

[0443] Step 1: Dissolve ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (16-a, 100 mg, 0.59 mmol) in 6 mL of a methanol / water (5:1) mixture, add potassium hydroxide (200 mg, 3.54 mmol), heat to reflux and stir overnight. TLC monitors the reaction completion. The reaction solution is completely concentrated, and 5N HCl solution is slowly added to the residue until a solid precipitates. Filter the product to obtain 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (16-b, 70 mg, 0.49 mmol, 83.8% yield). MS Calcd: 142.11; MS Found: 143.07 ([M+H] + ).

[0444] Step 2: 3-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (16-b, 40 mg, 0.28 mmol) and 1-chloro-N,N,2-trimethylpropenamine (42 mg, 0.31 mmol) were added to 5 mL of dichloromethane solution, stirred at room temperature for 3 hours, and then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1, 2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-280 mg, 0.14 mmol) and DIPEA (90 mg, 0.71 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 h. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM and washed with saturated brine. After concentration under reduced pressure, the residue was dissolved in 4 mL of a mixed solvent of methanol / water (5:1), and then sodium hydroxide (15 mg, 0.37 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was monitored for completion by LCMS. The reaction solution was adjusted to pH 2 and purified by prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (16, 3 mg, 0.004 mmol, 3% yield). MS Calcd: 689.21; MS Found: 690.31 ([M+H] + ). 1 H NMR (400MHz, DMSO) δ10.45(s,1H)8.37(s,1H),8.08(d,J=8.8Hz,1H),7.98(d,J=2.0Hz,1H),7.90(s,1H),7.73(dd,J=8.8,2.0Hz,1H),6.84(s,2H),5. 32(s,2H),4.28-4.23(m,3H),3.82(t,J=5.2Hz,2H),3.67(s,3H),3.50-3.3 0(m,6H),3.04-2.98(m,2H),2.74(d,J=10.0Hz,2H),1.25(t,J=7.2Hz,3H).

[0445] Example 6 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 17)

[0446] Step 1: Diethyl ethoxymethylenemalonate (17-a, 1.41 g, 6.53 mmol), 1-cyclobutylhydrazine hydrochloride (0.8 g, 6.53 mmol), and potassium carbonate (1.8 g, 13.05 mmol) were added to 10 mL of aqueous solution and stirred at 100°C for 6 hours. The reaction was monitored by TLC. The reaction solution was lyophilized, dissolved in a small amount of methanol, and adjusted to pH 2 with 5N HCl. The product was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 900 mg, 4.28 mmol, 65.6% yield). MS Calcd: 210.10; MS Found: 211.12 ([M+H] + ).

[0447] Step 2: Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 50 mg, 0.24 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2 45 mg, 0.06 mmol) were added to 4 mL of 2-methyl-2-butanol solution, placed in a microwave reactor, heated to 180 ° C and stirred for 30 min. The reaction was monitored for completion by LCMS. The reaction solution was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (17.5 mg, 0.01 mmol, 3% yield). MS Calcd: 729.24; MS Found: 730.24 ([M+H] + ). 1H NMR (400MHz, DMSO) δ10.38(s,1H),8.08(d,J=8.8Hz,1H),7.97(d,J=2.0Hz,1H),7.73( dd,J=8.8,2.0Hz,1H),7.70(s,1H),6.85(s,1H),5.33(s,2H),4.83-4.76(m,1H),4.36 -4.26(m,2H),4.25(s,2H),3.82(t,J=5.2Hz,2H),3.52-3.17(m,6H),3.00(t,J=7.2Hz ,2H),2.76(d,J=11.2Hz,2H),2.32–2.23(m,2H),1.83-1.72(m,2H),1.26–1.19(m,5H).

[0448] Example 7 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 18)

[0449] Step 1: Diethyl ethoxymethylenemalonate (17-a, 2.0 g, 9.22 mmol), cyclopropylhydrazine hydrochloride (1.0 g, 9.22 mmol), and potassium carbonate (2.55 g, 18.43 mmol) were added to 10 mL of aqueous solution and stirred at 100°C for 6 hours. The reaction was monitored by TLC. The reaction solution was lyophilized, dissolved in a small amount of methanol, and adjusted to pH 2 with 5N HCl. The solution was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 1.2 g, 6.12 mmol, 66.4% yield). MS Calcd: 196.08; MS Found: 197.12 ([M+H] + ).

[0450] Step 2: Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 117 mg, 0.6 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2 45 mg, 0.06 mmol) were added to 4 mL of 2-methyl-2-butanol solution, placed in a microwave reactor, heated to 180 ° C and stirred for 30 min. The reaction was monitored for completion by LC-MS. The reaction solution was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (18.3 mg, 0.004 mmol, 6.2% yield). MS Calcd: 715.22; MS Found: 716.28 ([M+H] + ). 1 H NMR (400MHz, DMSO) δ10.36(s,1H),8.08(d,J=8.8Hz,1H),7.97(d,J=2.0Hz,1H),7.72(d,J=8.8,2.0Hz,1H),7.55(s,1H),6.83(s,1H),5.32(s, 2H),4.36-4.26(m,4H),3.84-3.81(m,2H),3.51-3.17(m,5H),3.05-2.9 8(m,2H),2.75(d,J=11.2Hz,2H),1.26-1.20(m,5H),0.99-0.93(m,2H).

[0451] Example 8 Preparation of 2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 19)

[0452] Step 1: tert-Butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 2.2 g, 5.15 mmol), N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-2-iodoacetamide (2.0 g, 5.67 mmol) and DIPEA (2.0 g, 15.45 mmol) were added to 60 mL of dioxane solution and stirred at 80 ° C for 4 hours. The reaction was monitored for completion by TLC. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to obtain tert-butyl 4-(2-bromo-5-ethyl-4-(2-((5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (19-a, 1.44 g, 2.18 mmol, 42.3% yield). MS Calcd: 659.15; MS Found: 560.21 ([M-100+H] + ).

[0453] Step 2: tert-Butyl 4-(2-bromo-5-ethyl-4-(2-((5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (19-a, 1.44 g, 2.18 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (687 mg, 3.27 mmol), Pd(dppf)Cl2·CH2Cl2 (357 mg, 0.44 mmol) and potassium phosphate (1.39 g, 6.54 mmol) were added sequentially to 20 mL of a mixed solution of dioxane / water (4:1), and the mixture was evacuated with nitrogen three times. The temperature was raised to 80°C and stirred for 2 h. The reaction was monitored for completion by TLC. The reaction solution was completely concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (19-b, 1.4 g, 2.11 mmol, 96.8% yield). MS Calcd: 663.28; MS Found: 664.32 ([M+H] + ).

[0454] Step 3: Add tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (19-b, 1.4 g, 2.11 mmol) to 20 mL of hydrochloric acid-dioxane solution and stir at room temperature overnight. The reaction solution was completely concentrated, and a saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 0.73 g, 1.30 mmol, 61.4% yield). MS Calcd: 563.23; MS Found: 564.21 ([M+H] + ).

[0455] Step 4: Add 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 80 mg, 0.41 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, place in a microwave reactor, heat to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19.3 mg, 0.004 mmol, 6.2% yield). MS Calcd: 713.27; MS Found: 714.24 ([M+H] + ). 1H NMR (400MHz, DMSO) δ10.06(s,1H),7.79(t,J=12.8Hz,1H),7.68(t,J=8.4Hz,1H),7.60(s ,1H),6.82(dd,J=3.2,1.6Hz,1H),5.32(s,2H),4.36(d,J=12.8Hz,1H),4.29-4.26(m,2H ),3.82(t,J=5.6Hz,2H),3.51-3.17(m,4H),3.05-2.97(m,2H),2.76(d,J=11.2Hz,2H),2 .71–2.69(m,1H),2.38(s,3H),2.36–2.34(m,1H),1.26-1.20(m,5H),1.01–0.94(m,4H).

[0456] Example 9 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 20)

[0457] Step 1: tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 550 mg, 0.83 mmol) and 2-(4-methoxycyclohex-1-en-1-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (237 mg, 1 mmol) were dissolved in 1,4-dioxane (8 mL) and H2O (4 mL), and Pd(dppf)Cl2 (60 mg, 0.09 mmol) and potassium phosphate (570 mg, 2.49 mmol) were added in sequence. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 5.0 hours. The reaction solution was concentrated, and 30 mL of ethyl acetate was added to the residue. The mixture was filtered through celite, and the filtrate was concentrated and purified by column chromatography (DCM:MeOH=20%:80%) to give tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (20-a, 370 mg, 0.53 mmol, 64% yield). MS Calcd: 693.27; MS Found: 694.27 ([M+H] + ).

[0458] Step 2: Dissolve tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (20-a, 370 mg, 0.53 mmol) in 8 mL of dichloromethane solution, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. The reaction solution was directly concentrated, and 20 mL of saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried, and concentrated to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 300 mg, 0.51 mmol, 95% yield). MS Calcd: 593.21; MS Found: 594.27 ([M+H] + ).

[0459] Step 3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 50 mg, 0.08 mmol) and 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.10 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of DCM was added thereto to dissolve, and then PyBOP (43 mg, 0.08 mmol) and DIPEA (0.04 mL, 0.22 mmol) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated and purified by Prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20, 6 mg, 0.01 mmol, 9% yield) MS Calcd: 714.24; MS Found: 718.31 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),10.40(s,1H),8.08(d,J=8.8Hz,1H),7.98(d,J=2.4Hz, 1H),7.90(s,1H),7.73(dd,J=8.8,2.4Hz,1H),6.75(t,J=4.0Hz,1H),5.33(s,2H),4.23(s,2H) ,3.67(s,3H),3.54-3.43(m,4H),3.30(s,3H),3.12–2.98(m,3H),2.74(d,J=11.2Hz,2H),2.61 –2.41(m,3H),2.20-2.12(m,1H),1.99–1.93(m,1H),1.73-1.63(m,1H),1.21(t,J=7.2Hz,3H).

[0460] Example 10 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 21)

[0461] Step 1: Diethyl ethoxymethylenemalonate (17-a, 1.95 g, 9.04 mmol), isopropylhydrazine hydrochloride (1.0 g, 9.04 mmol), and potassium carbonate (2.05 g, 18.08 mmol) were added to 10 mL of aqueous solution and stirred at 100°C for 6 hours. The reaction solution was lyophilized, dissolved in a small amount of methanol, and adjusted to pH 2 with 5N HCl. The solution was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 1.2 g, 6.05 mmol, 67.0% yield). MS Calcd: 198.10; MS Found: 199.11 ([M+H] + ).

[0462] Step 2: The compound 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (21-a, 83 mg, 0.42 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask and 2 mL of 2-methyl-2-butanol was added. The reaction mixture was then stirred at 180°C for 30 minutes, and the reaction solution was concentrated and purified by Prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (21, 30 mg, 0.04 mmol, 47% yield). MS Calcd: 745.27; MS Found: 746.51 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.11-8.08(m,1H),7.99(d,J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz, 1H),7.68(s,1H),6.75(t,J=4.0Hz,1H),5.34(s,2H),4.54-4.47(m,1H),4.36(d,J=12.8Hz,2H),3.56–3 .41(m,3H),3.27(s,3H),3.20-3.13(m,2H),3.02-2.97(m,2H),2.79(d,J=11.2Hz,2H),2.62-2.47(m,4H ),2.21-2.13(m,1H),2.00-1.94(m,1H),1.73-1.64(m,1H),1.37(d,J=6.8Hz,6H),1.23(t,J=7.2Hz,3H).

[0463] Example 11 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 22)

[0464] Step 1: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 60 mg, 0.10 mmol), DIPEA (13 mg, 0.10 mmol), ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 102 mg, 0.5 mmol) were added to 2-methyl-2-butanol (1 mL). The oil bath was heated to 180°C and stirred for 30 minutes. The reaction system was dissolved in methanol and directly purified by prep-HPLC to obtain the title compound: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (22,17 mg, 0.023 mmol, 23.2% yield). MS Calcd: 731.26; MS Found: 732.31 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.09(d,J=8.8Hz,1H),7.99(d,J=2.0Hz,1H),7.75(dd,J=8.8,2.0Hz,1H),7. 67(s,1H),6.89-6.85(m,1H),5.35(d,J=2.4Hz,2H),4.71-4.63(m,1H),4.54-4.47(m,1H),4.32-4.26(m,3H),3.83( t,J=5.6Hz,2H),3.71(d,J=11.2Hz,1H),3.52(t,J=11.2Hz,1H),3.22-3.15(m,1H),2.99-2.92(m,1H),2.80(d,J=1 0.0Hz,1H),2.68(d,J=10.0Hz,1H),2.55-2.51(m,3H),1.45(brs,3H),1.36(d,J=6.8Hz,6H),1.25(t,J=7.2Hz,3H).

[0465] Example 12 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 26)

[0466] Step 1: Weigh 3-hydroxy-2-methylquinoline-4-carboxylic acid (26-a, 19 mg, 0.09 mmol), PyBOP (46.8 mg, 0.09 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 60 mg, 0.09 mmol) into a 25 mL single-necked bottle, add DCM (2 mL) and DIPEA (0.04 mL, 0.27 mmol), and stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (26,19 mg, 0.02 mmol, 26.9% Yield). MS Calcd: 750.23; MS Found: 751.12 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.08(d,J=8.8Hz,1H),7.97(d,J=2.0Hz,1H),7.9 1–7.87(m,1H),7.73(dd,J=8.8,2.0Hz,1H),7.68–7.65(m,1H),7.59–7.47(m,2H),6.85– 6.83(m,1H),5.33(s,2H),4.72(d,J=12.8Hz,1H),4.27(t,J=2.8Hz,2H),3.82(t,J=5.2 Hz,2H),3.60–3.54(m,1H),3.34–2.83(m,7H),2.63-2.53(m,6H),1.20(t,J=7.2Hz,3H).

[0467] Example 13 Preparation of 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 27)

[0468] Step 1: Add 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 80 mg, 0.38 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, place in a microwave reactor, heat to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (27, 10 mg, 0.01 mmol, 14.6% yield). MS Calcd: 727.29; MS Found: 728.32 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.09 (s, 1H), 7.81 (d, J = 12.8Hz, 1H), 7.70-7.68 (m, 3H),6.85–6.83(m,1H),5.32(s,2H),4.84-4.74(m,1H),4.36-4.26(m,4H),3 .82(t,J=5.2Hz,2H),3.52–3.17(m,6H),3.05-2.99(m,2H),2.78(d,J=11.2H z,2H),2.38(s,3H),2.35–2.27(m,2H),1.84-1.75(m,2H),1.26–1.20(m,5H).

[0469] Example 14 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 28)

[0470] Step 1: 5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 40 mg, 0.28 mmol) and 1-chloro-N,N,2-trimethylpropenamine (42 mg, 0.31 mmol) were added to 5 mL of dichloromethane solution, stirred at room temperature for 3 hours, and then 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 80 mg, 0.14 mmol) and DIPEA (90 mg, 0.71 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, extracted with DCM, and washed with saturated brine. After concentration under reduced pressure, the residue was dissolved in 4 mL of a 5:1 methanol / water mixture, followed by the addition of sodium hydroxide (15 mg, 0.37 mmol) and stirred at room temperature overnight. The reaction mixture was adjusted to pH 2 and analyzed by prep-HPLC to yield the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (28 g, 10 mg, 0.01 mmol, 11.2% yield). MS Calcd:687.25; MS Found:688.42([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.43(s,1H),7.90(s,1H),7.81(d,J=12.8Hz,1H),7.68(d,J=8.0Hz,1H),6.84(s,1H),5.34(s,2H),4 .28-4.26(m,2H),3.82(t,J=5.6Hz,2H),3.68(s,3H),3.56–2.98(m,10H),2.75(d,J=11.2Hz,2H),2.38-2.34(m,3H),1.23(t,J=7.2Hz,3H).

[0471] Example 15 Preparation of 2-(6-(4-(5-chloro-3-hydroxy-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 29)

[0472] Step 1: Dissolve ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (16-a, 500 mg, 2.94 mmol) in 10 mL of dichloromethane. Slowly add sulfonyl chloride (0.47 g, 3.53 mmol) at 0°C. Slowly warm the mixture to room temperature and stir overnight. Add water to terminate the reaction, extract with dichloromethane, and concentrate under reduced pressure. The residue is purified by prep-HPLC to obtain ethyl 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (29-a, 120 mg, 0.59 mmol, 20% yield). MS Calcd: 204.03; MS Found: 205.10 ([M+H] + ).

[0473] Step 2: Dissolve 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (29-a, 120 mg, 0.59 mmol) in 4 mL of a methanol / water (5:1) mixture, add potassium hydroxide (200 mg, 3.52 mmol), heat to reflux and stir overnight, concentrate the reaction solution completely, slowly add 5N HCl solution to the residue until a solid precipitates, and filter to obtain 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (29-b, 90 mg, 0.51 mmol, 86.9% yield). MS Calcd: 176.00; MS Found: 177.01 ([M+H] + ).

[0474] Step 3: 5-Chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (29-b, 44 mg, 0.25 mmol) and 1-chloro-N,N,2-trimethylpropenamine (36 mg, 0.27 mmol) were added to 5 mL of dichloromethane solution respectively, stirred at room temperature for 3 hours, and then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 70 mg, 0.12 mmol) and DIPEA (80 mg, 0.62 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound: 2-(6-(4-(5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (29, 16 mg, 0.02 mmol, 18% yield). MS Calcd: 723.17; MS Found: 724.30 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.75 (s, 1H), 10.38 (s, 1H), 8.08 (d, J = 8.8Hz, 1H), 7.9 8(d,J=2.0Hz,1H),7.73(dd,J=8.8,2.0Hz,1H),6.86–6.84(m,1H),5.33(s,2H) ,4.27(q,J=2.8Hz,2H),3.82(t,J=5.2Hz,2H),3.64(s,3H),3.49-3.42(m,2H), 3.04-2.98(m,2H),2.75-2.68(m,2H),2.54-2.51(m,6H),1.21(t,J=7.2Hz,3H).

[0475] Example 16 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 30)

[0476] Step 1: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) and ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 87.9 mg, 0.44 mmol) were added to 4 mL of 2-methyl-2-butanol solution, placed in a microwave reactor, heated to 180 ° C and stirred for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (30, 10 mg, 0.01 mmol, 15% yield). MS Calcd: 715.29; MS Found: 716.30 ([M+H] + ). 1 H NMR(400MHz, DMSO-d6)δ10.09(s,1H),7.81(d,J=12.8Hz,1H),7.70–7.67(m,2H), 6.85–6.82(m,1H),5.32(s,2H),4.54-4.47(m,1H),4.36(d,J=12.8Hz,2H),4.27( q,J=2.8Hz,2H),3.82(t,J=5.6Hz,2H),3.52–3.19(m,6H),3.02(q,J=7.2Hz,2H), 2.79(d,J=11.2Hz,2H),2.37(s,3H),1.36(d,J=6.8Hz,6H),1.23(t,J=7.2Hz,3H).

