CN120603834A

CN120603834A - Bis-heterocyclic WRN inhibitor, preparation method and application thereof

Info

Publication number: CN120603834A
Application number: CN202480008168.9A
Authority: CN
Inventors: 王伟; 孙晓阳; 刘自强; 张继鑫; 卿盈; 张萍; 刘航; 山松; 潘德思; 鲁先平
Original assignee: Chengdu Weixin Pharmaceutical Co ltd
Current assignee: Chengdu Weixin Pharmaceutical Co ltd
Priority date: 2023-01-18
Filing date: 2024-01-17
Publication date: 2025-09-05
Also published as: WO2024153155A1

Abstract

本发明涉及一种式(I)所示的双杂环WRN抑制剂、其制备方法及其应用。本发明还涉及包含所述化合物作为活性成分的药物组合物以及所述化合物或药物组合物用于治疗和/或预防与WRN生物学活性相关的疾病的用途。 The present invention relates to a biheterocyclic WRN inhibitor represented by formula (I), a preparation method thereof, and its use. The present invention also relates to a pharmaceutical composition comprising the compound as an active ingredient, and the use of the compound or pharmaceutical composition for treating and/or preventing diseases associated with the biological activity of WRN.

Description

Biheterocycle WRN inhibitor, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a double-heterocycle WRN inhibitor, a preparation method and application thereof.

Background

WRN is one of the RecQ family members of DNA helicases, involved in DNA damage repair, maintenance of genomic stability, maintenance of telomeres, etc., and WRN gene deficiency can lead to Werner syndrome (presenility syndrome), a recessive genetic disorder characterized by increased staged premature senility and cancer susceptibility (NAT REV CANCER 2003,3,169-178). In 2019, a project CANCER DEPENDENCY MAP (DepMap) aimed at finding new tumor therapeutic targets through gene screening, drug sensitivity and drug predictive models found that WRN was necessary for the survival of microsatellite instability (MSI) tumors. The results of the study show that the absence of WRN causes DNA Double Strand Breaks (DSBs), cell cycle arrest and thus apoptosis in MSI cells, while it has no effect on microsatellite stabilized (MSS) cells (Nature 2019,568,511-516). Further mechanism studies showed that the integrity of WRN exonuclease domain function is essential for MSI cell survival without significant impact on MSI cell survival (LIFE SCI ALLIANCE 4). In addition, large scale expanded and highly unstable TA-dinucleotide repeats are present in MSI cells, the expanded TA repeats form a non-B-shaped cross-shaped DNA secondary structure, the extension of replication fork is hindered, WRN can unwind the structure to restore the normal replication of DNA, when WRN is lost, the cross-shaped structure is cut by nuclease MUS81 to cause the damage of chromosome genome and further cause cell death, and in MSS cells, the TA repeats do not form a cross-shaped structure, so the WRN deletion specifically causes MSI cell death (Nature 2020,586,292-298). Thus, inhibitors targeting the WRN helic domain may be effective measures for the treatment of MSI cancers.

At present, medicines related to WRN target inhibition are not found on the market, and based on potential medical value of the WRN target inhibition in microsatellite instability (MSI) tumor treatment, the development of the compounds related to the WRN target inhibition has very important social significance and medical value.

Disclosure of Invention

Problems to be solved by the invention:

Although several patent applications for WRN inhibitors have been published, new compounds still need to be further developed based on the lack of current marketing of WRN target drugs and the potential medical value of WRN target inhibition in microsatellite instability (MSI) tumor treatment. Through continuous efforts, the present inventors devised compounds having a structure represented by general formula (I), and found that compounds having such a structure exhibit excellent WRN inhibition effects and actions, and are useful for treating MSI tumor-related diseases.

Solution for solving the problem:

the present inventors have made intensive studies in order to solve the above-mentioned problems and as a result, have found that a compound having a double ring structure represented by the formula (I) and its derivatives can achieve the desired objects, and as a result, have completed the present application.

The invention protects the following specific embodiments:

A compound of formula (I), or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof:

Wherein, the

R ₁ 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 heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more identical or different R _g;

Each R _g is independently selected from hydroxy, halogen, C _1-4 alkyl, C _1-4 alkoxy, HOC (O) - (CH ₂)_n-、H₃C-C(O)(CH₂)_n-、C_1-4 alkyl-O-C (O) (CH ₂)_n -, = O, azetidinyl, pyrrolidinyl, 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 is attached to the R ₁ main group through an N atom, the C _1-4 alkyl, C _1-4 alkoxy, azetidinyl, pyrrolidinyl are each independently unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, C _1-2 alkoxy;

r ₂ is selected from Wherein L is selected from 7-10 membered spiroheterocycloalkyl,The spiroheterocycloalkyl group contains 2 to 3N atoms;

R ₃ is selected from cyclopropyl, methoxy, -SCH ₃、C_1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more substituents selected from hydroxy or halogen;

R ₄ is selected from H, halogen, hydroxy, cyano, C _1-4 alkyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

R ₆ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more halogen;

R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

X is selected from N or CR ₈,R₈ is H or halogen;

R _2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each unsubstituted or each independently substituted with one or more R _c, which may be the same or different;

R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocycloalkyl, 5-14 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, -CH ₂ -on the 5-14 membered heterocycloalkylyl, 5-14 membered heterocycloalkenyl ring each independently optionally being replaced by-C (=O) -, 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocycloalkyl, 5-14 membered heterocycloalkenyl each independently being substituted by one or more R _d;

r _2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each being unsubstituted or each independently substituted with one or more R _f, which may be the same or different;

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 the group consisting of 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, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6-membered heteroaryl independently containing 1 to 3 heteroatoms selected from N, O or S, said 5-or 6-membered heteroaryl, phenyl being unsubstituted or 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 cycloalkyl;

Each R _f is independently selected from the group consisting of hydroxy, cyano, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _3-6 halocycloalkyl.

Wherein, the

R ₁ 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 heterocyclyl, 5-or 6-membered heteroaryl, phenyl containing 1-2 heteroatoms selected from N, O or S, said alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl being unsubstituted or substituted with 1 or more R _g, which may be the same or different;

Each R _g is independently selected from hydroxy, halogen, C _1-4 alkyl, C _1-4 alkoxy, HOC (O) - (CH ₂)_n-、H₃C-C(O)(CH₂)_n-、C_1-4 alkyl-O-C (O) (CH ₂)_n -, = O, azetidinyl, pyrrolidinyl, 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 being attached to the R ₁ main group through an N atom, the C _1-4 alkyl, C _1-4 alkoxy, azetidinyl, pyrrolidinyl being unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, C _1-2 alkoxy;

r ₂ is selected from Wherein L is selected from 7-10 membered spiroheterocyclic groups,

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

X is selected from N or CR ₈,R₈ is H or halogen;

R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl independently substituted with one or more R _d;

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, 4-7 membered heterocycloalkyl, hydroxy, or halogen, each of said 4-7 membered heterocycloalkyl independently containing 1 or 2 heteroatoms selected from N, O or S;

Wherein, the

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

X is selected from N or CR ₈,R₈ is H or halogen;

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;

In one embodiment, the above compound, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, R ₂ is selected from

In one embodiment, R ₂ is selected from

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, each of said 5-membered heteroaryl, 8-14 membered heteroaryl independently contains 1-4 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, 8-14 membered heteroaryl independently being substituted with one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, each independently containing 1-4 heteroatoms selected from N, O and S, each independently substituted with one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, 5-membered heteroaryl-5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, each of said 5-membered heteroaryl, 6-membered heteroaryl independently containing 1-2 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, 5-membered heteroaryl-5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl independently substituted with one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl, each of said 5-membered heteroaryl, 6-membered heteroaryl independently containing 1-2 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl independently substituted with one or more R _d.

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, benzooxazolyl, benzofuranyl, and benzofuranyl benzisoxazolyl, pyridopyrrolyl, pyridofuranyl, pyridothienyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridoisothiazolyl, pyridooxazolyl, pyridoisoxazolyl, benzopyridyl, benzopyrimidinyl; the pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuranyl, and the like benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzidine.

In a specific embodiment, R _2b is selected from pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridopyrrolyl, pyridothienyl; the pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridopyrrolyl, pyridothienyl are each independently substituted with one or more R _d.

In one embodiment, R _2b is selected from The said Each independently substituted with one or more R _d.

In one embodiment, R _2b is selected from

In a specific embodiment, each R _d is independently selected from the group consisting of 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, halo, wherein one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S, and said 5-or 6 membered heteroaryl each independently contains 1 to 3 heteroatoms selected from N, O and S.

In a specific embodiment, each R _d is independently selected from the group consisting of 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 one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S, and said 5-or 6-membered heteroaryl each independently contains 1,2 or 3 heteroatoms selected from N, O and S.

In a specific embodiment, each R _d is independently selected from the group consisting of C _1-4 alkyl, C _3-4 cycloalkyl, C _5-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 alkoxy, 4-7 membered heterocycloalkyl, 6 membered heteroaryl, phenyl, hydroxy, halogen, wherein one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl contains 1 or 2O heteroatoms, and said 6 membered heteroaryl contains 1 or 2N heteroatoms.

In a specific embodiment, each R _d is independently selected from the group consisting of 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, hydroxy, halo, wherein only and only one R _d is hydroxy, and wherein said 4-7 membered heterocycloalkyl contains 1O heteroatom.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, pyridinyl, hydroxy, F, cl, br, phenyl, wherein only and only one R _d is hydroxy, and wherein the 4-7 membered heterocycloalkyl contains 1O heteroatom.

In one embodiment, each R _d is independently selected from the group consisting of methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃,Methoxy group, Cl, phenyl, hydroxy, wherein one and only one R _d is hydroxy.

In one embodiment, the above hydroxy group is substituted on a carbon atom ortho or meta to the point of attachment of R _2b to the main group.

In one embodiment, the above hydroxy group is substituted on a carbon atom ortho to the point of attachment of R _2b to the main group.

In one embodiment, R _2b is selected from

In a specific embodiment, each R _d is independently selected from the group consisting of 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, halogen, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, said 5-or 6 membered heteroaryl each independently containing 1 to 3 heteroatoms selected from N, O and S.

In a specific embodiment, each R _d is independently selected from the group consisting of 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, halogen, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, said 5-or 6-membered heteroaryl each independently containing 1,2 or 3 heteroatoms selected from N, O and S.

In a specific embodiment, each R _d is independently selected from the group consisting of C _1-4 alkyl, C _3-4 cycloalkyl, C _5-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 alkoxy, 4-7 membered heterocycloalkyl, 6 membered heteroaryl, phenyl, halo, said 4-7 membered heterocycloalkyl containing 1 or 2O heteroatoms, and said 6 membered heteroaryl containing 1 or 2N heteroatoms.

In a specific embodiment, each R _d is independently selected from the group consisting of 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, halo, said 4-7 membered heterocycloalkyl containing 1O heteroatom.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, pyridinyl, F, cl, br, phenyl, said 4-7 membered heterocycloalkyl containing 1O heteroatom.

In one embodiment, each R _d is independently selected from the group consisting of methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃,Methoxy group, Cl, phenyl.

In one embodiment, R _2b is selected from

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, each independently of the other-CH ₂ -on the 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl ring optionally replaced by-C (=O) -, each independently of the other, and each independently of the 5-10 membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl is substituted by one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 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 and 5-6 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, each-CH ₂ -on the heterocycloalkyl, 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 and 5-6-membered heterocycloalkenyl is independently substituted by one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 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 and 5-6 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, each independently-CH ₂ -on the heterocycloalkyl ring is optionally replaced by-C (=O) -, and each independently-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 and 5-6-membered heterocycloalkenyl is substituted independently by one or more R _d.

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl, 5-or 6-membered heterocycloalkyl-5-or 6-membered heterocycloalkenyl, -CH ₂ -on the heterocycloalkenyl ring is each independently optionally substituted with-C (=O) -, the heteroaryl, heterocycloalkyl, heterocycloalkenyl each independently contains 1-2 heteroatoms selected from N, O or S, the 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl, 5-or 6-membered heterocycloalkyland 5-or 6-membered heterocycloalkenyl each independently is substituted with 1,2, 3 or 4R _d.

In a specific embodiment, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 1, 5-dihydro-2H-pyrrol-2-onyl, pyridonyl, 6-membered heterocycloalkyl-pyridonyl, each independently containing 1-2 heteroatoms selected from N, O or S, and each independently substituted with 1,2, 3 or 4R _d.

In a specific embodiment, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, and the like, Each independently substituted with 1, 2, 3 or 4R _d.

In a specific embodiment, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, and,The isoxazolyl, pyrazolyl, isothiazolyl, and the like,Each independently substituted with 1, 2, 3 or 4R _d.

In one embodiment, R _2b is selected fromThe saidEach independently substituted with 1, 2, 3 or 4R _d.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, 5-or 6-membered heteroaryl, phenyl, amino, or hydroxy, each of the 4-7 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, and each of the 5-or 6-membered heteroaryl, phenyl is unsubstituted or 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 cycloalkyl.

In a specific embodiment, 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 of said 4-7 membered heterocycloalkyl independently containing 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6 membered heteroaryl independently containing 1,2 or 3 heteroatoms selected from N, O or S, said 5-or 6 membered heteroaryl, phenyl being unsubstituted or 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 cycloalkyl.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano, or hydroxy, each of said 4-7 membered heterocycloalkyl independently containing 1O heteroatom, said phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl being unsubstituted or substituted with one or more substituents selected from F, cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoromethoxy.

In a specific embodiment, each R _d is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, CH ₂CF₃, and combinations thereof,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.

In a specific embodiment, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, 5-or 6-membered heteroaryl, phenyl, hydroxy, or halo, wherein at least one R _d is hydroxy, each of the 4-7 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, and each of the 5-or 6-membered heteroaryl, phenyl is unsubstituted or each independently substituted with one or more substituents selected from halo, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _3-5 cycloalkyl.

In a specific embodiment, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, 5-or 6 membered heteroaryl, phenyl, cyano, or hydroxy, wherein at least one R _d is hydroxy, each of the 4-7 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, and the 5-or 6 membered heteroaryl, phenyl is unsubstituted or 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 cycloalkyl.

In a specific embodiment, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, 5-or 6 membered heteroaryl, phenyl, cyano or hydroxy, wherein none and only one R _d is hydroxy, each of the 4-7 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, and the 5-or 6 membered heteroaryl, phenyl is unsubstituted or 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 cycloalkyl.

In a specific embodiment, 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 one and only one R _d is hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6 membered heteroaryl independently contains 1,2 or 3 heteroatoms selected from N, O or S, each of said 5-or 6 membered heteroaryl, phenyl is unsubstituted or 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 cycloalkyl.

In a specific embodiment, 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, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano, or hydroxy, wherein only and only one R _d is hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1O heteroatom, said phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl being unsubstituted or substituted with one or more substituents selected from F, cl, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoromethoxy.

In a specific embodiment, each R _d is independently selected from phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, CH ₂CF₃, and combinations thereof,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 pyridinyl, fluoro-substituted pyridinyl, chloro-substituted pyridinyl, methyl-substituted pyridinyl, methoxy-substituted pyridinyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridinyl, trifluoromethoxy-substituted pyridinyl, cyano-substituted pyridinyl or hydroxy, wherein only and none of R _d is hydroxy.

In a specific embodiment, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl, wherein one and only one R _d is hydroxy.

In a specific embodiment, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl, wherein one and only one R _d is hydroxy, and the hydroxy is substituted ortho to the point of attachment of R _2b to the main group.

In one embodiment, R _2b is selected from

In a specific embodiment, the above compound, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, R _2b is selected from the group consisting of 5 membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, and 5-10 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, and each independently substituted with one or more R _d.

In some embodiments, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, phenyl, naphthyl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each independently substituted with one or more R _d.

In some embodiments, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each independently substituted with one or more R _d.

In some embodiments, R _2b is selected from the group consisting of a 5-membered heteroaryl, a phenyl-5-or 6-membered heteroaryl, a 5-or 6-membered heterocyclyl, and a 5-or 6-membered heterocyclyl; the heteroaryl, heterocyclyl each independently contains 1-2 heteroatoms selected from N, O or S, the 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocyclyl-5-or 6-membered heterocyclyl each independently being substituted with 1,2, 3 or 4R _d.

In some embodiments, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 6-membered heteroaryl-5-membered heterocyclyl, 6-membered heterocyclyl-pyridonyl, each of which independently contains 1-2 heteroatoms selected from N, O or S, and each of which is independently substituted with 1,2, 3 or 4R _d.

In some embodiments, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, and the like, Each independently substituted with 1, 2, 3 or 4R _d.

In some embodiments, the compounds described above, or stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts thereof, 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, 4-7 membered heterocycloalkyl, amino, or hydroxy, each of said 4-7 membered heterocycloalkyl independently containing 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, 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 which independently contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, each R _d is independently selected from halogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 alkoxy, 4-7 membered heterocycloalkyl, cyano, or hydroxy, each of which independently contains 1O heteroatom.

In some embodiments of the present invention, in some embodiments, each R _d is independently selected from methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃,Methoxy, ethoxy,Or hydroxy.

In some embodiments, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl.

In some embodiments, the compounds described above, or stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts thereof, 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, 4-7 membered heterocycloalkyl, hydroxy, or halogen, wherein at least one R _d is hydroxy, and each of said 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, cyano, or hydroxy, wherein at least one R _d is hydroxy, and each of the 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, cyano, or hydroxy, wherein one and only one R _d is hydroxy, and wherein each 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, 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 one and only one R _d is hydroxy, and each of the 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S.

In some embodiments, each R _d is independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, 4-7 membered heterocycloalkyl, cyano, or hydroxy, wherein one and only one R _d is hydroxy, and each of the 4-7 membered heterocycloalkyl independently contains 1O heteroatom.

In some embodiments of the present invention, in some embodiments, each R _d is independently selected from methyl, ethyl, propyl, isopropyl, t-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃,Methoxy, ethoxy,Or hydroxy, wherein one and only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl, wherein one and only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃,Methoxy group, Or Cl, wherein one and only one R _d is hydroxy, and the hydroxy is substituted ortho to the point of attachment of R _2b to the main group.

In some embodiments, R _2b is selected from

In some embodiments of the present invention, in some embodiments,

In some embodiments, R ₂ is selected from

In some embodiments, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each independently substituted with one or more R _d.

In some embodiments, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 6-membered heterocyclyl-pyridonyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently substituted with 1,2, 3, or 4R _d.

In some embodiments, R _2b is selected from the group consisting of pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenyl-pyridopyridyl, pyridopyrrolyl, morpholino-pyridonyl, said pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenyl-pyridopyridyl, pyridopyrrolyl, morpholino-pyridonyl, pyridonyl each independently substituted with 1,2, 3, or 4R _d.

In some embodiments, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, cyano, amino, or hydroxy.

In some embodiments, 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.

In some embodiments, each R _d is independently selected from halogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, cyano, or hydroxy.

In some embodiments, each R _d is independently selected from methyl, ethyl, propyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, or hydroxy.

In some embodiments, each R _d is independently selected from methyl, cl, br, cyclopropyl, or hydroxy.

In some embodiments, each R _d is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, cyano, amino, hydroxy, or halogen, wherein at least one R _d is hydroxy.

In some embodiments, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, cyano, or hydroxy, wherein at least one R _d is hydroxy.

In some embodiments, each R _d is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, cyano, or hydroxy, wherein one and only one R _d is hydroxy.

In some embodiments, 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 hydroxy, wherein only one and only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, or hydroxy, wherein one and only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from methyl, ethyl, propyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, or hydroxy, where one and only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from methyl, cl, br, cyclopropyl, or hydroxy, wherein only one R _d is hydroxy.

In some embodiments, each R _d is independently selected from methyl, cl, br, cyclopropyl, or hydroxy, wherein one and only one R _d is hydroxy and the hydroxy substitution is ortho to the point of attachment of R _2b to the main group.

In some embodiments, R _2b is selected from Each independently may be further substituted with 1, 2 or 3R _d.

In some embodiments, R _2b is selected from

In some embodiments, R _2b is selected from 5-membered heteroaryl, each of which is independently substituted with 1,2, 3, or 4R _d.

In some embodiments, R _2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, each independently substituted with 1,2, 3, or 4R _d.

In some embodiments, R _2b is selected from May be further substituted with 1, 2 or 3R _d.

In some embodiments, R _2b is selected fromMay be further substituted with 1, 2 or 3R _d.

In some embodiments, R _2b is selected from:

In some embodiments, R _2b is selected from the group consisting of a 6-membered heterocyclyl, a 6-membered heterocyclyl and a 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, each of said 6-membered heterocyclyl, 6-membered heterocyclyl and 6-membered heterocyclyl being independently substituted with 1,2, 3 or 4R _d.

In some embodiments, R _2b is selected from morpholino-pyridonyl, each independently substituted with 1,2, 3, or 4R _d.

In some embodiments, R _2b is selected from the group consisting of pyridonyl, said pyridonyl being substituted with 1,2,3, or 4R _d.

In some embodiments, R _2b is selected from 2-pyridonyl, said 2-pyridonyl being substituted with 1,2,3 or 4R _d.

In some embodiments, R _2b is selected from

In some embodiments, R _2b is selected from phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl, said heteroaryl containing 1-2 heteroatoms selected from N, O or S, said phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl each independently substituted with 1, 2,3 or 4R _d.

In some embodiments, R _2b is selected from the group consisting of phenyl-6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, said heteroaryl containing 1-2 heteroatoms selected from N, O or S, each independently substituted with 1,2, 3 or 4R _d.

In some embodiments, R _2b is selected from the group consisting of phenyl-and pyrido-pyridinyl, each independently substituted with 1,2, 3, or 4R _d.

In some embodiments, R _2b is selected from

In a specific embodiment, the above compound, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, R ₁ is selected from the group consisting of halogen, C _1-6 alkyl, 5-or 6-membered cycloalkenyl, 5-to 10-membered heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more R _g.

In a specific embodiment, R ₁ is selected from the group consisting of 5-or 6-membered cycloalkenyl, 5-10 membered heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more R _g.

In a specific embodiment, R ₁ is selected from 5-or 6-membered cycloalkenyl, 5-10 membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more R _g.

In a specific embodiment, R ₁ is selected from the group consisting of 6 membered cycloalkenyl, 6-9 membered heterocycloalkyl, 6 membered heterocycloalkenyl, pyridinyl, pyrimidinyl, pyridazinyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently unsubstituted or substituted with 1 or more R _g.

In a specific embodiment, the above compound, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-4 alkyl, C _1-4 alkoxy, = O, R 'R' N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy, wherein R ', R' are each independently selected from the group consisting of H, C _1-4 alkyl, C _1-4 haloalkyl.

In a specific embodiment, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-2 alkyl, C _3- ₄ alkyl, C _1-2 alkoxy, C _3-4 alkoxy, = O, R 'R "N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy, wherein R', R" are each independently selected from the group consisting of H, C _1-2 alkyl, C _3-4 alkyl, C _1-2 haloalkyl, C _3-4 haloalkyl.

In a specific embodiment, each R _g is independently selected from the group consisting of hydroxy, F, cl, C _1-2 alkyl, C _1-2 alkoxy, = O, R 'R "N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halogen, hydroxy, C _1-2 alkoxy, wherein R', R" are each independently selected from the group consisting of H, C _1-2 alkyl, C _1-2 haloalkyl.

In a specific embodiment, each R _g is independently selected from hydroxy, F, methyl, methoxy, = O, R 'R "N-, wherein each R' R" is independently selected from H, methyl, or substituted with 1 or more substituents selected from F, cl, hydroxy, methoxy.

In one embodiment, the above compound, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, R ₁ is selected from

In one embodiment, R ₁ is selected from

In some embodiments, R ₁ is selected from halogen, C _1-6 alkyl, a 5-or 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, said alkyl, heterocyclyl being unsubstituted or substituted with 1 or more R _g.

In some embodiments, R ₁ is selected from a 5-or 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, said heterocyclyl being unsubstituted or substituted with 1 or more R _g.

In some embodiments, R ₁ is selected from 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S, said heterocycloalkyl, heterocycloalkenyl being unsubstituted or substituted with 1 or more R _g.

In some embodiments, R ₁ is selected from 5-or 6-membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O, said heterocycloalkenyl being unsubstituted or substituted with 1 or more R _g.

In some embodiments, R ₁ is selected from Is unsubstituted or substituted with 1 or more R _g.

In some embodiments, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-4 alkyl, C _1- ₄ alkoxy, wherein the C _1-4 alkyl, C _1-4 alkoxy is unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy.