[0477] Example 17 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 31)

[0478] Step 1: Add 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (21-a, 90 mg, 0.44 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, place in a microwave reactor, heat to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (31, 10 mg, 0.01 mmol, 15.7% yield). MS Calcd: 717.24; MS Found: 718.21 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.08(d,J=8.8Hz,1H),7.98(d,J=2.0Hz,1H),7.74 (dd,J=8.8,2.0Hz,1H),7.63(s,1H),6.86–6.84(m,1H),5.35(s,2H),4.53-4.46(m,1H),4 .37(d,J=12.8Hz,2H),4.27(d,J=3.2Hz,2H),3.82(t,J=5.6Hz,2H),3.52–3.18(m,6H),3. 03(q,J=7.2Hz,2H),2.78(d,J=11.2Hz,2H),1.34(d,J=6.8Hz,6H),1.23(t,J=7.2Hz,3H).

[0479] Example 18 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 32)

[0480] Step 1: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 55 mg, 0.10 mmol), DIPEA (13 mg, 0.10 mmol), 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 63 mg, 0.3 mmol) were added to 2-methyl-2-butanol and the mixture was stirred for 2 h. The bath was heated to 180°C and stirred for 30 minutes. The reaction system was dissolved in methanol and directly purified by prep-HPLC to obtain the target compound (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (32.7 mg, 0.0094 mmol, 9.4% yield). MS Calcd: 743.26; MS Found: 744.30 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.08(d,J=8.8Hz,1H),7.99(d,J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz,1H),7.7 0(s,1H),6.85(dd,J=3.6,2.0Hz,1H),5.35(s,2H),4.84-4.76(m,1H),4.29-4.26(m,2H),4.19-4.13(m,1H),4.10-4. 04(m,1H),3.82(t,J=5.2Hz,2H),3.71(d,J=11.2Hz,1H),3.53–3.14(m,4H),2.96-2.93(m,1H),2.80(d,J=10.2Hz,1H ),2.34–2.29(m,2H),1.94-1.88(m,1H),1.84–1.78(m,3H),1.66–1.57(m,1H),1.46-1.42(m,2H),1.26–1.19(m,5H).

[0481] Example 19 Preparation of (R)-2-(6-(4-(5-chloro-3-hydroxy-1-methyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Compound 33)

[0482] Step 1: 5-Chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (29-b, 30 mg, 0.17 mmol) was added to DCM (1 mL), followed by 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (23 mg, 0.17 mmol), stirred at room temperature for 2 hours, and then added to (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 40 mg, 0.07 mmol) and DIPEA (54 mg, 0.42 mmol). The mixture was added to a solution of 4-[(2-chloro-3-hydroxy-1-methyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (33.7 mg, 0.009 mmol, 13.5% yield). MS Calcd: 737.19; MS Found: 738.21 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=8.8Hz,1H),7.94(d,J=2.0Hz,1H),7.71(dd,J=8.8,2.0Hz,1H),6.83(t,J=2.0Hz, 1H),5.29(s,2H),4.25(t,J=2.8Hz,2H),3.67–3.45(m,10H),3.13-2.87(m,3H),2.76-2.63(m,3H),1.26–1.8(m,6H).

[0483] Example 20 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 34)

[0484] Step 1: Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88 mg, 0.42 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction mixture was concentrated directly and purified by Prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (34, 25 mg, 0.03 mmol, 39% yield). MS Calcd: 757.27; MS Found: 758.41 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),7.99(d,J=8.0Hz,1H),7.93(d,J=2.0Hz, 1H),7.69(dd,J=8.8,2.0Hz,1H),7.61(s,1H),6.72(t,J=4.0Hz,1H),5.27(s,2H ),4.79-4.73(m,1H),4.28–4.25(m,2H),4.13-4.01(m,1H),3.52–3.38(m,3H), 3.25(s,3H),3.13-2.96(m,4H),2.74(d,J=10.8Hz,1H),2.47-2.39(m,3H),2.24 2.11(m,2H),1.93–1.59(m,6H),1.20–1.12(m,5H).

[0485] Example 21 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 35)

[0486] Step 1: Place tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 200 mg, 0.47 mmol) in a 100 mL eggplant flask and add 10 mL of 1,4-dioxane solution. N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-2-iodoacetamide (int-4, 185.9 mg, 0.51 mmol) and DIPEA (0.23 mL, 1.4 mmol) were then added sequentially. Stir at 75°C for 5 hours. The reaction solution was directly concentrated and purified by column chromatography (PE:EA=60%:40%) to give tert-butyl 4-(2-bromo-5-ethyl-4-(2-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (35-a, 180 mg, 0.27 mmol, 58% yield). MS Calcd: 661.15; MS Found: 662.30 ([M+H] + ).

[0487] Step 2: tert-Butyl 4-(2-bromo-5-ethyl-4-(2-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (35-a, 180 mg, 0.27 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (85.9 mg, 0.41 mmol) were dissolved in 1,4-dioxane (6 mL) and H2O (3 mL), and Pd(dppf)Cl2 (20 mg, 0.03 mmol) and potassium phosphate (188 mg, 0.82 mmol) were added in sequence. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 5.0 hours. The reaction solution was concentrated, and 30 mL of ethyl acetate was added to the residue, followed by filtration through celite. The filtrate was concentrated and purified by column chromatography (DCM:MeOH=4:1) to give tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (35-b, 153 mg, 0.23 mmol, 85% yield). MS Calcd: 663.28; MS Found: 664.20 ([M+H] + ).

[0488] Step 3: Dissolve tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (35-b, 153 mg, 0.23 mmol) in 8 mL of dichloromethane solution, add 2 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. The reaction solution was directly concentrated, and 20 mL of saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried, and concentrated to give 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (35-c, 150 mg, 0.27 mmol, 98% yield). MS Calcd: 563.23; MS Found: 564.31 ([M+H] + ).

[0489] Step 4: 3-Hydroxy-2-methylquinoline-4-carboxylic acid (27.0 mg, 0.13 mmol) and HATU (102.8 mg, 0.27 mmol) were placed in a 25 mL eggplant flask. 5 mL of DCM was added, followed by DIPEA (0.04 mL, 0.27 mmol). After stirring for 2 minutes, 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (35-c, 50 mg, 0.09 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was directly concentrated and purified by Prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (35, 13 mg, 0.02 mmol, 19.6% yield) MS Calcd: 748.27; MS Found: 749.41 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.89(s,1H),7.91–7.88(m,1H),7.67–7.45(m,5H),6.82(s,1H),5.22(s,2H),4.70–4.66(m,1H),4.25( s,2H),3.83(t,J=5.2Hz,2H),3.59–3.53(m,1H),3.31-3.04(m,4H),2. 99-2.84(m,4H),2.63-2.60(m,5H),2.25(s,3H),1.17(t,J=7.2Hz,3H).

[0490] Example 22 Preparation of 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 36)

[0491] Step 1: Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88 mg, 0.42 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (35-c, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction solution was directly concentrated and purified by Prep-HPLC to obtain the title compound: 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (36, 24 mg, 0.03 mmol, 37% yield). MS Calcd: 727.29; MS Found: 728.40 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.67(s,1H),7.59-7.50(m,2H),6.82(s,1H),5 .24(s,2H),4.79-4.68(m,1H),4.27–4.23(m,4H),3.79(t,J=5.6Hz,2H),3.45–3.38(m ,2H),3.18–3.12(m,2H),3.01-2.95(m,2H),2.75(d,J=10.8Hz,2H),2.50-2.41(m,4H ),2.30–2.25(m,2H),2.20(d,J=2.0Hz,3H),1.79-1.71(m,2H),1.18(t,J=7.2Hz,3H).

[0492] Example 23 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 37)

[0493] Step 1: Dissolve (2,2,2-trifluoroethyl)hydrazine hydrochloride (37-a, 4000 mg, 35.06 mmol) in 40 mL of water. Slowly add diethyl 2-(ethoxymethylene)malonate (7579.3 mg, 35.06 mmol) and KCO (9675 mg, 17.53 mmol) at 0°C. Then, heat the mixture to 100°C and stir for 5 h. TLC indicates the reaction is complete. The reaction solution was cooled to room temperature, and some of the solvent was evaporated. The residue was adjusted to pH 2 with 5N HCl, extracted with dichloromethane (50 mL × 3), washed with saturated brine (100 mL), and the organic phases were combined and dried. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=20%:80%) to give ethyl 5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (37-b, 3500 mg, 42% yield) MS Calcd: 238.06; MS Found: 239.10 ([M+H] + ).

[0494] Step 2: Ethyl 5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (37-b, 100 mg, 0.44 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction solution was directly concentrated and purified by Prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (37, 20 mg, 0.02 mmol, 97% yield, racemate). MS Calcd: 785.23; MS Found: 786.37 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.95 (d, J = 2.0 Hz,1H),7.73-7.70(m,2H),6.73(d,J=4.0Hz,1H),5.30(s,2H),4.79(q,J=8. 8Hz,2H),4.25(d,J=12.0Hz,2H),3.54–3.41(m,3H),3.27(s,3H),3.21-3.12 (m,2H),2.99(q,J=7.2Hz,2H),2.76(d,J=10.8Hz,2H),2.58-2.44(m,3H),2. 18–2.11(m,1H),1.95–1.91(m,1H),1.72–1.62(m,1H),1.20(t,J=7.2Hz,3H).

[0495] Preparation of intermediate 38-f: N-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0496] Step 1: Weigh 5-chloro-2-methyl-4-(trifluoromethyl)aniline (38-a, 6.0 g, 28.63 mmol) into a 50 mL single-necked flask. Add DCM (30 mL) and then triethylamine (7.94 mL, 57.25 mmol). Add chloroacetyl chloride (3.40 mL, 34.35 mmol) in DCM (10 mL) dropwise under ice-cooling. Return the mixture to room temperature and allow to react overnight. Concentrate the reaction mixture, and the residue is purified by flash column chromatography (PE:EA = 20:1) to afford 2-chloro-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (38-b, 3.7 g, 12.93 mmol, 45.1% yield). MS Calcd: 284.99; MS Found: 283.97 ([MH] - ).

[0497] Step 2: Add 2-chloro-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (38-b, 3.7 g, 12.93 mmol) and acetone (15 mL) to a 100 mL eggplant flask. Then, add potassium iodide (5.4 g, 32.33 mmol) and stir at 50°C for 3 hours. The solvent is evaporated to dryness under reduced pressure to obtain a crude product, which is then purified by column chromatography (PE:EA = 3:1) to obtain N-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-2-iodoacetamide (38-c, 3.4 g, 9.01 mmol, 69.4% yield). MS Calcd: 376.93; MS Found: 375.97 ([MH] - ).

[0498] Step 3: To a 100 mL eggplant-shaped flask, add N-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-2-iodoacetamide (38-c, 1.1 g, 2.81 mmol), tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-1, 1.0 g, 2.34 mmol), and 1,4-dioxane (15 mL). Then, add DIPEA (0.9 g, 7.02 mmol) and stir at 90°C for 2 hours. The solvent was evaporated to dryness under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE:EA=1:4) to afford tert-butyl 4-(2-bromo-4-(2-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (38-d, 940 mg, 1.39 mmol, 59.3% yield). MS Calcd: 676.92.; MS Found: 578.12 ([M+H-100] + ).

[0499] Step 4: To a 100 mL eggplant flask was added tert-butyl 4-(2-bromo-4-(2-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (38-d, 940 mg, 1.39 mmol) and solvent 1,4-dioxane (10 mL) and H2O (5 mL). Then, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (438 mg, 2.08 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and potassium phosphate (960 mg, 4.17 mmol) were added thereto, and the mixture was stirred at 100°C for 6 hours under nitrogen protection. LCMS detection showed that the reaction of the raw material was complete, and water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM:MeOH=30:1) to give tert-butyl 4-(4-(2-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (38-e, 800 mg, 1.18 mmol, 84.7% yield) MS Calcd: 679.25.; MS Found: 624.21 ([M+H-56] + ).

[0500] Step 5: To a 100 mL eggplant-shaped flask was added tert-butyl 4-(4-(2-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (38-e, 800 mg, 1.18 mmol) and DCM (5 mL). TFA (0.5 mL) was then added and the mixture was stirred at room temperature overnight. H2O (20 mL) was added thereto, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give N-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (38-f, 500 mg, 0.86 mmol, 73.3% yield) MS Calcd: 579.20.; MS Found: 580.22 ([M+H] + ).

[0501] Example 24 Preparation of N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 39)

[0502] Step 1: Add 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (21-a, 85 mg, 0.43 mmol) and N-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (38-f, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, place in a microwave reactor, heat to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (39.8 mg, 0.01 mmol, 12.3% yield). MS Calcd: 731.26; MS Found: 732.26 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.12(s,1H),7.98(s,1H),7.78(s,1H),7.67(s,1H ),6.84(t,J=2.4Hz,1H),5.30(s,2H),4.53-4.46(m,1H),4.37(d,J=12.4Hz, 2H),4.28(d,J=2.8Hz,2H),3.82(t,J=5.2Hz,2H),3.52–3.17(m,6H),3.06-3.00(m,2 H), 2.79 (d, J = 11.2Hz, 2H), 2.38 (s, 3H), 1.35 (d, J = 6.8Hz, 6H), 1.20 (t, J = 7.2Hz, 3H).

[0503] Example 25 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 40)

[0504] Step 1: Dissolve 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (40-a, 120 mg, 0.77 mmol) in 3 mL of a methanol / water (5:1) mixture, add potassium hydroxide (258 mg, 4.61 mmol), heat to reflux and stir overnight, concentrate the reaction solution completely, slowly add 5N HCl solution to the residue to adjust the pH to 2, and concentrate under reduced pressure to obtain 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (40-b, 100 mg, 0.7 mmol, 91.6% yield). MS Calcd: 142.04; MS Found: 143.06 ([M+H] + ).

[0505] Step 2: 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (40-b, 34 mg, 0.24 mmol) and 1-chloro-N,N,2-trimethylpropenamine (36 mg, 0.27 mmol) were added to 5 mL of dichloromethane solution respectively, stirred at room temperature for 3 hours, and then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 70 mg, 0.12 mmol) and DIPEA (80 mg, 0.62 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, concentrated under reduced pressure, and purified by Prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (40, 6 mg, 0.01 mmol, 7% yield). MS Calcd: 689.21; MS Found: 690.18 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.36(s,1H),8.00(d,J=8.8Hz,1H),7.93(d,J= 2.0Hz,1H),7.70(dd,J=8.8,2.0Hz,1H),6.84–6.82(m,1H),5.29(s,2H),4.78(s,1H), 4.46(s,1H),4.25(t,J=2.8Hz,2H),3.80(t,J=5.6Hz,2H),3.51(s,3H),3.44–3.38(m ,2H),3.29-3.23(m,1H),3.00-2.91(m,4H),2.74–2.68(m,3H),1.19(t,J=7.2Hz,3H).

[0506] Example 26 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 41)

[0507] Step 1: Weigh 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (41-a, 65 mg, 0.30 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 40 mg, 0.06 mmol) into a 25 mL single-necked flask, add 2-methyl-1-butanol (2 mL) and DIPEA (0.01 mL, 0.06 mmol), and after the addition, heat to 180 °C and stir for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (41, 10 mg, 0.01 mmol, 21.0% Yield). MS Calcd: 743.26; MS Found: 744.36 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.08(d,J=8.8Hz,1H),7.98(d,J=2.0Hz,1H),7.74(dd, J=8.8,2.0Hz,1H),7.68(s,1H),6.85(t,J=2.0Hz,1H),5.34(s,2H),4.70–4.59(m,1H),4.35(d ,J=12.6Hz,2H),4.27(d,J=3.0Hz,2H),3.82(t,J=5.2Hz,2H),3.50-3.18(m,3H),3.02(q,J=7. 2Hz,2H),2.79(d,J=11.1Hz,2H),2.02–1.77(m,8H),1.66–1.58(m,3H),1.23(t,J=7.2Hz,3H).

[0508] Example 27 Preparation of 2-(6-(4-(1-(tert-butyl)-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 42)

[0509] Step 1: Diethyl ethoxymethylenemalonate (17-a, 1.74 g, 8.03 mmol), tert-butylhydrazine hydrochloride (1.0 g, 8.03 mmol), and potassium carbonate (2.21 g, 16.05 mmol) were added to 10 mL of aqueous solution and stirred at 100°C for 6 hours. The pH was adjusted to 2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 1-(tert-butyl)-5-hydroxy-1H-pyrazole-4-carboxylate (42-a, 0.45 g, 2.12 mmol, 26.4% yield). MS Calcd: 212.12; MS Found: 213.21 ([M+H] + ).

[0510] Step 2: 1-(tert-Butyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (42-a, 94 mg, 0.44 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) were added to 2 mL of 2-methyl-2-butanol solution, placed in a microwave reactor and heated to 180 ° C and stirred for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(6-(4-(1-(tert-butyl)-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (42.6 mg, 0.01 mmol, 9.1% yield). MS Calcd: 729.30; MS Found: 730.27 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.09 (s, 1H), 7.81 (d, J = 12.8Hz, 1H), 7.73–7.68 (m, 2H), 6. 85–6.83(m,1H),5.32(s,2H),4.41(d,J=12.8Hz,2H),4.28(d,J=2.8Hz,2H),3.82(t ,J=5.6Hz,2H),3.53-3.46(m,2H),3.27-3.22(m,2H),3.03(q,J=7.2Hz,2H),2.81(d ,J=11.2Hz,2H),2.55-2.51(m,2H),2.38(s,3H),1.57(s,9H),1.23(t,J=7.2Hz,3H).

[0511] Example 28 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 43)

[0512] Step 1: 1,1,1-Trifluoroacetone (43-a, 4.9 g, 44.05 mmol) and benzohydrazide (43-b, 4.0 g, 29.37 mmol) were added sequentially to 40 mL of toluene solution. The mixture was placed in a sealed container and heated to 110°C with stirring overnight. The reaction solution was completely concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1) to obtain N'-(1,1,1-trifluoropropane-2-ylidene)benzohydrazide (43-c, 5.1 g, 22.15 mmol, 75.4% yield). MS Calcd: 230.07; MS Found: 231.20 ([M+H] + ).

[0513] Step 2: Dissolve N'-(1,1,1-trifluoropropane-2-ylidene)benzohydrazide (43-c, 3.0 g, 13.3 mmol) in 40 mL of tetrahydrofuran. Add borane tetrahydrofuran solution (26.06 mL, 26.06 mmol) dropwise slowly at 0°C. After completion, slowly warm to room temperature and stir overnight. The reaction solution was cooled to 0°C again, 5 mL of methanol was added, and the reaction solution was completely concentrated. Water was added to the residue, extracted with dichloromethane, washed with saturated ammonium chloride solution, and concentrated under reduced pressure to obtain crude N'-(1,1,1-trifluoropropane-2-yl)benzohydrazide (43-d, 2.8 g, 12.06 mmol, 92.5% yield). The product was used directly in the next reaction without purification. MS Calcd: 232.08; MS Found: 233.1 ([M+H] + ).

[0514] Step 3: Dissolve N'-(1,1,1-trifluoropropan-2-yl)benzohydrazide (43-d, 1.0 g, 4.31 mmol) in 5 mL of methanol, then add 8 mL of concentrated hydrochloric acid. Heat to 100°C and stir overnight. Monitor the disappearance of the starting material by TLC. Concentrate the reaction mixture completely to obtain the crude product (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (43-e, 1.5 g, 9.2 mmol).

[0515] Step 4: Diethyl ethoxymethylenemalonate (17-a, 1.0 g, 94.68 mmol), (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (43-e, 1.5 g, 9.2 mmol), and potassium carbonate (2.6 g, 18.74 mmol) were added to 10 mL of aqueous solution and stirred at 100°C for 6 hours. The pH was adjusted to 2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 5-hydroxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxylate (43-f, 0.56 g, 2.2 mmol, 23.7% yield). MS Calcd: 252.07; MS Found: 253.16 ([M+H] + ).

[0516] Step 5: Add 5-hydroxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (43-f, 140 mg, 0.54 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, place in a microwave reactor, heat to 180°C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (43.5 mg, 0.01 mmol, 6.5% yield). MS Calcd: 769.26; MS Found: 770.28 ([M+H] + ). 1H NMR(400MHz, DMSO-d6)δ10.09(s,1H),7.81(d,J=12.8Hz,1H),7.71–7.68( m,2H),6.85–6.83(m,1H),5.32(s,2H),4.35–4.27(m,4H),3.82(t,J=5.6Hz ,2H),3.53–3.17(m,4H),3.02(q,J=7.2Hz,2H),2.78(d,J=11.2Hz,2H),2. 55-2.51(m,2H),2.38(s,3H),1.61(d,J=7.2Hz,3H),1.23(t,J=7.2Hz,3H).

[0517] Example 29 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3R)-4-(5-hydroxy-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 44)

[0518] Step 1: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 50 mg, 0.09 mmol), DIPEA (13 mg, 0.10 mmol), ethyl 5-hydroxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxylate (43-f, 126 mg, 0.5 mmol) were added to 2-methyl-2-butanol (1 mL). The oil bath was heated to 180°C and stirred for 30 minutes. The reaction system was dissolved in methanol and directly purified by prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3R)-4-(5-hydroxy-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (44, 12 mg, 0.0152 mmol, 17.0% yield). MS Calcd: 785.23; MS Found: 786.31 ([M+H] + ). 1H NMR (400 MHz, DMSO-d6 + heavy water) δ 8.02 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.72 (dd, J = 8.8, 2.0 Hz, 1H), 6.84–6.82 (m, 1H), 5.30 (d, J = 2.4 Hz, 2H), 4.25 (d, J = 3.2 Hz, 2H), 3.66 (d, J = 11.2 Hz ,2H),3.81-3.76(m,2H),3.48(t,J=11.2Hz,2H),3.16-3.11(m,2H),2.95-2.85(m,2H),2.79(d,J= 9.6Hz,2H),2.55-2.51(m,2H),1.61(d,J=7.2Hz,3H),1.43(d,J=9.2Hz,3H),1.22(t,J=7.2Hz,3H).

[0519] Example 30 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 45)

[0520] Step 1: Dissolve ethyl 2-(ethoxycarbonyl)-3-oxobutanoate (45-a, 1 g, 4.95 mmol) and isopropylhydrazine hydrochloride (45-b, 0.4 g, 4.95 mmol) in EtOH (20 mL). Add HCl (1 mL, 4.95 mmol) and react at 85°C for 2 hours. The solvent is dried by rotary evaporation, 30 mL of water is added, and the mixture is extracted with dichloromethane (30 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product, which is then purified by column chromatography (DCM:MeOH = 30:1) to afford ethyl 5-hydroxy-1-isopropyl-3-methyl-1H-pyrazole-4-carboxylate (45-c, 500 mg, 2.36 mmol, 47.6% yield). MS Calcd: 212.12; MS Found: 213.22 ([M+H] + ).

[0521] Step 2: Add 5-hydroxy-1-isopropyl-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (45-c, 104 mg, 0.45 mmol) and 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (19-c, 50 mg, 0.09 mmol) to 4 mL of 2-methyl-2-butanol solution, heat the oil bath to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (45.8 mg, 0.01 mmol, 11.9% yield). MS Calcd: 729.30; MS Found: 730.47 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.81(d,J=12.8Hz,1H),7.68(d,J=8 .0Hz,1H),6.85–6.82(m,1H),5.31(s,2H),4.46-4.41(m,1H),4.28-4.26( m,2H),4.12(brs,2H),3.82(t,J=5.6Hz,2H),3.51-3.44(m,2H),3.09-2.9 8(m,5H),2.73–2.69(m,3H),2.37(s,3H),2.16(s,3H),1.29–1.19(m,9H).

[0522] Example 31 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 47)

[0523] Step 1: Dissolve ethyl 4-chloroacetoacetate (47-a, 2.2 g, 13.37 mmol) in 10 mL of acetic acid. Place at 0°C and slowly add a 10 mL aqueous solution of sodium nitrite (1.2 g, 16.71 mmol). After addition, slowly warm the mixture to room temperature and stir overnight. Add water to the reaction mixture, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate (47-b, 1300 mg, 6.71 mmol, 50.2% yield). 1 H NMR (400MHz, DMSO) δ13.60 (s, 1H), 4.91 (s, 2H), 4.28 (q, J = 7.2Hz, 2H), 1.24 (t, J = 7.2Hz, 3H).

[0524] Step 2: Ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate (47-b, 500 mg, 2.58 mmol) was added to 3 mL of DMF solution, followed by urea (1.24 g, 20.66 mmol), and stirred at 100°C for 3 h. Water was added to the reaction solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA = 2:1) to obtain ethyl 4-hydroxyisoxazole-3-carboxylate (47-c, 210 mg, 1.34 mmol, 51.8% yield). 1 H NMR (400MHz, DMSO) δ9.72 (s, 1H), 8.71 (s, 1H), 4.35 (q, J = 7.2Hz, 2H), 1.31 (t, J = 7.2Hz, 3H).

[0525] Step 3: Ethyl 4-hydroxyisoxazole-3-carboxylate (47-c, 70 mg, 0.44 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 50 mg, 0.09 mmol) were added to 4 mL of 2-methyl-2-butanol solution, placed in an oil bath and heated to 180°C and stirred for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (47.4 mg, 0.01 mmol, 6.7% yield). MS Calcd: 676.18; MS Found: 677.2 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.59(s,1H),8.07(d,J=8.8Hz,1H),7.97(d,J=2.0Hz ,1H),7.73(dd,J=8.8,2.0Hz,1H),6.85(t,J=2.0Hz,1H),5.34(s,2H),4.53(d,J=12.4Hz,1 H),4.26(t,J=2.8Hz,2H),3.82(t,J=5.2Hz,2H),3.63(d,J=12.4Hz,1H),3.51-3.36(m,4H) ,3.06-2.97(m,4H),2.84(d,J=11.2Hz,1H),2.73(d,J=11.2Hz,1H),1.21(t,J=7.2Hz,3H).

[0526] Example 32 Preparation of N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 48)

[0527] Step 1: To a 50 mL eggplant-shaped flask, add N-(2-chloro-5-methyl-3-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (38-f, 50 mg, 0.09 mmol) and 2-methyl-2-butanol (2 mL). Then, add ethyl 1-cyclobutyl-5-hydroxypyrazole-4-carboxylate (17-b, 91 mg, 0.45 mmol) and DIPEA (0.04 mL, 0.27 mmol) and stir at 180°C for 30 minutes. Methanol (1.5 mL) was added thereto, and the crude product was purified by Pre-HPLC to give the title compound: N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (48, 10 mg, 0.01 mmol, 14.5% yield). MS Calcd: 743.26; MS Found: 744.31 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.98(s,1H),7.78(s,1H),7.67(s,1H),6.85–6.84 (m,1H),5.30(s,2H),4.82–4.75(m,1H),4.35(d,J=12.8Hz,2H),4.28(d,J=2.8Hz,2H),3 .82(t,J=5.6Hz,2H),3.57–3.18(m,4H),3.03(q,J=7.2Hz,2H),2.78(d,J=11.2Hz,2H),2 .54-2.45(m,2H),2.38(s,3H),2.32-2.19(m,2H),1.83-1.71(m,2H),1.22-1.17(m,5H).

[0528] Example 33 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetyl (Compound 49)

[0529] Step 1: To a 50 mL eggplant-shaped flask, add N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 100 mg, 0.18 mmol) and 2-methyl-2-butanol (1.5 mL). Then, add ethyl 5-hydroxy-3-methyl-1-(propan-2-yl)pyrazole-4-carboxylate (45-c, 49 mg, 0.23 mmol) and DIPEA (0.09 mL, 0.53 mmol) and stir at 180°C for 30 minutes. After concentration under reduced pressure, the crude product was purified by Pre-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-isopropyl-3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetyl (49, 13 mg, 0.02 mmol, 9.4% yield) MS Calcd: 731.26; MS Found: 732.30 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.08(d, J=8.8Hz,1H),7.98(d,J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz,1H),6.86–6 .84(m,1H),5.34(s,2H),4.46-4.39(m,1H),4.27(q,J=2.8Hz,2H),4.13(d ,J=12.4Hz,2H),3.82(t,J=5.6Hz,2H),3.51–3.44(m,2H),3.09–2.99(m,4 H),2.72–2.68(m,2H),2.54–2.51(m,2H),2.15(s,3H),1.28–1.19(m,9H).

[0530] Example 34 Preparation of N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-(6-{4-[(1-cyclobutyl-5-hydroxypyrazol-4-yl)carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (Compound 51)

[0531] Step 1: Add 2-chloro-6-(trifluoromethyl)pyridin-3-amine (51-a, 4.8 g, 24.42 mmol) and dichloromethane (30 mL) to a 250 mL eggplant flask. Then, add triethylamine (4.9 g, 48.83 mmol) and chloroacetyl chloride (2.8 g, 24.42 mmol) and stir at room temperature overnight. Add 150 mL of dichloromethane to dilute the mixture. Wash the organic phase with water (100 mL x 2) and dry it over anhydrous sodium sulfate. The organic phase is then evaporated to dryness under reduced pressure to obtain the crude product. The crude product is purified by column chromatography (PE:EA = 4:1) to obtain 2-chloro-N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]acetamide (51-b, 1.8 g, 6.41 mmol, 26.3% yield). MS Calcd: 271.97.; MS Found: 270.97 ([MH] - ).

[0532] Step 2: 2-Chloro-N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]acetamide (51-b, 1.8 g, 6.41 mmol) and acetone (30 mL) were added to a 100 mL eggplant flask. Potassium iodide (2.6 g, 16.03 mmol) was then added and the mixture was stirred at 50°C for 3 hours. The solvent was evaporated to dryness under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 4:1) to give N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-iodoacetamide (51-c, 1.8 g, 4.86 mmol, 75.8% yield). MS Calcd: 363.91.; MS Found: 362.91 ([MH] - ).

[0533] Step 3: To a 100 mL eggplant-shaped flask, add N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-iodoacetamide (51-c, 457 mg, 1.25 mmol), tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-5, 450 mg, 1.05 mmol), and 1,4-dioxane (15 mL). DIPEA (405 mg, 3.15 mmol) was then added, and the mixture was stirred at 60°C overnight. The solvent was evaporated to dryness under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE:EA=1:3) to afford tert-butyl 4-(4-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (51-d, 650 mg, 0.97 mmol, 93.2% yield). MS Calcd: 666.23.; MS Found: 567.22 ([M+H-100] + ).

[0534] Step 4: To a 100 mL eggplant-shaped flask was added tert-butyl 4-(4-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (51-d, 650 mg, 0.97 mmol) and DCM (8 mL). TFA (1 mL) was then added and the mixture was stirred at room temperature overnight. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (51-e, 500 mg, 0.88 mmol, 90.5% yield) MS Calcd: 566.18; MS Found: 567.12 ([M+H] + ).

[0535] Step 5: To a 50 mL eggplant-shaped flask, add N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (51-e, 70 mg, 0.12 mmol) and 2-methyl-2-butanol (2 mL). Then, add ethyl 1-cyclobutyl-5-hydroxypyrazole-4-carboxylate (17-b, 104 mg, 0.49 mmol) and DIPEA (48 mg, 0.37 mmol) and stir at 180°C for 30 minutes. Methanol (1.5 mL) was added thereto, and the crude product was purified by Pre-HPLC to give the title compound: N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-(6-{4-[(1-cyclobutyl-5-hydroxypyrazol-4-yl)carbonyl]piperazin-1-yl}-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (51, 20 mg, 0.03 mmol, 21.1% yield). MS Calcd: 730.24; MS Found: 731.28 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.58(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.70(s,1H ),7.09–6.65(m,1H),5.39(s,2H),4.84-4.75(m,1H),4.34(d,J=12.4Hz,2H),4.27(q,J=2.8Hz ,2H),3.82(t,J=5.6Hz,2H),3.52-3.45(m,3H),3.21-3.15(m,2H),3.05-2.99(m,3H),2.78(d, J=11.2Hz,2H),2.55–2.51(m,2H),2.35–2.26(m,2H),1.83-1.75(m,2H),1.22(t,J=7.2Hz,3H).

[0536] Example 35 Preparation of 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (Compound 52)

[0537] Step 1: To a 25 mL eggplant-shaped flask, add 2,5-dichloro-4-(trifluoromethyl)aniline (52-a, 800 mg, 3.48 mmol) and dichloromethane (10 mL). Then, add chloroacetyl chloride (589 mg, 5.22 mmol) and triethylamine (1056 mg, 10.43 mmol) and stir at room temperature for 2 hours. Add water (40 mL) and extract with DCM (30 mL). The organic phase is washed twice with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-chloro-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52-b, 1000 mg, 3.26 mmol, 93.8% yield). This was used in the next step without purification. MS Calcd: 304.94; MS Found: 303.95 ([MH] - ).

[0538] Step 2: Add 2-chloro-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52-b, 1000 mg, 3.26 mmol) and acetone (20 mL) to a 25 mL eggplant flask. Then, add potassium iodide (1624.8 mg, 9.79 mmol) and heat to 50°C with stirring for 2 hours. The reaction mixture was filtered and the filtrate was dried under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (EA:PE = 10%) to obtain 2-iodo-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52-c, 700 mg, 1.76 mmol, 53.9% yield). MS Calcd: 396.87; MS Found: 395.9 ([MH] - ).

[0539] Step 3: To a 25 mL eggplant-shaped flask, add tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-5, 200 mg, 0.46 mmol) and 1,4-dioxane (10 mL). Then, add 2-iodo-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52-c, 184.9 mg, 0.46 mmol) and DIPEA (178.3 mg, 1.38 mmol), and heat to 75° C. and stir overnight. Water (30 mL) was added, and the mixture was extracted with EA (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified on a thin layer silica gel plate (MeOH:DCM = 1:20) to obtain tert-butyl 4-(4-(2-((2,5-dichloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (52-d, 200 mg, 0.29 mmol, 61.9% yield). MS Calcd: 699.20; MS Found: 700.3 ([M+H] + ).

[0540] Step 4: To a 25 mL eggplant-shaped flask was added tert-butyl 4-(4-(2-((2,5-dichloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (52-d, 100 mg, 0.14 mmol) and dichloromethane (50 mL). HCl / 1,4-dioxane (2 mL, 4 mmol / L) was then added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (40 mL) was added, and the mixture was extracted with DCM (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (52-e, 79 mg, 0.13 mmol, 92.2% yield), which was directly used in the next step without purification. MS Calcd: 599.14; MS Found: 600.20 ([M+H] + ).

[0541] Step 5: To a 25 mL eggplant-shaped flask, add N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (52-e, 35 mg, 0.06 mmol) and solvent tert-amyl alcohol (2 mL). Then, 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 50.4 mg, 0.24 mmol) was added thereto, and the mixture was heated to 180°C and stirred for 1 hour. After that, the reaction solution was directly concentrated. The crude product was purified by Pre-HPLC to give the title compound: 2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52, 18 mg, 0.02 mmol, 40.4% yield). MS Calcd: 763.20; MS Found: 764.22 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.30(s,1H),8.07(s,1H),7.71(s,1H),6.84 (s,1H),5.37(s,2H),4.84-4.76(m,1H),4.34(d,J=12.4Hz,2H),4.27(d,J=3.2Hz, 2H),3.82(t,J=5.6Hz,2H),3.52–3.45(m,3H),3.22-3.19(m,2H),3.06-2.99(m,3H ),2.79(d,J=11.2Hz,2H),2.32–2.28(m,2H),1.84-1.77(m,2H),1.26-1.20(m,5H).

[0542] Example 36 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 53)

[0543] Step 1: Ethyl 5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (37-b, 105 mg, 0.44 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction mixture was concentrated and purified by Prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (53, 10 mg, 0.01 mmol, 14.3% yield). MS Calcd: 757.20; MS Found: 758.27 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.08(d,J=8.4Hz,1H),7.98(d,J=2.0Hz, 1H),7.81–7.62(m,2H),7.02–6.76(m,1H),5.34(s,2H),4.87-4.80(m,2H),4.31 –4.26(m,4H),3.82(t,J=5.6Hz,2H),3.52-3.46(m,2H),3.21–3.15(m,2H),3.05 -2.99(m,2H),2.78(d,J=11.2Hz,2H),2.53-2.50(m,2H),1.22(t,J=7.2Hz,3H).

[0544] Example 37 Preparation of (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 54)

[0545] Step 1: 2-Bromo-5-ethyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-7-one (int-3a, 700 mg, 2.88 mmol) and N-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-2-iodoacetamide (38-c, 1087.0 mg, 2.88 mmol) were added to a 100 mL round-bottom flask, and dioxane (20 mL) and DIPEA (1.43 mL, 8.64 mmol) were added in sequence. The mixture was stirred at 80 ° C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, and solid precipitated. The product was filtered and washed with EA. The filtrates were combined and concentrated by flash column chromatography (DCM:MeOH=5:1) to give 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (54-a, 603 mg, 1.22 mmol, 42.5% yield).

[0546] Step 2: 2-(2-Bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (54-a, 600 mg, 1.22 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (383.8 mg, 1.83 mmol) were dissolved in 1,4-dioxane (8 mL) and H2O (4 mL), and Pd(dppf)Cl2 (89 mg, 0.09 mmol) and potassium phosphate (860 mg, 3.65 mmol) were added in sequence. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 5.0 hours. The reaction solution was concentrated, and 30 mL of ethyl acetate was added to the residue. The mixture was filtered through celite, and the filtrate was concentrated and purified by column chromatography (DCM:MeOH=4:1) to obtain N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-b, 200 mg, 0.4 mmol, 33% yield). MS Calcd: 495.13; MS Found: 496.10 ([M+H] + ).

[0547] Step 3: Place N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-b, 450 mg, 0.91 mmol) and N-bromosuccinimide (192.7 mg, 1.09 mmol) in a 100 mL eggplant-shaped flask, add 10 mL of acetonitrile, and then raise the temperature to 60°C for reaction for 1 hour. The reaction solution was poured into 20 mL of water and extracted with EA (3×20 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM:MeOH=6:1) to give 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (54-c, 300 mg, 0.52 mmol, 57% yield). MS Calcd: 575.04; MS Found: 576.20 ([M+H] + ).