In some embodiments, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-2 alkyl, C _3- ₄ alkyl, C _1-2 alkoxy, C _3-4 alkoxy, wherein the alkyl, alkoxy are unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy.

In some embodiments, each R _g is independently selected from the group consisting of hydroxy, F, cl, C _1-2 alkyl, C _1-2 alkoxy, which alkyl, alkoxy is unsubstituted or substituted with 1 or more substituents selected from the group consisting of halogen, hydroxy, C _1-2 alkoxy.

In some embodiments, each R _g is independently selected from hydroxy, F, methyl, ethyl, which is unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, methoxy.

In some embodiments, R ₁ is selected from

In some embodiments, R ₃ is selected from C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3 substituents selected from hydroxy or halogen.

In some embodiments, R ₃ is selected from C _1-4 alkyl, which alkyl is unsubstituted.

In some embodiments, R ₃ is selected from C _1-2 alkyl, which alkyl is unsubstituted.

In some embodiments, R ₃ is selected from methyl or ethyl.

In some embodiments, R ₃ is selected from ethyl.

In some embodiments, R ₄ is selected from H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3 halogens.

In some embodiments, R ₄ is selected from H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₄ is selected from H, F, cl, br, C _1-4 alkyl, which C _1-4 alkyl is unsubstituted.

In some embodiments, R ₄ is selected from H, F, cl, br, C _1-2 alkyl, said C _1-2 alkyl being unsubstituted or substituted with 1,2 or 3F.

In some embodiments, R ₄ is selected from H, F, cl, br, methyl, ethyl, each independently unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₄ is selected from H, F, cl, br, methyl, -CF ₃.

In some embodiments, R ₄ is selected from Cl, methyl, -CF ₃.

In some embodiments, R ₄ is selected from H, F, cl, br, methyl, ethyl, which are unsubstituted.

In some embodiments, R ₄ is selected from H, F, cl, br or methyl.

In some embodiments, R ₄ is selected from Cl or methyl.

In some embodiments, R ₅ is selected from H, methyl, halogen.

In some embodiments, R ₅ is selected from H, F, cl or methyl.

In some embodiments, R ₅ is selected from H, cl or methyl.

In some embodiments, R ₅ is selected from H.

In some embodiments, R ₆ is selected from H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3 halogens.

In some embodiments, R ₆ is selected from H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, halogen, C _1-2 alkyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, F, cl, methyl, ethyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, F, cl, methyl, or-CF ₃.

In some embodiments, R ₆ is selected from H, F or Cl.

In some embodiments, R ₆ is selected from H, halogen, C _1-4 alkyl, substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, halogen, C _1-2 alkyl, substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, F, cl, methyl, ethyl substituted with 1,2, or 3F.

In some embodiments, R ₆ is selected from H, F, cl or-CF ₃.

In some embodiments, R ₆ is selected from H, F or Cl.

In some embodiments, R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, said alkyl, cycloalkyl being unsubstituted or substituted with 1 or more halogens.

In some embodiments, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3 halogens.

In some embodiments, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-4 alkyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-2 alkyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, F, cl, br, methyl, ethyl, which is unsubstituted or substituted with 1,2, or 3F.

In some embodiments, R ₇ is selected from-CF ₃、-CHF₂、-CH₂CH₃、Cl、Br、-SF₅ or-C (O) H.

In some embodiments, R ₇ is selected from-CF ₃.

In some embodiments, R ₇ is selected from-OCF ₃.

In some embodiments, X is selected from N or CR ₈,R₈ is selected from H, F, cl or Br.

In some embodiments, R ₈ is selected from H or F.

In some embodiments, functional groupsSelected from the group consisting of

In some embodiments, formula (I) has a general structure selected from the group consisting of those represented by formula (IB):

wherein R ₁、R_2b、R₃、R₄ is each as defined in formula (I).

In some embodiments, formula (I) has a structure represented by formula (IB-1):

wherein R ₁、R_2b、R₄ is as defined in formula (I).

In some embodiments, formula (I) has a structure selected from the group consisting of those represented by formula (IIA):

Wherein R ₁、R_2b、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIA) has the structure of formula (IIA-1):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIA-1) has a structure represented by formula (IIA-1-1):

Wherein R ₁、R_d is as defined in formula (I).

In some embodiments, the formula (IIA) has the structure of formula (IIA-2):

wherein R ₁、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIA-2) has a structure represented by formula (IIA-2-1):

Wherein R ₁ is as defined in formula (I).

In some embodiments, the formula (IIA) has the structure of formula (IIA-3):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIA-3) has a structure represented by formula (IIA-3-1):

Wherein R ₁、R_d is as defined in formula (I).

In some embodiments, the formula (IIA) has the structure of formula (IIA-4):

Wherein ring B is a 5-membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, said 5-membered heteroaryl group being unsubstituted or substituted by 1 or more C _1-4 alkyl groups, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is a 5-membered heteroaryl, the 5-membered heteroaryl containing 1 heteroatom selected from N, O and S, the 5-membered heteroaryl being unsubstituted or substituted with 1 or more C _1-4 alkyl groups, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, each independently unsubstituted or substituted with 1 or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, thienyl, each independently unsubstituted or substituted with 1 or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, each independently unsubstituted or substituted with 1 or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, thienyl, wherein the pyrrolyl is unsubstituted or substituted with 1 or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X, R ₄、R₅、R₆、R₇ is as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, which is unsubstituted or substituted with 1 or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, thienyl, wherein the pyrrolyl is unsubstituted or substituted with 1 methyl group, X, R ₄、R₅、R₆、R₇ is as defined above.

In some embodiments, ring B is selected from furyl, pyrrolyl, which is unsubstituted or substituted with 1 methyl group, X, R ₄、R₅、R₆、R₇ being as defined above.

In some embodiments, formula (I) has a structure selected from the group consisting of those represented by formula (IIB):

Wherein R ₁、R_2b、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIB) has a structure represented by formula (IIB-1):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIB-1) has a structure represented by formula (IIB-1-1):

Wherein R ₁、R_d is as defined in formula (I).

In some embodiments, the formula (IIB) has a structure represented by formula (IIB-2):

wherein R ₁、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIB-2) has a structure represented by formula (IIB-2-1):

Wherein R ₁ is as defined in formula (I).

In some embodiments, the formula (IIB) has a structure represented by formula (IIB-3):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIB-3) has a structure represented by formula (IIB-3-1):

Wherein R ₁、R_d is as defined in formula (I).

In some embodiments, the formula (IIB) has a structure represented by formula (IIB-4):

In some embodiments, formula (I) has a structure selected from the group consisting of those represented by formula (IIC):

Wherein R ₁、R_2b、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIC) has a structure represented by formula (IIC-1):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIC-1) has a structure represented by formula (IIC-1-1):

Wherein R ₁、R_d is as defined in formula (I).

In some embodiments, the formula (IIC) has a structure represented by formula (IIC-2):

wherein R ₁、R₄、R₅、R₆、R₇ is as defined in formula (I).

In some embodiments, the formula (IIC-2) has a structure represented by formula (IIC-2-1):

Wherein R ₁ is as defined in formula (I).

In some embodiments, formula (I) is selected from the following specific compounds:

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.

The term "prodrug" refers to derivatives of compounds of formula (I) found herein to have a specific substituent, which may themselves have a weaker activity or even no activity, but which upon administration are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the compounds found herein to have the specific substituent, resulting in the corresponding biological activity in vivo.

The term "metabolite" refers to the product of the present invention obtained by the in vivo metabolism of a compound of formula (I) found to have a specific substituent. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

The term "deuterated compound" means that the compound of the invention comprises at least one deuterium atom, in particular that one or more hydrogen atoms in the compound of the invention may be replaced or substituted by 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 including isotopes into organic compounds are known in the art.

The preparation method comprises the following steps:

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and methods of the present invention. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to literature (as provided by SCIFINDER) or purchased.

The compounds of the general formula (I) according to the invention can be synthesized according to the route described by the following method:

Scheme one:

1) Carrying out substitution reaction on A and C to obtain an intermediate D;

2) Removing the protecting group to obtain an intermediate E;

3) Intermediate E is condensed with the corresponding carboxylic acid to give the product F or G.

Wherein W represents halogen, PG is a protecting group, e.g. -Boc (t-butoxycarbonyl), benzyl, PMB, R ₁、R₃、R₄、R₅、R₆、R₇、X、R_2a and R _2b are as defined in formula (I).

Scheme II:

1) Carrying out substitution reaction on H and I to obtain an intermediate J;

2) Intermediate J is subjected to halogenation reaction to obtain intermediate K;

3) The intermediate K is substituted with corresponding amine to obtain an intermediate L or M;

4) The intermediate L or M is deprotected and then condensed with the corresponding carboxylic acid to give the product N, O or P.

Wherein W represents halogen, PG is a protecting group such as Boc (t-butoxycarbonyl), benzyl, PMB, R ₁、R₃、L、R₄、R₅、R₆、R₇、X、R_2a、R_2b and R _2e are as defined in formula (I).

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a compound as described above, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient. Preferably, the pharmaceutical excipients are preferably pharmaceutically acceptable carriers, diluents, excipients or combinations thereof.

The invention also provides a pharmaceutical composition for treating and/or preventing a disease associated with biological activity of WRN, the pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound as described above, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, and optionally a pharmaceutical adjuvant. Preferably, the pharmaceutically acceptable adjuvant is preferably a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

In some embodiments, the pharmaceutical composition may further comprise other agents useful for treating and/or preventing diseases associated with WRN biological activity.

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

In some embodiments, the disease associated with biological activity of WRN is MSI tumor or MSI cancer.

Methods of preparing various pharmaceutical compositions containing certain amounts of the active ingredient are known or will be apparent to those of skill in the art in light of the present disclosure. As described in REMINGTON' S PHARMACEUTICAL SCIENCES, martin, e.w., ed., mack Publishing Company,19th ed. (1995), the method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, and the like.

The present invention also provides a WRN inhibitor comprising a therapeutically and/or prophylactically effective amount of a compound as described previously, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof.

The medical application comprises the following steps:

The invention also provides the use of a compound as described hereinbefore, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described hereinbefore, in the preparation of a WRN inhibitor.

The invention also provides the use of a compound as described above, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with WRN biological activity.

The invention also provides the use of a compound as described hereinbefore, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described hereinbefore, in the treatment and/or prophylaxis of a disease associated with biological activity of WRN.

The invention also provides a compound as described above, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for use in the treatment and/or prevention of a disease associated with WRN biological activity.

The present invention also provides a method of treating and/or preventing a disease associated with biological activity of WRN comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound as described above, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

In the present invention, "treatment" generally means obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including (a) preventing a disease or condition that is susceptible to infection but has not yet been diagnosed in a patient suffering from the disease or condition, (b) inhibiting the symptoms of the disease, i.e., preventing its progression, or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or condition.

In the present invention, "subject" refers to a vertebrate. In certain embodiments, a 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.

In the present invention, an "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosages and times. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the substance/molecule to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the substance/molecule that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells, reduce the tumor volume, inhibit (i.e., slow, preferably stop) infiltration of cancer cells into surrounding organs, inhibit (i.e., slow, preferably stop) tumor metastasis, inhibit tumor growth to a degree, and/or reduce to a degree one or more symptoms associated with the cancer.

Definition of terms:

In accordance with the convention in the art, A bond as used in the formulae herein is described as the point of attachment of the moiety or substituent to the parent or host structure.

A dash "-" that does not appear between two letters or symbols is used to indicate a point of attachment for a substituent. For example, C _3-6 cycloalkyl- (C ₁-₆ alkyl) _r -means attached to the remainder of the molecule by (C ₁-C₆ alkyl) _r -.

The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group are replaced with a selection from the designated group, provided that the designated atom's normal valence is not exceeded.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl, or independently disclosed "C _1-4 alkyl", or independently disclosed "C _1-3 alkyl".

The term "alkyl" is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C ₁-₆ alkyl" refers to C ₁、C₂、C₃、C₄、C₅ and C ₆. 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 such that one or more hydrogens thereof are replaced with 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 appreciated by those skilled in the art that C _1-6 alkyl herein comprises monovalent C _1-6 alkyl, divalent C _1-6 alkylene, e.g., C ₁-C₆ alkyl in C ₃-C₆ cycloalkyl- (C ₁-C₆ alkyl) _r -refers to C ₁-C₆ alkylene.

The term "alkoxy" refers to any of the above alkyl groups (e.g., C ₁-₆ alkyl, C ₁-₄ alkyl, C ₁-₃ alkyl, etc.) that are attached to the remainder of the molecule through an oxygen atom (-O-).

The term "C _1-6 haloalkyl" or "C _1-6 haloalkoxy" means that one or more (e.g. 2, 3) hydrogen atoms in the alkyl or alkoxy group are replaced by halogen atoms, such as fluorine, chlorine, bromine. The definition of alkyl or alkoxy is as described above. In some embodiments, the term "halogenated C _1-6 alkyl" is preferably fluoro, e.g., -CF₃、-CHF₂、-CH₂F、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃, etc. In some embodiments, the term "halogenated C _1-6 alkoxy" is preferably fluoro, e.g., -OCF₃、-OCHF₂、-OCH₂F、-OCH₂CH₂F、-OCH₂CHF₂、-OCH₂CF₃, etc.

The term "hydroxy-substituted C _1-6 alkyl" means that one hydrogen atom of the alkyl group is replaced with a hydroxy group, the definition of the alkyl group being as described above. As an example, the "hydroxy-substituted C _1-6 alkyl" may be hydroxymethyl.

The term "alkenyl" refers to a hydrocarbon group comprising a straight or branched chain configuration and having one or more carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C _2-6 alkenyl" is meant to include C ₂、C₃、C₄、C₅ and C ₆. Examples of alkenyl groups include, but are not limited to, vinyl, 1-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.

The term "alkynyl" refers to a hydrocarbon group comprising a straight or branched configuration 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 alkynyl" is meant to include C ₂、C₃、C₄、C₅ and C ₆ alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

The term "cycloalkyl" refers to a cyclized alkyl group and includes monocyclic, bicyclic, or polycyclic ring systems. When cycloalkyl is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or residue of a carbocyclic ring, and bicyclic or polycyclic cycloalkyl groups may include bridging, fused or spiro linkages per two rings in any manner. For example, C _3-10 cycloalkyl is meant to include C ₃、C₄、C₅、C₆、C₇、C₈、C₉ and C ₁₀ cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Etc.

The term "cycloalkenyl" refers to a carbocyclic group having at least one carbon-carbon double bond in a cycloalkyl group as defined above, e.g

The term "carbocycle" or "carbocycle residue" refers to any stable 3-, 4-, 5-, 6-, or 7-membered single ring or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-membered bi-or polycyclic ring wherein any of the rings may be saturated, partially saturated, unsaturated, or aromatic. Bicyclic or polycyclic carbocycles may include bridging, fused or spiro-linked every two rings. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2, 2] bicyclooctane,Etc.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 5 to 14 carbon atoms in the ring portion, each of which is an aromatic ring when the "aryl" is bicyclic or tricyclic. The bi-or tri-cyclic aryl groups may be linked in any manner including bridging, fused, threaded. Such as phenyl and naphthyl, each of which may be substituted.

The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 4-8 membered mono-or bicyclic groups, 8-10 membered bi-or tricyclic groups and 10-14 membered tri-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 radical 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 refer to N or O only, and the total number of heteroatoms is no more than 3, preferably only 1-2 heteroatoms. The carbon and sulfur atoms may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the ring atoms on the heterocycle may optionally be substituted with =o (oxo) when the valency permits. (e.g.: ). The fused rings completing the bi-and tri-cyclic 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 heterocyclyl herein completes fused rings of both bicyclic and tricyclic groups as non-aromatic rings. As previously mentioned, heterocyclyl includes "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-oxoazepanyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1, 3-dioxanyl, quininyl, quinazolinyl, Etc.

The term "heterocycloalkyl" refers to a heterocyclic group in which all ring atoms are fully saturated in the heterocyclic ring as defined above, e.gWhen bicyclic or tricyclic, "heterocycloalkyl" includes "heterobridged cycloalkyl", "heterospirocycloalkyl", "heteroacenaphthylene".

The term "heterocycloalkenyl" refers to a heterocyclic group having at least one carbon-carbon double bond in a heterocycle as defined above, e.gWhen bicyclic or tricyclic, "heterocycloalkenyl" includes "heterobridged cycloalkenyl", "heterospirocycloalkenyl", "heteroheterocycloalkenyl". When the heterocycloalkenyl group is bicyclic or tricyclic, the ring as a whole is unsaturated and cannot develop aromaticity.

The term "heteroaryl" refers to substituted and unsubstituted aryl groups as 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, the heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, N or S. Each heteroatom-containing ring of a 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 that each ring has at least one carbon atom. Heteroaryl groups which are bicyclic or tricyclic are each aromatic.

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

The term "spiroheterocyclyl" refers to a bicyclic structure having one common ring atom, and each monocyclic ring is a saturated or unsaturated monocyclic group having 3-8 ring atoms, wherein at least one ring has 1 or 2 ring atoms being a heteroatom 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, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. Exemplary spiroheterocyclyl groups include, but are not limited to, 5-azaspiro [2.3] hexane, 6-oxaspiro [3.4] -7-octanone. Herein, the spiroheterocyclyl does not include heteroaryl groups as defined above.

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

The term "halogen" shall include "F, cl, br, I".

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.

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

From all of the above description it will be apparent to those skilled in the art that any group whose name is a compound name, such as "pyridothienyl", moieties derived therefrom, are built from pyridyl or thienyl, preferably thienyl, and other similar compound names can be understood with reference to the foregoing.

The term "optional" means optional or not. For example, "C _1- ₆ alkyl optionally substituted with 1 to 3R ^d" means that the C _1-6 alkyl may or may not be substituted with 1 to 3R ^d. Other similar definitions may be understood with reference to the foregoing.

Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds useful as pharmaceutically acceptable compounds and/or intermediate compounds useful in the preparation of pharmaceutically acceptable compounds.

As used herein, unless expressly indicated otherwise, the terms "description," "each independently selected from the group consisting of" do not affect each other between the specific terms expressed between the same or different symbols in different groups, "or" do not affect each other between the specific terms expressed between the same or different symbols in the same groups.

The term "XXX substituted with one or more substituents selected from yyyy" means that XXX may be substituted with one or more substituents selected from yyyy at any substitutable position. When XXX is substituted with a plurality of substituents selected from YYY at any substitutable position, the plurality of substituents may be the same or different. Wherein the plurality is 2 or more, preferably 2,3 or 4, more preferably 2 or 3. For example, C _1-6 alkyl is substituted at any substitutable position with one or more substituents selected from cyano and hydroxy, which means that C _1-6 alkyl may be substituted at any substitutable position with one or more cyano groups, may be substituted at any substitutable position with one or more hydroxy groups, and may be substituted at any substitutable position with one or more cyano groups and hydroxy groups (e.g., one cyano group and one hydroxy group, or two cyano groups and two hydroxy groups, etc.), simultaneously.

Reference to "one or more H atoms in XXX being further substituted with one or more identical or different YYY's" means that the H atoms in XXX may or may not be substituted with YYY's, and that the H atoms in XXX may or may not be substituted with one or more identical YYY's, and that each substituent should not be identical in sign but interfere with each other.

The invention has the following effects:

the compound shown in the formula (I) has good WRN inhibition effect, can be used as a medicament related to the treatment and/or prevention of diseases related to the effect, and is particularly applicable to the treatment and/or prevention of MSI tumor related diseases.

Detailed Description

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR measurements were performed using a Bruker ASCENA-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD), with an internal standard Tetramethylsilane (TMS), and chemical shifts given in units of 10 ^- ⁶ (ppm).

Reaction monitoring and determination of MS using Thermofisher ESQ (ESI) mass spectrometer.

HPLC was performed using a Siemens flight U3000DAD high pressure liquid chromatograph (GL SCIENCES ODS-HL HP 3.mu.m3.0X100 mm column).

The thin layer chromatography silica gel plate uses Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.9-1.0 mm. The column chromatography uses 200-300 mesh silica gel of Qingdao ocean as a carrier, and the system used by the developing agent comprises a methylene dichloride and methanol system, a petroleum ether and ethyl acetate system and a solvent volume ratio which is adjusted according to different polarities of the compounds. The medium pressure preparative liquid phase purification uses a type biotage isera one preparative liquid phase. The model of the preparative liquid chromatograph (prep-HPLC) is Agilent 1290 Infinicity 2 generation.

In the following examples, unless otherwise indicated, all of the reaction materials were purchased from such manufacturers as Saen chemical technology (Shanghai), shanghai Shaoshao reagent, nanjing medical science and technology, jiangsu Aikang biological medicine research and development, shanghai Bi medicine and technology.

Brief description of the drawings

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

Step 1 methyl 3-oxopentanoate (int-1 a,70g,538.05 mmol) was dissolved in DCM (500 mL), NBS (100.6 g,564.95 mmol) was added followed by TSOH.H257O (20.4 g,107.61 mmol) and stirred at room temperature for 3 hours. Suction filtration and concentration of the filtrate under reduced pressure gave crude methyl 2-bromo-3-oxopentanoate (int-1 b,126.5g,602.87 mmol). MS Calcd:207.97;MS Found:206.98 ([ M-H ] ^-).

Step 2 methyl 2-bromo-3-oxopentanoate (int-1 b,10g,47.85 mmol), tert-butyl piperazine-1-carboxylate (int-1 c,49.0g,263.16 mmol), potassium carbonate (39.7 g,287.08 mmol) was dissolved in MeCN (100 mL) and stirred at room temperature for 30min. After filtration, the filtrate was neutralized with dilute hydrochloric acid and washed with water, DCM was extracted, the organic phase was concentrated and the residue was chromatographed to give tert-butyl 4- (1-methoxy-1, 3-dioxo-pentan-2-yl) piperazine-1-carboxylate (int-1 d,10.97g,34.89mmol, 72.9%). MS Calcd:314.18;MS Found:315.23 ([ M+H ] ⁺).

Step 3H ₃PO₄ (4.5 g,46.01 mmol) was added to a solution of 5-bromo-2H-1, 2, 4-triazol-3-amine (int-1 e,5g,30.67 mmol) and tert-butyl 4- (1-methoxy-1, 3-dioxo-pentan-2-yl) piperazine-1-carboxylate (int-1 d,10.6g,33.74 mmol) in absolute ethanol (50 mL) at room temperature and heated to 80℃and stirred for two days. Saturated sodium bicarbonate was added to quench and adjust pH to 6-7, the reaction was concentrated, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, and concentrated 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, 2.09g,4.89mmol, 15.9%). MS Calcd:426.10;MS Found:427.07 ([ M+H ] ⁺).

Preparation of intermediate int-2N- (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

Step 1 to a 50mL eggplant bottle was added 4- (2-bromo-5-ethyl-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) piperazine-1-carboxylic acid tert-butyl ester (int-1, 400mg,0.94 mmol) and solvent 1, 4-dioxane (5 mL). N- (2-chloro-4- (trifluoromethyl) phenyl) -2-iodoacetamide (374 mg,1.03 mmol), DIPEA (383 mg,2.81 mmol) was then added thereto and stirred at 85℃for 5 hours, water (20 mL) was added thereto, the organic phase was extracted with EA (20 mL. Times.3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude product which 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-2 a,430mg,0.65mmol,69.3% yieldd). MS Calcd:662.89;MS Found:564.15 ([ M+H-100] ⁺).

Step 2 to a 50mL eggplant bottle was added 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-carboxylic acid tert-butyl ester (int-2 a,350mg,0.53 mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (166 mg,0.79 mmol) and the solvent 1, 4-dioxane (3 mL), H ₂ O (1.5 mL). Then Pd (dppf) Cl ₂ (39 mg,0.053 mmol), potassium phosphate (365 mg,1.58 mmol) and water (20 mL) were added thereto under stirring overnight at 80℃under nitrogen protection, the organic phase (20 mL) was washed with EA, dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude product, which was purified by column chromatography (PE: EA=1:2) to give 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-carboxylic acid tert-butyl ester (int-2 b,220mg,0.33mmol,61.8% yield) MS Calcd:666.10;MS Found:610.19 ([ M-56] ⁺).

Step 3 to a 50mL eggplant bottle was added 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-carboxylic acid tert-butyl ester (int-2 b,220mg,0.33 mmol) and solvent DCM (5 mL). Trifluoroacetic acid (1 mL) was then added thereto, stirred overnight at room temperature, and after completion of the reaction by LCMS, a saturated sodium bicarbonate solution (20 mL) was added thereto, the organic phase (20 mL) was extracted with EA (20 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give 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, 140mg,0.25mmol,75.7% yield). MS Calcd:565.18;MS Found:566.26 ([ M+H ] ⁺).

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

Step 1 5-bromo-2H-1, 2, 4-triazole-3-ammonia (int-1 e,2.0g,12.3 mmol) and methyl 3-oxopentanoate (int-1 a,2.2g,15.3 mmol) were added to a 25mL round bottom flask, acOH (7 mL) was added, and heated to 80℃and stirred overnight. After cooling to room temperature, stirring for 1H at 0 ℃, filtering, washing the filter cake with a small amount of EtOH (10 mL), drying, concentrating the filtrate to dryness, washing with a small amount of EtOH (10 mL), drying the solid to obtain a second part of the product, and combining to obtain 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,1.63g,6.71mmol,54.5% yieldd). MS Calcd:241.98, 243.98;MS Found:242.98, 244.98 ([ M+H ] ⁺).

Step 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,1.63g,6.71 mmol) and N- [ 2-chloro-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (2.67 g,7.35 mmol) were added to a 25mL round bottom flask, 1, 4-dioxane (7 mL) was added and stirred for 4H at 80℃under nitrogen. Cooling to room temperature, precipitating a white precipitate, filtering, concentrating the filtrate, adding EA, precipitating a white solid again, filtering, washing with EA (10 mL), combining the solids, and removing the solvent 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 (int-3 b,3.02g,6.31mmol,94.0% yieldd). MS Calcd:476.98, 478.98;MS Found:477.94, 479.95 ([ M+H ] ⁺).

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-3 b,3.0g,6.27 mmol) and 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.71 g,8.14 mmol) were added to a 100mL two-necked flask, followed by potassium phosphate (3.99 g,18.80 mmol), pd (dppf) Cl ₂ (458 mg,0.63 mmol), 1, 4-dioxane (40 mL) and purified water (20 mL) in the form of a brown suspension, and stirred under nitrogen at 80℃for 2H. Cooling to room temperature, spinning off excess solvent, adding DCM (100 mL) and water (100 mL), separating the aqueous phase, extracting with DCM (50 mL x 3), combining the organic phases, washing with saturated brine (100 mL), removing the solvent under reduced pressure, adding EA/PE (2:1) to give a brown precipitate, and column chromatography (DCM: meoh=10:1) to give 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-3 c,1.58g,3.28mmol,52.3% yield). MS Calcd:481.11;MS Found:479.94 ([ M-H ] ^-).

Step 4N- (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, 1.35g,2.80 mmol) was added to a 50mL flask followed by NBS (548 mg) and acetonitrile (50 mL) and heated to 80℃for further reaction for 6H. After cooling, the solid precipitated, 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, 0.51g,0.91mmol,32.5% yield). MS Calcd:559.02, 561.02;MS Found:559.8, 562.0 ([ M+H ] ⁺).

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

Step 1 to a 250mL eggplant-shaped bottle was added 4-bromo-2-fluoro-1- (trifluoromethyl) benzene (int-4 a,9.5g,39.09 mmol) and solvent THF (20 mL) and cooled to-78 ℃. LDA (4.6 g,43.00 mmol) was slowly added dropwise thereto under nitrogen atmosphere, stirred at-78℃for 2 hours, then methyl iodide (4.76 g,76mL,58.64 mmol) was added thereto, warmed to room temperature and reacted overnight. Quenching with saturated ammonium chloride in ice bath, extracting with dichloromethane (50 ml. Times.3), washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude 1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene (int-4b,9.0g,35.02mmol,89.6％yield).¹H 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).

Step 2 to a 250mL eggplant-shaped bottle were added 1-bromo-3-fluoro-2-methyl-4- (trifluoromethyl) benzene (int-4 b,9.0g,35.02 mmol), tert-butyl carbamate (4.5 g,38.52 mmol) and solvent 1, 4-dioxane (20 mL), and then Xantphos(1.4g,2.45mmol),Pd₂(dba)₃(1.6g,1.75mmol),Cs₂CO₃(17.1g,52.53mmol), nitrogen was added thereto to raise the temperature to 85℃for reaction for 3 hours. Cooled to room temperature, filtered, the filter cake was washed with dichloromethane and the organic phase was dried under reduced pressure to give crude product, which was purified by flash column chromatography (PE: ea=20:1) to give tert-butyl 3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) carbamate (int-4 c,7.3g,24.89mmol,71.1% yield). MS Calcd:293.10;MS Found:292.1 ([ M-H ] ^-).

Step 3 to a 250mL eggplant-shaped bottle was added 3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) carbamic acid tert-butyl ester (int-4 c,7.26g,24.75 mmol), methanol hydrochloride solution (20 mL) and reacted at room temperature for two hours. Sodium hydroxide was added to the reaction solution to adjust the pH to neutrality, insoluble matters were removed by filtration, the organic phase was washed with 2X 30mL of water, dried over anhydrous sodium sulfate, and concentrated to give crude product of 3-fluoro-2-methyl-4-trifluoromethylaniline (int-4 d,4.3g,22.27mmol,89.6% yieldd). MS Calcd:193.05;MS Found:192.11 ([ M-H ] ^-).

Step 4 3-fluoro-2-methyl-4-trifluoromethylaniline (int-4 d,4.3g,22.27 mmol), dichloromethane (30 mL), triethylamine (6.17 mL,44.54 mmol) and a solution of chloroacetyl chloride (2.65 mL,26.72 mmol) in dichloromethane (10 mL) were added dropwise under ice bath, followed by natural resumption of the reaction overnight at room temperature. The reaction solution 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-4 e,5.5g,18.77mmol,84.3% yield): MS Calcd:269.02;MS Found:268.07 ([ M-H ] ^-).

Step 5 to a 250mL eggplant-shaped bottle was added 2-chloro-N- [ 3-fluoro-2-methyl-4-trifluoromethylphenyl ] acetamide (int-4 e,5.5g,18.77 mmol), potassium iodide (6.8 g,40.80 mmol) and solvent acetone (30 mL), followed by reaction at 50℃for 3 hours. The reaction solution was dried under reduced pressure to give a crude product, which was purified by flash column chromatography (PE: EA=5:1) to give N- [ 3-fluoro-2-methyl-4-trifluoromethylphenyl ] -2-iodoacetamide ((int-4, 6.12g,16.95mmol,82.7% yield): MS Calcd:360.96;MS Found:359.99 ([ M-H ] ^-).

Preparation of intermediate int-5 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-carboxylic acid tert-butyl ester

Step 1 t-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, 14g,32.8 mmol) was placed in a 250mL three-port flask of dioxane (150 mL) and water (50 mL), followed by sequential addition of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (10.3 g,49.1 mmol), K ₂CO₃(9.1g,65.6mmol),Pd(dppf)cl₂ (1.2 g,1.64 mmol), displacement three times under nitrogen atmosphere, reaction to 100℃for 14 hours, cooling to room temperature, addition of 300mL of water, extraction of 3 times with 300mL of dichloromethane, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, spin-drying, washing the participants with column chromatography (DCM/MeOH=100/0-95/5) to obtain the crude product, and beating the crude product with methyl t-butyl ether to obtain 4- (3, 6-dihydro-2-H-pyran-4-dihydro-1, 7-triazolo [1, 4-7-2-amino ] triazolo [1, 4-7-yl ] piperazine by beating three times under nitrogen atmosphere (int-5,9.2g,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).

Preparation of intermediate int-6 (R) -4- (2-bromo-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

Step 1 Ethyl 3-oxopentanoate (int-6 a,100.00g,693.63 mmol) was dissolved in dichloromethane (1L) and NBS (129.62 g,728.31 mmol), tsOH H ₂ O (26.39 g,138.73 mmol) was added sequentially. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was poured into saturated brine (1L) and extracted twice with dichloromethane (1 l×2). The combined organic phases were backwashed twice with brine, dried over anhydrous sodium sulfate, filtered and spun-dried. The crude product obtained was purified by flash column chromatography (petroleum ether/ethyl acetate=10:1) to give ethyl 2-bromo-3-oxopentanoate (int-6 b,120.0g, yield 77.6%). MS calculated 221.99;MS Found:229.2[M+H: ⁺.

Step 2 Ethyl 2-bromo-3-oxopentanoate (int-6 b,60.00g,268.98 mmol) was dissolved in acetonitrile (300 mL) in a 1L single-necked flask followed by K ₂CO₃ (74.36 g,537.96 mmol) and (R) -1-N-Boc-2-methylpiperazine (56.56 g,282.43 mmol). The resulting reaction mixture was stirred at room temperature overnight. Undissolved inorganic salts are filtered off and the filtrate is concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate=5:1) to give (2R) -4- (1-ethoxy-1, 3-dioxo-pentan-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (int-6 c,64.0g, 69.5% yield). MS calculated 342.22;MS Found:343.22[M+H: ⁺.

Step 3. Tert-butyl (2R) -4- (1-ethoxy-1, 3-dioxo-pentan-2-yl) -2-methylpiperazine-1-carboxylate (int-6C, 91.32g,266.68 mmol) was weighed into a 1L single-necked flask, dissolved in ethanol (150 mL), then added with 5-bromo-2H-1, 2, 4-triazole-3-ammonia (int-1 e,47.81g,293.35 mmol) and phosphoric acid (27.44 g,280.01 mmol) in sequence, the whole reaction system was nitrogen-shifted three times and stirred at 90℃for 44 hours and cooled to room temperature. To a single vial was added DIPEA (103.40 g,800.04 mmol), boc ₂ O (29.10 g,133.34 mmol) and reacted for 2h at room temperature. After completion of the reaction, the reaction mixture was poured into saturated brine (500 mL), and extracted three times with ethyl acetate (1 l×3). The combined organic phases were backwashed twice with brine, dried over anhydrous sodium sulfate, filtered and spun-dried to give the residue. The residue was purified by flash column chromatography (dichloromethane/methanol=17:3) to give the title compound (R) -4- (2-bromo-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 (int-6, 50.0g, yield 38.6％).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).

Preparation of intermediate int-7, 4-hydroxyisoxazole-3-carboxylic acid

Step 1 Ethyl 4-chloro-3-oxobutyrate (int-7 a,10g,60.75 mmol) was dissolved in AcOH (48 mL) and placed under 0℃to slowly add NaNO ₂ (5.2 g,75.94 mmol) in H ₂ O (40 mL) and the reaction system turned red and then warmed to room temperature and stirred overnight. To the reaction solution was added 100mL of H ₂ O, 100mL of ethyl acetate was extracted 3 times, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: ea=3:1) to give ethyl 4-chloro-2- (hydroxyimino3-oxobutyrate (int-7 b,11g,56.82mmol,93.5% yield).

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

Step 3 Ethyl 4-hydroxyisoxazole-3-carboxylate (int-7 c,2000mg,12.73 mmol) was dissolved in THF (20 mL), naOH (2546 mg,63.65 mmol) was added under ice bath and reacted at room temperature for 2.0h. The solvent was dried and separated by column chromatography (DCM: meoh=1:1) to give the title compound, 4-hydroxyisoxazole-3-carboxylic acid (int-7, 1000mg,7.75mmol,60.8% yieldd). MS Calcd:129.01;MS Found:128.0 ([ M+H ] ⁺).

Preparation of intermediate int-8 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

Step 1 4-methoxycyclohex-1-one (int-8 a,1g,7.8 mmol), 1-trifluoro-N-phenyl-N- (trifluoromethyl) sulfonyl) methanesulfonamide (2.8 g,7.8 mmol) was added to dry THF (20 mL), the temperature was reduced to-78 ℃, then a solution of LiHMDS in THF (1N, 7.8 mL) was added dropwise, stirred at this temperature for 2 hours, then slowly returned to room temperature, and stirred overnight, quenched with saturated aqueous ammonium chloride and extracted with EA (20 mL x 2), the organic layers were combined, dried over anhydrous sodium sulfate, suction filtered, and the residue was purified by column chromatography (EA: pe=1:5) to give crude 4-methoxycyclohex-1-en-1-yl triflate (int-8 b,1.3g,5mmol, 64%).

Step 2: 4-Methoxycyclohex-1-en-1-yl triflate (int-8 b,1.3g,5 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (1.9 g,7.5 mmol), potassium acetate (1.5 g,15 mmol), 1-bis (diphenylphosphine) bis-mandoline palladium dichloride (365 mg,0.5 mmol) were added to dioxane (15 mL), nitrogen was replaced for 3 min, the temperature was raised to 85 ℃, stirred for 3 hours, the residue was concentrated under reduced pressure, poured into water, extracted with ethyl acetate (20 mLx 3), the organic layers were combined, the residue was purified by column chromatography (EA: PE=1:20) to give the title compound 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (int-8, 910mg,3.82mmol, 76%). MS Calcd:238.17;MS Found:239.21 ([ M+H ] ⁺).

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

Step 1 in a 100mL single-necked flask were successively added 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, 1000mg,2.34 mmol), 2-iodo-N- (2-methyl-4-trifluoromethylphenyl) acetamide (660 mg,2.57 mmol), DIPEA (907 mg,7.02 mmol) and solvent DMF (5 mL), and stirred overnight at room temperature. LCMS monitored completion of reaction, and the reaction solution was washed with 100ml DCM,3 x 30ml water, dried over anhydrous sodium sulfate and filtered, and the crude 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, 1200mg,1.87mmol,79% yield). MS Calcd:641.16;MS Found:640.05 ([ M-H ] ^-).

Step 2 into a 30mL microwave tube was added the reactant 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, 900mg,1.40 mmol), 2- (3, 6-dihydropyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (441 mg,2.10 mmol), pd (dppf) Cl ₂ (102 mg,0.14 mmol), anhydrous potassium phosphate (967 mg,4.20 mmol) and solvent 1, 4-dioxane (10 mL) as well as water (2 mL), nitrogen was replaced 3 times, and microwaved at 90℃for 2hr. LCMS monitored completion of the reaction, reaction mixture was filtered through celite, the filter cake was washed with 3 x 10ml methanol, the filtrates were combined and dried under reduced pressure. Purification by flash column chromatography (MeOH: DCM=0:100% to 10%:90% in 30 min) afforded 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, 630 mg,1.27mmol,90% yield), MS Calcd:645.29;MS Found:644.23 ([ M-H ] ^-).

Step 3 to a 100mL single vial was added 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, 500mg,0.77 mmol), dioxane hydrochloride solution (4M, 5 mL) and solvent DCM (10 mL), and the solution was stirred at room temperature for 2hr, and the solution became cloudy. The reaction mixture 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, 380mg,0.7mmol,89% yield). MS Calcd:545.24;MS Found:546.21 ([ M+H ] ⁺).

Example 12 preparation of- (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)

Step 1 diethyl ethoxymethylenemalonate (3-a, 1.5g,6.94 mmol) and methylhydrazine sulfate (1.0 g,6.94 mmol) were added to 10mL of an aqueous solution, respectively, and stirred at 100℃for 6 hours. The reaction solution was cooled to room temperature, and a solid was precipitated, and the crude 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3-b, 350mg,2.06mmol,29.6% yield) was obtained by suction filtration. MS Calcd:170.17;MS Found:171.11 ([ M+H ] ⁺).

Step 2. 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3-b, 250mg,1.47 mmol) was dissolved in 6mL of methanol/water (5:1) mixture, potassium hydroxide (284 mg,14.7 mmol) was added, the reaction was stirred at room temperature under reflux overnight, TLC monitoring was completed, the reaction solution was concentrated completely, 5N HCl solution was slowly added to the residue until solid precipitated, and 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 150mg,1.06mmol,71.9% yieldd) was obtained by suction filtration. MS Calcd:142.11;MS Found:143.05 ([ M+H ] ⁺).

Step 3 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-C, 78mg,0.55 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (80 mg,0.60 mmol) were added separately to a solution of 5mL of dichloromethane and stirred at room temperature for 3 hours, 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, 150mg,0.27 mmol), DIPEA (178 mg,1.37 mmol) were added and stirring was continued at 40℃for 5 hours. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue 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-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (3,8mg,0.01mmol,4％yield).MS Calcd:669.26;MS Found:670.27([M+H]⁺).¹H NMR(400MHz,DMSO)δ10.42(brs,1H),10.02(s,1H),7.88(s,1H),7.72(d,J＝8.4Hz,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).

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)

Step 1 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-C, 45mg,0.32 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (46 mg,0.35 mmol) were added separately to a solution of 5mL of dichloromethane and stirred at room temperature for 3 hours, 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, 90mg,0.16 mmol), DIPEA (102 mg,0.8 mmol) was added and the temperature was raised to 40℃and stirred for 5 hours. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue 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-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (8,10mg,0.01mmol,9.1％yield).MS Calcd:689.21;MS Found:690.32([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.45(s,1H),8.08(d,J＝8.4Hz,1H),7.99(d,J＝2.0Hz,1H),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).

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)

Step 1 silver tetrafluoroborate (35 mg,0.18 mmol) was added to dry DMSO (2 mL), then the temperature was raised to 120 ℃ under nitrogen protection, stirred for 4 hours, the starting material was reacted, cooled to room temperature, saturated aqueous sodium bicarbonate was added, then extracted with ethyl acetate (10 mL x 3), the organic layer was dried over anhydrous sodium sulfate, 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-oxo-2-ethyl) -2-7-oxo-1, 6-dihydro- [1, 5-triazolo ] pyrimidin-4 (7H) -yl) acetamide (int-3, 100mg,0.18 mmol) and (35 mg,0.18 mmol) of (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester, followed by nitrogen protection, raising the temperature to 120 ℃ and stirring for 4 hours, the starting material was cooled to room temperature, saturated aqueous sodium bicarbonate was added, then extracted with ethyl acetate (10 mL x 3), the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA: pe=1:1), 74mg,0.11mmol, 60%). MS Calcd:679.25;MS Found:680.33 ([ M+H ] ⁺).

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, 74mg,0.11 mmol) was added to DCM (5 mL), trifluoroacetic acid (1 mL) was then added, stirring was carried out at room temperature for 4 hours, the starting material was reacted, the reaction mixture was concentrated under reduced pressure, the residue was added to saturated aqueous sodium bicarbonate, then (5 mLx 3) was extracted with DCM, the organic layer was dried over anhydrous sodium sulfate, 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) -1, 7-oxo-1- [2, 4-triazolo ] pyrimidine [1, 4-b ] acetamide (1, 4, 80mg, 09 mg, 4-80 mmol) acetamide. MS Calcd:579.20;MS Found:580.31 ([ M+H ] ⁺).

Step 3 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 17mg,0.11 mmol) was added to DCM (1 mL), followed by 1-chloro-N, N, 2-trimethylpropyl-1-en-1-amine (16 mg,0.11 mmol), stirred at room temperature for 2 hours, 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, 51mg,0.09 mmol) and DIPEA (70 mg,0.54 mmol) in dichloromethane, and stirred at room temperature overnight. Then water (3 mL) was added, the (3 mLx 3) was extracted with DCM, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, 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 (14,8mg,0.011mmol,12.6％yield).MS Calcd:703.22;MS Found:704.31([M+H]⁺).¹H 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).

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)

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, 60mg,0.10 mmol), DIPEA (13 mg,0.10 mmol), ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 60mg,0.3 mmol) was added to 2-methyl-2-butanol, the oil bath was warmed to 180℃and stirred for 30min, the reaction was dissolved in methanol and purified by direct prep-HPLC, to give 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 (15,15mg,0.020mmol,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),2.71-2.69(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).

Example 52 preparation of- (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)

Step 1. Ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (16-a, 100mg,0.59 mmol) was dissolved in 6mL of methanol/water (5:1) mixture, potassium hydroxide (200 mg,3.54 mmol) was added, the reaction was stirred at reflux overnight, TLC monitored for completion of the reaction, the reaction solution was concentrated completely, 5N HCl solution was slowly added to the residue until solid precipitated, and the product 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (16-b, 70mg,0.49mmol,83.8% yieldd) was obtained by suction filtration. MS Calcd:142.11;MS Found:143.07 ([ M+H ] ⁺).

Step 2 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (16-b, 40mg,0.28 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (42 mg,0.31 mmol) were added separately to 5mL of dichloromethane solution, stirred at room temperature for 3 hours, 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), DIPEA (90 mg,0.71 mmol) was added to the reaction mixture, stirred at 40℃for 5H, saturated sodium bicarbonate solution, DCM was added, saturated brine was washed, the residue was dissolved in 4mL of methanol/water (5:1) mixed solvent after reduced pressure concentration, then sodium hydroxide (15 mg,0.37 mmol) was added, and the mixture was left to stand overnight at room temperature. LCMS was monitored for completion of the reaction, the reaction solution was adjusted to pH=2, prep-HPLC was purified 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 (16,3mg,0.004mmol,3％yield).MS Calcd:689.21;MS Found:690.31([M+H]⁺).¹H 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),3.50-3.30(m,6H),3.04-2.98(m,2H),2.74(d,J＝10.0Hz,2H),1.25(t,J＝7.2Hz,3H).

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)

Step 1 diethyl ethoxymethylene malonate (17-a, 1.41g,6.53 mmol), 1-cyclobutylhydrazine hydrochloride (0.8 g,6.53 mmol) and potassium carbonate (1.8 g,13.05 mmol) were added respectively to 10mL of aqueous solution and stirred at 100℃for 6 hours. TLC monitored the completion of the reaction, the reaction was lyophilized, dissolved in a small amount of methanol, adjusted to ph=2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (DCM: meoh=20:1) to give 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 900mg,4.28mmol,65.6% yield). MS Calcd:210.10;MS Found:211.12 ([ M+H ] ⁺).

Step 2 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 50mg,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 45mg,0.06 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. LCMS was monitored for completion of the reaction, the reaction mixture was concentrated completely 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 (17,5mg,0.01mmol,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).

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)

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

Step 2 Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 117mg,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 45mg,0.06 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. LC-MS monitoring the completion of the reaction, concentrating the reaction solution completely, purifying the residue 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 (18,3mg,0.004mmol,6.2％yield).MS Calcd:715.22;MS Found:716.28([M+H]⁺).¹H 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),3.05-2.98(m,2H),2.75(d,J＝11.2Hz,2H),1.26-1.20(m,5H),0.99-0.93(m,2H).

Example 82 preparation of- (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)

Step 14- (2-bromo-5-ethyl-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) piperazine-1-carboxylic acid tert-butyl ester (int-1, 2.2g,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 separately to 60mL dioxane solution and stirred at 80℃for 4 hours. TLC monitored completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EA: pe=1:1) to give 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, 1.44g,2.18mmol,42.3% yield). MS Calcd:659.15;MS Found:560.21 ([ M-100+H ] ⁺).

Step 2 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-carboxylic acid tert-butyl ester (19-a, 1.44g,2.18 mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (687 mg,3.27 mmol), pd (dppf) Cl ₂·CH₂Cl₂ (357 mg,0.44 mmol) and potassium phosphate (1.39 g,6.54 mmol) were added sequentially to a20 mL dioxane/water (4:1) mixed solution, the mixture was purged 3 times with nitrogen, and heated to 80 ℃ and stirred for 2H. TLC monitored completion of the reaction, and the reaction was concentrated completely and the residue was purified by silica gel column chromatography (DCM: meoh=20:1) to give 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, 1.4g,2.11mmol,96.8% yield). MS Calcd:663.28;MS Found:664.32 ([ M+H ] ⁺).

Step 3 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-carboxylic acid tert-butyl ester (19-b, 1.4g,2.11 mmol) was added to 20mL of a solution of hydrochloric acid-dioxane and left to stir at room temperature overnight. The reaction solution was concentrated completely, and a saturated sodium hydrogencarbonate solution, dichloromethane extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave crude 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, 0.73g,1.30mmol,61.4% yieldd). MS Calcd:563.23;MS Found:564.21 ([ M+H ] ⁺).

Step 4 Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 80mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. The reaction mixture was concentrated completely 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 (19,3mg,0.004mmol,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).

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)

Step 1 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-carboxylic acid tert-butyl ester (int-2 a,550mg,0.83 mmol) and 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (237 mg,1 mmol) were dissolved in 1, 4-dioxane (8 mL) and H ₂ O (4 mL), pd (dppf) Cl ₂ (60 mg,0.09 mmol), potassium phosphate (570 mg,2.49 mmol) were then added in sequence, and the reaction was carried out at 80℃for 5.0 hours with three nitrogen substitutions. The reaction solution was concentrated, 30mL of ethyl acetate was added to the residue, 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, 370mg,0.53mmol,64% yield) MS Calcd:693.27;MS Found:694.27 ([ M+H ] ⁺).