[0548] Step 4: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (54-c, 250 mg, 0.43 mmol) and compound 2-methylpropan-2-yl (2R)-2-methylpiperazine-1-carboxylate (871 mg, 4.35 mmol) and AgBF4 (101.3 mg, 0.52 mmol) were added to dry DMSO (3 mL), replaced with nitrogen for 1 minute, and then the temperature was raised to 120°C for reaction for 18 hours. The reaction system was poured into water (20 mL), then extracted with EA (20 mL×3). The organic phases were combined, dried, and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=20:1) to give (R)-tert-butyl 4-(4-(2-((5-chloro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylate (54-d, 127 mg, 0.18 mmol, 42% yield). MS Calcd: 693.27; MS Found: 694.10 ([M+H] + ).

[0549] Step 5: (R)-4-(4-(2-((5-chloro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (54-d, 127 mg, 0.18 mmol) was dissolved in 8 mL of dichloromethane solution, and 2 mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated, and 20 mL of saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried, and concentrated to give crude (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-e, 90 mg, 0.15 mmol, 82% yield). MS Calcd: 593.21; MS Found: 594.27 ([M+H] + ).

[0550] Step 6: (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-e, 50 mg, 0.08 mmol) and ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88 mg, 0.42 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction mixture was concentrated and purified by Prep-HPLC to give the title compound: (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54 mg, 13 mmol, 20% yield). MS Calcd: 757.27; MS Found: 758.37 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.98(s,1H),7.78(s,1H),7.69(s,1H),6.84(t,J=2.0Hz, 1H),5.30(d,J=2.7Hz,2H),4.80(p,J=9.3,8.8Hz,2H),4.28(q,J=2.8Hz,2H),3.83(t,J=5.6Hz,2 H),3.73-3.67(m,2H),3.54-3.49(m,2H),3.22-3.15(m,2H),2.99-2.94(m,2H),2.80(d,J=10.0H z,2H),2.38(s,3H),2.32–2.28(m,2H),1.84-1.76(m,2H),1.46-1.43(m,3H),1.27-1.23(m,5H).

[0551] Example 38 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 55)

[0552] Step 1: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 63 mg, 0.10 mmol), DIPEA (15 mg, 0.10 mmol), 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (41-a, 112 mg, 0.5 mmol) were added to 2-methyl-2-butanol (1 mL). The oil bath was heated to 180°C and stirred for 30 minutes. The reaction system was dissolved in methanol and directly purified by prep-HPLC to obtain the title compound: (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (55, 19 mg, 0.025 mmol, 25.0% yield). MS Calcd: 757.27; MS Found: 758.31 ([M+H]+ ). 1 H NMR(400MHz,Chloroform-d)δ9.03(s,1H),8.53(d,J=8.8Hz,1H),7.68(d,J=2.0Hz,1H),7.6 3–7.50(m,2H),7.01(s,1H),5.14(s,2H),4.80-4.73(m,1H),4.41–4.39(m,2H),4.01–3.94(m ,3H),3.83-3.78(m,1H),3.34-3.18(m,2H),2.85–2.67(m,4H),2.24–2.04(m,1H),2.12–2.0 7(m,4H),2.00-1.94(m,3H),1.76-1.70(m,3H),1.40(t,J=7.2Hz,3H),1.29(d,J=9.2Hz,3H).

[0553] Example 39 Preparation of (R)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 56)

[0554] Step 1: Add 2-bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 4 g, 16.5 mmol), N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-2-iodoacetamide (int-4, 6 g, 16.5 mmol), and DIPEA (6.4 g, 49.5 mmol) to DMF (50 mL), raise the temperature to 80°C, and stir for 2 hours. After cooling to room temperature, the reaction system was poured into water. Solid precipitated and filtered. The filter cake was washed with water (50 mL x 2). The solid was collected and purified by slurrying with a mixed solvent of ethyl acetate and petroleum ether (1:3) to obtain 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-a, 5.9 g, 12.4 mmol, 75% yield). MS Calcd: 475.03; MS Found: 476.11 ([M+H] + ).

[0555] Step 2: 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-a, 5.9 g, 12.4 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (2.6 g, 12.4 mmol), potassium phosphate (7.9 g, 37.2 mmol), 1,1-bis(diphenylphosphino)dichloropalladium iron (906 mg, 1.24 mmol) were added to the mixture. mol) was added to a mixed solvent of dioxane (40 mL) and water (10 mL), the atmosphere was replaced with nitrogen for 3 minutes, the temperature was raised to 85°C, the mixture was stirred for 3 hours, and the mixture was concentrated under reduced pressure. The residue was poured into water, and the solid was collected by filtration and then purified by ethanol slurrying to obtain 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-b, 4.8 g, 10.0 mmol, 81% yield). MS Calcd: 479.16; MS Found: 480.21 ([M+H] + ).

[0556] Step 3: Add 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-b, 4.8 g, 10.0 mmol) to DMF (50 mL), then add NBS (1.78 g, 10.0 mmol), raise the temperature to 60°C and stir for 3 hours. The reaction system was then poured into water, and solids precipitated. The solids were collected by filtration and then purified by ethanol slurrying to give 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-c, 3.4 g, 6.1 mmol, 61%). MS Calcd: 557.07; MS Found: 558.07 ([M+H] + ).

[0557] Step 4: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-c, 1 g, 1.8 mmol), (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 18 mmol), silver tetrafluoroborate (351 mg, 1.8 mmol) were added to dry DMSO (10 mL), and then under nitrogen protection, the temperature was raised to 120 ° C, stirred for 4 hours, cooled to room temperature, and saturated The mixture was stirred for 2 h at 4 ℃ for 10 min, and then extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 1:1) to give (R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(-2-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (56-d, 810 mg, 1.20 mmol, 66%). MS Calcd: 677.29; MS Found: 678.31 ([M+H] + ).

[0558] Step 5: (R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(-2-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (56-d, 810 mg, 1.20 mmol) was added to DCM (10 mL), followed by addition of trifluoroacetic acid (3 mL), stirred at room temperature for 4 hours, and concentrated under reduced pressure. The residue was added to a saturated aqueous sodium bicarbonate solution, followed by extraction with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-e, 483 mg, 0.84 mmol, 70%). MS Calcd: 577.24; MS Found: 578.28 ([M+H]+).

[0559] Step 6: (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-e, 60 mg, 0.10 mmol), DIEA (15 mg, 0.10 mmol), 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 100 mg, 0.5 mmol) were added to 2-methyl-2-butanol ( The mixture was stirred for 30 minutes in an oil bath (1 mL), heated to 180°C, and stirred for 30 minutes. The mixture was purified by prep-HPLC to give the title compound: (R)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56, 21 mg, 0.029 mmol, 29.0% yield). MS Calcd: 727.29; MS Found: 728.31 ([M+H] + ).

[0560] Example 40 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-(4-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 57)

[0561] Step 1: To a 25 mL eggplant-shaped flask, tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 100 mg, 0.15 mmol) and DMSO (2 mL) were added. N-methylpiperazine (45.1 mg, 0.45 mmol) and potassium acetate (44.1 mg, 0.45 mmol) were then added, and the mixture was heated to 120°C and stirred overnight. Water (40 mL) was added, and the mixture was extracted with EA (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (MeOH:DCM = 1:20) to obtain tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl 1-2-(4-methylpiperazin-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl 1))piperazine-1-carboxylate (57-a, 45 mg, 0.07 mmol, 44% yield). MS Calcd: 681.28; MS Found: 682.4 ([M+H] + ).

[0562] Step 2: To a 25 mL eggplant-shaped flask, tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl 1-2-(4-methylpiperazin-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl 1))piperazine-1-carboxylate (57-a, 45 mg, 0.07 mmol, 44% yield) and dichloromethane (5 mL) were added. Hydrogen chloride-1,4-dioxane (2 mL, 4 mol / L) was then added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with DCM (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methylpiperazin-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (57-b, 40 mg, 0.07 mmol), which was used directly in the next step. MS Calcd: 581.22; MS Found: 582.3 ([M+H] + ).

[0563] Step 3: To a 25 mL eggplant-shaped flask, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methylpiperazin-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (57-b, 40 mg, 0.07 mmol) and tert-amyl alcohol (2 mL) were added. Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 57.8 mg, 0.27 mmol) and DIPEA (17.8 mg, 0.14 mmol) were then added, and the mixture was heated to 180° C. and stirred for 1 hour. The reaction mixture was directly concentrated, and the crude product was purified by Pre-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-(4-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (57, 15 mg, 0.02 mmol, 28.3% yield). MS Calcd: 745.28; MS Found: 746.4 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.06(dd,J=8.4,6.0Hz,1H),7.98(d,J=2.0Hz,1H),7. 74(dd,J=8.4,2.0Hz,1H),7.63(s,1H),5.23(s,2H),4.83-4.75(m,1H),4.34(d,J=12.4Hz,2H ),3.50–3.42(m,8H),3.17-3.10(m,1H),2.97(q,J=7.2Hz,2H),2.72(d,J=11.2Hz,2H),2.54- 2.51(m,2H),2.42-2.39(m,4H),2.27-2.22(m,5H),1.82-1.75(m,2H),1.19(t,J=7.2Hz,3H).

[0564] Example 41 Preparation of N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 58)

[0565] Step 1: To a 50 mL eggplant-shaped flask, add N-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (51-e, 70 mg, 0.12 mmol) and 2-methyl-2-butanol (2 mL). Then, add ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 97 mg, 0.49 mmol) and DIPEA (48 mg, 0.37 mmol) and stir at 180°C for 30 minutes. Methanol (1.5 mL) was added thereto, and the crude product was purified by Pre-HPLC to give the title compound: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (58, 20 mg, 0.03 mmol, 21.9% yield). MS Calcd: 716.22; MS Found: 717.20 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.59(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.5 9(s,1H),6.84(q,J=1.6Hz,1H),5.39(s,2H),4.34(d,J=12.4Hz,2H),4.27(d,J=3.2Hz,2 H),3.82(t,J=5.6Hz,2H),3.51–3.38(m,3H),3.16(t,J=12.4Hz,2H),3.02(q,J=7.2Hz,2 H),2.77(d,J=11.2Hz,2H),2.53–2.51(m,2H),1.22(t,J=7.2Hz,3H),1.01–0.94(m,4H).

[0566] Example 42 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-8-methoxyquinolin-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 59)

[0567] Step 1: Weigh 4-hydroxy-8-methoxyquinoline-3-carboxylic acid (59-a, 23 mg, 0.09 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 40 mg, 0.06 mmol) into a 25 mL single-necked bottle, add 2-methyl-2-butanol (2 mL) and DIPEA (0.01 mL, 0.06 mmol), and after the addition, heat to 180 ° C and react for 2 hours. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxy-8-methoxyquinolin-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (59.2 mg, 0.002 mmol, 4.3% Yield). MS Calcd: 766.22; MS Found: 767.36 ([M+H] + ).

[0568] Example 43 Preparation of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 60)

[0569] Step 1: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 26 mg, 0.20 mmol) was added to DCM (1 mL), followed by 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (29 mg, 0.20 mmol), stirred at room temperature for 2 hours, and then added to (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (14-b, 60 mg, 0.10 mmol) and DIPEA (64 mg, 0.50 The mixture was added to a solution of 4-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (60, 16 mg, 0.023 mmol, 23.1% yield). MS Calcd: 690.19; MS Found: 691.21 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.84(s,1H),8.59(d,J=2.0Hz,1H),8.08(d,J=8.8Hz,1H),7. 98(d,J=2.0Hz,1H),7.73(dd,J=8.8,2.0Hz,1H),6.86-6.84(m,1H),5.34(s,2H),3.82-3.78(m,0.5H ),4.40(d,J=12.8Hz,,0.5H),4.27(d,J=2.8Hz,2H),3.89-3.82(m,3H),3.72-3.67(m,1H),3.54–3. 44(m,2H),3.31–3.12(m,3H),2.96-2.68(m,3H),1.43(dd,J=6.8,2.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0570] Example 44 Preparation of (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 61)

[0571] Step 1: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 26 mg, 0.20 mmol) was added to DCM (1 mL), followed by 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (29 mg, 0.20 mmol), stirred at room temperature for 2 hours, and then added to (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (56-e, 60 mg, 0.10 mmol) and DIPEA (64 mg, 0.5 The mixture was added to a dichloromethane solution of (100 mg, 0.016 mmol) and stirred at room temperature overnight. Water (3 mL) was then added and the mixture was extracted with DCM (3 mL×3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC to give the title compound: (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (61, 11 mg, 0.016 mmol, 16% yield). MS Calcd: 688.24; MS Found: 689.27 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),9.79(s,1H),8.59(d,J=1.6Hz,1H),7.63-7.57(m,2H),6.8 4(t,J=2.0Hz,1H),5.28(s,2H),4.82–4.78(m,0.5H),4.39(d,J=12.8Hz,0.5H),4.29-4.26(m,2H) ,3.88-3.81(m,3H),3.72-3.66(m,1H),3.53–3.44(m,2.5H),3.26–3.13(m,2H),2.97-2.90(m,1H ),2.85–2.62(m,2.5H),2.26(d,J=2.4Hz,3H),1.43(dd,J=6.8,2.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0572] Example 45 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 62)

[0573] Step 1: To a 25 mL eggplant-shaped flask, tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 200 mg, 0.30 mmol) and DMSO (2 mL) were added. Morpholine (78.8 mg, 0.91 mmol) and potassium acetate (88.8 mg, 0.91 mmol) were then added, and the mixture was heated to 120°C and stirred overnight. Water (40 mL) was added, and the mixture was extracted with EA (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified by chromatography on silica gel (MeOH:DCM = 1:20) to obtain tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-morpholino-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl))piperazine-1-carboxylate (62-a, 55 mg, 0.08 mmol, 27.2% yield). MS Calcd: 668.24; MS Found: 613.25 ([M+H-56] + ).

[0574] Step 2: To a 25 mL eggplant-shaped flask, tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-morpholino-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (62-a, 55 mg, 0.08 mmol) and dichloromethane (5 mL) were added. A hydrogen chloride-1,4-dioxane solution (2 mL, 4 mol / L) was then added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with DCM (30 mL). The organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (62-b, 40 mg, 0.08 mmol). The crude product was directly used in the next step. MS Calcd: 568.19; MS Found: 569.34 ([M+H] + ).

[0575] Step 3: To a 25 mL eggplant-shaped flask, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (62-b, 40 mg, 0.08 mmol) and solvent tert-amyl alcohol (2 mL) were added. Then, 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 66.5 mg, 0.32 mmol) and DIPEA (20.4 mg, 0.16 mmol) were added thereto, and the mixture was heated to 180°C and stirred for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by Pre-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (62, 10 mg, 0.01 mmol, 16.7% yield). MS Calcd: 732.25; MS Found: 733.3 ([M+H] + ). 1H NMR (400 MHz, DMSO-d6 + heavy water exchange) δ 8.02 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.66 (s, 1H), 5.21 (s, 2H), 4.81-4.72 (m, 1H), 4.29 (d, J = 12.4 Hz, 2H), 3.69-3.64(m,2H),3.46-3.37(m,7H),3.16-3.10(m,2H),2.97-2.91(m,2H),2.72(d,J= 11.2Hz,2H),2.49–2.43(m,3H),2.27(s,2H),1.81-1.73(m,2H),1.18(t,J=7.2Hz,3H).

[0576] Example 46 Preparation of N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 63)

[0577] Step 1: 4-hydroxyisoxazole-3-carboxylic acid (int-7, 12.9 mg, 0.10 mmol) and solvent DCM (3 mL) were added to a 10 mL eggplant-shaped flask. 1-Chloro-N,N,2-trimethylpropenamine (10 mg, 0.08 mmol) was then added. After stirring at room temperature for 1 hour, N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (52-e, 30 mg, 0.05 mmol) and DIPEA (19.4 mg, 0.15 mmol) were added. Stirring was continued at room temperature for 2 hours, and water (20 mL) was added. The mixture was extracted with DCM (20 mL), and the organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give the title compound: N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (63.7 mg, 0.01 mmol, 17.7% yield). MS Calcd: 710.14; MS Found: 711.3 ([M+H] + ). 1 H NMR(400MHz,Methanol-d4)δ11.32(s,1H),10.59(s,1H),9.42(s,1H),9.11(s,1H),8.87(s ,1H),7.65(s,1H),6.16(s,2H),5.35(d,J=12.4Hz,1H),5.08(q,J=2.8Hz,2H),4.63(t,J=5 .2Hz,2H),4.44(d,J=12.4Hz,1H),4.33–4.26(m,2H),4.18–4.10(m,1H),3.88-3.80(m,3H) ,3.65(d,J=11.6Hz,1H),3.55(d,J=11.6Hz,1H),3.35-3.31(m,2H),2.02(t,J=7.2Hz,3H).

[0578] Example 47 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((R)-4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 64)

[0579] Step 1: To a 250 mL eggplant-shaped flask, add N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (8.2 g, 22.62 mmol), 2-bromo-5-ethyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-7-one (int-3a, 5.0 g, 20.57 mmol), and 1,4-dioxane (120 mL). DIPEA (8.0 g, 61.70 mmol) was then added and stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was filtered and the solid was washed with ethyl acetate (50 mL). The solid was dissolved in DCM (300 mL) and washed twice with water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (64-a, 5.7 g, 11.91 mmol, 57.9% yield). MS Calcd: 478.65.; MS Found: 479.94 ([M+H] + ).

[0580] Step 2: To a 100 mL eggplant-shaped flask, 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (64-a, 800 mg, 1.67 mmol), 2-(4-methoxycyclohex-1-enyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.67 mmol), 1,4-dioxane (6 mL), and H2O (2 mL) were added. Potassium phosphate (960 mg, 4.18 mmol) and Pd(dppf)Cl2 (120 mg, 1.67 mmol) were then added, and the mixture was stirred at 90°C overnight. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE:EA=1:3) to give N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-b, 720 mg, 1.41 mmol, 84.5% yield) MS Calcd: 509.91.; MS Found: 510.12 ([M+H] + ).

[0581] Step 3: To a 100 mL eggplant-shaped flask, add N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-b, 650 mg, 1.27 mmol) and acetonitrile (10 mL). Then, add NBS (250 mg, 1.40 mmol) and stir at 60°C for 1 hour. The solvent was dried, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE:EA=1:1) to give 2-[6-bromo-5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (64-c, 500 mg, 0.87 mmol, 67.9% yield) MS Calcd: 587.05.; MS Found: 588.04 ([M+H] + ).

[0582] Step 4: To a 100 mL eggplant-shaped flask, 2-[6-bromo-5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide (64-c, 500 mg, 0.85 mmol), 2-methylpropan-2-yl (2R)-2-methylpiperazine-1-carboxylate (1700 mg, 8.49 mmol), and DMSO (10 mL) were added. Silver tetrafluoroborate (198 mg, 1.02 mmol) was then added and stirred at 120°C for 24 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phase was washed 4 times with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE:EA=1:3) to give 2-methylpropan-2-yl (2R)-4-[4-(2-{[2-chloro-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-2-methylpiperazine-1-carboxylate (64-d, 340 mg, 0.48 mmol, 56.5% yield) MS Calcd: 707.28.; MS Found: 608.24 ([M+H-100] + ).

[0583] Step 5: To a 100 mL eggplant-shaped flask was added 2-methylpropan-2-yl (2R)-4-[4-(2-{[2-chloro-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-5-ethyl-2-(4-methoxycyclohex-1-enyl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-2-methylpiperazine-1-carboxylate (64-d, 340 mg, 0.48 mmol) and DCM (3 mL). TFA (0.5 mL) was then added and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-6-[(3R)-3-methylpiperazin-1-yl]-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-e, 150 mg, 0.25 mmol, 51.4% yield) MS Calcd: 607.23; MS Found: 608.20 ([M+H] + ).