Step 2 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, 370mg,0.53 mmol) was dissolved in 8mL of dichloromethane, 2mL of trifluoroacetic acid was added thereto, and stirring was performed at room temperature for 2 hours. The reaction solution was concentrated directly, 20mL of saturated sodium hydrogencarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and concentrated by drying 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, 300mg,0.51mmol,95% yield) MS Calcd:593.21;MS Found:594.27 ([ M+H ] ⁺).

Step 3N- (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, 50mg,0.08 mmol) and 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (15 mg,0.10 mmol) were placed in a 25mL eggplant bottle, 5mL DCM was added thereto for dissolution, and PyBOP (43 mg,0.08 mmol), DIPEA (0.04 mL,0.22 mmol) was added sequentially and 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 (20,6mg,0.01mmol,9％yield)MS Calcd:714.24;MS Found:718.31([M+H]⁺).¹H 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).

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)

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

Step 2 Ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 83mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. The reaction solution was then directly concentrated by stirring at 180℃for 30 minutes 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 (21,30mg,0.04mmol,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).

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)

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, 60mg,0.10 mmol), DIPEA (13 mg,0.10 mmol), 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (21-a, 102mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30min, the reaction was dissolved in methanol and purified directly by prep-HPLC, 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-acyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide was obtained (22,17mg,0.023mmol,23.2％yield).MS Calcd:731.26;MS Found:732.31([M+H]⁺).¹H 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＝10.0Hz,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).

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)

Step 1 3-hydroxy-2-methylquinoline-4-carboxylic acid (26-a, 19mg,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, 60mg,0.09 mmol) was weighed into a 25mL single-necked flask, and DCM (2 mL) and DIPEA (0.04 mL,0.27 mmol) were added and stirred overnight at room temperature after the addition. 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-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (26,19mg,0.02mmol,26.9％Yeild).MS Calcd:750.23;MS Found:751.12([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.37(s,1H),8.08(d,J＝8.8Hz,1H),7.97(d,J＝2.0Hz,1H),7.91–7.87(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＝5.2Hz,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).

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)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 80mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. The reaction mixture was concentrated completely 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 (27,10mg,0.01mmol,14.6％yield).MS Calcd:727.29;MS Found:728.32([M+H]⁺).¹H 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＝11.2Hz,2H),2.38(s,3H),2.35–2.27(m,2H),1.84-1.75(m,2H),1.26–1.20(m,5H).

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)

Step 1 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-C, 40mg,0.28 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (42 mg,0.31 mmol) were added separately to a solution of 5mL of dichloromethane, stirred at room temperature for 3 hours, 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, 80mg,0.14 mmol), DIPEA (90 mg,0.71 mmol) were added and stirring was continued at 40℃for 5 hours. To the reaction solution was added saturated sodium bicarbonate solution, extracted with DCM, washed with saturated brine, concentrated under reduced pressure, and the residue was dissolved in 4mL of a methanol/water (5:1) mixture, followed by sodium hydroxide (15 mg,0.37 mmol) and left to stir at room temperature overnight. The reaction mixture was adjusted to ph=2 and prep-HPLC was performed to give 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 (28,10mg,0.01mmol,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).

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)

Step 1 Ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (16-a, 500mg,2.94 mmol) was dissolved in 10mL dichloromethane, and sulfonyl chloride (0.47 g,3.53 mmol) was slowly added at 0deg.C, and the mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by addition of water to the reaction mixture, extracted with dichloromethane, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give ethyl 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (29-a, 120mg,0.59mmol,20% yield). MS Calcd:204.03;MS Found:205.10 ([ M+H ] ⁺).

Step 2 Ethyl 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (29-a, 120mg,0.59 mmol) was dissolved in 4mL of a methanol/water (5:1) mixture, potassium hydroxide (200 mg,3.52 mmol) was added, the reaction mixture was warmed to reflux and stirred overnight, the reaction solution was concentrated completely, 5N HCl solution was slowly added to the residue until solid precipitated, and 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (29-b, 90mg,0.51mmol,86.9% yieldd) was obtained by suction filtration. MS Calcd:176.00;MS Found:177.01 ([ M+H ] ⁺).

Step 3 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (29-b, 44mg,0.25 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (36 mg,0.27 mmol) were added separately to a solution of 5mL of dichloromethane and stirred at room temperature for 3 hours, 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, 70mg,0.12 mmol), DIPEA (80 mg,0.62 mmol) were added and stirring was continued at 40℃for 5 hours. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue by prep-HPLC to obtain the title compound of 2- (6- (4- (5-chloro-3-hydroxy-1-methyl-1H-pyrazol-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 (29,16mg,0.02mmol,18％yield).MS Calcd:723.17;MS Found:724.30([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.75(s,1H),10.38(s,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),5.33(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).

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)

Step 12- (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, 50mg,0.09 mmol) and ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 87.9mg,0.44 mmol) were added to 4ml of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180 ℃ for 30min under stirring. The reaction mixture was concentrated completely 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-acyl) 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 (30,10mg,0.01mmol,15％yield).MS Calcd:715.29;MS Found:716.30([M+H]⁺).¹H 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).

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)

Step 1 Ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 90mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min stirring. The reaction mixture was concentrated completely 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 (31,10mg,0.01mmol,15.7％yield).MS Calcd:717.24;MS Found:718.21([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),7.63(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).

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)

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, 55mg,0.10 mmol), DIPEA (13 mg,0.10 mmol), 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 63mg,0.3 mmol) was added to 2-methyl-2-butanol, the oil bath was warmed to 180℃and stirred for 30min, the reaction was dissolved in methanol and purified by direct 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 ] pyrimidine-4 (7H) -yl) acetamide (32,7mg,0.0094mmol,9.4％yield).MS Calcd:743.26;MS Found:744.30([M+H]⁺).¹H 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),7.70(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).

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)

Step 1 5-chloro-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (29-b, 30mg,0.17 mmol) was added to DCM (1 mL), then to a solution of 1-chloro-N, N, 2-trimethylpropyl-1-en-1-amine (23 mg,0.17 mmol), stirred at room temperature for 2 hours, then 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, 40mg,0.07 mmol) and DIPEA (54 mg,0.42 mmol) in dichloromethane and stirred at room temperature overnight, then to water (3 mL) extract with DCM (3 mLx 3), the organic layer was dried over sodium sulfate, the residue was concentrated by HPLC, purified by filtration, the title compound (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 was obtained (33,7mg,0.009mmol,13.5％yield).MS Calcd:737.19;MS Found:738.21([M+H]⁺).¹H 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).

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)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly concentrated 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 (34,25mg,0.03mmol,39％yield).MS Calcd:757.27;MS Found:758.41([M+H]⁺).¹H 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).

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)

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, 200mg,0.47 mmol) was placed in a 100mL eggplant bottle and 10mL of 1, 4-dioxane solution was added. N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) -2-iodoacetamide (int-4, 185.9mg,0.51 mmol) and DIPEA (0.23 mL,1.4 mmol) were then added sequentially thereto. Stirred at 75 ℃ 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, 180mg,0.27mmol,58% yield). MS Calcd:661.15;MS Found:662.30 ([ m+h ] ⁺).

Step 2 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-carboxylic acid tert-butyl ester (35-a, 180mg,0.27 mmol) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (85.9 mg,0.41 mmol) were dissolved in 1, 4-dioxane (6 mL) and H ₂ O (3 mL), pd (dppf) Cl ₂ (20 mg,0.03 mmol), potassium phosphate (188 mg,0.82 mmol) were sequentially added, and the reaction was carried out at 80℃for 5.0 hours with replacement of nitrogen. The reaction solution was concentrated, 30mL of ethyl acetate was added to the residue, filtered through celite, and 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, 153mg,0.23mmol,85% yield) MS Calcd:663.28;MS Found:664.20 ([ m+h ] ⁺).

Step 3 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, 153mg,0.23 mmol) was dissolved in 8mL dichloromethane solution, 2mL trifluoroacetic acid was added thereto, and stirred at room temperature for 2 hours. The reaction solution was concentrated directly, 20mL of saturated sodium hydrogencarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and concentrated by drying 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, 150mg,0.27mmol,98% yield) MS Calcd:563.23;MS Found:564.31 ([ M+H ] ⁺).

Step 4 Compound 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 25mL eggplant-shaped bottle, 5mLDCM was added thereto, followed by DIPEA (0.04 mL,0.27 mmol) and stirred for 2 minutes after the addition. 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, 50mg,0.09 mmol) was then added and reacted 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 (35,13mg,0.02mmol,19.6％yield)MS Calcd:748.27;MS Found:749.41([M+H]⁺).¹H 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).

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)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction mixture was directly concentrated and purified by Prep-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-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 (36,24mg,0.03mmol,37％yield).MS Calcd:727.29;MS Found:728.40([M+H]⁺).¹H 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).

Example 23 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (4- (5-hydroxy-1- (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)

Step 1 (2, 2-trifluoroethyl) hydrazine hydrochloride (37-a, 4000mg,35.06 mmol) was dissolved in 40mL of water, followed by slow addition of diethyl 2- (ethoxymethylene) malonate (7579.3 mg,35.06 mmol) and K ₂CO₃ (9675 mg,17.53 mmol) at 0℃and stirring to 100℃for 5h. TLC detects the completion of the starting material reaction. The reaction solution was cooled to room temperature, part of the solvent was dried, the residue was adjusted to ph=2 with 5N HCl, extracted with dichloromethane (50 ml×3), washed with saturated brine (100 mL), the organic phases were combined, dried, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (DCM: meoh=20%: 80%) to give ethyl 5-hydroxy-1- (2, 2-trifluoroethyl) -1H-pyrazole-4-carboxylate (37-b, 350 mg,42% yield) MS Calcd:238.06;MS Found:239.10 ([ m+h ] ⁺).

Step 2 Ethyl 5-hydroxy-1- (2, 2-trifluoroethyl) -1H-pyrazole-4-carboxylate (37-b, 100mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. 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- (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, 20mg,0.02mmol,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＝2.0Hz,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).

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

Step 1 5-chloro-2-methyl-4- (trifluoromethyl) aniline (38-a, 6.0g,28.63 mmol) was weighed into a 50mL single port flask, DCM (30 mL) was added, then triethylamine (7.94 mL,57.25 mmol) was added, a solution of chloroacetyl chloride (3.40 mL,34.35 mmol) in DCM (10 mL) was added dropwise under ice-bath, and then the reaction was allowed to spontaneously recover at room temperature overnight. The reaction was concentrated and the residue was subjected to flash column chromatography (PE: ea=20:1) to give 2-chloro-N- (5-chloro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (38-b, 3.7g,12.93mmol,45.1% yield). MS Calcd:284.99;MS Found:283.97 ([ M-H ] ^-).

Step 2 to a 100mL eggplant-shaped bottle were added 2-chloro-N- (5-chloro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (38-b, 3.7g,12.93 mmol) and solvent acetone (15 mL). Potassium iodide (5.4 g,32.33 mmol) was then added thereto and stirred at 50℃for 3 hours. The solvent was dried under reduced pressure to give a crude product, which was purified by column chromatography (PE: ea=3:1) to give N- [ 5-chloro-2-methyl-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (38-c, 3.4g,9.01mmol,69.4% yield). MS Calcd:376.93;MS Found:375.97 ([ M-H ] ^-).

Step 3 to a 100mL eggplant bottle was added N- [ 5-chloro-2-methyl-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (38-c, 1.1g,2.81 mmol), 4- (2-bromo-5-ethyl-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) piperazine-1-carboxylic acid tert-butyl ester (int-1, 1.0g,2.34 mmol) and solvent 1, 4-dioxane (15 mL). DIPEA (0.9 g,7.02 mmol) was then added thereto and stirred at 90℃for 2 hours. The solvent was dried under reduced pressure to give crude product, which was purified by column chromatography (PE: ea=1:4) to give 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, 940mg,1.39mmol,59.3% yieldd). MS Calcd: 676.92..MS found:578.12 ([ M+H-100] ⁺).

Step 4 to a 100mL eggplant bottle 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, 940mg,1.39 mmol) and solvent 1, 4-dioxane (10 mL), H ₂ O (5 mL). 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (438 mg,2.08 mmol), pd (dppf) Cl ₂ (102 mg,0.14 mmol), potassium phosphate (960 mg,4.17 mmol) was then added thereto and stirred under nitrogen at 100℃for 6 hours. After completion of the reaction, LCMS was performed to detect the completion of the reaction, water (50 mL) was added thereto, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude product, which was purified by column chromatography (DCM: meOH=30:1) to give 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-carboxylic acid tert-butyl ester (38-e, 800mg,1.18mmol,84.7% yieldd) MS Calcd: 679.25; MS Found:624.21 ([ M+H-56] ⁺).

Step 5 to a 100mL eggplant bottle 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, 800mg,1.18 mmol) and solvent DCM (5 mL). TFA (0.5 mL) was then added thereto and stirred overnight at room temperature. H ₂ O (20 mL) was added thereto, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spun-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, 500mg,0.86mmol,73.3% yieldd) MS Calcd: 579.20..MS Found:580.22 ([ M+H ] ⁺).

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)

Step 1 Ethyl 5-hydroxy-1-isopropyl-1H-pyrazole-4-carboxylate (21-a, 85mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. The reaction mixture was concentrated completely 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 (39,8mg,0.01mmol,12.3％yield).MS Calcd:731.26;MS Found:732.26([M+H]⁺).¹H 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,2H),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).

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)

Step 1 methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (40-a, 120mg,0.77 mmol) was dissolved in 3mL of methanol/water (5:1) mixture, potassium hydroxide (258 mg,4.61 mmol) was added, the reaction mixture was warmed to reflux and stirred overnight, the reaction mixture was concentrated completely, 5N HCl solution was slowly added to the residue, pH=2, and concentrated under reduced pressure to give 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (40-b, 100mg,0.7mmol,91.6% yieldd). MS Calcd:142.04;MS Found:143.06 ([ M+H ] ⁺).

Step 2 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (40-b, 34mg,0.24 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (36 mg,0.27 mmol) were added separately to a solution of 5mL of dichloromethane, stirred at room temperature for 3 hours, 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, 70mg,0.12 mmol), DIPEA (80 mg,0.62 mmol) was added and the temperature was raised to 40℃and stirred for 5 hours. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, concentrating under reduced pressure, purifying 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-3-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (40,6mg,0.01mmol,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).

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)

Step 1 Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 65mg,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, 40mg,0.06 mmol) was weighed into a 25mL single-necked flask, 2-methyl-1-butanol (2 mL) and DIPEA (0.01 mL,0.06 mmol) were added, and after the addition was warmed to 180℃and stirred 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 (41,10mg,0.01mmol,21.0％Yeild).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).

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)

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

Step 2 Ethyl 1- (tert-butyl) -5-hydroxy-1H-pyrazole-4-carboxylate (42-a, 94mg,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, 50mg,0.09 mmol) were added to 2mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min under stirring. The reaction mixture was concentrated completely 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 (42,6mg,0.01mmol,9.1％yield).MS Calcd:729.30;MS Found:730.27([M+H]⁺).¹H 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).

EXAMPLE 28 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (5-hydroxy-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 (Compound 43)

Step 1, 1-trifluoroacetone (43-a, 4.9g,44.05 mmol) and benzoyl hydrazine (43-b, 4.0g,29.37 mmol) were added sequentially to 40mL toluene solution, placed in a jar, warmed to 110℃and stirred overnight. The reaction solution was concentrated completely, and the residue was separated and purified by silica gel column chromatography (PE: ea=10:1) to give N' - (1, 1-trifluoropropan-2-ylidene) benzoyl hydrazine (43-c, 5.1g,22.15mmol,75.4% yield). MS Calcd:230.07;MS Found:231.20 ([ M+H ] ⁺).

Step 2N' - (1, 1-trifluoropropan-2-ylidene) benzoyl hydrazine (43-C, 3.0g,13.3 mmol) was dissolved in 40mL tetrahydrofuran solution, borane tetrahydrofuran solution (26.06 mL,26.06 mmol) was slowly added dropwise at 0℃and the mixture was slowly warmed to room temperature and stirred overnight. The reaction solution was cooled again to 0 ℃, 5mL of methanol was added, the reaction solution was concentrated completely, water was added to the residue, extracted with dichloromethane, washed with saturated ammonium chloride solution, and concentrated under reduced pressure to give crude N' - (1, 1-trifluoropropan-2-yl) benzohydrazide (43-d, 2.8g,12.06mmol,92.5% yield). The product was directly fed to the next reaction without purification. MS Calcd:232.08;MS Found:233.1 ([ M+H ] ⁺).

Step 3N' - (1, 1-trifluoropropan-2-yl) benzohydrazide (43-d, 1.0g,4.31 mmol) was dissolved in 5mL methanol solution, followed by addition of 8mL concentrated hydrochloric acid and stirring overnight at 100 ℃. TLC monitored the disappearance of starting material and the reaction solution was concentrated completely to give the crude product (1, 1-trifluoropropan-2-yl) hydrazine hydrochloride (43-e, 1.5g,9.2 mmol).

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

Step 5 Ethyl 5-hydroxy-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole-4-carboxylate (43-f, 140mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in a microwave reactor at a temperature of 180℃for 30min stirring. The reaction mixture was concentrated completely 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-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 (43,5mg,0.01mmol,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).

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-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)

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, 50mg,0.09 mmol), DIPEA (13 mg,0.10 mmol), ethyl 5-hydroxy-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole-4-carboxylate (43-f, 126mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30 min, the reaction system was dissolved in methanol and purified by direct prep-HPLC, 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-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 (44,12mg,0.0152mmol,17.0％yield).MS Calcd:785.23;MS Found:786.31([M+H]⁺).¹H NMR(400MHz,DMSO-d₆+ w/w )δ8.02(d,J＝8.8Hz,1H),7.95(d,J＝2.0Hz,1H),7.75(s,1H),7.72(dd,J＝8.8,2.0Hz,1H),6.84–6.82(m,1H),5.30(d,J＝2.4Hz,2H),4.25(d,J＝3.2Hz,2H),3.66(d,J＝11.2Hz,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).

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)

Step 1 Ethyl 2- (ethoxycarbonyl) -3-oxobutyrate (45-a, 1g,4.95 mmol) and isopropyl hydrazine hydrochloride (45-b, 0.4g,4.95 mmol) were dissolved in EtOH (20 mL), HCl (1 mL,4.95 mmol) was added and reacted at 85℃for 2 hours. After spin-drying the solvent, 30mL of water was added, extraction with dichloromethane (30 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (DCM: meoh=30:1) to give 5-hydroxy-1-isopropyl-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (45-c, 500mg,2.36mmol,47.6% yield). MS Calcd:212.12;MS Found:213.22 ([ M+H ] ⁺).

Step 2 Ethyl 5-hydroxy-1-isopropyl-3-methyl-1H-pyrazole-4-carboxylate (45-C, 104mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and the oil bath was warmed to 180deg.C and stirred for 30min. The reaction mixture was concentrated completely 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 (45,8mg,0.01mmol,11.9％yield).MS Calcd:729.30;MS Found:730.47([M+H]⁺).¹H 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),3.09-2.98(m,5H),2.73–2.69(m,3H),2.37(s,3H),2.16(s,3H),1.29–1.19(m,9H).

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)

Step 1 Ethyl 4-chloroacetoacetate (47-a, 2.2g,13.37 mmol) was dissolved in 10mL of acetic acid, and an aqueous solution (10 mL) of sodium nitrite (1.2 g,16.71 mmol) was slowly added at 0℃and the mixture was slowly warmed to room temperature and stirred overnight. Adding water into the reaction solution, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography to obtain ethyl 4-chloro-2- (hydroxyimino) -3-oxobutyrate (47-b,1300mg,6.71mmol,50.2％yield).¹H 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).

Step 2 Ethyl 4-chloro-2- (hydroxyimino) -3-oxobutanoate (47-b, 500mg,2.58 mmol) was added to 3mL of DMF solution followed by urea (1.24 g,20.66 mmol) and stirred at 100℃for 3h. Adding water into the reaction solution, extracting with dichloromethane, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography (PE: EA=2:1) to obtain 4-hydroxyisoxazole-3-ethyl formate (47-c,210mg,1.34mmol,51.8％yield).¹H 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).

Step 3 Ethyl 4-hydroxyisoxazole-3-carboxylate (47-C, 70mg,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, 50mg,0.09 mmol) were added to 4mL of 2-methyl-2-butanol solution and placed in an oil bath at a temperature of 180℃for stirring for 30min. The reaction solution was concentrated completely 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 (47,4mg,0.01mmol,6.7％yield).MS Calcd:676.18;MS Found:677.2([M+H]⁺).¹H 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,1H),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).

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)

Step 1 to a 50mL eggplant-shaped bottle were added 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, 50mg,0.09 mmol) and solvent 2-methyl-2-butanol (2 mL). 1-cyclobutyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (17-b, 91mg,0.45 mmol), DIPEA (0.04 mL,0.27 mmol) was then added thereto and stirred at 180℃for 30min. 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 (48,10mg,0.01mmol,14.5％yield).MS Calcd:743.26;MS Found:744.31([M+H]⁺).¹H 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).

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)

Step 1 to a 50mL eggplant bottle was added the 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, 100mg,0.18 mmol) and the solvent 2-methyl-2-butanol (1.5 mL). Ethyl 5-hydroxy-3-methyl-1- (propan-2-yl) pyrazole-4-carboxylate (45-C, 49mg,0.23 mmol), DIPEA (0.09 mL,0.53 mmol) was then added thereto and stirred at 180℃for 30 minutes. The crude product after concentration under reduced pressure 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 (49,13mg,0.02mmol,9.4％yield)MS Calcd:731.26;MS Found:732.30([M+H]⁺).¹H 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,4H),2.72–2.68(m,2H),2.54–2.51(m,2H),2.15(s,3H),1.28–1.19(m,9H).

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)

Step 1 to a 250mL eggplant-shaped bottle was added the compound 2-chloro-6- (trifluoromethyl) pyridin-3-amine (51-a, 4.8g,24.42 mmol) and solvent dichloromethane (30 mL). Triethylamine (4.9 g,48.83 mmol) and chloroacetyl chloride (2.8 g,24.42 mmol) were then added thereto, and stirred overnight at room temperature. 150mL of methylene chloride was added to dilute, the organic phase (100 mL. Times.2) was washed with water, dried over anhydrous sodium sulfate, and the organic phase was dried under reduced pressure to give a crude product, which was purified by column chromatography (PE: EA=4:1) to give 2-chloro-N- [ 2-chloro-6- (trifluoromethyl) pyridin-3-yl ] acetamide (51-b, 1.8g,6.41mmol,26.3% yield): MS Calcd:271.97.; MS Found:270.97 ([ M-H ] ^-).

Step 2 to a 100mL eggplant-shaped bottle was added 2-chloro-N- [ 2-chloro-6- (trifluoromethyl) pyridin-3-yl ] acetamide (51-b, 1.8g,6.41 mmol) and solvent acetone (30 mL). Potassium iodide (2.6 g,16.03 mmol) was then added thereto and stirred at 50℃for 3 hours. The solvent was dried under reduced pressure to give 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, 1.8g,4.86mmol,75.8% yield). MS Calcd: 363.91..MS found:362.91 ([ M-H ] ^-).

Step 3 to a 100mL eggplant bottle was added the compound N- [ 2-chloro-6- (trifluoromethyl) pyridin-3-yl ] -2-iodoacetamide (51-c, 457mg,1.25 mmol), 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-carboxylic acid tert-butyl ester (int-5, 450mg,1.05 mmol) and the solvent 1, 4-dioxane (15 mL). DIPEA (405 mg,3.15 mmol) was then added thereto and stirred overnight at 60 ℃. The solvent was dried under reduced pressure to give crude product, which was purified by column chromatography (PE: ea=1:3) to give 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, 650mg,0.97mmol,93.2% yieldd). MS Calcd: 666.23..MS found:567.22 ([ M+H-100] ⁺).

Step 4 to a 100mL eggplant bottle 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, 650mg,0.97 mmol) and solvent DCM (8 mL). TFA (1 mL) was then added thereto and stirred overnight at room temperature. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, the organic phase was extracted with dichloromethane (30 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and spun-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, 500mg,0.88mmol,90.5% yielder) MS Calcd: 566.18..MS Found:567.12 ([ M+H ] ⁺).

Step 5N- [ 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, 70mg,0.12 mmol) and solvent 2-methyl-2-butanol (2 mL) were added to a 50mL eggplant bottle. 1-cyclobutyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (17-b, 104mg,0.49 mmol), DIPEA (48 mg,0.37 mmol) was then added thereto and stirred at 180℃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 (51,20mg,0.03mmol,21.1％yield).MS Calcd:730.24;MS Found:731.28([M+H]⁺).¹H 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).