[0584] Step 6: To a 50 mL eggplant-shaped flask, add N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-6-[(3R)-3-methylpiperazin-1-yl]-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-e, 60 mg, 0.10 mmol) and 2-methyl-2-butanol (1.5 mL). Then, add ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 83 mg, 0.39 mmol) and DIPEA (39 mg, 0.30 mmol), and stir at 180°C for 30 minutes. Methanol (1.5 mL) was added thereto, and the crude product was purified by Pre-HPLC to give the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((R)-4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (64, 20 mg, 0.03 mmol, 26.2% yield, diastereomeric mixture). MS Calcd: 771.29; MS Found: 772.28 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.09(d,J=8.8Hz,1H),7.99(d,J=2.0Hz,1H),7.75–7.71(m,2H),6 .77-6.75(m,1H),5.34(s,2H),4.84-4.76(m,1H),3.72-3.68(m,1H),3.56-3.33(m,5H),3.29(s,3H),3.1 9-3.11(m,1H),2.99-2.92(m,1H),2.79(d,J=10.0Hz,1H),2.67–2.08(m,7H),2.35-2.26(m,2H),2.20-2 .13(m,1H),1.99-1.93(m,1H),1.84-1.74(m,2H),1.72-1.63(m,1H),1.44(s,3H),1.24(t,J=7.2Hz,3H).

[0585] Example 48 Preparation of N-[2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((R)-4-((4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (Compound 65)

[0586] Step 1: Add compound 4-hydroxyisoxazole-3-carboxylic acid (int-7, 31 mg, 0.24 mmol) and solvent DCM (1 mL) to a 50 mL eggplant flask. Then add (1-chloro-2-methylprop-1-enyl)dimethylamine (33 mg, 0.25 mmol) and stir at room temperature for 3 hours. Then add N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-6-[(3R)-3-methylpiperazin-1-yl]-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-e, 50 mg, 0.08 mmol) and DIPEA (103 mg, 0.8 mmol) and stir at room temperature for 2 hours. The solvent is dried by rotary evaporation and methanol (1.5 mL) is added to obtain a crude product. The title compound was purified by Pre-HPLC: N-[2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((R)-4-((4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (65, 20 mg, 0.03 mmol, 34.4% yield, diastereomeric mixture). MS Calcd: 718.22; MS Found: 719.19 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.88(s,1H),8.60(d,J=2.0Hz,1H),8.09(d,J=8.8Hz,1H),7.98 (d,J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz,1H),6.76(t,J=4.0Hz,1H),5.34(s,2H),3.91-3.84(m,1H), 3.72-6.67(m,1H),3.55–3.45(m,3H),3.31-3.13(m,4H),2.96–2.83(m,2H),2.71-2.43(m,5H),2.20– 2.14(m,1H),1.99–1.94(m,1H),1.74–1.63(m,1H),1.44(dd,J=6.8,2.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0587] Example 49 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((R)-4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 66)

[0588] Step 1: Add 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 12 mg, 0.08 mmol) and solvent DCM (1 mL) to a 50 mL eggplant flask. Then add (1-chloro-2-methylprop-1-enyl) dimethylamine (12 mg, 0.09 mmol) and stir at room temperature for 3 hours. Then add N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(4-methoxycyclohex-1-enyl)-6-[(3R)-3-methylpiperazin-1-yl]-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (64-e, 40 mg, 0.07 mmol) and DIPEA (27 mg, 0.21 mmol) and stir at room temperature for 2 hours. The solvent is dried by spin drying and methanol (1.5 mL) is added. The crude product is purified by pre Purification by p-HPLC afforded the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((R)-4-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (66.6 mg, 0.01 mmol, 11.4% yield, diastereomeric mixture). MS Calcd: 731.26; MS Found: 732.28 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.46(brs,2H),8.08(d,J=8.8Hz,1H),7.97(d,J=2.0Hz,1H),7.89( s,1H),7.73(dd,J=8.8,2.0Hz,1H),6.75(d,J=4.0Hz,1H),5.33(s,2H),3.72-3.65(m,4H),3 .56-3.48(m,4H),3.29(s,3H),3.19-3.10(m,1H),2.97-2.90(m,1H),2.74–2.42(m,6H),2.2 0-2.12(m,1H),1.98–1.93(m,1H),1.73-1.63(m,1H),1.40(brs,3H),1.23(t,J=7.2Hz,3H).

[0589] Example 50 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 67)

[0590] Step 1: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 26.1 mg, 0.20 mmol) and 1-chloro-N,N,2-trimethylpropenamine (29.7 mg, 0.22 mmol) were added to 3 mL of dichloromethane solution, stirred at room temperature for 3 hours, and then N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (20-b, 60 mg, 0.10 mmol) and DIEA (0.05 mL, 0.3 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. To the reaction solution was added 10 mL of saturated sodium bicarbonate solution, and the mixture was extracted with DCM (10 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (67 mg, 25 mmol, 35% yield). MS Calcd: 704.21; MS Found: 705.29 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.83(s,1H),8.61(s,1H),8.08(d,J=8.4Hz,1H),7.98(d,J=2.0Hz, 1H),7.73(dd,J=8.8,2.0Hz,1H),6.75(t,J=4.0Hz,1H),5.33(s,2H),4.53(d,J=12.4Hz,1H),3.62(d,J=1 2.4Hz,1H),3.54-3.44(m,4H),3.30(s,3H),3.05-2.97(m,3H),2.83(d,J=11.2Hz,1H),2.73(d,J=11.2Hz ,1H),2.62-2.42(m,3H),2.20–2.13(m,1H),1.99–1.95(m,1H),1.72–1.64(m,1H),1.21(t,J=7.2Hz,3H).

[0591] Example 51 Preparation of (R)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 68)

[0592] Step 1: Place 2-iodo-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (52-c, 420 mg, 1.06 mmol) in a 100 mL eggplant flask and add 10 mL of 1,4-dioxane solution. Then, add 2-bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 250 mg, 1.03 mmol) and DIPEA (0.5 mL, 3.09 mmol) sequentially. Stir at 75°C for 5 hours. The reaction solution was concentrated and purified by column chromatography (PE:EA=2:1) ​​to give 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (68-a, 300 mg, 0.58 mmol, 57% yield) MS Calcd: 512.94; MS Found: 513.94 ([M+H] + ).

[0593] Step 2: 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (68-a, 300 mg, 0.58 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (184.3 mg, 0.88 mmol) were dissolved in 1,4-dioxane (8 mL) and H2O (4 mL), and Pd(dppf)Cl2 (42.7 mg, 0.04 mmol) and potassium phosphate (403 mg, 1.75 mmol) were added in sequence. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 5.0 hours. The reaction solution was concentrated, and 30 mL of ethyl acetate was added to the residue. The mixture was filtered through celite, and the filtrate was concentrated and purified by column chromatography (DCM:MeOH=5:1) to give N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68-b, 220 mg, 0.33 mmol, 73% yield). MS Calcd: 515.07; MS Found: 516.28 ([M+H] + ).

[0594] Step 3: Place N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68-b, 220 mg, 0.33 mmol) and N-bromosuccinimide (69.9 mg, 0.40 mmol) in a 100 mL eggplant-shaped flask, add 10 mL of acetonitrile, and then raise the temperature to 60°C for reaction for 1 hour. The reaction solution was poured into 20 mL of water and extracted with EA (3×20 mL). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM:MeOH=6:1) to give 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (68-c, 50 mg, 0.08 mmol, 25% yield) MS Calcd: 594.98; MS Found: 595.92 ([M+H] + ).

[0595] Step 4: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)acetamide (68-c, 50 mg, 0.08 mmol) and (R)-1-N-Boc-2-methylpiperazine (168 mg, 0.84 mmol), AgBF4 (16.4 mg, 0.08 mmol) were added to dry DMSO (1 mL), replaced with nitrogen for 1 minute, and then the temperature was raised to 120 ° C for 18 hours. The reaction system was poured into water (20 mL), and then extracted with EA (20 mL×3). The organic phases were combined, dried, and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=20:1) to give (R)-4-(4-(2-((2,5-dichloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (68-d, 25 mg, 0.03 mmol, 41% yield) MS Calcd: 713.21; MS Found: 714.21 ([M+H] + ).

[0596] Step 5: Dissolve (R)-4-(4-(2-((2,5-dichloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (68-d, 25 mg, 0.03 mmol) in 4 mL of dichloromethane solution, add 1 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. The reaction solution was directly concentrated, and 20 mL of saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried, and concentrated to give crude (R)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68-e, 20 mg, 0.03 mmol, 93% yield). MS Calcd: 613.16; MS Found: 614.16 ([M+H] + ).

[0597] Step 6: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 12.6 mg, 0.10 mmol) and 1-chloro-N,N,2-trimethylpropenamine (13.0 mg, 0.10 mmol) were added to 3 mL of dichloromethane solution respectively, stirred at room temperature for 3 hours, and then (R)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68-e, 20 mg, 0.03 mmol) and DIPEA (0.02 mL, 0.1 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. To the reaction solution was added 10 mL of saturated sodium bicarbonate solution, and the mixture was extracted with DCM (10 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: (R)-N-(2,5-dichloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (68, 3 mg, 0.01 mmol, 12% yield). MS Calcd: 724.15; MS Found: 725.24 ([M+H] + ).

[0598] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.80(s,1H),8.60(d,J=1.6Hz,1H),8.30(s,1H),8.04 (s,1H),6.85-6.83(m,1H),5.34(s,2H),4.81-4.78(m,0.5H),4.40(d,J=12.8Hz,0.5H),4.2 7(d,J=2.8Hz,2H),3.88-3.80(m,3H),3.71–3.67(m,1H),3.54–3.44(m,2H),3.27–3.11(m,2 H),2.96–2.83(m,2H),2.73–2.63(m,2H),1.43(dd,J=6.8,2.0Hz,3H),1.24(t,J=7.2Hz,3H).

[0599] Example 52 Preparation of (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 69)

[0600] Step 1: Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 82 mg, 0.42 mmol) and (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-e, 50 mg, 0.08 mmol) were placed in a 25 mL eggplant flask, and 2 mL of 2-methyl-2-butanol was added. The mixture was then stirred at 180° C. for 30 minutes. The reaction mixture was concentrated directly and purified by Prep-HPLC to give the title compound: (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (69, 15 mg, 0.02 mmol, 24% yield). MS Calcd: 743.26; MS Found: 744.31 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.98(s,1H),7.78(s,1H),7.57(s,1H),6.84(t,J=2.0H z,1H),5.30(s,2H),4.68-4.61(m,1H),4.29-4.20(m,3H),3.82(t,J=5.2Hz,2H),3.72-3.68(m ,1H),3.53-3.48(m,1H),3.42–3.14(m,5H),2.99-2.94(m,1H),2.78(d,J=10.0Hz,1H),2.765( d,J=11.6Hz,1H),2.38(s,3H),1.43(d,J=6.4Hz,3H),1.24(t,J=7.2Hz,3H),1.00–092(m,4H).

[0601] Example 53 Preparation of (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 70)

[0602] Step 1: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 32.6 mg, 0.25 mmol) and 1-chloro-N,N,2-trimethylpropenamine (33.7 mg, 0.25 mmol) were added to 3 mL of dichloromethane solution respectively, and stirred at room temperature for 3 hours. Then, (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (54-e, 50 mg, 0.08 mmol) and DIPEA (0.04 mL, 0.2 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. To the reaction solution was added 10 mL of saturated sodium bicarbonate solution, and the mixture was extracted with DCM (10 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: (R)-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (70, 16 mg, 0.02 mmol, 27% yield). MS Calcd: 704.21; MS Found: 705.26 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.79(s,1H),8.60(d,J=2.0Hz,1H),7.98(s,1H),7.77(s,1H), 6.85–6.83(m,1H),5.29(s,2H),4.82–4.78(m,0.5H),4.40(d,J=12.8Hz,0.5H),4.27(d,J=2.8Hz,2H) ,3.89–3.81(m,3H),3.72-3.67(m,1H),3.54–3.4(m,2H),3.30-3.13(m,2H),2.97–2.83(m,1.5H),2.7 3–2.63(m,1.5H),2.54–2.51(m,1H),2.38(s,3H),1.43(dd,J=6.8,2.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0603] Example 54 Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 71)

[0604] Step 1: Weigh 4-hydroxyisoxazole-3-carboxylic acid (Int-7, 25 mg, 0.19 mmol) and HATU (97.5 mg, 0.26 mmol) into a 25 mL single-necked bottle, add DCM (2 mL) and DIPEA (0.06 mL, 0.38 mmol), stir at room temperature for 5 minutes, and then add 2-(2-(3,6-dihydropyran-4-yl)-5-ethyl-7-oxo-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)yl)-N-(2-methyl-4-trifluoromethylphenyl)acetamide (1-c, 70 mg, 0.13 mmol), and react at room temperature for 1 hour. The reaction mixture was added to 10 mL of saturated ammonium chloride solution and stirred. The mixture was then separated and the organic phase was concentrated. The residue was purified by prep-HPLC to give the title compound: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (71,22 mg, 0.03 mmol, 94% yield). MS Calcd: 656.23; MS Found: 657.32 ([M+H]+ ). 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.75(s,1H),8.60(s,1H),7.74(t,J=7.2Hz,1H),7.64(d,J=2.0 Hz,1H),7.56–7.53(m,1H),6.85(s,1H),5.27(s,2H),4.53(d,J=12.4Hz,1H),4.28(q,J=2.8Hz,2H),3. 83(t,J=5.6Hz,2H),3.63(d,J=12.4Hz,1H),3.52–3.45(m,2H),3.37–3.32(m,1H),3.07-2.99(m,4H), 2.84(d,J=11.2Hz,1H),2.73(d,J=11.2Hz,1H),2.55-2.48(m,1H),2.37(s,3H),1.22(t,J=7.2Hz,3H).

[0605] Example 55 Preparation of (R)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 72)

[0606] Step 1: 2-Bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 2.0 g, 8.23 ​​mmol), N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-2-iodoacetamide (3.0 g, 8.23 ​​mmol) and DIPEA (3.2 g, 24.68 mmol) were added to 60 mL of dioxane solution and stirred at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 2-(2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-a, 3.6 g, 7.56 mmol, 91.9% yield). MS Calcd: 475.03; MS Found: 476.05 ([M+H] + ).

[0607] Step 2: 2-(2-Bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-a, 3.6 g, 7.56 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.58 g, 7.5 mmol), Pd(dppf)Cl2·CH2Cl2 (1.07 g, 1.32 mmol) and potassium phosphate (4.77 g, 22.5 mmol) were added successively to 40 mL of a mixed solution of dioxane / water (4:1), the mixture was evacuated and replaced with nitrogen three times, and the temperature was raised to 80°C and stirred for 2 h. The reaction solution was completely concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-b, 1.5 g, 3.2 mmol, 41.6% yield). MS Calcd: 479.16; MS Found: 480.19 ([M+H] + ).

[0608] Step 3: Dissolve 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-b, 1.34 g, 2.8 mmol) in DMF (10 mL) solution, then slowly add NBS (0.55 g, 3.07 mmol), heat to 60 ° C and stir for 3 h. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA) to obtain 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-c, 1.3 g, 2.33 mmol, 83.3% yield). MS Calcd: 557.07; MS Found: 558.15 ([M+H] + ).

[0609] Step 4: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-c, 1.3 g, 2.33 mmol), (R)-1-N-Boc-2-methylpiperazine (5.02 g, 25.08 mmol) and silver tetrafluoroborate (0.58 g, 3.01 mmol) were added successively to a DMSO (10 mL) solution, the mixture was evacuated, replaced with nitrogen three times, and the temperature was raised to 120°C and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain (R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(-2-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (72-d, 1.2 g, 1.77 mmol, 75.9% yield). MS Calcd: 677.29; MS Found: 678.32 ([M+H] + ).

[0610] Step 5: (R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(-2-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (72-d, 1.2 g, 1.77 mmol) was added to a hydrochloric acid-dioxane solution (20 mL) and stirred at room temperature overnight. The reaction solution was completely concentrated and the residue was added to the mixture. Saturated sodium bicarbonate solution was added to the residue, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-e, 0.6 g, 1.03 mmol, 58.8% yield). MS Calcd: 577.24; MS Found: 578.06 ([M+H] + ).

[0611] Step 6: Add 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 102 mg, 0.52 mmol), DIPEA (40 mg, 0.31 mmol) and (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-e, 50 mg, 0.09 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180°C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: (R)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72, 20 mg, 0.03 mmol, 25.1% yield). MS Calcd: 727.29; MS Found: 728.37 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),7.81(d,J=12.4Hz,1H),7.69(d,J=8.4Hz,1H),7.59(s,1H),6.85–6 .83(m,1H),5.32(s,2H),4.67-4.58(m,1H),4.27-4.13(m,3H),3.82(t,J=5.2Hz,2H),3.70(dd,J=11.8,3. 6Hz,1H),3.54–3.39(m,3H),3.21-3.14(m,1H),2.99-2.91(m,1H),2.79(d,J=10.0Hz,1H),2.66(d,J=11. 6Hz,1H),2.54-2.49(m,2H),2.38(s,3H),1.43(d,J=6.4Hz,3H),1.24(t,J=7.2Hz,3H),1.03–0.93(m,4H).

[0612] Example 56 Preparation of (R)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 73)

[0613] Step 1: Add 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 105 mg, 0.5 mmol), DIPEA (40 mg, 0.31 mmol) and (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-e, 60 mg, 0.1 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to obtain the title compound: (R)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (73, 18 mg, 0.02 mmol, 23.7% yield). MS Calcd: 741.30; MS Found: 742.34 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.81(d,J=12.8Hz,1H),7.71–7.67(m,2H),6.85–6.83(m,1H),5.32(s,2 H),4.80(p,J=8.4Hz,1H),4.65–4.59(m,1H),4.28-4.18(m,3H),3.82(t,J=5.2Hz,2H),3.71(dd,J=12.0,3.6H z,1H),3.54–3.49(m,1H),3.21-3.14(m,1H),2.98-2.92(m,1H),2.79(d,J=10.0Hz,1H),2.69–2.64(m,1H),2. 56–2.49(m,3H),2.38(s,3H),2.37-2.27(m,2H),1.84-1.76(m,2H),1.44(d,J=6.4Hz,3H),1.32-1.22(m,5H).

[0614] Example 57 Preparation of (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazole-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 74)

[0615] Step 1: 4-Hydroxyisoxazole-3-carboxylic acid (int-7, 40 mg, 0.31 mmol) and 1-chloro-N,N,2-trimethylpropenamine (44 mg, 0.33 mmol) were added to a DCM solution (2 mL) respectively, stirred at room temperature for 3 hours, and then (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-e, 60 mg, 0.1 mmol) and DIPEA (80 mg, 0.62 mmol) were added, and the temperature was continued to rise to 40 ° C and stirred for 5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound: (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)-3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (74 mg, 15 mmol, 21.7% yield). MS Calcd: 688.24; MS Found: 689.24 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.90(s,1H),8.60(d,J=1.6Hz,1H),7.81(d,J=1 2.8Hz,1H),7.69(d,J=8.4Hz,1H),6.85–6.83(m,1H),5.32(s,2H),4.82-4.77(m,0.5H) ,4.40(d,J=12.8Hz,0.5H),4.27(d,J=2.8Hz,2H),3.89–3.81(m,3H),3.72-3.67(m,1H) ,3.54–3.44(m,2H),3.31-3.12(m,3H),2.96-2.83(m,1.5H),2.72-2.63(m,1.5H),2.37 (s,3H),1.43(dd,J=6.4,2.0Hz,3H),1.23(t,J=7.2Hz,3H).

[0616] Example 58 Preparation of N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 75)

[0617] Step 1: To a 250 mL eggplant flask, add 3-fluoro-4-(trifluoromethyl)aniline (75-a, 10 g, 55.83 mmol) and DCM (50 mL), followed by BF3OEt2 (7.9 g, 55.83 mmol) and NCS (8.2 g, 61.42 mmol). Stir and react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE:EA = 95:5) to obtain 2-chloro-5-fluoro-4-(trifluoromethyl)aniline (75-b, 8.1 g, 37.92 mmol, 67.9%). MS Calcd: 213.00; MS Found: 212.12 ([MH] - ).

[0618] Step 2: To a 250 mL eggplant flask, add 2-chloro-5-fluoro-4-(trifluoromethyl)aniline (75-b, 8.1 g, 37.92 mmol) and DCM (50 mL), followed by triethylamine (10.51 mL, 75.84 mmol). Chloroacetyl chloride (3.04 mL, 37.92 mmol) in DCM (10 mL) was slowly added under an ice bath and allowed to react overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (PE:EA = 92:8) to give 2-chloro-N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]acetamide (75-c, 4.5 g, 15.52 mmol, 40.9%). MS Calcd: 288.97; MS Found: 288.18 ([M+H] - ).

[0619] Step 3: 2-Chloro-N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]acetamide (75-c, 4.6 g, 27.59 mmol) and acetone (30 mL) were added to a 250 mL eggplant flask and reacted at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE:DCM=70:30) to give N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (75-d, 2.23 g, 5.85 mmol, 42.1%). MS Calcd: 380.90; MS Found: 379.93 ([MH] - ).

[0620] Step 4: To a 50 mL eggplant-shaped flask, tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-5, 205.2 mg, 0.48 mmol), dioxane (10 mL), N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (75-d, 200 mg, 0.55 mmol) and DIPEA (0.25 mL, 1.50 mmol) were added and the mixture was reacted at 80°C under nitrogen protection for 2 hr. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (DCM:MeOH=20:1) to give tert-butyl 4-(4-(2-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (75-e, 292 mg, 0.43 mmol, 89.6%). MS Calcd: 683.22; MS Found: 684.36 ([M+H] + ).

[0621] Step 5: To a 50 mL eggplant-shaped flask, add tert-butyl 4-(4-(2-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (75-e, 290 mg, 0.42 mmol) and solvent DCM (10 mL), add TFA (3 mL), and stir at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the pH was adjusted to 8. The solution was extracted with DCM (3*50 mL). The organic phases were combined to give N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (75-f, 221 mg, 0.38 mmol, 89.3%). MS Calcd: 583.17; MS Found: 584.2 ([M+H] + ).

[0622] Step 6: To a 25 mL eggplant-shaped flask, add N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (75-f, 60 mg, 0.10 mmol) and 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 21.6 mg, 0.10 mmol), and then add 2-methyl-2-butanol (1 mL) solution and DIPEA (0.04 mL). Vacuum the mixture and replace with nitrogen three times. Microwave the mixture at 180°C for 30 min. The crude product was dried under reduced pressure and purified by prep-HPLC to give the title compound: N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyrazol-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (75,16 mg, 0.02 mmol, 20.8% yield). MS Calcd: 747.23; MS Found: 748.28 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.13(d,J=12.8Hz,1H),8.03(d,J=7.2Hz,1H),7.5 6(s,1H),6.85–6.83(m,1H),5.39(s,2H),4.82-4.73(m,1H),4.37(d,J=12.4Hz,2H),4.27 (q,J=2.8Hz,2H),3.82(t,J=5.6Hz,2H),3.51-3.44(m,2H),3.12–2.98(m,4H),2.73(d,J= 11.2Hz,2H),2.48–2.43(m,2H),2.27-2.19(m,2H),1.85–1.64(m,2H),1.26-1.19(m,5H).

[0623] Example 59 Preparation of (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 76)

[0624] Step 1: Add 2-bromo-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (int-3a, 600 mg, 2.47 mmol) and N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (75-d, 986.9 mg, 2.71 mmol) to a 100 mL round-bottom flask, add dioxane (30 mL) and DIPEA (1.23 mL, 7.40 mmol) and stir at 80 ° C under nitrogen protection for 6 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (PE:EA=1:5) to give 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]acetamide (76-a, 1.04 g, 2.09 mmol, 84.8%). MS Calcd: 494.97, 496.97; MS Found: 495.99, 497.94 ([M+H] + ).

[0625] Step 2: Add 2-(2-bromo-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)-N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]acetamide (76-a, 1.0 g, 2.01 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.6 g, 3.02 mmol), Pd(dppf)Cl2 (0.1 g, 0.20 mmol), and potassium phosphate (1.4 g, 6.04 mmol) to a mixed solvent of water (5 mL) and dioxane (20 mL), raise the temperature to 85°C, and stir for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (PE:EA=1:5) to give N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (76-b, 508 mg, 1.02 mmol, 50.5%). MS Calcd: 499.10; MS Found: 500.15 ([M+H] + ).

[0626] Step 3: Dissolve N-[2-chloro-5-fluoro-4-(trifluoromethyl)phenyl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide (76-b, 0.45 g, 0.9 mmol) in DMF (5 mL) solution, then slowly add NBS (0.18 g, 1.0 mmol), heat to 60 ° C and stir for 3 h. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA% 100) to obtain 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)acetamide (76-c, 0.45 g, 0.78 mmol, 86.3% yield). MS Calcd: 577.01; MS Found: 578.07 ([M+H] + ).

[0627] Step 4: 2-(6-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)acetamide (76-c, 0.45 g, 0.78 mmol), (R)-1-N-Boc-2-methylpiperazine (1.56 g, 7.78 mmol) and silver tetrafluoroborate (0.18 g, 0.93 mmol) were added to DMSO (4 mL) solution in sequence, the mixture was evacuated and replaced with nitrogen three times, and the temperature was raised to 120°C and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA% 100) to obtain (R)-4-(4-(2-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (76-d, 0.48 g, 0.69 mmol, 88.4% yield). MS Calcd: 697.24; MS Found: 643.0 ([M-56+H] + ).

[0628] Step 5: (R)-4-(4-(2-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (76-d, 0.48 g, 0.69 mmol) was added to a hydrochloric acid-dioxane solution (20 mL) and stirred at room temperature overnight. The reaction solution was completely concentrated, and a saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (76-e, 0.3 g, 0.5 mmol, 73.0% yield). MS Calcd: 597.19; MS Found: 598.16 ([M+H] + ).

[0629] Step 6: Add 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 82 mg, 0.42 mmol), DIPEA (32 mg, 0.25 mmol) and (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (76-e, 50 mg, 0.08 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180°C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to obtain the title compound: R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclopropyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (75, 15 mg, 0.02 mmol, 23.4% yield). MS Calcd: 747.23; MS Found: 748.24 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.14(d,J=12.8Hz,1H),8.04(d,J=7.2Hz,1H),7.59(s,1H),6 .85-6.83(m,1H),5.39(s,2H),4.63(brs,1H),4.29-4.17(m,3H),3.82(t,J=5.2Hz,2H),3.70(d,J= 11.2Hz,1H),3.54–3.40(m,2H),3.18–3.13(m,1H),2.98-2.91(m,1H),2.79(d,J=10.0Hz,1H),2.66 (d,J=11.2Hz,1H),2.55-2.48(m,1H),1.43(d,J=6.4Hz,3H),1.27-1.22(m,5H),1.02–0.93(m,4H).

[0630] Example 60 Preparation of N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 77)

[0631] Step 1: To a 25 mL eggplant-shaped flask, 4-hydroxyisoxazole-3-carboxylic acid (int-7, 33.2 mg, 0.26 mmol), (1-chloro-2-methylprop-1-enyl)dimethylamine (35.3 mg, 0.27 mmol), and DCM (2 mL) were added, and the mixture was stirred under nitrogen for 3 hours. DIPEA (0.14 mL, 0.86 mmol) and N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (75-f, 50 mg, 0.09 mmol) were added and the mixture was reacted at room temperature for 2 hours. The crude product was dried under reduced pressure and purified by prep-HPLC to give the title compound: N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (77, 16.1 mg, 0.02 mmol, 24.4% yield). MS Calcd: 694.17; MS Found: 695.2 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ10.31(brs,1H),8.60(s,1H),8.14(d,J=12.8Hz,1H),7.99(d,J= 7.2Hz,1H),6.84(t,J=2.0Hz,1H),5.35(s,2H),4.54(d,J=12.4Hz,1H),4.27(q,J=2.8Hz, 2H),3.82(t,J=5.6Hz,2H),3.64(d,J=12.4Hz,1H),3.52-3.46(m,3H),3.07–2.97(m,3H), 2.84(d,J=11.2Hz,1H),2.74(d,J=11.2Hz,1H),2.54-2.48(m,2H),1.21(t,J=7.2Hz,3H).

[0632] Example 61 Preparation of (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 78)

[0633] Step 1: Add 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 88 mg, 0.42 mmol), DIPEA (32 mg, 0.25 mmol) and (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (76-e, 50 mg, 0.08 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180°C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to obtain the title compound: (R)-N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (78, 16 mg, 0.02 mmol, 24.3% yield). MS Calcd: 761.25; MS Found: 762.29 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6 + heavy water exchange) δ8.06 (d, J = 12.4 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 6.80 (s, 1H), 5.34 (s, 2H), 4.80-4.73 (m, 1H), 4.63 (brs, 1H), 4.25-4.18 (m, 3H), 3.79-3.76 (m, 2H), 3.64-3.60 (m,1H),3.48-3.42(m,1H),3.15-3.10(m,1H),2.94–2.88(m,1H),2.73(d,J=9.2Hz,1H),2.61(d,J=1 1.2Hz,1H),2.48–2.35(m,4H),2.16(brs,2H),1.73-1.67(m,2H),1.41(brs,4H),1.23-1.19(m,5H).

[0634] Example 62 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(tetrahydro-2H-pyridin-4-yl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 79)

[0635] Step 1: Diethyl ethoxymethylenemalonate (3-a, 0.7 g, 3.28 mmol), tetrahydro-2H-pyran-4-ylhydrazine hydrochloride (0.5 g, 3.28 mmol), and potassium carbonate (1.36 g, 9.83 mmol) were added to an aqueous solution (10 mL) and stirred at 100°C for 6 hours. The pH was adjusted to 2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain ethyl 5-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate (79-a, 0.6 g, 2.5 mmol, 76.2% yield). MS Calcd: 240.11; MS Found: 241.13 ([M+H] + ).

[0636] Step 2: Add 5-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (79-a, 106 mg, 0.44 mmol), DIPEA (34 mg, 0.27 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (int-2, 50 mg, 0.09 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180 ° C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-1-(tetrahydro-2H-pyridin-4-yl)-1H-pyrazol-4-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (79, 12 mg, 0.02 mmol, 17.1% yield). MS Calcd: 759.25; MS Found: 760.25 ([M+H] + ).1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.08(d,J=8.4Hz,1H),7.98(d,J=2.0Hz,1H),7.74(dd,J=8.8,2 .0Hz,1H),7.69(s,1H),6.86-6.84(m,1H),5.35(s,2H),4.42-4.34(m,4H),4.27(q,J=2.8Hz,2H),4.0 0–3.95(m,2H),3.82(t,J=5.6Hz,2H),3.52-3.45(m,4H),3.20-3.14(m,2H),3.03(q,J=7.2Hz,2H),2. 78(d,J=11.2Hz,2H),2.52–2.48(m,2H),2.06-1.96(m,2H),1.80–1.75(m,2H),1.23(t,J=7.2Hz,3H).

[0637] Example 63 Preparation of (R)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (Compound 80)

[0638] Step 1: Add 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (41-a, 97 mg, 0.43 mmol), DIPEA (34 mg, 0.26 mmol) and (R)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-methylpiperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (72-e, 50 mg, 0.09 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180°C and stir for 30 min. The reaction mixture was completely concentrated, and the residue was purified by prep-HPLC to give the title compound: (R)-2-(6-(4-(1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl)-3-methylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyrazin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (80.8 mg, 0.01 mmol, 11.1% yield). MS Calcd: 755.32; MS Found: 756.34 ([M+H] + ). 1 H NMR(400MHz, DMSO-d6)δ10.10(s,1H),7.81(d,J=12.8Hz,1H),7.70–7.67(m,2H),6.85–6.83(m,1H),5.3 2(s,2H),4.69–4.64(m,1H),4.28(q,J=2.8Hz,2H),3.83(t,J=5.2Hz,2H),3.73–3.69(m,1H),3.52(t,J= 11.2 Hz, 1H), 3.20-3.15 (m, 1H), 2.97-2.93 (m, 1H), 2.81 (d, J = 10.0 Hz, 1H), 2.70–2.66 (m, 1H), 2.52–2.48 (m, 2H), 2.38 (s, 3H), 2.03–1.78 (m, 7H), 1.68–1.62 (m, 2H), 1.45 (brs, 3H), 1.26–1.23 (m, 5H), amide hydrogen peak was not observed.

[0639] Example 64 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 81)

[0640] Step 1: tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 0.4 g, 0.6 mmol), cis-2,6-dimethylmorpholine (0.35 g, 3.02 mmol) and potassium acetate (0.35 g, 3.62 mmol) were added to DMSO solution (3 mL), heated to 120 ° C and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:1) to obtain tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (81-a, 0.17 g, 0.24 mmol, 40.4% yield). MS Calcd: 696.28; MS Found: 641.19 ([M-56+H] + ).

[0641] Step 2: Add tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (81-a, 0.17 g, 0.24 mmol) to a hydrochloric acid-dioxane solution (4 mL) and stir at room temperature overnight. The reaction solution was completely concentrated, and a saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (81-b, 0.11 g, 0.18 mmol, 75.6% yield). MS Calcd: 596.22; MS Found: 597.23 ([M+H] + ).

[0642] Step 3: Add 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 70 mg, 0.34 mmol), DIPEA (26 mg, 0.2 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (81-b, 40 mg, 0.07 mmol) to 2-methyl-2-butanol solution (2 mL), heat the oil bath to 180°C and stir for 30 min. The reaction solution was completely concentrated, and the residue was purified by prep-HPLC to obtain the title compound: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl)piperazin-1-yl)-2-(cis-2,6-dimethylmorpholinyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (81, 0.85 mg, 0.001 mmol, 1.6% yield). MS Calcd: 760.28; MS Found: 759.23 ([MH] - ).

[0643] Example 65 Preparation of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-(5-ethyl-6-{4-[(4-hydroxyisoxazol-3-yl)acyl]piperazin-1-yl}-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (Compound 83)

[0644] Step 1: To a 100 mL eggplant flask was added tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 400 mg, 0.60 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (202 mg, 0.91 mmol) and solvent 1,4-dioxane (8 mL) and H2O (2 mL). Then, potassium phosphate (417 mg, 1.81 mmol) and Pd(dppf)Cl2 (44 mg, 0.06 mmol) were added thereto, and the mixture was stirred at 90°C for 3 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM:MeOH=30:1) to give tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (83-a, 300 mg, 0.44 mmol, 73.2% yield). MS Calcd: 678.27.; MS Found: 679.31 ([M+H] + ).

[0645] Step 2: To a 100 mL eggplant-shaped flask, tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (83-a, 300 mg, 0.44 mmol) and DCM (2 mL) were added. TFA (0.5 mL) was then added and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (83-b, 200 mg, 0.35 mmol, 78.2% yield). MS Calcd: 578.21; MS Found: 579.41 ([M+H] + ).

[0646] Step 3: 4-hydroxyisoxazole-3-carboxylic acid (int-7, 34 mg, 0.26 mmol) and solvent DCM (2 mL) were added to a 50 mL eggplant flask. Then (1-chloro-2-methylprop-1-enyl)dimethylamine (36 mg, 0.27 mmol) was added and stirred at room temperature for 3 hours. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (83-b, 50 mg, 0.09 mmol) and DIPEA (101 mg, 0.86 mmol) were added and stirred at room temperature for 3 hours. The solvent was dried by rotary evaporation and methanol (1 .5 mL), and the residue was purified by prep-HPLC to give the title compound: N-[2-chloro-4-(trifluoromethyl)phenyl]-2-(5-ethyl-6-{4-[(4-hydroxyisoxazol-3-yl)acyl]piperazin-1-yl}-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4-yl)acetamide (83, 10 mg, 0.01 mmol, 16.6% yield) MS Calcd: 689.21; MS Found: 690.29 ([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.60(s,1H),8.29(s,1H),8.08(d,J=8.4Hz,1H),7.98(d, J=2.0Hz,1H),7.74(dd,J=8.8,2.0Hz,1H),6.79(t,J=3.2Hz,1H),5.34(s,2H),4.54(d,J=12.4H z,1H),3.64(d,J=12.4Hz,1H),3.52-3.45(m,2H),3.38-3.30(m,1H),3.04-2.98(m,4H),2.84(d ,J=11.2Hz,1H),2.74(d,J=11.2Hz,1H),2.58-2.50(m,5H),2.31(s,3H),1.21(t,J=7.2Hz,3H).

[0647] Example 66 Preparation of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6-(4-(4-hydroxyisoxazol-3-yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 84)

[0648] Step 1: To a 50 mL eggplant-shaped flask, tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (int-2a, 1 g, 1.51 mmol), 2-(5,6-dihydro-4H-pyran-2-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (0.5 g, 2.26 mmol), Pd(dppf)Cl2 (0.1 g, 0.15 mmol), potassium phosphate (1.0 g, 4.53 mmol), water (5 mL) and dioxane (20 mL) were added, the temperature was raised to 85°C and stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (PE:EA=5:1) to give tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (84-a, 641.3 mg, 0.96 mmol, 63.8%). MS Calcd: 665.23; MS Found: 664.27 ([MH] - ).

[0649] Step 2: Add tert-butyl 4-(4-(2-(2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (84-a, 600 mg, 0.90 mmol) and methanolic hydrochloric acid solution (10 mL) to a 50 mL eggplant-shaped flask and place at 50°C to react for 2 hours. The reaction mixture was adjusted to slightly alkaline and concentrated. The residue was purified by flash column chromatography (DCM:MeOH=10:1) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (84-b, 260 mg, 0.46 mmol, 51.0%). MS Calcd: 565.18; MS Found: 566.20 ([M+H] + ).

[0650] Step 4: To a 25 mL eggplant-shaped flask, 4-hydroxyisoxazole-3-carboxylic acid (36.4 mg, 0.27 mmol) and DCM (2 mL) were added, and the mixture was stirred under nitrogen for 3 hours. DIPEA (0.14 mL, 0.86 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (84-b, 50 mg, 0.09 mmol) were then added and the mixture was reacted at room temperature for 2 hou...