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)

Step 1 to a 25mL eggplant-shaped bottle were added 2, 5-dichloro-4- (trifluoromethyl) aniline (52-a, 800mg,3.48 mmol) and solvent dichloromethane (10 mL). Chloroacetyl chloride (589 mg,5.22 mmol) and triethylamine (1056 mg,10.43 mmol) were then added thereto, and stirred at room temperature for 2 hours. To this was added water (40 mL), extracted with DCM (30 mL), and the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give 2-chloro-N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) acetamide (52-b, 1000mg,3.26mmol,93.8% yield). MS Calcd:304.94;MS Found:303.95 ([ M-H ] ^-).

Step 2 to a 25mL eggplant-shaped bottle were added 2-chloro-N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) acetamide (52-b, 1000mg,3.26 mmol) and solvent acetone (20 mL). Potassium iodide (1624.8 mg,9.79 mmol) was then added thereto, and heated to 50℃and stirred for 2 hours. The reaction solution was filtered, and the filtrate was dried under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EA: pe=10%) to give 2-iodo-N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) acetamide (52-c, 700mg,1.76mmol,53.9% yield). MS Calcd:396.87;MS Found:395.9 ([ M-H ] ^-).

Step 3 to a 25mL eggplant bottle was added the compound 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, 200mg,0.46 mmol) and the solvent 1, 4-dioxane (10 mL). 2-iodo-N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) acetamide (52-C, 184.9mg,0.46 mmol) and DIPEA (178.3 mg,1.38 mmol) were then added thereto, heated to 75℃and stirred overnight. To this was added water (30 mL), extracted with EA (30 mL), the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the crude product, which was purified by thin layer silica gel plate (MeOH: DCM=1:20) to give 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, 200mg,0.29mmol,61.9% yieldd). MS Calcd:699.20;MS Found:700.3 ([ M+H ] ⁺).

Step 4 to a 25mL eggplant bottle 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, 100mg,0.14 mmol) and solvent dichloromethane (50 mL). HCl/1, 4-dioxane (2 mL,4 mmol/L) was then added thereto and stirred at room temperature for 1 hour. To this was added saturated sodium bicarbonate solution (40 mL), the organic phase was extracted with DCM (30 mL), washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl l) -5-ethyl-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (52-e, 79mg,0.13mmol,92.2% yieldd) as the direct next step without purification. MS Calcd:599.14;MS Found:600.20 ([ M+H ] ⁺).

Step 5 to a 25mL eggplant bottle were added N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl l) -5-ethyl-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (52-e, 35mg,0.06 mmol) and solvent tert-amyl alcohol (2 mL). Then ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 50.4mg,0.24 mmol) was added thereto, the reaction solution was directly concentrated after stirring at 180℃for 1 hour, and 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 (52,18mg,0.02mmol,40.4％yield).MS Calcd:763.20;MS Found:764.22([M+H]⁺).¹H 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).

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-trifluoroethyl) -1H-pyrazol-4-yl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 53)

Step 1 Ethyl 5-hydroxy-1- (2, 2-trifluoroethyl) -1H-pyrazole-4-carboxylate (37-b, 105mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly 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-trifluoroethyl) -1H-pyrazol-4-yl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (53,10mg,0.01mmol,14.3％yield).MS Calcd:757.20;MS Found:758.27([M+H]⁺).¹H 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).

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)

Step 1 2-bromo-5-ethyl-4, 7-dihydro [1,2,4] triazolo [1,5-a ] pyrimidin-7-one (int-3 a,700mg,2.88 mmol) and N- [ 5-chloro-2-methyl-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (38-C, 1087.0mg,2.88 mmol) were added to a 100mL round bottom flask, followed by dioxane (20 mL) and DIPEA (1.43 mL,8.64 mmol) and stirred at 80℃for 3 hours under nitrogen. The reaction was cooled to room temperature, solid precipitated, filtered, 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, 603mg,1.22mmol,42.5% yieldd).

Step 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, 600mg,1.22 mmol) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (383.8 mg,1.83 mmol) were dissolved in 1, 4-dioxane (8 mL) and H ₂ O (4 mL), pd (dppf) Cl ₂ (89 mg,0.09 mmol), potassium phosphate (860 mg,3.65 mmol) were then sequentially added, and the mixture was reacted at 80℃for 5.0 hours with three nitrogen substitutions. The reaction solution was concentrated, 30mL of ethyl acetate was added to the residue, which was filtered through celite, and the filtrate was concentrated, and purified by column chromatography (DCM: meoh=4:1) to give 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, 200mg,0.4mmol,33% yield). MS Calcd:495.13;MS Found:496.10 ([ M+H ] ⁺).

Step 3N- (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, 450mg,0.91 mmol) and N-bromosuccinimide (192.7 mg,1.09 mmol) were placed in a 100mL eggplant bottle, 10mL acetonitrile was added, and the temperature was then raised to 60℃for 1 hour. The reaction solution was poured into 20mL of water, extracted with EA (3×20 mL), the organic phases combined, 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, 300mg,0.52mmol,57% yieldd). MS Calcd:575.04;MS Found:576.20 ([ M+H ] ⁺).

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, 250mg,0.43 mmol) and the compound 2-methylpropan-2-yl (2R) -2-methylpiperazine-1-carboxylate (871 mg,4.35 mmol), agBF ₄ (101.3 mg,0.52 mmol) were added to dry DMSO (3 mL), nitrogen sparged for 1 minute, and then the temperature was raised to 120℃for reaction for 18H. The reaction was poured into water (20 mL), then extracted with EA (20 mL x 3), the organic phases combined, dried and concentrated, and the residue was purified by Prep-TLC (DCM: meoh=20:1) to give (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, 127mg,0.18mmol,42% yield). MS Calcd:693.27;MS Found:694.10 ([ M+H ] ⁺).

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, 127mg,0.18 mmol) was dissolved in 8mL dichloromethane solution, 2mL trifluoroacetic acid was added thereto, and stirred at room temperature for 2 hours. The reaction solution was concentrated directly, 20mL of saturated sodium bicarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and concentrated by drying 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, 90mg,0.15mmol,82% yieldd). MS Calcd:593.21;MS Found:594.27 ([ M+H ] ⁺).

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, 50mg,0.08 mmol) and ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88mg,0.42 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly 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 (54,13mg,0.02mmol,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,2H),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＝10.0Hz,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).

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)

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, 63mg,0.10 mmol), DIPEA (15 mg,0.10 mmol), ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 112mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30min, the reaction was dissolved in methanol and purified directly by prep-HPLC, 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 was obtained (55,19mg,0.025mmol,25.0％yield).MS Calcd:757.27;MS Found:758.31([M+H]⁺).¹H NMR(400MHz,Chloroform-d)δ9.03(s,1H),8.53(d,J＝8.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.63–7.50(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),2.12–2.07(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).

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)

Step 1 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,4g,16.5 mmol), N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) -2-iodoacetamide (int-4, 6g,16.5 mmol), DIPEA (6.4 g,49.5 mmol) was added to DMF (50 mL), the temperature was raised to 80℃and stirred for 2 hours, cooled to room temperature, the reaction was poured into water, solid precipitated, suction filtered, the filter cake was washed with water (50 mL x 2), the solid was collected, and purified with a mixed solvent of ethyl acetate and petroleum ether (1:3) to give 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, 5.12.9 mmol,75% yie. MS Calcd:475.03;MS Found:476.11 ([ M+H ] ⁺).

Step 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, 5.9g,12.4 mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (2.6 g,12.4 mmol), potassium phosphate (7.9 g,37.2 mmol), 1-bis (diphenylphosphine) bis-iron palladium dichloride (906 mg,1.24 mmol) was added to a mixed solvent of dioxane (40 mL) and water (10 mL), nitrogen was replaced for 3 minutes, the temperature was raised to 85 ℃ C, stirred for 3 hours, the residue was concentrated under reduced pressure, and the solid was collected by filtration and then purified with ethanol to give 2- (2- (3, 6-dihydro-pyran-1, 3-5-dioxa-1, 3-4-fluoro- [1, 5-oxo ] pyrimidine (56-1, 4-methyl-4-1, 8 mmol), and 2- (4-fluoro-phenyl) bis- [1, 4-b ] pyrimidine-4 (40 mL). MS Calcd:479.16;MS Found:480.21 ([ M+H ] ⁺).

Step 3 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, 4.8g,10.0 mmol) was added to DMF (50 mL) followed by NBS (1.78 g,10.0 mmol) at an elevated temperature of 60℃with stirring for 3 hours. The reaction was then poured into water, the solid precipitated, and the solid was collected by filtration and then purified by beating with ethanol 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, 3.4g,6.1mmol, 61%). MS Calcd:557.07;MS Found:558.07 ([ M+H ] ⁺).

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, 1g,1.8 mmol), (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (3.6 g,18 mmol), silver tetrafluoroborate (351 mg,1.8 mmol) was added to dry DMSO (10 mL), then heated to 120℃under nitrogen, stirred for 4 hours, cooled to room temperature, saturated aqueous sodium bicarbonate was added, then (10 mLx 3) was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, 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, 810mg,1.20mmol, 66%). MS Calcd:677.29;MS Found:678.31 ([ M+H ] ⁺).

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, 810mg,1.20 mmol) was added to DCM (10 mL), trifluoroacetic acid (3 mL) was then added, stirred at room temperature for 4 hours, concentrated under reduced pressure, the residue was added to saturated aqueous sodium bicarbonate, then extracted with DCM (10 mL x 3), the organic layer was dried over anhydrous sodium sulfate, 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 ] pyrimidine-4- (3-methylpiperazin-1-yl) -7-oxo- [ 4- (3, 4-methyl-4-a) -pyrimidine (4, 4-methyl-4-fluoro-phenyl) -48 mg (0.70 mg, 48 mg). MS Calcd:577.24;MS Found:578.28 ([ M+H ] +).

Step 6 (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (56-e, 60mg,0.10 mmol), DIEA (15 mg,0.10 mmol), ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 100mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30 min and purified by prep-HPLC, 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, 21mg,0.029mmol,29.0% yield) was obtained. MS Calcd:727.29;MS Found:728.31 ([ M+H ] ⁺).

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)

Step 1 to a 25mL eggplant bottle 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-2 a,100mg,0.15 mmol) and solvent DMSO (2 mL). N-methylpiperazine (45.1 mg,0.45 mmol) and potassium acetate (44.1 mg,0.45 mmol) were then added thereto, followed by heating to 120℃and stirring overnight. To this was added water (40 mL), extracted with EA (30 mL), the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the crude product, which was purified by column chromatography (MeOH: DCM=1:20) to give tert-butyl 4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl l-2- (4-methylpiperazin-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl l)) piperazine-1-carboxylate (57-a, 45mg,0.07mmol,44% yield). MS Calcd:681.28;MS Found:682.4 ([ M+H ] ⁺).

Step 2 to a 25mL eggplant bottle was added tert-butyl 4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl l-2- (4-methylpiperazin-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl l)) piperazine-1-carboxylate (57-a, 45mg,0.07mmol,44% yield) and solvent dichloromethane (5 mL). Then, hydrogen chloride-1, 4-dioxane (2 mL,4 mol/L) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added saturated sodium bicarbonate solution (20 mL), extracted with DCM (30 mL), and the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and spun-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, 40mg,0.07 mmol) which was used directly in the next step. MS Calcd:581.22;MS Found:582.3 ([ M+H ] ⁺).

Step 3 to a 25mL eggplant-shaped bottle were added 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, 40mg,0.07 mmol) and solvent tert-amyl alcohol (2 mL). 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 57.8mg,0.27 mmol) and DIPEA (17.8 mg,0.14 mmol) were then added thereto, heated to 180℃and stirred for 1 hour. The reaction mixture was concentrated directly 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-acyl) piperazin-1-yl) -5-ethyl-2- (4-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (57,15mg,0.02mmol,28.3％yield).MS Calcd:745.28;MS Found:746.4([M+H]⁺).¹H 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).

Example 41N- (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) preparation

Step 1N- [ 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, 70mg,0.12 mmol) and solvent 2-methyl-2-butanol (2 mL) were added to a 50mL eggplant bottle. 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (18-a, 97mg,0.49 mmol), DIPEA (48 mg,0.37 mmol) was then added thereto and stirred at 180℃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 (58,20mg,0.03mmol,21.9％yield).MS Calcd:716.22;MS Found:717.20([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H),8.59(d,J＝8.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.59(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,2H),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,2H),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).

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)

Step 1-4-hydroxy-8-methoxyquinoline-3-carboxylic acid (59-a, 23mg,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, 40mg,0.06 mmol) was weighed into a 25mL single-necked flask, 2-methyl-2-butanol (2 mL) and DIPEA (0.01 mL,0.06 mmol) were added, and the temperature was raised to 180℃after the addition to react for 2 hours. The reaction solution was concentrated and the residue 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, 2mg,0.002mmol,4.3% Yeild). MS Calcd:766.22;MS Found:767.36 ([ M+H ] ⁺).

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-hydroxyisoxazol-3-acyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 60)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 26mg,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, 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, 60mg,0.10 mmol) and DIPEA (64 mg,0.50 mmol) in dichloromethane and stirred at room temperature, then (3 mL) was extracted with DCM, the organic layer was sodium sulfate, suction filtered, the residue was concentrated overnight, the filtrate was purified by Prep-HPLC, the title compound (R) -N- (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 was obtained (60,16mg,0.023mmol,23.1％yield).MS Calcd:690.19;MS Found:691.21([M+H]⁺).¹H 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).

Example 44 preparation of (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- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 61)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 26mg,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, then to (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (56-e, 60mg,0.10 mmol) and DIPEA (64 mg,0.50 mmol) in dichloromethane and stirred at room temperature overnight, then water (3 mL) was added, the organic layer was extracted with DCM (3 mLx 3), dried over anhydrous sodium sulfate, the filtrate was filtered, the residue was concentrated by HPLC, 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- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide was obtained (61,11mg,0.016mmol,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),6.84(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).

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-morpholin-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 62)

Step 1 to a 25mL eggplant bottle 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-2 a,200mg,0.30 mmol) and solvent DMSO (2 mL). Then, morpholine (78.8 mg,0.91 mmol) and potassium acetate (88.8 mg,0.91 mmol) were added thereto, followed by heating to 120℃and stirring overnight. To this was added water (40 mL), extracted with EA (30 mL), the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give the crude product, which was purified by chromatography on a silica gel plate (MeOH: DCM=1:20) to give tert-butyl 4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl l) -5-ethyl-2-morpholin-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl l)) piperazine-1-carboxylate (62-a, 55mg,0.08mmol,27.2% yield). MS Calcd:668.24;MS Found:613.25 ([ M+H-56] ⁺).

Step 2 to a 25mL eggplant bottle was added tert-butyl 4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl l) -5-ethyl-2-morpholin-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl l)) piperazine-1-carboxylate (62-a, 55mg,0.08 mmol) and solvent dichloromethane (5 mL). Then, a hydrogen chloride-1, 4-dioxane solution (2 mL,4 mol/L) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added saturated sodium bicarbonate solution (20 mL), extracted with DCM (30 mL), and the organic phase was washed twice with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give crude N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2-morpholin-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (62-b, 40mg,0.08 mmol) as the crude product. MS Calcd:568.19;MS Found:569.34 ([ M+H ] ⁺).

Step 3 to a 25mL eggplant bottle were added N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2-morpholin-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (62-b, 40mg,0.08 mmol) and solvent tert-amyl alcohol (2 mL). Then ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 66.5mg,0.32 mmol) and DIPEA (20.4 mg,0.16 mmol) were added thereto, heated to 180℃and stirred for 1 hour, the reaction mixture was concentrated directly 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-morpholin-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (62,10mg,0.01mmol,16.7％yield).MS Calcd:732.25;MS Found:733.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆+ weight water exchange )δ8.02(d,J＝8.4Hz,1H),7.95(d,J＝2.0Hz,1H),7.73(dd,J＝8.4,2.0Hz,1H),7.66(s,1H),5.21(s,2H),4.81-4.72(m,1H),4.29(d,J＝12.4Hz,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).

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-hydroxyisoxazol-3-yl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 63)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 12.9mg,0.10 mmol) and solvent DCM (3 mL) were added to a 10mL eggplant-shaped bottle. 1-chloro-N, N, 2-trimethylpropenamine (10 mg,0.08 mmol) was then added thereto and stirred at room temperature for 1 hour, after which time N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl l) -5-ethyl-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (52-e, 30mg,0.05 mmol) and DIPEA (19.4 mg,0.15 mmol) were added, stirring was continued at room temperature for 2 hours, water (20 mL) was added thereto, the organic phase was washed with DCM (20 mL), saturated brine (20 mL. Times.2) was dried over anhydrous sodium sulfate, and the crude product was dried by vacuum spin-drying to give the title compound N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-oxazol-4- (7H) -yl ] acetamide (3, 6-dihydro-4-oxa-yl) 2- (3, 5-oxa-yl) 1-4-oxazol-yl) acetamide purified by Pre-HPLC (63,7mg,0.01mmol,17.7％yield).MS Calcd:710.14;MS Found:711.3([M+H]⁺).¹H 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).

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)

Step 1 to a 250mL eggplant bottle was added the compound 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-3 a,5.0g,20.57 mmol) and solvent 1, 4-dioxane (120 mL). DIPEA (8.0 g,61.70 mmol) was then added thereto and stirred at 80℃for 4 hours. After cooling to room temperature, the solid was filtered, washed with ethyl acetate (50 mL), the solid (300 mL) was dissolved with DCM, washed twice with water, and 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, 5.7g,11.91mmol,57.9% yield) MS Calcd: 478.65; MS Found:479.94 ([ M+H ] ⁺).

Step 2 to a 100mL eggplant bottle were added 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, 800mg,1.67 mmol), 2- (4-methoxycyclohex-1-enyl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (400 mg,1.67 mmol) and solvent 1, 4-dioxane (6 mL), H ₂ O (2 mL). Potassium phosphate (960 mg,4.18 mmol) Pd (dppf) Cl ₂ (120 mg,1.67 mmol) was then added thereto and stirred overnight at 90 ℃. 50mL of water was added, the organic phase was extracted with ethyl acetate (50 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give the crude product, which 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, 720mg,1.41mmol,84.5% yielder) MS Calcd: 509.91; MS Found:510.12 ([ M+H ] ⁺).

Step 3N- [ 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, 650mg,1.27 mmol) and acetonitrile (10 mL) were added to a 100mL eggplant bottle. NBS (250 mg,1.40 mmol) was then added thereto and stirred at 60℃for 1 hour. The solvent was dried by spin-drying, 20mL of water was added, the organic phase was washed with ethyl acetate (20 mL. Times.3), saturated brine was dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product, which 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, 500mg,0.87mmol,67.9% yielder) MS Calcd:587.05.; MS Found:588.04 ([ M+H ] ⁺).

Step 4 to a 100mL eggplant bottle was added 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, 500mg,0.85 mmol), 2-methylpropan-2-yl (2R) -2-methylpiperazine-1-carboxylate (1700 mg,8.49 mmol) and solvent DMSO (10 mL). Silver tetrafluoroborate (198mg, 1.02 mmol) was then added thereto and stirred at 120℃for 24 hours. 30mL of water was added, the organic phase was washed 4 times with saturated brine, dried over anhydrous sodium sulfate and spun dry under reduced pressure to give crude product, which 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, 340mg,0.48mmol,56.5% yieldd) MS Calcd: 707.28; MS Founda: 608.24 ([ M+H-100] ⁺).

Step 5 to a 100mL eggplant-shaped bottle 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, 340mg,0.48 mmol) and solvent DCM (3 mL). TFA (0.5 mL) was then added thereto and stirred at room temperature for 3 hours. The pH was adjusted to alkaline by addition of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spun-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, 150mg,0.25mmol,51.4% yield) MS Calcd:607.23;MS Found:608.20 ([ M+H ] ⁺).

Step 6N- [ 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, 60mg,0.10 mmol) and solvent 2-methyl-2-butanol (1.5 mL) were added to a 50mL eggplant bottle. 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (17-b, 83mg,0.39 mmol) was then added thereto, DIPEA (39 mg,0.30 mmol) was stirred at 180℃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, 20mg,0.03mmol,26.2% yielder, diastereomeric mixture) ).MS Calcd:771.29;MS Found:772.28([M+H]⁺).¹H 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),3.19-3.11(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).

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)

Step 1 to a 50mL eggplant bottle was added the compound 4-hydroxyisoxazole-3-carboxylic acid (int-7, 31mg,0.24 mmol) and solvent DCM (1 mL). (1-chloro-2-methylprop-1-enyl) dimethylamine (33 mg,0.25 mmol) was then added thereto and stirred at room temperature for 3 hours. 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, 50mg,0.08 mmol) and DIPEA (103 mg,0.8 mmol) were then added thereto, the solvent was dried by stirring at room temperature for 2 hours, 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- (5-ethyl-6- ((R) -4- ((4-hydroxyisoxazol-3-acyl) -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, 20mg, 0.34.03.03 d, a. Diastereomer, a mixture of diastereomers ).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).

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)

Step 1 to a 50mL eggplant-shaped bottle was added 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (3-c, 12mg,0.08 mmol) and solvent DCM (1 mL). (1-chloro-2-methylprop-1-enyl) dimethylamine (12 mg,0.09 mmol) was then added thereto and stirred at room temperature for 3 hours. To this was added 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, 40mg,0.07 mmol) and DIPEA (27 mg,0.21 mmol), the solvent was dried by stirring at room temperature for 2 hours, methanol (1.5 mL) was added thereto and the crude product was purified by prep-HPLC to give the title compound N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- ((R) -4- (5-hydroxy-1-methyl-1H-pyrazol-4-acyl) -3-methylpiperazin-1-yl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo- [1,2,4] o [1,5-a ] pyrimidin-4 (7H) -acetamide (7, 66mg, 6.01 mmol) of the diastereomer of the non-enantiomer was obtained as a mixture of the title compound ).MS Calcd:731.26;MS Found:732.28([M+H]⁺).¹H 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),2.20-2.12(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).

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)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 26.1mg,0.20 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (29.7 mg,0.22 mmol) were added separately to a 3mL dichloromethane solution and stirred for 3 hours at room temperature, 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, 60mg,0.10 mmol), DIEA (0.05 mL,0.3 mmol) was added and stirring was continued at 40℃for 5 hours. 10mL of saturated sodium bicarbonate solution was added to the reaction solution, DCM (10 mL. Times.2) was used for extraction, the organic phases were combined, concentrated under reduced pressure, 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) piperazin-1-yl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (67,25mg,0.04mmol,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＝12.4Hz,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).

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-hydroxyisoxazol-3-acyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 68)

Step 1 2-iodo-N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) acetamide (52-c, 420mg,1.06 mmol) was placed in a 100mL eggplant-shaped bottle and 10mL of 1, 4-dioxane solution was added. 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,250mg,1.03 mmol) and DIPEA (0.5 mL,3.09 mmol) were then added sequentially thereto. Stirred at 75 ℃ 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, 300mg,0.58mmol,57% yield) MS Calcd:512.94;MS Found:513.94 ([ m+h ] ⁺).

Step 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, 300mg,0.58 mmol) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (184.3 mg,0.88 mmol) were dissolved in 1, 4-dioxane (8 mL) and H ₂ O (4 mL), then Pd (dppf) Cl ₂ (42.7 mg,0.04 mmol) and potassium phosphate (403 mg,1.75 mmol) were added sequentially, and the mixture was reacted at 80℃for 5.0 hours with three nitrogen substitutions. The reaction solution was concentrated, 30mL of ethyl acetate was added to the residue, which 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, 220mg,0.33mmol,73% yield) MS Calcd:515.07;MS Found:516.28 ([ m+h ] ⁺).

Step 3N- (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, 220mg,0.33 mmol) and N-bromosuccinimide (69.9 mg,0.40 mmol) were placed in a 100mL eggplant bottle, 10mL acetonitrile was added, and the temperature was then raised to 60℃for 1 hour. The reaction solution was poured into 20mL of water, extracted with EA (3X 20 mL), the organic phases were combined, dried and 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, 50mg,0.08mmol,25% yield) MS Calcd:594.98;MS Found:595.92 ([ M+H ] ⁺).

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, 50mg,0.08 mmol) and (R) -1-N-Boc-2-methylpiperazine (168 mg,0.84 mmol) AgBF ₄ (16.4 mg,0.08 mmol) were added to dry DMSO (1 mL), nitrogen sparged for 1 minute, and then the temperature was raised to 120℃for reaction 18H. The reaction was poured into water (20 mL), then extracted with EA (20 mL x 3), the organic phases were combined, dried and concentrated, and 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, 25mg,0.03mmol,41% yield) MS Calcd:713.21;MS Found:714.21 ([ M+H ] ⁺).