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof: Among them, R1 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5- or 6-membered cycloalkenyl, 5- to 10-membered heterocyclic group, 5- or 6-membered heteroaryl, phenyl, the heterocyclic group and heteroaryl each independently contain 1 to 2 heteroatoms selected from N, O or S, and the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic group, heteroaryl, phenyl are each independently unsubstituted or substituted by one or more identical or different R g substituents; Each R g is independently selected from: hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, C 1-4 alkyl-O-C(O)(CH2) n -, =O, azetidinyl, pyrrolidinyl, R'R"N-, where R' and R" are independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl is attached to the R1 main group through the N atom; the C 1-4 alkyl, C 1-4 alkoxy, azetidinyl, pyrrolidinyl are each independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; R2 is selected from wherein, L is selected from 7- to 10-membered spiroheterocycloalkyl, the spiroheterocycloalkyl group contains 2 to 3 N atoms; R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from hydroxy or halogen; R4 is selected from H, halogen, hydroxy, cyano, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 alkoxy, and the alkyl, cycloalkyl, and alkoxy are unsubstituted or substituted by one or more halogens; R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen; R6 is selected from H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted by one or more halogens; R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 1-4 alkoxy; the alkyl, cycloalkyl, alkoxy are unsubstituted or substituted by one or more halogens substitution; X is selected from N or CR8, and R8 is H or halogen; R 2a selected from 6- to 14-membered aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, wherein each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R c substituents; R 2b Selected from 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocycloalkyl, 5-14-membered heterocycloalkenyl, wherein each of the heteroaryl, heterocycloalkyl, and heterocycloalkenyl independently contains 1-4 heteroatoms selected from N, O, or S; each -CH2- on the 5-14-membered heterocycloalkyl and 5-14-membered heterocycloalkenyl rings is independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-14-membered heteroaryl, 6-14-membered aryl, 5-14-membered heterocycloalkyl, and 5-14-membered heterocycloalkenyl are each independently substituted by one or more R d substituted; R 2e selected from 5- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group, wherein each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R f substituents; Each R c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, cyano, amino; Each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 halocycloalkyl, hydroxy, halogen, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl and phenyl are unsubstituted or independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 cycloalkyl; Each R f is independently selected from hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl.

2. The compound represented by formula (I), or its stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: Among them, R1 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5- or 6-membered cycloalkenyl, 5- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, phenyl, wherein the heterocyclic group and heteroaryl contain 1-2 heteroatoms selected from N, O or S, and the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic group, heteroaryl, phenyl are unsubstituted or substituted by one or more identical or different R g substituents; Each R g is independently selected from: hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, C 1-4 alkyl-O-C(O)(CH2) n -, =O, azetidinyl, pyrrolidinyl, R’R”N-, wherein R’ and R” are independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl is attached to the R1 main group through the N atom; the C 1-4 alkyl, C 1-4 alkoxy, azetidinyl, pyrrolidinyl is unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; R2 is selected from wherein, L is selected from a 7- to 10-membered spiroheterocyclic group, R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 alkyl, where the alkyl is unsubstituted or substituted by one or more substituents selected from hydroxy or halogen; R4 is selected from H, halogen, hydroxy, cyano, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 alkoxy, and the alkyl, cycloalkyl and alkoxy are unsubstituted or substituted by one or more halogens; R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen; R6 is selected from H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted by one or more halogens; R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 1-4 alkoxy; the alkyl, cycloalkyl, alkoxy are unsubstituted or substituted by one or more halogens; X is selected from N or CR8, and R8 is H or halogen; R 2a selected from 6- to 14-membered aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, wherein each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R c substituents; R 2b selected from 5-membered heteroaryl, 8- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group, wherein each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, 8- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group is independently substituted by one or more R d substituted; R 2e selected from 5- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group, each of the heteroaryl and heterocyclic group independently containing 1 to 4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R f substituents; Each R c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, cyano, amino; Each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 halocycloalkyl, hydroxy, 4- to 7-membered heterocycloalkyl or halogen; said 4- to 7-membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; Each R f is independently selected from hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl.

3. The compound represented by formula (I), or its stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: Among them, R1 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5- or 6-membered cycloalkenyl, 5- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, phenyl, the heterocyclic group and heteroaryl contain 1-2 heteroatoms selected from N, O or S, and the alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclic group, heteroaryl, phenyl are unsubstituted or substituted by one or more identical or different R g substituents; Each R g is independently selected from: hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, C 1-4 alkyl-O-C(O)(CH2) n -, =O, azetidinyl, pyrrolidinyl, R'R"N-, where R' and R" are independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, n = 0, 1 or 2; the azetidinyl or pyrrolidinyl is attached to the R1 main group through the N atom; the C 1-4 alkyl, C 1-4 alkoxy, azetidinyl, pyrrolidinyl is unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; R2 is selected from wherein, L is selected from a 7- to 10-membered spiroheterocyclic group, R3 is selected from cyclopropyl, methoxy, -SCH3, C 1-4 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from hydroxy or halogen; R4 is selected from H, halogen, hydroxy, cyano, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 alkoxy, and the alkyl, cycloalkyl, alkoxy are unsubstituted or substituted by one or more halogens; R5 is selected from H, methoxy, hydroxy, cyano, methyl, halogen; R6 is selected from H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted by one or more halogens; R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 1-4 alkoxy; the alkyl, cycloalkyl, and alkoxy are unsubstituted or substituted with one or more halogens; X is selected from N or CR8, and R8 is H or halogen; R 2a selected from 6- to 14-membered aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the aryl, heteroaryl and heterocyclic group are unsubstituted or each independently substituted by one or more identical or different R c substituents; R 2b selected from 5-membered heteroaryl, 8- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group, each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group are each independently substituted by one or more R d substituted; R 2e selected from 5- to 14-membered heteroaryl, 6- to 14-membered aryl, 5- to 14-membered heterocyclic group, each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the heteroaryl, aryl and heterocyclic group are unsubstituted or each is independently substituted by one or more identical or different R f substituted; Each R c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, cyano, amino; Each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 halocycloalkyl, hydroxy or halogen; Each R f is independently selected from hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl.

4. The compound according to any one of claims 1-3, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R2 is selected from Preferably, R2 is selected from Preferably, R2 is selected from R 2b selected from 5-membered heteroaryl and 8-14-membered heteroaryl; each of the 5-membered heteroaryl and 8-14-membered heteroaryl independently contains 1-4 heteroatoms selected from N, O, and S; each of the 5-membered heteroaryl and 8-14-membered heteroaryl is independently substituted with one or more R d substituted; Preferably, R 2b is selected from 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl; the The 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl each independently contain 1-4 heteroatoms selected from N, O, and S; the 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl are each independently substituted with one or more R d substituted; Preferably, R 2b is selected from 5-membered heteroaryl, 5-membered heteroaryl-fused-5-membered heteroaryl, benzo-5-membered heteroaryl, 6-membered heteroaryl-fused-5-membered heteroaryl, benzo-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl; each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-2 heteroatoms selected from N, O, and S; each of the 5-membered heteroaryl, 5-membered heteroaryl-fused-5-membered heteroaryl, benzo-5-membered heteroaryl, 6-membered heteroaryl-fused-5-membered heteroaryl, benzo-6-membered heteroaryl, 6-membered heteroaryl-fused-6-membered heteroaryl is independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, benzo-5-membered heteroaryl, 6-membered heteroaryl-fused-5-membered heteroaryl, benzo-6-membered heteroaryl; each of the 5-membered heteroaryl and 6-membered heteroaryl independently contains 1-2 heteroatoms selected from N, O, and S; each of the 5-membered heteroaryl, benzo-5-membered heteroaryl, 6-membered heteroaryl-fused-5-membered heteroaryl, and benzo-6-membered heteroaryl is independently substituted by one or more R d substituents; Preferably, R 2b is selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuryl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrrolyl, pyridofuryl, pyridothienyl, pyridopyrazolyl, pyridimidazolyl, pyridothiazolyl, pyridoisothiazolyl, pyridooxazolyl, pyridoisoxazolyl, benzopyridyl, benzopyrimidyl; the pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuryl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrrolyl, pyridofuryl, pyridothienyl, pyridopyrazolyl, pyridimidazolyl, pyridothiazolyl, pyridoisothiazolyl, pyridooxazolyl, pyridoisoxazolyl, benzopyridyl, benzopyrimidyl are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridopyrimidyl, pyridofuryl, pyridopyrrolyl, pyridothienyl; the pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridopyrimidyl, pyridofuryl, pyridopyrrolyl, pyridothienyl are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from The said Each is independently substituted by one or more Rs d substituted; Preferably, R 2b is selected from Preferably, R 2b is selected from Each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, hydroxy, halogen, wherein exactly one R d is hydroxy; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S; the 5- or 6-membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O and S; Preferably, each R d is independently selected from C 1-4 alkyl, C 5-6 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 1-4 alkoxy, C 5-6 alkoxy, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, hydroxy, halogen, wherein exactly one R d is hydroxy; the 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S; the 5- or 6-membered heteroaryl independently contains 1, 2 or 3 heteroatoms selected from N, O and S; Preferably, each R d is independently selected from C 1-4 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, 6-membered heteroaryl, phenyl, hydroxy, halogen, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl contains 1 or 2 O heteroatoms; the 6-membered heteroaryl contains 1 or 2 N heteroatoms; Preferably, each R d is independently selected from C 1-2 alkyl, C 3-4 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-2 fluoroalkyl, C 3-4 fluoroalkyl, C 1-2 alkoxy, C 3-4 alkoxy, 4-7 membered heterocycloalkyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, hydroxy, halogen, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl group contains 1 O heteroatom; Preferably, each R d is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, methoxy, ethoxy, 4- to 7-membered heterocycloalkyl, pyridyl, hydroxy, F, Cl, Br, phenyl, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl contains 1 O heteroatom; Preferably, each R d is independently selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy Cl, phenyl, hydroxyl group, where there is exactly one R d is a hydroxyl group; Preferably, the hydroxyl group is substituted on a carbon atom at the ortho- or meta-position to the connection site with the main group; 2b ​ Preferably, the hydroxyl group is substituted on the carbon atom adjacent to the connection site of R 2b to the main group; Most preferably, R 2b is selected from 5. The compound according to any one of claims 1-3, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R2 is selected from Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and each of the heteroaryl, heterocycloalkyl, and heterocycloalkenyl independently contains 1-4 A heteroatom selected from N, O or S; each -CH2- on the 5- to 10-membered heteroalkyl or 5- to 10-membered heteroalkenyl ring is independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8- to 10-membered heteroaryl, 6- to 10-membered aryl, 5- to 10-membered heteroalkyl, 5- to 10-membered heteroalkenyl are each independently substituted by one or more R d substituted; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl fused to 5-6-membered heterocycloalkenyl, and each of the heteroaryl, heterocycloalkyl, and heterocycloalkenyl independently contains 1-4 heteroatoms selected from N, O, or S; each -CH2- on the heterocycloalkyl or heterocycloalkenyl ring is independently optionally replaced by -C(=O)-; and each of the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl fused to 5-6-membered heterocycloalkenyl is independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl-fused-5-6-membered heterocycloalkenyl, each of the heteroaryl, heterocycloalkyl, and heterocycloalkenyl independently contains 1-4 heteroatoms selected from N, O, or S; each -CH2- on the heterocycloalkyl or heterocycloalkenyl ring is independently optionally replaced by -C(=O)-; the 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 8-10-membered heterocycloalkyl, 8-10-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl-fused-5-6-membered heterocycloalkenyl are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 5- or 6-membered heterocycloalkyl-fused 5- or 6-membered heterocycloalkenyl; each -CH2- on the heterocycloalkyl or heterocycloalkenyl ring is independently optionally replaced by -C(=O)-; the heteroaryl, heterocycloalkyl, and heterocycloalkenyl each independently contain 1-2 heteroatoms selected from N, O, or S; the 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, 5- or 6-membered heterocycloalkyl-fused 5- or 6-membered heterocycloalkenyl are each independently substituted by 1, 2, 3, or 4 R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 1,5-dihydro-2H-pyrrol-2-one group, pyridone group, 6-membered heterocycloalkyl-fused pyridone group, and each of the heteroaryl and heterocycloalkyl independently contains 1 to 2 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 1,5-dihydro-2H-pyrrol-2-one group, pyridone group, 6-membered heterocycloalkyl-fused pyridone group is independently substituted with 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridinone group, 1,5-dihydro-2H-pyrrol-2-one group, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridinone group, 1,5-dihydro-2H-pyrrol-2-one group, Each is independently substituted by one, two, three or four Rs d ; Preferably, R 2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, The isoxazolyl, pyrazolyl, isothiazolyl, Each is independently substituted by one, two, three or four Rs d ; Preferably, R 2b is selected from The said Each is independently substituted by 1, 2, 3 or 4 Rs d ; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, amino or hydroxy; each of the 4- to 7-membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S; each of the 5- or 6-membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl and phenyl are unsubstituted or each is independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 1-4 alkoxy, C 5-6 alkoxy, 4-7 membered heterocycloalkyl, 5 or 6 membered heteroaryl, phenyl, cyano or hydroxy; each 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S; each 5 or 6 membered heteroaryl independently contains 1, 2 or 3 heteroatoms selected from N, O or S; the 5 or 6 membered heteroaryl and phenyl are unsubstituted or are each independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 O heteroatom; the phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl are unsubstituted or substituted by one or more substituents selected from F, Cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoromethoxy; Preferably, each R d is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, fluorine-substituted phenyl, chlorine-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxy-substituted phenyl, cyano-substituted pyridyl, fluorine-substituted pyridyl, chlorine-substituted pyridyl, methyl-substituted pyridyl, methoxy-substituted pyridyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridyl, trifluoromethoxy-substituted pyridyl, cyano-substituted pyridyl or hydroxy; Preferably, each R d is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy or Cl; Alternatively, preferably, each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, hydroxy or halogen, wherein at least one R d is hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl each independently contains 1 to 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl and phenyl are unsubstituted or each independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein at least one R d is hydroxy; each of the 4- to 7-membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S; each of the 5- or 6-membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl and phenyl are unsubstituted or are each independently substituted with one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 substituted by a substituent of cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein exactly one R d is hydroxy; each of the 4- to 7-membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S; each of the 5- or 6-membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryl and phenyl are unsubstituted or are each independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3- 5-cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 alkoxy, C 5-6 alkoxy, 4-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein exactly one R d is hydroxy; the 4-7 membered heterocycloalkyls each independently contain 1 or 2 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryls each independently contain 1, 2 or 3 heteroatoms selected from N, O or S; the 5- or 6-membered heteroaryls and phenyl are unsubstituted or each independently substituted by one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-5 cycloalkyl; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 O heteroatom; the phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl are unsubstituted or substituted with one or more substituents selected from F, Cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoromethoxy; Preferably, each R d is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, A fluorine-substituted phenyl, chlorine-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoromethoxy-substituted phenyl, cyano-substituted pyridyl, fluorine-substituted pyridyl, chlorine-substituted pyridyl, methyl-substituted pyridyl, methoxy-substituted pyridyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridyl, trifluoromethoxy-substituted pyridyl, cyano-substituted pyridyl or hydroxyl group, wherein there is exactly one R d is a hydroxyl group; Preferably, each R d is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, iso propyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy or Cl, where exactly one of R d is a hydroxyl group; Preferably, each R d is independently selected from phenyl, thienyl, pyridyl, hydroxyl, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy or Cl, where only one of the Rs d is a hydroxyl group, and the hydroxyl group is substituted at the R 2b ortho position to the attachment site of the main group; Preferably, R 2b is selected from Most preferably, R 2b is selected from 6. The compound according to any one of claims 1-3, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R2 is selected from or R2 is selected from or R2 is selected from Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group, and each of the heteroaryl and heterocyclic group independently contains 1-4 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, 8-10-membered heteroaryl, 6-10-membered aryl, 5-10-membered heterocyclic group is independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group, and each of the heteroaryl and heterocyclic group independently contains 1-4 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group is independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group, each of the heteroaryl and heterocyclic group independently contains 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group, 5- or 6-membered heterocyclic group-fused 5- or 6-membered heterocyclic group; each of the heteroaryl and heterocyclic group independently contains 1-2 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group, 5- or 6-membered heterocyclic group-fused 5- or 6-membered heterocyclic group is independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 5-membered heterocyclic group, 6-membered heterocyclic group, 6-membered heterocyclic group-fused pyridone group, and each of the heteroaryl group and the heterocyclic group independently contains 1 to 2 heteroatoms selected from N, O or S; the 5-membered heteroaryl, phenyl-fused 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 5-membered heterocyclic group, 6-membered heterocyclic group, 6-membered heterocyclic group-fused pyridone group are each independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridinone, 1,5-dihydro-2H-pyrrol-2-one, the isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholine bipyridinonyl, 1,5-dihydro-2H-pyrrol-2-onyl, Each is independently substituted by one, two, three or four Rs d ; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, amino or hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 1-4 alkoxy, C 5-6 alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy; each of said 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, cyano or hydroxy; each of the 4- to 7-membered heterocycloalkyl independently contains 1 O heteroatom; Preferably, each R d is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, or hydroxy; Preferably, each R d is independently selected from a hydroxyl group, a methyl group, an isopropyl group, a tert-butyl group, a cyclobutyl group, a cyclopentyl group, a cyclopropyl group, -CH2CF3, Methoxy or Cl; Alternatively, preferably, each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, hydroxy or halogen, wherein at least one R d is hydroxy; the 4- to 7-membered heterocycloalkyls each independently contain 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, cyano or hydroxy, wherein at least one R d is hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 4- to 7-membered heterocycloalkyl, cyano or hydroxy, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 alkoxy, C 5-6 alkoxy, 4-7-membered heterocycloalkyl, cyano or hydroxy, wherein exactly one R d is hydroxy; the 4-7-membered heterocycloalkyls are each independently contains 1 or 2 heteroatoms selected from N, O or S; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, 4- to 7-membered heterocycloalkyl, cyano or hydroxy, wherein exactly one R d is hydroxy; the 4- to 7-membered heterocycloalkyl each independently contains 1 O heteroatom; Preferably, each R d is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, -CH2CF3, Methoxy, ethoxy, or a hydroxyl group, where exactly one of the Rs d is a hydroxyl group; Preferably, each R d is independently selected from hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy or Cl, and exactly one of the Rs d is a hydroxyl group; Preferably, each R d is independently selected from hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH2CF3, Methoxy Or Cl, and there is exactly one R d is a hydroxyl group, and the hydroxyl group is substituted at R 2b at the ortho position of the connection site with the main group; Preferably, R 2b is selected from Most preferably, R 2b is selected from 7. The compound according to any one of claims 1-3, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R2 is selected from or R2 is selected from or R2 is selected from Preferably, R 2b is selected from 5-membered heteroaryl, 8- to 10-membered heteroaryl, 6- to 10-membered aryl, 5- to 10-membered heterocyclic group, and each of the heteroaryl and heterocyclic group independently contains 1 to 4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8- to 10-membered heteroaryl, 6- to 10-membered aryl, 5- to 10-membered heterocyclic group are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group, and each of the heteroaryl and heterocyclic group independently contains 1-4 heteroatoms selected from N, O or S; the 5-membered heteroaryl, 8-10-membered heteroaryl, phenyl, naphthyl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group are each independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group, and each of the heteroaryl and heterocyclic group independently contains 1-4 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, 8-10-membered heteroaryl, 5- or 6-membered heterocyclic group, 8-10-membered heterocyclic group is independently substituted by one or more R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group, 5- or 6-membered heterocyclic group-fused 5- or 6-membered heterocyclic group; each of the heteroaryl and heterocyclic group independently contains 1-2 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group, 5- or 6-membered heterocyclic group-fused 5- or 6-membered heterocyclic group is independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from 5-membered heteroaryl, phenyl-fused 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 6-membered heterocyclic group, 6-membered heterocyclic group-fused pyridone group, and each of the heteroaryl group and the heterocyclic group independently contains 1-2 heteroatoms selected from N, O or S; each of the 5-membered heteroaryl, phenyl-fused 6-membered heteroaryl, 6-membered heteroaryl-fused 5-membered heteroaryl, 6-membered heterocyclic group, 6-membered heterocyclic group-fused pyridone group is independently substituted with 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenylpyridyl, pyridopyrrolyl, morpholinopyridinone group, pyridone group; the pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenylpyridyl, pyridopyrrolyl, morpholinopyridinone group, pyridone group are each independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino or hydroxy; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, cyano or hydroxy; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, cyano or hydroxy; Preferably, each R d is independently selected from methyl, ethyl, propyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl or hydroxy; Preferably, each R d is independently selected from methyl, Cl, Br, cyclopropyl or hydroxyl; Alternatively, preferably, each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano, amino, hydroxy or halogen, provided that at least one R d is hydroxy; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano or hydroxy, with at least one R d being hydroxy; Preferably, each R d is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, cyano or hydroxy, wherein exactly one R d is hydroxy; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 5-6 alkyl, C 1-4 haloalkyl, C 5-6 haloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, cyano or hydroxyl, wherein exactly one R d is hydroxyl; Preferably, each R d is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, cyano or hydroxy, with exactly one R d being hydroxy; Preferably, each R d is independently selected from methyl, ethyl, propyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl or hydroxyl, and exactly one of the Rs d is hydroxyl; Preferably, each R d is independently selected from methyl, Cl, Br, cyclopropyl or hydroxyl, and exactly one of the Rs d is hydroxyl; Preferably, each R d is independently selected from methyl, Cl, Br, cyclopropyl or hydroxyl, and exactly one of the Rs d is hydroxyl, and the hydroxyl is substituted at the ortho position of the connection site of R 2b to the main group; Preferably, R 2b is selected from Each may independently be further substituted by 1, 2 or 3 Rs d substituted; Most preferably, R 2b is selected from Alternatively, preferably, R 2b is selected from 5-membered heteroaryl groups, each of which is independently substituted with one, two, three or four R d substituents; Further preferably, R 2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, and each of the pyrazolyl, thiazolyl, thienyl, and isothiazolyl is independently substituted with 1, 2, 3, or 4 R d substituents; Further preferably, R 2b is selected from may be further substituted by 1, 2 or 3 R d substituents; Further preferably, R 2b is selected from may be further substituted by 1, 2 or 3 R d substituents; Or preferably, R 2b is selected from: More preferably, R 2b is selected from: Preferably, R 2b is selected from a 6-membered heterocyclic group, a 6-membered heterocyclic group fused to a 6-membered heterocyclic group, the heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S; the 6-membered heterocyclic group, the 6-membered heterocyclic group fused to a 6-membered heterocyclic group are each independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from morpholinopyridinone group and pyridinone group; each of the morpholinopyridinone group and pyridinone group is independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from pyridone groups; the pyridone groups are substituted with 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from 2-pyridone groups; the 2-pyridone groups are substituted with 1, 2, 3 or 4 R d groups; Preferably, R 2b is selected from may be further substituted by one, two or three Rs d substituted Preferably, R 2b is selected from may be further substituted by one, two or three Rs d ; Preferably, R 2b is selected from Alternatively, preferably, R 2b is selected from Alternatively, preferably, R 2b is selected from phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl; the heteroaryl contains 1-2 heteroatoms selected from N, O or S; the phenyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-fused 5- or 6-membered heteroaryl are each independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from phenyl-fused 6-membered heteroaryl and 6-membered heteroaryl-fused 5-membered heteroaryl, and the heteroaryl contains 1 to 2 heteroatoms selected from N, O or S; the phenyl-fused 6-membered heteroaryl and 6-membered heteroaryl-fused 5-membered heteroaryl are each independently substituted by 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from phenylpyridyl and pyridylpyrrolyl; each of the phenylpyridyl and pyridylpyrrolyl is independently substituted with 1, 2, 3 or 4 R d substituents; Preferably, R 2b is selected from may be further substituted by one, two or three Rs d substituted Preferably, R 2b is selected from 8. The compound according to any one of claims 1-7, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R1 is selected from halogen, C 1-6 alkyl, 5- or 6-membered cycloalkenyl, 5- to 10-membered heterocyclic group, 5- or 6-membered heteroaryl, phenyl, wherein the heterocyclic group and heteroaryl each independently contain 1 to 2 heteroatoms selected from N, O or S, and the alkyl, cycloalkenyl, heterocyclic group, heteroaryl, phenyl are each independently unsubstituted or substituted by 1 or more R g substituents; Preferably, R1 is selected from a 5- or 6-membered cycloalkenyl group, a 5- to 10-membered heterocyclic group, a 5- or 6-membered heteroaryl group, or a phenyl group. Each of the heterocyclic group and the heteroaryl group independently contains 1 to 2 heteroatoms selected from N, O, or S. Each of the cycloalkenyl group, the heterocyclic group, the heteroaryl group, and the phenyl group is independently unsubstituted or substituted by 1 or more R g substituents; Preferably, R1 is selected from a 5- or 6-membered cycloalkenyl group, a 5- to 10-membered heterocycloalkyl group, a 5- or 6-membered heterocycloalkenyl group, a 5- or 6-membered heteroaryl group, a phenyl group, and the heterocycloalkyl group, heterocycloalkenyl group, and heteroaryl group each independently contain 1 to 2 heteroatoms selected from N, O, or S, and the cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, heteroaryl group, and phenyl group are each independently unsubstituted or substituted by 1 or more R g substituents; Preferably, R1 is selected from a 6-membered cycloalkenyl group, a 6-9 membered heterocycloalkyl group, a 6-membered hetero-cycloalkenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group. Each of the heterocycloalkyl group and the hetero-cycloalkenyl group independently contains 1-2 heteroatoms selected from N, O or S. Each of the cycloalkenyl group, the heterocycloalkyl group and the hetero-cycloalkenyl group is independently unsubstituted or substituted by one or more R g substituents; Preferably, each R g is independently selected from hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, =O, R’R”N-; the alkyl and alkoxy are each independently unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; wherein, R’ and R” are each independently selected from H, C 1-4 alkyl, C 1- 4-haloalkyl; Preferably, each R g is independently selected from hydroxy, halogen, C 1-2 alkyl, C 3-4 alkyl, C 1-2 alkoxy, C 3-4 alkoxy, =O, R’R”N-; the alkyl and alkoxy are each independently unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; wherein, R’ and R” are each independently selected from H, C 1-2 alkyl, C 3-4 alkyl, C 1-2 haloalkyl, C 3-4 haloalkyl; Preferably, each R g is independently selected from a hydroxyl group, F, Cl, C 1-2 alkyl, C 1-2 alkoxy, =O, R'R''N-; the alkyl and alkoxy are each independently unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl, C 1-2 alkoxy; wherein, R' and R'' are each independently selected from H, C 1-2 alkyl, C 1- 2-haloalkyl; Preferably, each R g is independently selected from hydroxy, F, methyl, methoxy, =O, R'R"N-; the methyl is unsubstituted or substituted with 1 or more substituents selected from F, Cl, hydroxy, methoxy; wherein, R' and R" are each independently selected from H, methyl; Preferably, R1 is selected from Preferably, R1 is selected from Most preferably, R1 is selected from 9. The compound according to any one of claims 1-7, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R1 is selected from halogen, C 1-6 alkyl, a 5- or 6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O or S, and the alkyl and heterocyclic group are unsubstituted or substituted by one or more R g substituents; Preferably, R1 is selected from a 5- or 6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O or S, and the heterocyclic group is unsubstituted or substituted by one or more R g substituents; Preferably, R1 is selected from a 5- or 6-membered heteroalkyl group or a 5- or 6-membered heteroalkenyl group, and the heteroalkyl group and heteroalkenyl group contain 1 or 2 heteroatoms selected from N, O or S, and the heteroalkyl group and heteroalkenyl group are unsubstituted or substituted by 1 or more R g substituents; Preferably, R1 is selected from 5- or 6-membered heteroalkenyl, the heteroalkenyl contains 1-2 heteroatoms selected from N or O, and the heteroalkenyl is unsubstituted or substituted by one or more R g substituents; Alternatively or preferably, R1 is selected from is unsubstituted or substituted by one or more R g substituted; Preferably, each R g is independently selected from hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy; the C 1-4 alkyl and C 1-4 alkoxy are unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; Preferably, each R g is independently selected from hydroxy, halogen, C 1-2 alkyl, C 3-4 alkyl, C 1-2 alkoxy, C 3-4 alkoxy; the alkyl and alkoxy are unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, C 1-2 alkoxy; Preferably, each R g is independently selected from hydroxy, F, Cl, C 1-2 alkyl, C 1-2 alkoxy; provided that The alkyl and alkoxy groups are unsubstituted or substituted by 1 or more substituents selected from halogen, hydroxyl, C 1-2 alkoxy groups; Preferably, each R g is independently selected from a hydroxyl group, F, a methyl group, and an ethyl group; the methyl group and the ethyl group are unsubstituted or substituted with one or more substituents selected from a halogen, a hydroxyl group, and a methoxy group; Preferably, R1 is selected from Preferably, R1 is selected from Preferably, R1 is selected from 10. The compound according to any one of claims 1-9, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R3 is selected from C 1-4 alkyl, said alkyl being unsubstituted or substituted by one, two or three substituents selected from hydroxy or halogen; Preferably, R3 is selected from C 1-4 alkyl, and the alkyl is unsubstituted; Preferably, R3 is selected from C 1-2 alkyl, and the alkyl is unsubstituted; Preferably, R3 is selected from methyl or ethyl; Preferably, R3 is selected from ethyl.