Step 5 (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, 25mg,0.03 mmol) was dissolved in 4mL of dichloromethane, 1mL of trifluoroacetic acid was added thereto, and stirring was continued at room temperature for 2 hours. The reaction solution was concentrated directly, 20mL of saturated sodium hydrogencarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and concentrated by drying 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, 20mg,0.03mmol,93% yielder) MS Calcd:613.16;MS Found:614.16 ([ M+H ] ⁺).

Step 6 4-hydroxyisoxazole-3-carboxylic acid (int-7, 12.6mg,0.10 mmol) and 1-chloro-N, N, 2-trimethylpropenamide (13.0 mg,0.10 mmol) were added separately to a 3mL dichloromethane solution and stirred for 3 hours at room temperature, 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, 20mg,0.03 mmol), DIPEA (0.02 mL,0.1 mmol) was added and stirring was continued at 40℃for 5 hours. To the reaction was added 10mL of saturated sodium bicarbonate solution, DCM (10 mL. Times.2) was used to extract, the organic phases were combined, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give 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, 3mg,0.01mmol,12% yield). MS Calcd:724.15;MS Found:725.24 ([ M+H ] ⁺).

¹H 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),4.27(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,2H),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).

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)

Step 1 Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 82mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly concentrated 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 (69,15mg,0.02mmol,24％yield).MS Calcd:743.26;MS Found:744.31([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.13(s,1H),7.98(s,1H),7.78(s,1H),7.57(s,1H),6.84(t,J＝2.0Hz,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).

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-hydroxyisoxazol-3-acyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 70)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 32.6mg,0.25 mmol) and 1-chloro-N, N, 2-trimethylpropenamide (33.7 mg,0.25 mmol) were added separately to a solution of 3mL of dichloromethane and stirred for 3 hours at room temperature, 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, 50mg,0.08 mmol), DIPEA (0.04 mL,0.2 mmol) were added and the temperature was raised to 40℃and stirred for 5 hours. 10mL of saturated sodium bicarbonate solution was added to the reaction solution, DCM (10 mL. Times.2) was used for extraction, the organic phases were combined, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give 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 (70,16mg,0.02mmol,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),2.73–2.63(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).

Example 54 preparation of 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 (compound 71)

Step 1-4-hydroxyisoxazole-3-carboxylic acid (Int-7, 25mg,0.19 mmol), HATU (97.5 mg,0.26 mmol) were weighed into a 25mL single port flask, DCM (2 mL) and DIPEA (0.06 mL,0.38 mmol) were added, after addition was stirred at room temperature for 5 minutes, 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, 70mg,0.13 mmol) was added and reacted at room temperature for 1 hour after addition. The reaction mixture was added to 10mL of saturated ammonium chloride solution and stirred, then the organic phase was separated, and the residue was prep-HPLC purified 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 (71,22mg,0.03mmol,94％Yield).MS Calcd:656.23;MS Found:657.32([M+H]⁺).¹H 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＝2.0Hz,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).

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)

Step 1 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,2.0g,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 separately to 60mL dioxane solution and stirred at 80℃for 4 hours. The reaction was concentrated under reduced pressure and the residue was isolated and purified by silica gel column chromatography (DCM: meoh=20:1) to give 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, 3.6g,7.56mmol,91.9% yield). MS Calcd:475.03;MS Found:476.05 ([ M+H ] ⁺).

Step 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, 3.6g,7.56 mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.58 g,7.5 mmol), pd (dppf) Cl ₂·CH₂Cl₂ (1.07 g,1.32 mmol) and potassium phosphate (4.77 g,22.5 mmol) were sequentially added to a 40mL dioxane/water (4:1) mixture, vacuum nitrogen substitution was performed 3 times, and the mixture was warmed to 80℃and stirred for 2H. The reaction was concentrated completely and the residue was isolated and purified by silica gel column chromatography (DCM: meoh=20:1) to give 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, 1.5g,3.2mmol,41.6% yield). MS Calcd:479.16;MS Found:480.19 ([ M+H ] ⁺).

Step 3 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, 1.34g,2.8 mmol) was dissolved in DMF (10 mL) and then NBS (0.55 g,3.07 mmol) was slowly added and the mixture was warmed to 60℃and stirred for 3H. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA) 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-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (72-c, 1.3g,2.33mmol,83.3% yieldd). MS Calcd:557.07;MS Found:558.15 ([ M+H ] ⁺).

Step 42- (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, 1.3g,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 sequentially added to a DMSO (10 mL) solution, evacuated, nitrogen displaced 3 times, and warmed to 120℃overnight under stirring. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give tert-butyl (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-carboxylate (72-d, 1.2g,1.77mmol,75.9% yield). MS Calcd:677.29;MS Found:678.32 ([ M+H ] ⁺).

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, 1.2g,1.77 mmol) was added to a solution of hydrochloric acid-dioxane (20 mL) and left to stir at room temperature overnight. The reaction solution was concentrated completely, and a saturated sodium hydrogencarbonate solution, dichloromethane extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave 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, 0.6g,1.03mmol,58.8% yieldd). MS Calcd:577.24;MS Found:578.06 ([ M+H ] ⁺).

Step 6 Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 102mg,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, 50mg,0.09 mmol) were added to a solution of 2-methyl-2-butanol (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely 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 (72,20mg,0.03mmol,25.1％yield).MS Calcd:727.29;MS Found:728.37([M+H]⁺).¹H 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).

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)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 105mg,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, 60mg,0.1 mmol) were added to a 2-methyl-2-butanol solution (2 mL) and the oil bath warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely and the residue was purified by prep-HPLC to give 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 (73,18mg,0.02mmol,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,2H),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＝12.0,3.6Hz,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).

Example 57 preparation of (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 (Compound 74)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 40mg,0.31 mmol) and 1-chloro-N, N, 2-trimethylpropenamide (44 mg,0.33 mmol) were added separately to DCM solution (2 mL), stirred at room temperature for 3 hours, 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, 60mg,0.1 mmol), DIPEA (80 mg,0.62 mmol) was added and stirring was continued at 40℃for 5H. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue 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-acyl) -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 (74,15mg,0.02mmol,21.7％yield).MS Calcd:688.24;MS Found:689.24([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.11(s,1H),9.90(s,1H),8.60(d,J＝1.6Hz,1H),7.81(d,J＝12.8Hz,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).

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)

Step 1 3-fluoro-4- (trifluoromethyl) aniline (75-a, 10g,55.83 mmol), DCM (50 mL), BF ₃OEt₂ (7.9 g,55.83 mmol), NCS (8.2 g,61.42 mmol) were added to a 250mL eggplant-shaped bottle and the reaction was stirred at room temperature for 3 hours after the addition. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (PE: EA=95:5) to give 2-chloro-5-fluoro-4- (trifluoromethyl) aniline (75-b, 8.1g,37.92mmol, 67.9%). MS Calcd:213.00;MS Found:212.12 ([ M-H ] ^-).

Step 2 to a 250mL eggplant flask was added 2-chloro-5-fluoro-4- (trifluoromethyl) aniline (75-b, 8.1g,37.92 mmol), DCM (50 mL), then triethylamine (10.51 mL,75.84 mmol) and a solution of chloroacetyl chloride (3.04 mL,37.92 mmol) in DCM (10 mL) was slowly added under ice-bath and the reaction was allowed to spontaneously recover at room temperature overnight. The reaction was concentrated and the residue was subjected to flash column chromatography (PE: ea=92:8) to give 2-chloro-N- [ 2-chloro-5-fluoro-4- (trifluoromethyl) phenyl ] acetamide (75-c, 4.5g,15.52mmol, 40.9%). MS Calcd:288.97;MS Found:288.18 ([ M+H ] ^-).

Step 3 2-chloro-N- [ 2-chloro-5-fluoro-4- (trifluoromethyl) phenyl ] acetamide (75-C, 4.6g,27.59 mmol), acetone (30 mL) and then reacted at 50℃for 3 hours were added to a 250mL eggplant-shaped bottle. The reaction was concentrated under reduced pressure and the residue was subjected to flash column chromatography (PE: dcm=70:30) to give N- [ 2-chloro-5-fluoro-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (75-d, 2.23g,5.85mmol, 42.1%). MS Calcd:380.90;MS Found:379.93 ([ M-H ] ^-).

Step 4 to a 50mL eggplant bottle was added 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-carboxylic acid tert-butyl ester (int-5, 205.2mg,0.48 mmol), dioxane (10 mL), N- [ 2-chloro-5-fluoro-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (75-d, 200mg,0.55 mmol) and DIPEA (0.25 mL,1.50 mmol) and reacted at 80℃under nitrogen for 2hr. The reaction was concentrated and the residue was chromatographed on flash column (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, 292mg,0.43mmol, 89.6%). MS Calcd:683.22;MS Found:684.36 ([ M+H ] ⁺).

Step 5 to a 50mL eggplant bottle were added 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, 290mg,0.42 mmol) and solvent DCM (10 mL), TFA (3 mL) was added and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction, ph=8, dcm (3×50 ml) was added to extract, and 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, 221mg,0.38mmol, 89.3%). MS Calcd:583.17;MS Found:584.2 ([ M+H ] ⁺).

Step 6 to a 25mL eggplant-shaped bottle was added 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, 60mg,0.10 mmol) and ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 21.6mg,0.10 mmol), followed by a 2-methyl-2-butanol (1 mL) solution, DIPEA (0.04 mL), vacuum nitrogen displacement 3 times, 180℃microwave reaction for 30min. 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 (75,16mg,0.02mmol,20.8％yield).MS Calcd:747.23;MS Found:748.28([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),8.13(d,J＝12.8Hz,1H),8.03(d,J＝7.2Hz,1H),7.56(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).

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)

Step 1 2-bromo-5-ethyl- [1,2,4] triazolo [1,5-a ] pyrimidin-7 (4H) -one (int-3 a,600mg,2.47 mmol), N- [ 2-chloro-5-fluoro-4- (trifluoromethyl) phenyl ] -2-iodoacetamide (75-d, 986.9mg,2.71 mmol) was added to a 100mL round bottom flask, dioxane (30 mL) was added, and DIPEA (1.23 mL,7.40 mmol) was stirred at 80℃for 6H under nitrogen. The reaction was concentrated and the residue was flash column chromatographed (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, 1.04g,2.09mmol, 84.8%). MS Calcd:494.97,496.97;MS Found:495.99,497.94 ([ M+H ] ⁺).

Step 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, 1.0g,2.01 mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.6 g,3.02 mmol), pd (dppf) Cl ₂ (0.1 g,0.20 mmol), potassium phosphate (1.4 g,6.04 mmol) was added to a mixed solvent of water (5 mL) and dioxane (20 mL), the temperature was raised to 85℃and stirring was carried out for 2 hours. The reaction mixture was concentrated and the residue was subjected to 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, 508mg,1.02mmol, 50.5%). MS Calcd:499.10;MS Found:500.15 ([ M+H ] ⁺).

Step 3N- [ 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, 0.45g,0.9 mmol) was dissolved in DMF (5 mL) and NBS (0.18 g,1.0 mmol) was then slowly added and the temperature was raised to 60℃and stirred for 3H. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA% 100) 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-chloro-5-fluoro-4- (trifluoromethyl) phenyl) acetamide (76-c, 0.45g,0.78mmol,86.3% yield). MS Calcd:577.01;MS Found:578.07 ([ M+H ] ⁺).

Step 42- (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, 0.45g,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 sequentially to a DMSO (4 mL) solution, evacuated, nitrogen displaced 3 times, warmed to 120℃and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA% 100) to give tert-butyl (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-carboxylate (76-d, 0.48g,0.69mmol,88.4% yield). MS Calcd:697.24;MS Found:643.0 ([ M-56+H ] ⁺).

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, 0.48g,0.69 mmol) was added to a solution of hydrochloric acid-dioxane (20 mL) and left to stir at room temperature overnight. The reaction solution was concentrated completely, and a saturated sodium hydrogencarbonate solution, dichloromethane extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave (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, 0.3g,0.5mmol,73.0% yieldd). MS Calcd:597.19;MS Found:598.16 ([ M+H ] ⁺).

Step 6 Ethyl 1-cyclopropyl-5-hydroxy-1H-pyrazole-4-carboxylate (18-a, 82mg,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, 50mg,0.08 mmol) were added to a solution of 2-methyl-2-butanol (2 mL) and the oil bath warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely and the residue was purified by prep-HPLC to give 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 (75,15mg,0.02mmol,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).

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-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 77)

Step 1 to a 25mL eggplant bottle was added 4-hydroxyisoxazole-3-carboxylic acid (int-7, 33.2mg,0.26 mmol), (1-chloro-2-methylpropan-1-enyl) dimethylamine (35.3 mg,0.27 mmol), DCM (2 mL), and DIPEA (0.14 mL,0.86 mmol), 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, 50mg,0.09 mmol) and reacted at room temperature for 2hr. 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-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (77,16.1mg,0.02mmol,24.4％yield).MS Calcd:694.17;MS Found:695.2([M+H]⁺).¹H 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).

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)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 88mg,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, 50mg,0.08 mmol) were added to a solution of 2-methyl-2-butanol (2 mL) and the oil bath warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely and the residue was purified by prep-HPLC to give 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 (78,16mg,0.02mmol,24.3％yield).MS Calcd:761.25;MS Found:762.29([M+H]⁺).¹H NMR(400MHz,DMSO-d₆+ g by water exchange )δ8.06(d,J＝12.4Hz,1H),7.99(d,J＝7.2Hz,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＝11.2Hz,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).

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)

Step 1 diethyl ethoxymethylene malonate (3-a, 0.7g,3.28 mmol), tetrahydro-2H-pyran-4-yl hydrazine hydrochloride (0.5 g,3.28 mmol) and potassium carbonate (1.36 g,9.83 mmol) were added separately to an aqueous solution (10 mL) and stirred at 100℃for 6 hours. The mixture was adjusted to ph=2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM: meoh=20:1) to give ethyl 5-hydroxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-4-carboxylate (79-a, 0.6g,2.5mmol,76.2% yieldd). MS Calcd:240.11;MS Found:241.13 ([ M+H ] ⁺).

Step 2 Ethyl 5-hydroxy-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-4-carboxylate (79-a, 106mg,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, 50mg,0.09 mmol) were added to a solution of 2-methyl-2-butanol (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely 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- (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 (79,12mg,0.02mmol,17.1％yield).MS Calcd:759.25;MS Found:760.25([M+H]⁺).¹H 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),4.00–3.95(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).

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)

Step 1 Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 97mg,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, 50mg,0.09 mmol) were added to a solution of 2-methyl-2-butanol (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely 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 (80,8mg,0.01mmol,11.1％yield).MS Calcd:755.32;MS Found:756.34([M+H]⁺).¹H 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),5.32(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＝11.2Hz,1H),3.20-3.15(m,1H),2.97-2.93(m,1H),2.81(d,J＝10.0Hz,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 without peaks.

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)

Step 14- (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-carboxylic acid tert-butyl ester (int-2 a,0.4g,0.6 mmol), cis-2, 6-dimethylmorpholine (0.35 g,3.02 mmol) and potassium acetate (0.35 g,3.62 mmol) were added separately to a DMSO solution (3 mL) and stirred overnight at 120 ℃. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:1) to give 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, 0.17g,0.24mmol,40.4% yieldd). MS Calcd:696.28;MS Found:641.19 ([ M-56+H ] ⁺).

Step 2 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, 0.17g,0.24 mmol) was added to a solution of hydrochloric acid in dioxane (4 mL) and left to stir at room temperature overnight. The reaction solution was concentrated completely, and a saturated sodium hydrogencarbonate solution, dichloromethane extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave crude 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, 0.11g,0.18mmol,75.6% yield). MS Calcd:596.22;MS Found:597.23 ([ M+H ] ⁺).

Step 3 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 70mg,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, 40mg,0.07 mmol) were added to a 2-methyl-2-butanol solution (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction mixture was concentrated completely 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-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, 0.85mg,0.001mmol,1.6% yieldd). MS Calcd:760.28;MS Found:759.23 ([ M-H ] ^-).

Example 65N- [ 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)

Step 1 to a 100mL eggplant bottle was added 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-carboxylic acid tert-butyl ester (int-2 a,400mg,0.60 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,2,3, 6-tetrahydropyridine (202 mg,0.91 mmol) and solvent 1, 4-dioxane (8 mL) and H ₂ O (2 mL). Potassium phosphate (417 mg,1.81 mmol) Pd (dppf) Cl ₂ (44 mg,0.06 mmol) was then added thereto and stirred at 90℃for 3 hours. 30mL of water was added, the organic phase was extracted with ethyl acetate (30 mL. Times.3), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the crude product, which was purified by column chromatography (DCM: meOH=30:1) to give tert-butyl 4- (4- (2- (2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxo-ethyl) -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, 300mg,0.44mmol,73.2% yield): MS Calcd: 678.27; MS Found:679.31 ([ M+H ] ⁺).

Step 2 to a 100mL eggplant bottle was added 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, 300mg,0.44 mmol) as solvent DCM (2 mL). TFA (0.5 mL) was then added thereto and stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to adjust pH to alkaline, the organic phase was extracted with dichloromethane (20 mL. Times.3), 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, 200mg,0.35mmol,78.2% yieldd) MS Calcd:578.21;MS Found:579.41 ([ M+H ] ⁺).

Step 3 4-hydroxyisoxazole-3-carboxylic acid (int-7, 34mg,0.26 mmol) and solvent DCM (2 mL) were added to a 50mL eggplant-shaped bottle. (1-chloro-2-methylprop-1-enyl) dimethylamine (36 mg,0.27 mmol) was then added thereto 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, 50mg,0.09 mmol) and DIPEA (101 mg,0.86 mmol) were then added thereto, the solution was stirred at room temperature for 3 hours, the solvent was dried, methanol (1.5 mL) was added thereto, 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] triazolo [1,5-a ] pyrimidin-4-yl) acetamide (83,10mg,0.01mmol,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＝12.4Hz,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).

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)

Step 1 to a 50mL eggplant-shaped bottle was added 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-carboxylic acid tert-butyl ester (int-2 a,1g,1.51 mmol), 2- (5, 6-dihydro-4H-pyran-2-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (0.5 g,2.26 mmol), pd (dppf) Cl ₂ (0.1 g,0.15 mmol), potassium phosphate (1.0 g,4.53 mmol), water (5 mL) and dioxane (20 mL) and the temperature was raised to 85℃and stirred for 2 hours. The reaction solution was concentrated, and the residue was subjected to 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, 641.3mg,0.96mmol, 63.8%). MS Calcd:665.23;MS Found:664.27 ([ M-H ] ^-).

Step 2 to a 50mL eggplant-shaped bottle was added 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, 600mg,0.90 mmol), methanol hydrochloride solution (10 mL) and reacted at 50℃for 2 hours. The reaction was taken up slightly to base, concentrated and the residue was subjected to 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, 260mg,0.46mmol, 51.0%). MS Calcd:565.18;MS Found:566.20 ([ M+H ] ⁺).

Step 4 to a 25mL eggplant-shaped bottle was added 4-hydroxyisoxazole-3-carboxylic acid (36.4 mg,0.27 mmol), DCM (2 mL), and DIPEA (0.14 mL,0.86 mmol), 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, 50mg,0.09 mmol) and reacted at room temperature 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, 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 (84,6mg,0.01mmol,10.0％).MS Calcd:676.18;MS Found:677.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.32(s,1H),8.60(s,1H),8.09(d,J＝8.8Hz,1H),7.97(d,J＝2.0Hz,1H),7.74–7.71(m,1H),5.89(t,J＝4.0Hz,1H),5.33(s,2H),4.54(d,J＝12.4Hz,1H),4.12(t,J＝5.2Hz,2H),3.64(d,J＝12.4Hz,1H),3.49(t,J＝11.2Hz,2H),3.06-2.99(m,4H),2.84(d,J＝11.2Hz,1H),2.74(d,J＝11.2Hz,1H),2.20(q,J＝5.6Hz,2H),1.87(q,J＝5.6Hz,2H),1.21(t,J＝7.2Hz,3H).

EXAMPLE 67 preparation of (R) -N- (5-chloro-2-methyl-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 85)

Step 1 Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 94mg,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, 50mg,0.08 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly concentrated and purified by Prep-HPLC to give the title compound (R) -N- (5-chloro-2-methyl-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 (85,13mg,0.02mmol,20％yield).MS Calcd:771.29;MS Found:772.44([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),7.98(s,1H),7.78(s,1H),7.66(s,1H),6.85–6.83(m,1H),5.30(s,2H),4.71–4.63(m,1H),4.31-4.26(m,3H),3.83(t,J＝5.2Hz,2H),3.71(d,J＝11.2Hz,1H),3.52(t,J＝11.2Hz,1H),3.20–3.16(m,1H),2.99–2.90(m,1H),2.80(d,J＝10.0Hz,1H),2.70–2.66(m,1H),2.54-2.50(m,2H),2.38(s,3H),2.00–1.80(m,8H),1.66-1.62(m,2H),1.45(brs,3H),1.25(t,J＝7.2Hz,3H).

Example 68 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl) -3-methylpiperazin-1-yl) -5-ethyl-2-morpholinyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 86)

Step 1N- (2-chloro-4- (trifluoromethyl) phenyl) -2-iodoacetamide (296.5 mg,0.82 mmol) was placed in a 100mL eggplant-shaped bottle and 10mL of 1, 4-dioxane solution was added. (R) -4- (2-bromo-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 (int-6, 300mg,0.68 mmol) and DIPEA (0.34 mL,2.04 mmol) were then added thereto in this order and stirred at 75℃for 5 hours. The reaction solution was directly concentrated and purified by column chromatography (PE: ea=1:1) to give (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 360mg,0.53mmol,78% yield). MS Calcd:677.12;MS Found:678.20 ([ m+h ] ⁺).

Step 2 (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 360mg,0.53 mmol) was placed in a 25mL eggplant bottle and 3mL of DMSO solution was added. Morpholine (0.09 mL,1.37 mmol) and potassium acetate (134 mg,1.37 mmol) were then added sequentially. Heated to 120 ℃ and stirred overnight. To the reaction solution was added water (20 mL), diluted, EA extracted (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration, and the crude product was purified by column chromatography (DCM: meoh=50:1) to give (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxo-ethyl) -5-ethyl-2-morpholino-7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-b, 180mg,0.26mmol,57% yield) MS Calcd:682.26;MS Found:683.23 ([ m+h ] ⁺).

Step 3 (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-b, 180mg,0.26 mmol) was dissolved in 4mL of dichloromethane, 1mL of trifluoroacetic acid was added thereto, and stirring was carried out at room temperature for 2 hours. The reaction solution was concentrated directly, 20mL of saturated sodium hydrogencarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and dried and concentrated to give crude (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (3-methylpiperazin-1-yl) -2-morpholino-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (86-c, 150mg,0.26mmol,97% yield) MS Calcd:582.26;MS Found:583.23 ([ M+H ] ⁺).

Step 4 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 90mg,0.42 mmol) and (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (3-methylpiperazin-1-yl) -2-morpholino-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (86-c, 50mg,0.08 mmol) was placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. The reaction solution was then directly concentrated by stirring at 180℃for 30min and purified by Prep-HPLC to give the title compound (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazol-4-carbonyl) -3-methylpiperazin-1-yl) -5-ethyl-2-morpholinyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (86,13mg,0.02mmol,18.6％yield)MS Calcd:746.27;MS Found:747.38([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.35(s,1H),8.07(d,J＝8.4Hz,1H),7.98(d,J＝2.0Hz,1H),7.75(dd,J＝8.8,2.0Hz,1H),7.70(s,1H),5.25(s,2H),4.80(p,J＝8.4Hz,1H),4.62(brs,1H),4.21-4.17(m,1H),3.71-3.68(m,5H),3.51(t,J＝11.6Hz,1H),3.40-3.36(m,5H),3.17-3.09(m,1H),2.96-2.88(m,1H),2.76(d,J＝10.0Hz,1H),2.63(d,J＝11.6Hz,1H),2.58-2.48(m,2H),2.35-2.27(m,2H),1.84-1.76(m,2H),1.47–1.40(m,3H),1.22(t,J＝7.2Hz,3H).

Example 69 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (3-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 87)

Step 1 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid (87-a, 200mg,0.82 mmol) was placed in a 25mL eggplant-shaped bottle, to which was added methylamine methanol solution (3 mL), and heated at 80℃under reflux overnight. The reaction solution was concentrated directly to give crude 3- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridine-2-carboxylic acid (87-b, 200mg,0.78mmol,95% yield) MS Calcd:259.08;MS Found:260.13 ([ M+H ] ⁺).

Step 2N- (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, 200mg,0.35 mmol) and 3- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridine-2-carboxylic acid (87-b, 137mg,0.69 mmol) were placed in a 25mL eggplant bottle to which was added DMF solution (3 mL) followed by HATU (268 mg,0.88 mmol), DIPEA (0.18 mL,1.33 mmol) and reacted overnight at room temperature. To the reaction solution was added water (20 mL), diluted, EA extracted (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration, and the crude product was purified by Prep-TLC (DCM: meoh=20:1) to give 2- (6- (4- (3- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-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) -N- (2-chloro-4- (trifluoromethyl) phenyl) acetamide (87-c, 70mg,0.09mmol,25% yield) MS Calcd:806.26;MS Found:807.24 ([ m+h ] ⁺).

Step 3 2- (6- (4- (3- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-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) -N- (2-chloro-4- (trifluoromethyl) phenyl) acetamide (87-C, 70mg,0.09 mmol) was placed in a 25mL eggplant bottle, DCM solution (3 mL) was added thereto, and p-toluenesulfonic acid hydrate (82 mg,0.43 mmol) was added and reacted overnight at 50 ℃. The reaction solution 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- (3-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (87,20mg,0.03mmol,30％yield)MS Calcd:716.21;MS Found:717.23([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.37(s,1H),8.08(dd,J＝8.8,2.0Hz,1H),7.97(d,J＝2.0Hz,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.63(dd,J＝11.8,7.2Hz,1H),6.86-6.84(m,1H),6.18(dd,J＝7.0,2.0Hz,1H),5.34(s,2H),4.54(t,J＝13.2Hz,1H),4.27(q,J＝2.8Hz,2H),3.72–3.32(m,11H),3.09–2.96(m,3H),2.85(t,J＝10.0Hz,1H),2.76–2.69(m,1H),1.21(t,J＝7.2Hz,3H).

Example 70 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (cis-2, 6-dimethylmorpholinyl) -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 88)

Step 1 4-hydroxyisoxazole-3-carboxylic acid (int-7, 32mg,0.25 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (36 mg,0.27 mmol) were added separately to DCM solution (2 mL), stirred at room temperature for 3 hours, then 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, 50mg,0.08 mmol), DIPEA (65 mg,0.5 mmol) was added and stirring was continued for 5H at 40 ℃. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue by prep-HPLC to obtain the title compound N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (cis-2, 6-dimethylmorpholinyl) -5-ethyl-6- (4- (4-hydroxyisoxazol-3-acyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (88,7mg,0.01mmol,11.8％yield).MS Calcd:707.22;MS Found:708.46([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.34(s,1H),8.59(s,1H),8.06(d,J＝8.8Hz,1H),7.98(d,J＝2.0Hz,1H),7.74(dd,J＝8.8,2.0Hz,1H),5.23(s,2H),4.52(d,J＝12.8Hz,1H),3.89(dd,J＝12.8,2.4Hz,2H),3.66–3.58(m,4H),3.51-3.44(m,2H),3.35–3.30(m,1H),3.04–2.93(m,4H),2.80(d,J＝11.2Hz,1H),2.71–2.68(m,1H),1.19(t,J＝7.2Hz,3H),1.13(d,J＝6.4Hz,6H).

Example 71 preparation of (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- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 90)

Step 1 2-iodo-N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (234 mg,0.68 mmol) was weighed out, tert-butyl (int-6, 300mg,0.68 mmol) of (R) -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, 300mg,0.68 mmol) was added to a 25mL single-necked flask, and 1, 4-dioxane (5 mL) and DIEA (0.34 mL,2.04 mmol) were added and reacted at 80℃for 2 hours after the addition. Concentrated under reduced pressure and the residue was purified by column chromatography (DCM: meoh=20:1) to give (R) -4- (2-bromo-5-ethyl-4- (2- (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 (90-a, 389mg,0.56mmol,82.8% yieldd). MS Calcd:655.17, 657.17;MS Found:556.12, 558.09 ([ M+H-100] ⁺).

Step 2 (R) -4- (2-bromo-5-ethyl-4- (2- (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 (90-a, 389mg,0.56 mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (177.4 mg,0.84 mmol), potassium phosphate (388.9 mg,1.69 mmol), pd (dppf) Cl ₂ (82.4 mg,0.11 mmol) to a 50mL single-port bottle were weighed, dioxane (5 mL) and water (2 mL) were added, nitrogen was replaced three times after the addition was completed, and then reacted at 90℃for 2 hours. The reaction solution was purified by column chromatography (DCM: meoh=20:1) to give (R) -4- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-4- (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 (90-b, 312mg,0.43mmol,75.6% yieldd). MS Calcd:659.30;MS Found:604.24 ([ M+H-56] ⁺).

Step 3 (R) -4- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-4- (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 (90-b, 312mg,0.43 mmol) was weighed into a 50mL single-necked flask, DCM (5 mL) and trifluoroacetic acid (2 mL) were added, and after the addition was stirred at room temperature for 1 hour. The reaction was concentrated in part of the solvent, then saturated sodium bicarbonate solution was added, the ethyl acetate was extracted, the organic phase was dehydrated, concentrated, and the residue was purified by column chromatography (DCM: meoh=10:1) to give (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-c, 211mg,0.36mmol,84.2% yield). MS Calcd:559.25;MS Found:560.20 ([ M+H ] ⁺).

Step 4-4-hydroxyisoxazole-3-carboxylic acid (int-7, 16.4mg,0.13 mmol) and HATU (102.7 mg,0.27 mmol) were weighed into a 25mL single port flask, DCM (1 mL) was then added followed by DIPEA (0.03 mL,0.17 mmol), stirring at room temperature for 5 min after addition was complete, (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-c, 50mg,0.08 mmol) was added and reacted at room temperature for 2H after addition was complete. Adding 2mL of ammonium chloride aqueous solution into the reaction solution, separating an organic phase, concentrating, purifying the residue 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-acyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90,25mg,0.04mmol,43.1％Yield).MS Calcd:670.25;MS Found:671.33([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.78(s,1H),8.60(d,J＝1.6Hz,1H),7.74(d,J＝8.4Hz,1H),7.64(d,J＝2.0Hz,1H),7.55(d,J＝8.4Hz,1H),6.86-6.84(m,1H),5.27(s,2H),4.28(d,J＝2.9Hz,2H),3.88-3.81(m,3H),3.69(d,J＝11.6Hz,1H),3.54–3.43(m,2H),3.32–3.17(m,3H),2.96-2.90(m,1H),2.84(d,J＝11.2Hz,1H),2.73–2.63(m,2H),2.37(s,3H),1.43(dd,J＝6.8,2.0Hz,3H),1.24(t,J＝7.2Hz,3H).

Example 72 preparation of 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) -N- (5-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 91)

Step 1 (R) -4- (2-bromo-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 (int-6, 0.3g,0.68 mmol), N- (5-fluoro-2-methyl-4- (trifluoromethyl) phenyl) -2-iodoacetamide (254 mg,0.82 mmol) and DIPEA (264 mg,2.04 mmol) were added separately to a dioxane solution (10 mL) and stirred at 80℃for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: ea=1:1) to give (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (91-a, 0.2g,0.3mmol,43.6% yield). MS Calcd:673.16;MS Found:574.20 ([ M-100+H ] ⁺).

Step 2 (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (91-a, 0.2g,0.3 mmol), 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (307 mg,1.29 mmol), pd (dppf) Cl ₂·CH₂Cl₂ (70 mg,0.09 mmol) and potassium phosphate (274 mg,1.29 mmol) were sequentially added to a 10mL dioxane/water (4:1) mixed solution, which was purged with nitrogen 3 times under vacuum, and stirred for 2 hours at 80 ℃. The reaction was concentrated completely and the residue was separated and purified by silica gel column chromatography (PE: ea=1:1) to give (2R) -4- (5-ethyl-4- (2- ((5-fluoro-2-methyl-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (91-b, 190mg,0.27mmol,62.6% yieldr, diastereomer mixture). MS Calcd:705.33;MS Found:650.25 ([ M-56+H ] ⁺).

Step 3 (2R) -4- (5-ethyl-4- (2- ((5-fluoro-2-methyl-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (91-b, 190mg,0.27 mmol) was added to a solution of hydrochloric acid-dioxane (4 mL) and left to stir at room temperature overnight. The reaction solution was concentrated completely, 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 2- (5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -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 (91-c, 0.12g,0.2mmol,73.6% yielda diastereomeric mixture). MS Calcd:605.27;MS Found:606.31 ([ M+H ] ⁺).

Step 4 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 87mg,0.41 mmol), DIPEA (32 mg,0.25 mmol) and 2- (5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -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 (91-C, 50mg,0.08 mmol) were added to a 2-methyl-2-butanol solution (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction solution was concentrated completely and the residue was purified by Prep-HPLC to give the title compound 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) -N- (5-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (91, 18mg,0.02mmol,26.7% yield, diastereomeric mixture ).MS Calcd:769.33;MS Found:770.34([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),8.24(s,1H),7.80(d,J＝12.8Hz,1H),7.68(d,J＝8.0Hz,1H),7.36(s,1H),6.74-6.72(m,1H),5.30(s,2H),4.83–4.60(m,2H),4.24–4.15(m,1H),3.68-3.15(m,8H),2.97–2.93(m,1H),2.75–2.68(m,1H),2.60–2.34(m,6H),2.19-2.12(m,4H),2.00–1.94(m,2H),1.74-1.66(m,4H),1.47-1.43(m,3H),1.23(t,J＝7.2Hz,3H).

Example 73 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrazol-6-yl) -5-ethyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 92)

Step 1 to a 25mL eggplant-shaped bottle were added 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, 60mg,0.11 mmol), ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 22.3mg,0.11 mmol), 2-methyl-2-butanol (2 mL) and DIPEA (0.04 mL), nitrogen was displaced 3 times, and 180℃stirring was performed for 2 hours, and 1mL of methanol was added thereto to dissolve the residue, which was 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-2- (3, 4-dihydro-2-hydroxy-1H-pyrazol-4-yl) -piperazin-1- (3, 5-hydroxy-1-H-yl) -2-hydroxy-triazolo [1, 5-hydroxy-4-yl ] -acetamide (0.04 mL).

Example 74 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclopentyl-5-hydroxy-1H-pyrazol-4-yl) -3-methylpiperazin-1-yl) -5-ethyl-2-morpholinyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 93)

Step 1 Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 115mg,0.51 mmol) and (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (3-methylpiperazin-1-yl) -2-morpholino-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (86-c, 60mg,0.1 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction was concentrated directly and the residue was purified by Prep-HPLC to give the title compound (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclopentyl-5-hydroxy-1H-pyrazol-4-acyl) -3-methylpiperazin-1-yl) -5-ethyl-2-morpholino-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (93,25mg,0.03mmol,32％yield).MS Calcd:760.28;MS Found:761.34([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.35(s,1H),8.06(d,J＝8.8Hz,1H),7.98(d,J＝2.0Hz,1H),7.74(dd,J＝8.8,2.0Hz,1H),7.67(s,1H),5.24(s,2H),4.70–4.63(m,1H),3.72-3.66(m,6H),3.50(t,J＝6.4Hz,1H),3.41-3.38(m,6H),3.16-3.07(m,1H),2.96-2.86(m,1H),2.76(d,J＝10.0Hz,1H),2.63(d,J＝11.6Hz,1H),2.03–1.74(m,6H),1.67-1.57(m,2H),1.43(d,J＝6.4Hz,3H),1.22(d,J＝7.2Hz,3H), hydroxy without peaks.

Example 75 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] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 94)

Step 1 Ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (17-b, 85mg,0.40 mmol) and (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-C, 50mg,0.08 mmol) were weighed into a 25mL single-necked flask, 2-methyl-2-butanol (2 mL) was added, followed by DIPEA (0.04 mL,0.24 mmol) and the mixture was warmed to 180℃for 2 hours. The reaction solution was concentrated, and the residue was prepared and purified to give 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- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (94,4.0mg,0.01mmol,6.8％Yield).MS Calcd:723.31;MS Found:724.30([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),7.74(d,J＝8.4Hz,1H),7.67-7.64(m,2H),7.57–7.54(m,1H),6.86–6.84(m,1H),5.28(s,2H),4.84-4.76(m,1H),4.30-4.24(m,3H),3.83(t,J＝5.6Hz,2H),3.70(d,J＝11.6Hz,1H),3.52-3.48(m,2H),3.21-3.16(m,2H),3.00-2.95(m,1H),2.79(d,J＝10.0Hz,1H),2.70–2.65(m,1H),2.56-2.48(m,2H),2.38(s,3H),2.32-2.26(m,2H),1.83-1.75(m,2H),1.45(brs,3H),1.31-1.24(m,5H).

EXAMPLE 76 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- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 95)

Step 1 Ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 90mg,0.40 mmol) and (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-C, 50mg,0.08 mmol) were weighed into a 25mL single-necked flask, 2-methyl-2-butanol (2 mL) was added, followed by DIPEA (0.04 mL,0.24 mmol), and the mixture was warmed to 180℃for 2 hours. The reaction solution was concentrated, and the residue was purified 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- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (95,18mg,0.02mmol,29.7％Yield).MS Calcd:737.33;MS Found:738.38([M+H]⁺).¹H NMR(400MHz,DMSO-d_6, d by heavy water exchange )δ7.72(d,J＝8.4Hz,1H),7.66(s,1H),7.63(d,J＝2.0Hz,1H),7.55(d,J＝8.4Hz,1H),6.86–6.84(m,1H),5.26(s,2H),4.69-4.62(m,1H),4.27(q,J＝2.8Hz,2H),3.82(t,J＝5.6Hz,2H),3.69-3.49(m,2H),3.19-3.10(m,1H),2.98-2.92(m,1H),2.80(d,J＝10.0Hz,1H),2.69-2.66(m,1H),2.36(s,3H),2.54-2.50(m,1H),2.03-1.99(m,2H),1.88–1.78(m,4H),1.65–1.61(m,2H),1.43(brs,3H),1.27–1.22(m,5H).

Example 77 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-phenyl-1H-pyrazol-4-yl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 96)

Step 1 diethyl ethoxymethylene malonate (3-a, 1.49g,6.92 mmol), phenylhydrazine hydrochloride (1.0 g,6.92 mmol) and potassium carbonate (2.86 g,20.75 mmol) were added to an aqueous solution (10 mL), respectively, and stirred at 100℃for 6 hours. The mixture was adjusted to ph=2 with 5N HCl, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: meoh=20:1) to give ethyl 5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (96-a, 0.63g,2.71mmol,39.2% yield). MS Calcd:232.08;MS Found:233.04 ([ M+H ] ⁺).

Step 2 Ethyl 5-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (96-a, 100mg,0.43 mmol), DIPEA (34 mg,0.27 mmol) and (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, 50mg,0.09 mmol) were added to a 2-methyl-2-butanol solution (2 mL) and the oil bath was warmed to 180℃and stirred for 30min. The reaction solution was concentrated completely 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-phenyl-1H-pyrazol-4-yl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (96,16mg,0.02mmol,23.5％yield).MS Calcd:765.24;MS Found:766.24([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.02(d,J＝8.4Hz,1H),7.94(d,J＝2.0Hz,1H),7.90-7.85(m,1H),7.72-7.69(m,2H),7.44-7.40(m,2H),7.23-7.20(m,1H),6.83(s,1H),5.31(s,2H),4.67(brs,1H),4.24(brs,3H),3.84-3.80(m,4H),3.68(d,J＝10.8Hz,1H),3.48(d,J＝12.0Hz,1H),3.18-3.12(m,1H),2.95-2.90(m,1H),2.78(d,J＝9.2Hz,1H),2.65(d,J＝11.2Hz,1H),2.54-2.51(m,2H),1.44(brs,3H),1.23(t,J＝7.2Hz,3H).

Example 78 preparation of 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) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 98)

Step 12- (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, 1g,2.1 mmol), 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (int-8, 760mg,3.2 mmol), potassium phosphate (1.4 g,6.3 mmol), 1-bis (diphenylphosphine) iron-dichloropalladium (150 mg,0.21 mmol) were added to a mixed solvent of dioxane (15 mL) and water (4 mL), nitrogen was replaced for 3 minutes, the temperature was raised to 85 ℃ and stirred for 3 hours, the remainder was concentrated under reduced pressure, extracted with ethyl acetate (20 mLx 3), the organic layers were combined, and the remainder was purified by chromatography over (PE=1, 4-fluoro-1-2-triazolo [1,5-a ] pyrimidin-4 (4H) -1, 4-methyl-4-yl) 2- (2-methyl-4-phenyl) acetamide (150 mL) and water (4 mL), 730mg,1.43mmol, 68%) MS Calcd:507.19;MS Found:508.21 ([ M+H ] ⁺).

Step 2- (5-Ethyl-2- (4-methoxycyclohex-1-en-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (98-a, 730mg,1.43 mmol) was added to DMF (10 ml), followed by NBS (255 mg,1.43 mmol) at elevated temperature to 60℃with stirring for 3 hours. The reaction was then poured into water, extracted with EA (20 ml x 3), the organic layer was dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the residue was purified by column chromatography (EA: pe=1:1) to give 2- (6-bromo-5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (98-b, 510mg,0.87mmol, 61%) MS Calcd:585.10;MS Found:586.15 ([ m+h ] ⁺).

Step 3-2- (6-bromo-5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (98-b, 510mg,0.87 mmol), (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.7 g,8.7 mmol), silver tetrafluoroborate (170 mg,0.87 mmol) was added to dry DMSO (5 mL), then heated to 120℃under nitrogen protection, stirred for 4 hours, cooled to room temperature, saturated aqueous sodium bicarbonate was added, then extracted with ethyl acetate (10 mLx 3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography (EA: PE=1:1), to give (2R) -4- (5-ethyl-4- (2- ((3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (98-c, 410mg,0.58mmol,66%, diastereomeric mixture). MS Calcd:705.33;MS Found:706.38 ([ M+H ] ⁺).

Step 4: (2R) -4- (5-ethyl-4- (2- ((3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4-methoxycyclohex-1-en-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (98-c, 410mg,0.58 mmol) was added to DCM (10 mL), then trifluoroacetic acid (3 mL) was added, stirring was carried out at room temperature for 4 hours, the starting materials reacted completely, concentrated under reduced pressure, the residue was added to saturated aqueous sodium bicarbonate, then extracted with DCM (10 mL x 3), the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate concentrated under reduced pressure to give 2- (5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -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 (98-d, 230mg,0.38mmol,65% yieldr, enantiomer mixture). MS Calcd:605.27;MS Found:606.31 ([ M+H ] ⁺).

Step 52- (5-Ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -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 (98-d, 60mg,0.1 mmol), DIPEA (15 mg,0.10 mmol), ethyl 1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carboxylate (105 mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30 min, the reaction was dissolved in methanol and purified by prep-HPLC, the title compound 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) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (98, 15mg,0.019mmol,19.0% yield, diastereomeric mixture) was obtained. MS Calcd:769.33;MS Found:770.38 ([ M+H ] ⁺).¹H NMR(400MHz,DMSO-d₆), heavy water exchange )δ7.68(s,1H),7.63–7.56(m,2H),6.74(brs,1H),5.26(s,2H),4.81-4.76(m,1H),3.68-3.45(m,5H),3.29(s,3H),3.18-3.11(m,1H),2.96-2.91(m,1H),2.78(d,J＝10.0Hz,1H),2.66(d,J＝11.6Hz,1H),2.58-2.40(m,4H),2.35–2.13(m,7H),1.96-1.92(m,1H),1.82-1.65(m,2H),1.42(brs,3H),1.24-1.21(m,5H).

Example 79 preparation of 2- (6- ((R) -4- (1-cyclopentyl-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) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 99)

Step 12- (5-Ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -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 (98-d, 60mg,0.1 mmol), DIEA (15 mg,0.10 mmol), ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 110mg,0.5 mmol) was added to 2-methyl-2-butanol (1 mL), the oil bath was warmed to 180℃and stirred for 30min, the reaction was dissolved in methanol and purified by prep-HPLC, the title compound 2- (6- ((R) -4- (1-cyclopentyl-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) -N- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (99, 11mg,0.014mmol,14.0% yield, diastereomeric mixture was obtained ).MS Calcd:783.35;MS Found:784.39([M+H]⁺).¹H NMR(400MHz,DMSO-d₆)δ10.23(s,1H),7.65–7.58(m,3H),6.74(d,J＝4.0Hz,1H),5.27(s,2H),4.68–4.63(m,1H),3.70(d,J＝11.6Hz,1H),3.56-3.47(m,2H),3.31-3.12(m,4H),2.99-2.93(m,1H),2.78(d,J＝10.0Hz,1H),2.69–2.64(m,1H),2.55-2.41(m,2H),2.26–2.14(m,5H),2.02–1.79(m,9H),1.72–1.61(m,4H),1.43(brs,3H),1.26-1.22(t,J＝7.2Hz,3H).

Example 80 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- (4- (dimethylamino) piperidin-1-yl) -5-ethyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 101)

Step 1 to a 100mL eggplant bottle were added (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 300mg,0.44 mmol), 4- (dimethylamino) piperidine (284 mg,2.22 mmol) and solvent DMSO (5 mL). Potassium acetate (217 mg,2.22 mmol) was then added thereto and stirred overnight at 120 ℃. The organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate and spun dry under reduced pressure to give crude product, which was purified by column chromatography (DCM: meoh=10:1) to give (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4- (dimethylamino) piperidin-1-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 (101-a, 200mg,0.28mmol,62.3% yield): MS Calcd: 723.32..ms Found:724.37 ([ m+h ] ⁺).

Step 2 to a 100mL eggplant bottle was added (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -2- (4- (dimethylamino) piperidin-1-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 (101-a, 200mg,0.28 mmol) solvent DCM (2 mL). TFA (0.5 mL) was then added thereto and stirred at room temperature for 2 hours. The pH was adjusted to alkaline by addition of saturated sodium bicarbonate solution, extracted with DCM (20 mL. Times.3), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate and spun-dried under reduced pressure to give crude (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (4- (dimethylamino) piperidin-1-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (101-b, 120mg,0.19mmol,69.6% yield). MS Calcd:623.27;MS Found:624.31 ([ M+H ] ⁺).

Step 3 to a 10mL microwave tube was added (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (4- (dimethylamino) piperidin-1-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (101-b, 50mg,0.08 mmol) and solvent 2-methyl-2-butanol (1 mL). Then, ethyl 1-cyclobutyl-5-hydroxypyrazole-4-carboxylate (17-b, 67mg,0.32 mmol) and DIPEA (31 mg,0.24 mmol) were added thereto and reacted at 180℃for 1 hour. The solvent was dried by spin-drying, methanol (1 mL) was added thereto, and the crude product was purified by Prep-HPLC to give the title compound, (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazole-4-carbonyl) -3-methylpiperazin-1-yl) -2- (4- (dimethylamino) piperidin-1-yl) -5-ethyl-7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (101,10mg,0.01mmol,15.4％yield).MS Calcd:787.33;MS Found:788.20([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.01(d,J＝8.4Hz,1H),7.94(s,1H),7.72(d,J＝8.4Hz,1H),7.42(s,1H),5.20(s,2H),4.75(p,J＝8.4Hz,1H),4.61(brs,1H),4.16(d,J＝12.8Hz,2H),3.63(d,J＝10.4Hz,1H),3.44(d,J＝11.6Hz,1H),3.17–3.03(m,3H),2.92-2.86(m,3H),2.70-2.62(m,7H),2.43–2.34(m,3H),2.16(d,J＝9.2Hz,2H),1.98(d,J＝11.6Hz,2H),1.72–1.64(m,3H),1.55-1.46(m,2H),1.35(d,J＝6.0Hz,3H),1.19(t,J＝7.2Hz,3H).

Example 81 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazol-4-yl) -3-methylpiperazin-1-yl) -5-ethyl-7-oxo-2- (pyridin-3-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 103)

Step 1 to a 50mL eggplant bottle was added (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 500mg,0.74 mmol), pyridin-3-ylboronic acid (136.2 mg,1.11 mmol), pd (dppf) Cl ₂ (53.6 mg,0.07 mmol), potassium phosphate (509.7 mg,2.22 mmol), water (5 mL) and dioxane (20 mL), and the temperature was raised to 85℃and stirred for 3 hours. The reaction was concentrated and the residue was subjected to flash column chromatography (PE: ea=4:1) to give (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl-7-oxo-2- (pyridin-3-yl) -4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (103-a, 403.5mg,0.60mmol, 80.9%). MS Calcd:674.23;MS Found:675.26 ([ M+H ] ⁺).