11. The compound according to any one of claims 1-10, or its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, characterized in that: R4 is selected from H, halogen, C 1-4 alkyl, where the alkyl is unsubstituted or substituted by one, two or three halogens; Preferably, R4 is selected from H, halogen, C 1-4 alkyl, and the alkyl is unsubstituted or substituted by 1, 2 or 3 F; Preferably, R4 is selected from H, F, Cl, Br, C 1-4 alkyl, and the C 1-4 alkyl is unsubstituted; Preferably, R4 is selected from H, F, Cl, Br, C 1-2 alkyl, and the C 1-2 alkyl is unsubstituted or substituted by one, two or three F; Preferably, R4 is selected from H, F, Cl, Br, methyl, ethyl, and the methyl and ethyl are each independently unsubstituted or substituted by 1, 2 or 3 F; Preferably, R4 is selected from H, F, Cl, Br, methyl, -CF3; Preferably, R4 is selected from Cl, methyl, -CF3; Preferably, R4 is selected from H, F, Cl, Br, methyl, ethyl, and the methyl and ethyl are unsubstituted; Preferably, R4 is selected from H, F, Cl, Br or methyl; Preferably, R4 is selected from Cl or methyl; Or, R5 is selected from H, methyl, halogen; Preferably, R5 is selected from H, F, Cl or methyl; Preferably, R5 is selected from H, Cl or methyl; Preferably, R5 is selected from H; Or, R6 is selected from H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted by one, two or three halogens; Preferably, R6 is selected from H, halogen, C 1-4 alkyl, where the alkyl is unsubstituted or substituted by 1, 2 or 3 F; Preferably, R6 is selected from H, halogen, C 1-2 alkyl, where the alkyl is unsubstituted or substituted by 1, 2 or 3 F; Preferably, R6 is selected from H, F, Cl, methyl, ethyl, and the methyl and ethyl are unsubstituted or substituted by 1, 2 or 3 F; Preferably, R6 is selected from H, F, Cl, methyl or -CF3; Preferably, R6 is selected from H, F or Cl; Alternatively or preferably, R6 is selected from H, halogen, C 1-4 alkyl, wherein the alkyl is substituted with one, two or three F; Preferably, R6 is selected from H, halogen, C 1-2 alkyl, wherein the alkyl is substituted by one, two or three F; Preferably, R6 is selected from H, F, Cl, methyl, ethyl, and the methyl and ethyl are substituted by 1, 2 or 3 F; Preferably, R6 is selected from H, F, Cl or -CF3; Preferably, R6 is selected from H, F or Cl; Or, R7 is selected from H, -SF5, -C(O)H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl; the alkyl and cycloalkyl are unsubstituted or substituted by one or more halogens; Preferably, R7 is selected from -SF5, -C(O)H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted by one, two or three halogens; Preferably, R7 is selected from -SF5, -C(O)H, halogen, C 1-4 alkyl; the alkyl is unsubstituted or substituted with 1, 2 or 3 F; Preferably, R7 is selected from -SF5, -C(O)H, halogen, C 1-2 alkyl; the alkyl is unsubstituted or substituted with 1, 2 or 3 F; Preferably, R7 is selected from -SF5, -C(O)H, F, Cl, Br, methyl, ethyl; the methyl and ethyl are unsubstituted or substituted by 1, 2 or 3 F; Preferably, R7 is selected from -CF3, -CHF2, -CH2CH3, Cl, Br, -SF5 or -C(O)H; Preferably, R7 is selected from -CF3; Preferably, R7 is selected from -OCF3; Or, X is selected from N or CR8, and R8 is selected from H, F, Cl or Br; Preferably, R8 is selected from H or F; Preferably, the functional group Selected from Preferably, the functional group Selected from Preferably, the functional group Selected from Preferably, the functional group Selected from Preferably, the functional group Selected from 12. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, characterized in that: Formula (I) has a general formula structure selected from the general formula shown in formula (IB): Among them, R1, R 2b , R3, and R4 are each defined as defined in formula (I); Preferably, formula (I) has the structure shown in formula (IB-1): Among them, R1, R 2b , and R4 are defined as described in formula (I).

13. A compound according to any one of claims 1-12, or a stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, characterized in that: Formula (I) has the structures selected from formula (IIA) and formula (IIB): Among them, R1, R 2b , R4, R5, R6, R7 are defined as described in formula (I); Furthermore, formula (IIA) has the structure shown in formula (IIA-1) or formula (IIA-2) or formula (IIA-3): Among them, R1, R d , R4, R5, R6, R7 are defined as described in formula (I); Furthermore, formula (IIA-1) has the structure shown in formula (IIA-1-1): Among them, R1, R d is defined as defined in formula (I); Wherein, R1, R4, R5, R6, R7 are defined as defined in formula (I); Furthermore, formula (IIA-2) has the structure shown in formula (IIA-2-1): Wherein, R1 is defined as defined in formula (I); wherein, R1, R d , R4, R5, R6, R7 are defined as defined in formula (I); Furthermore, formula (IIA-3) has the structure shown in formula (IIA-3-1): Among them, R1, R d is defined as defined in formula (I); Among them, R1, R 2b , R4, R5, R6, R7 are defined as described in formula (I); Further, the formula (IIB) has a structure shown in formula (IIB-1) or formula (IIB-2) or formula (IIB-3): wherein, R1, R d , R4, R5, R6, R7 are defined as defined in formula (I); Further, the formula (IIB-1) has a structure shown in formula (IIB-1-1): Among them, R1, R d is defined as defined in formula (I); Wherein, R1, R4, R5, R6, and R7 are defined as defined in formula (I); Further, the formula (IIB-2) has a structure shown in formula (IIB-2-1): Wherein, R1 is defined as defined in formula (I); Among them, R1, R d , R4, R5, R6, R7 are defined as described in formula (I); Further, the formula (IIB-3) has a structure shown in formula (IIB-3-1): Among them, R1, R d is defined as defined in formula (I).

14. A compound according to any one of claims 1-12, or a stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, characterized in that: Formula (I) has a structure selected from the structures shown in Formula (IIA-4) or Formula (IIB-4): Among them, ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O, and S; the 5-membered heteroaryl group is unsubstituted or substituted by one or more C 1-4 alkyl groups; Preferably, ring B is a 5-membered heteroaryl group; the 5-membered heteroaryl group contains 1 heteroatom selected from N, O, and S; the 5-membered heteroaryl group is unsubstituted or substituted by 1 or more C 1-4 alkyl groups; Preferably, ring B is selected from furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl; the furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl are each independently unsubstituted or substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; Preferably, ring B is selected from furyl, pyrrolyl, thienyl; the furyl, pyrrolyl, thienyl are each independently unsubstituted or substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; Preferably, ring B is selected from furyl, pyrrolyl; the furyl, pyrrolyl are each independently unsubstituted or substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; Preferably, ring B is selected from furyl, pyrrolyl, thienyl; the pyrrolyl is unsubstituted or substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; Preferably, ring B is selected from furyl, pyrrolyl; the pyrrolyl is unsubstituted or substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; Preferably, ring B is selected from furyl, pyrrolyl, thienyl; the pyrrolyl is unsubstituted or substituted by one methyl; Preferably, ring B is selected from furyl, pyrrolyl; the pyrrolyl is unsubstituted or substituted by one methyl.

15. The compound according to claim 1, or a stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, characterized in that: The formula (I) is selected from the following specific compounds:

16. A pharmaceutical composition for treating and / or preventing a disease related to WRN biological activity, characterized in that: The pharmaceutical composition comprises a therapeutically and / or prophylactically effective amount of the compound as described in any one of claims 1-15, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and optionally pharmaceutical excipients; Preferably, the disease related to the biological activity of WRN is tumor or cancer; Preferably, the disease related to the biological activity of WRN is MSI tumor or MSI cancer; Preferably, a pharmaceutical composition, characterized in that: it comprises the compound as described in any one of claims 1-15, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and optionally pharmaceutical excipients.

17. A compound according to any one of claims 1 - 15, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in the manufacture of a medicament for the treatment and / or prevention of a disease associated with WRN biological activity, and / or, for use in the treatment and / or prevention of a disease associated with WRN biological activity; Preferably, the disease associated with WRN biological activity is a tumor or cancer; Preferably, the disease associated with WRN biological activity is an MSI tumor or MSI cancer.

18. A method for the treatment and / or prevention of a disease associated with WRN biological activity, which comprises administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of a compound according to any one of claims 1 - 15, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16; Preferably, the disease associated with WRN biological activity is a tumor or cancer; Preferably, the disease associated with WRN biological activity is an MSI tumor or MSI cancer.

19. A compound according to any one of claims 1 - 15, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in the treatment and / or prevention of a disease associated with WRN biological activity, Preferably, the disease associated with WRN biological activity is a tumor or cancer; Preferably, the disease associated with WRN biological activity is an MSI tumor or MSI cancer.

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