Step 2 to a 50mL eggplant-shaped bottle were added (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl-7-oxo-2- (pyridin-3-yl) -4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (103-a, 400mg,0.59 mmol) and methanol hydrochloride solution (10 mL) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to the reaction solution, ph=7, the reaction solution was concentrated, dissolved in water (50 mL), and DCM (3 x 30 mL) was extracted, and concentrated to give crude (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo-2- (pyridin-3-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (103-b, 321.3mg,0.56mmol, 94.3%). MS Calcd:574.18;MS Found:575.17 ([ M+H ] ⁺).

Step 3 to a 25mL eggplant bottle was added (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo-2- (pyridin-3-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (103-b, 50mg,0.09 mmol), ethyl 1-cyclobutyl-5-hydroxypyrazole-4-carboxylate (36.6 mg,0.17 mmol), 2-methyl-2-butanol (2 mL) and DIPEA (0.04 mL) in vacuo with nitrogen sparge for 3 times, 180℃reaction for 2 hours. The reaction mixture was concentrated, dissolved in 2mL of methanol, and purified by prep-HPLC to give the title compound, (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (4- (1-cyclobutyl-5-hydroxy-1H-pyrazol-4-acyl) -3-methylpiperazin-1-yl) -5-ethyl-7-oxo-2- (pyridin-3-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (103,9mg,0.01mmol,11.7％yield).MS Calcd:738.24;MS Found:739.0([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g of heavy water exchange )δ9.24(d,J＝2.0Hz,1H),8.70(dd,J＝4.8,1.6Hz,1H),8.45-8.42(m,1H),8.03(d,J＝8.4Hz,1H),7.96(d,J＝2.0Hz,1H),7.73–7.69(m,2H),7.59(dd,J＝8.0,4.8Hz,1H),5.40(s,2H),4.78(p,J＝8.4Hz,1H),3.72-3.67(m,1H),3.53-3.47(m,1H),3.21-3.16(m,1H),3.00-2.93(m,1H),2.82(d,J＝9.6Hz,1H),2.71–2.68(m,1H),2.58-2.44(m,3H),2.32–2.28(m,2H),1.82-1.74(m,2H),1.43(brs,3H),1.27-1.21(m,5H).

Example 82 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (((R) -4- (1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carbonyl) -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 104)

Step 1. Compound (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 300mg,0.44 mmol) and 2- (4-methoxycyclohex-1-en-1-yl) -4, 5-5-tetramethyl-1, 3, 2-dioxaborane (211 m g,0.89 mmol) were dissolved in 1, 4-dioxane (10 mL) and H ₂ O (2 mL), pd (dppf) Cl ₂ (32 mg,0.04 mmol), potassium phosphate (305 mg,1.33 mmol) were added sequentially, and the reaction was carried out at 80℃for 5.0 hours with nitrogen substitution. The reaction solution was concentrated, 30mL of ethyl acetate was added to the residue, filtered through celite, and the filtrate was concentrated, and purified by column chromatography (DCM: meoh=50:1) to give (2R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (104-a, 130mg,0.18mmol,41% yield, diastereomer mixture). MS Calcd:707.28;MS Found:708.30 ([ m+h ] ⁺).

Step 2 (2R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (104-a, 130mg,0.18 mmol) was dissolved in 4mL of dichloromethane solution, 1mL of trifluoroacetic acid was added thereto, and stirring was carried out at room temperature for 2 hours. The reaction mixture was concentrated directly, 20mL of saturated sodium bicarbonate solution was added to the residue, the mixture was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, and the mixture was dried and concentrated to give crude N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (104-b, 105mg,0.17mmol,94% yield, diastereomer mixture) MS Calcd:607.23;MS Found:608.20 ([ M+H ] ⁺).

Step 3N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2- (4-methoxycyclohex-1-en-1-yl) -6- ((R) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (104-b, 50mg,0.08 mmol) and ethyl 1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carboxylate (41-a, 92mg,0.41 mmol) were placed in a 25mL eggplant bottle and 2mL 2-methyl-2-butanol was added. Followed by stirring at 180 ℃ for 30 minutes. The reaction solution was directly concentrated and purified by Prep-HPLC to give the title compound N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (6- (((R) -4- (1-cyclopentyl-5-hydroxy-1H-pyrazole-4-carbonyl) -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

(104, 35Mg,0.04mmol,52% yield, diastereomer mixture). MS Calcd:785.30;MS Found:786.33 ([ M+H ] ⁺).¹H NMR(400MHz,DMSO-d₆), heavy water exchange )δ8.08(d,J＝8.8Hz,1H),7.98(d,J＝2.0Hz,1H),7.74(dd,J＝8.8,2.0Hz,1H),7.60(s,1H),6.75(t,J＝4.0Hz,1H),5.33(s,2H),4.65(q,J＝7.2Hz,1H),3.69(d,J＝11.2Hz,1H),3.54-3.51(m,2H),3.30(s,3H),3.18-3.12(m,1H),2.98-2.92(m,1H),2.79(d,J＝9.6Hz,1H),2.66(d,J＝11.2Hz,1H),2.56-2.42(m,3H),2.17(d,J＝18.8Hz,1H),1.98–1.78(m,9H),1.71–1.62(m,4H),1.44(brs,3H),1.24(t,J＝7.2Hz,3H).

Example 83 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (4- (4-hydroxyisoxazole-3-carbonyl) -3-methylpiperazin-1-yl) -2- (4-methoxypiperidin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 106)

Step 1 (R) -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) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (86-a, 0.6g,0.89 mmol), 4-methoxypiperidine (0.51 g,4.43 mmol) and potassium acetate (0.52 g,5.32 mmol) were added separately to a DMSO solution (3 mL) and stirred overnight at a temperature of 120 ℃. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: PE=1:1) to give tert-butyl (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl-2- (4-methoxypiperidin-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylate (106-a, 0.4g,0.56mmol,63.5% yield). MS Calcd:710.29;MS Found:655.22 ([ M-56+H ] ⁺).

Step 2 (R) -4- (4- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) -2-oxoethyl) -5-ethyl-2- (4-methoxypiperidin-1-yl) -7-oxo-4, 7-dihydro- [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (106-a, 0.4g,0.56 mmol) was added to a solution of hydrochloric acid-dioxane (4 mL) and left to stir at room temperature overnight. The reaction solution was concentrated completely, and a saturated sodium hydrogencarbonate solution, dichloromethane extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave the product (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2- (4-methoxypiperidin-1-yl) -6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (106-b, 0.2g,0.33mmol,58.2% yield). MS Calcd:610.24;MS Found:611.24 ([ M+H ] ⁺).

Step 3 4-hydroxyisoxazole-3-carboxylic acid (int-7, 51mg,0.39 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (55 mg,0.41 mmol) were added separately to DCM solution (2 mL) and stirred for 3 hours at room temperature, then (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-2- (4-methoxypiperidin-1-yl) -6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (106-b, 60mg,0.10 mmol), DIPEA (76 mg,0.59 mmol) was added and the temperature was raised to 40℃and stirred for 5 hours. Adding saturated sodium bicarbonate solution into the reaction solution, extracting with DCM, washing with saturated saline solution, concentrating under reduced pressure, purifying the residue under high pressure to obtain the title compound (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (5-ethyl-6- (4- (4-hydroxyisoxazole-3-carbonyl) -3-methylpiperazin-1-yl) -2- (4-methoxypiperidin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (106,8mg,0.01mmol,11.2％yield).MS Calcd:721.24;MS Found:722.32([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.40(s,1H),8.02(d,J＝8.8Hz,1H),7.95(d,J＝2.0Hz,1H),7.72(dd,J＝8.8,2.0Hz,1H),5.20(s,2H),3.79-3.73(m,2H),3.67–3.63(m,1H),3.51–3.36(m,3H),3.26(s,3H),3.21-3.06(m,4H),2.88–2.78(m,2H),2.69–2.65(m,1H),1.88–1.83(m,2H),1.44-1.35(m,6H),1.18(t,J＝7.2Hz,3H).

Example 84 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (2-hydroxypyrazolo [1,5-a ] pyridin-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1.5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 107)

Step 1-aminopyridine iodide (107-a, 6000mg,27.02 mmol), diethyl malonate (6492.5 mg,40.54 mmol) and K ₂CO₃ (9336.6 mg,67.56 mmol) were added sequentially to a solution of EtOH (100 mL) and left to stir at room temperature overnight. The reaction was filtered and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: meoh=20:1) to give 1- (3-ethoxy-3-oxopropionylamino) pyridin-1-ium (107-b, 3200mg,9.52mmol, 56.6%). MS Calcd:209.09 ([ M-I ] ⁺);MS Found:209.11([M-I]⁺).

Step 21- (3-ethoxy-3-oxopropionylamino) pyridin-1-ium (107-b, 280mg, 8.33 mmol) was dissolved in THF (20 mL) and t-BuOK (1854.4 mg,16.53 mmol) was added portionwise at room temperature and left to stir at room temperature for 30min. The reaction solution was concentrated completely, water was added to the residue, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meoh=20:1) to give ethyl 2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (107-c, 1500mg,7.28mmol, 52.9%). MS Calcd:206.07;MS Found:207.06 ([ M+H ] ⁺).

Step 3 Ethyl 2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (107-C, 500mg,2.43 mmol) and NaOH (486.0 mg,12.15 mmol) were added sequentially to a EtOH/H ₂ O (6 mL, 2:1) mixture and warmed to 80℃and stirred overnight. The reaction was concentrated completely, and 5N HCl solution was added slowly to the residue until solid precipitated, which was filtered off with suction to give 2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylic acid (107-d, 200mg,1.12mmol, 46.3%). MS Calcd:178.04;MS Found:179.08 ([ M+H ] ⁺).

Step 4 2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylic acid (107-d, 50mg,0.28 mmol), HATU (160 mg,0.42 mmol), DIPEA (90 mg,0.7 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, 190mg,0.34 mmol) were added to a DCM solution (6 mL) and stirred overnight at room temperature. The reaction mixture was concentrated completely 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- (2-hydroxypyrazolo [1,5-a ] pyridine-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1.5-a ] pyrimidin-4 (7H) -yl) acetamide (107,25mg,0.03mmol,11.9％yield).MS Calcd:725.21;MS Found:726.23([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, as a heavy water exchange )δ8.46(d,J＝6.8Hz,1H),8.06(d,J＝8.4Hz,1H),7.96(d,J＝2.0Hz,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.37-7.32(m,1H),6.90–6.83(m,2H),5.32(s,2H),4.26(d,J＝2.8Hz,2H),4.19(d,J＝12.4Hz,2H),3.81(t,J＝5.6Hz,2H),3.54-3.47(m,2H),3.17-3.10(m,2H),3.01(q,J＝7.2Hz,2H),2.75(d,J＝10.8Hz,2H),2.53-2.51(m,2H),1.22(t,J＝7.2Hz,3H).

Example 85 preparation of 2- (6- (4- (7-chloro-2-hydroxypyrazolo [1,5-a ] pyridin-3-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-chloro-4- (trifluoromethyl) phenyl) acetamide (Compound 108)

Step 1 Ethyl 2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (107-C, 1.0g,4.85 mmol), boc anhydride (1.16 g,5.33 mmol) and cesium carbonate (3.55 g,10.91 mmol) were added sequentially to 10mL of DMF solution and heated to 80℃and stirred for 8h. To the residue was added water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: ea=4:1) to give ethyl 2- ((t-butoxycarbonyl) oxy) pyrazolo [1,5-a ] pyridine-3-carboxylate (108-a, 640mg,2.09mmol,43.1% yieldd). MS Calcd:306.12;MS Found:207.1 ([ M-100+H ] ⁺).

Step 2 Ethyl 2- ((tert-Butoxycarbonyl) oxy) pyrazolo [1,5-a ] pyridine-3-carboxylate (108-a, 480mg,1.57 mmol) was dissolved in 4mL THF, and LiHMDS (2.51 mL,2.51 mmol) was slowly added dropwise at-78℃and stirring was continued at this temperature for 1h. A solution of hexachloroethane (445 mg,1.88 mmol) in THF (4 mL) was then added and stirring continued for 30min, slowly warmed to room temperature and stirred for 1h. To the reaction solution was added saturated ammonium chloride solution to terminate the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: ea=4:1) to give ethyl 2- ((t-butoxycarbonyl) oxy) -7-chloropyrazolo [1,5-a ] pyridine-3-carboxylate (108-b, 400mg,1.17mmol,74.9% yieldd). MS Calcd:340.08;MS Found:241.1 ([ M-100+H ] ⁺).

Step 3 Ethyl 2- ((tert-butoxycarbonyl) oxy) -7-chloropyrazolo [1,5-a ] pyridine-3-carboxylate (108-b, 350mg,1.03 mmol) was added to 2mL of dichloromethane, followed by 1mL of trifluoroacetic acid and stirred at room temperature for 2h. The reaction solution was concentrated completely, a saturated sodium hydrogencarbonate solution was added to the residue, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (100% ea) to give ethyl 7-chloro-2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (108-c, 220mg,0.91mmol,89.0% yieldd). MS Calcd:240.03;MS Found:240.99 ([ M+H ] ⁺).

Step 4 Ethyl 7-chloro-2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (108-C, 100mg,0.42mmol, and sodium hydroxide (83 mg,2.08 mmol) were added sequentially to a 2mL EtOH/H ₂ O (5:1) mixture, the reaction was warmed to 80 ℃ and stirred for 4h.TLC to monitor completion of the reaction, and the reaction solution was concentrated to complete 7-chloro-2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylate (108-d, 83mg,0.29mmol,70.0% yieldd) MS Calcd:212.00;MS Found:213.04 ([ M+H ] ⁺).

Step 5 7-chloro-2-hydroxypyrazolo [1,5-a ] pyridine-3-carboxylic acid (108-d, 55mg,0.26 mmol), HATU (118 mg,0.31 mmol), DIPEA (83 mg,0.65 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, 160mg,0.28 mmol) were added to a DMF solution (2 mL) and stirred at room temperature overnight. Ethyl acetate is added into the reaction liquid for extraction, decompression concentration is carried out, the residue is purified by prep-HPLC to obtain the title compound, namely 2- (6- (4- (7-chloro-2-hydroxy pyrazolo [1,5-a ] pyridine-3-carbonyl) piperazine-1-yl) -2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-7-oxo- [1,2,4] triazolo [1.5-a ] pyrimidine-4 (7H) -yl) -N- (2-chloro-4- (trifluoromethyl) phenyl) acetamide (108,16mg,0.02mmol,7.8％yield).MS Calcd:759.17;MS Found:760.21([M+H]⁺).¹H NMR(400MHz,DMSO, heavy water exchange )δ7.96(d,J＝8.4Hz,1H),7.86(s,1H),7.63(d,J＝8.8Hz,1H),7.52(d,J＝8.8Hz,1H),7.27(t,J＝8.4Hz,1H),7.06(d,J＝7.2Hz,1H),6.75(s,1H),5.23(s,2H),4.18–4.09(m,4H),3.72(t,J＝5.6Hz,2H),3.67(s,2H),3.44-3.37(m,2H),3.06(t,J＝12.0Hz,2H),3.01(q,J＝7.2Hz,2H),2.75(d,J＝10.8Hz,2H),1.21(t,J＝7.2Hz,3H).

Example 86 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (2-hydroxyimidazo [1,2-a ] pyridin-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 109)

Step 1 2-aminopyridine (109-a, 2.0g,21.25 mmol) and diethyl bromomalonate (6.3 g,26.57 mmol) were added sequentially to a 40mL ethanol solution, and the mixture was stirred overnight at reflux. The reaction was concentrated completely and the residue was isolated and purified by silica gel column chromatography (DCM: meoh=20:1) to give ethyl 2-hydroxyimidazo [1,2-a ] pyridine-3-carboxylate (109-b, 3.2g,15.52mmol,73.0% yield). MS Calcd:206.07;MS Found:207.10 ([ M+H ] ⁺).

Step 2 Ethyl 2-hydroxyimidazo [1,2-a ] pyridine-3-carboxylate (109-b, 2.1g,10.18 mmol), 1- (chloromethyl) -4-methoxybenzene (1.9 g,12.22 mmol) and cesium carbonate (8.29 g,25.46 mmol) are added sequentially to 40mL of DMF solution, and the mixture is warmed to 60℃and stirred for 5h. To the reaction solution was added water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE: ea=5:1) to give ethyl 2- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridine-3-carboxylate (109-c, 0.5g,1.53mmol,15.0% yieldd). MS Calcd:326.13;MS Found:327.10 ([ M+H ] ⁺).

Step 3 Ethyl 2- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridine-3-carboxylate (109-C, 90mg,0.28 mmol) and sodium hydroxide (55 mg,1.38 mmol) are added sequentially to a 2mL EtOH/H ₂ O (5:1) mixture, and the mixture is warmed to 80℃and stirred for 4H. The reaction was concentrated to give 2- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridine-3-carboxylic acid (109-d, 83mg,0.28mmol,99.4% yield). MS Calcd:298.10;MS Found:299.1 ([ M+H ] ⁺).

Step 42- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridine-3-carboxylic acid (109-d, 83mg,0.28 mmol), pyBOP (237 mg,0.46 mmol), DIPEA (98 mg,0.76 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, 180mg,0.3 mmol) were added to a DMF solution (4 mL) and stirred at room temperature overnight. Water was added to the reaction mixture to precipitate a solid, which was suction-filtered to give N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (2- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridine-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (109-e, 130mg,0.11mmol,51.3% yieldd). MS Calcd:845.27;MS Found:846.3 ([ M+H ] ⁺).

Step 5N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (2- ((4-methoxybenzyl) oxy) imidazo [1,2-a ] pyridin-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (109-e, 130mg,0.11 mmol) was dissolved in 2mL trifluoroacetic acid and then added to the solution was stirred at room temperature for 4H. The reaction mixture was concentrated to completion, saturated sodium bicarbonate solution was added, DCM was used for extraction, saturated brine was used for washing, and the residue was 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- (2-hydroxyimidazo [1,2-a ] pyridin-3-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (109,8mg,0.01mmol,9.7％yield).MS Calcd:725.21;MS Found:726.21([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g of heavy water exchange )δ9.01(d,J＝6.8Hz,1H),8.07(d,J＝8.4Hz,1H),7.97(d,J＝2.0Hz,1H),7.73(dd,J＝8.8,2.0Hz,1H),7.53-7.49(m,1H),7.29(d,J＝8.4Hz,1H),7.17-7.13(m,1H),6.85-6.83(m,1H),5.33(s,2H),4.28-4.23(m,4H),3.81(t,J＝5.6Hz,2H),3.57-3.53(m,2H),3.12–2.99(m,4H),2.73(d,J＝10.8Hz,2H),2.53-2.51(m,2H),1.23(t,J＝7.2Hz,3H).

Example 87 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 110)

Step 1 methyl 2-methylfuran-3-carboxylate (110-a, 100g, 514 mmol) was dissolved in CCl ₄ (1000 mL), NBS (152.6 g,857.14 mmol) was added, AIBN (5.9 g,35.71 mmol) was stirred overnight under nitrogen at 50 ℃. The reaction was concentrated and the residue was subjected to flash column chromatography (PE: ea=20:1) to give methyl 2- (bromomethyl) furan-3-carboxylate (110-b, 150g,684.93mmol,95% yield).

Step 2 methyl 2- (bromomethyl) furan-3-carboxylate (110-b, 70g,319.63 mmol), methyl tosylglycine (93.3 g,383.56 mmol) and K ₂CO₃ (97.2 g,703.20 mmol) were dissolved in acetonitrile (500 mL) and stirred overnight at 30 ℃. The reaction solution was filtered, the reaction solution was concentrated, and the residue was subjected to flash column chromatography (PE: ea=6:1) to give methyl 2- (((N- (2-methoxy-2-oxoethyl) -4-methylphenyl) sulfonyl) methyl) furan-3-carboxylate (110-c, 109g,285.79mmol,89% yieldd).

Step 3 methyl 2- (((N- (2-methoxy-2-oxo-ethyl) -4-methylphenyl) sulfonyl) methyl) furan-3-carboxylate (110-c, 4.0g,10.49 mmol) was dissolved in THF solution (40 mL), liHMDS (31.46 mL,31.46 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 1h. To the reaction mixture was added saturated ammonium chloride to terminate the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=4:1) to give methyl 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylate (110-d, 0.6g,3.11mmol,29.6% yield). MS Calcd:193.04;MS Found:194.1 ([ M+H ] ⁺).

Step 4 methyl 4-hydroxyfuro [2,3-C ] pyridine-5-carboxylate (110-d, 0.12g,0.62 mmol) and sodium hydroxide (75 mg,1.86 mmol) were added sequentially to a 4mL MeOH/H ₂ O (4:1) mixture and warmed to 80℃and stirred overnight. The reaction was concentrated completely and 5N HCl solution was added to the residue until solid precipitated, which was suction filtered to give 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 80mg,0.45mmol,71.9% yield).

MS Calcd:179.02;MS Found:180.02([M+H]⁺).

Step 5 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 26mg,0.15 mmol), DIPEA (40 mg,0.31 mmol), pyBOP (77 mg,0.15 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, 70mg,0.12 mmol) were added to DMF (2 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, 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- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (110,15mg,0.02mmol,16.4％yield).MS Calcd:726.19;MS Found:727.22([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.51(d,J＝1.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(d,J＝8.8Hz,1H),7.96(d,J＝2.0Hz,1H),7.72(dd,J＝8.8,2.0Hz,1H),7.22(dd,J＝2.4,1.2Hz,1H),6.85-6.82(m,1H),5.32(s,2H),4.60(s,1H),4.26(q,J＝2.8Hz,2H),3.81(t,J＝5.6Hz,3H),3.54-3.48(m,2H),3.26(s,1H),3.03-2.97(m,3H),2.83–2.65(m,2H),2.53-2.51(m,2H),1.20(t,J＝7.2Hz,3H).

Example 88 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-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 111)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 24mg,0.13 mmol), DIPEA (36 mg,0.27 mmol), pyBOP (69 mg,0.13 mmol) and 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, 60mg,0.11 mmol) were added to DMF (2 mL) and stirred overnight at room temperature. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, 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- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (111,8mg,0.01mmol,10.2％yield).MS Calcd:706.25;MS Found:707.31([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.51(d,J＝1.2Hz,1H),8.13(d,J＝2.0Hz,1H),7.71(d,J＝8.4Hz,1H),7.63–7.62(m,1H),7.54(dd,J＝8.8,2.0Hz,1H),7.22(dd,J＝2.4,1.2Hz,1H),6.85-6.83(m,1H),5.25(s,2H),4.60(brs,1H),4.27(q,J＝2.8Hz,2H),3.83-3.76(m,3H),3.51(t,J＝11.6Hz,2H),3.27(brs,1H),3.03-2.98(m,3H),2.83–2.65(m,2H),2.53-2.51(m,2H),2.35(s,3H),1.21(t,J＝7.2Hz,3H).

Example 89 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) 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 112)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 23mg,0.13 mmol), DIPEA (35 mg,0.27 mmol), pyBOP (66 mg,0.13 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, 60mg,0.11 mmol) were added to DMF (2 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, and the residue was prep-HPLC purified to give the title compound 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) 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 (112,10mg,0.01mmol,12.8％yield).MS Calcd:724.24;MS Found:725.32([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g water exchange )δ8.38(brs,1H),8.03(brs,1H),7.61–7.53(m,2H)7.14(brs,1H),6.84-6.82(m,1H),5.26(s,2H),4.61(brs,1H),4.27(q,J＝2.8Hz,2H),3.81(t,J＝5.6Hz,3H),3.53-3.46(m,2H),3.29(brs,1H),3.03-2.98(m,3H),2.85–2.65(m,2H),2.53-2.51(m,2H),2.24(s,3H),1.19(t,J＝7.2Hz,3H).

Example 90 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 113)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 47mg,0.27 mmol), DIPEA (78 mg,0.6 mmol), pyBOP (150 mg,0.29 mmol) and (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, 140mg,0.24 mmol) were added to DMF (3 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, 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- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (113,18mg,0.02mmol,9.9％yield).MS Calcd:740.21;MS Found:741.29([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g water exchange )δ8.38(s,1H),8.05(s,1H),8.03(s,1H),7.95(s,1H),7.71(d,J＝8.8Hz,1H),7.17(s,1H),6.83(s,1H),5.31(s,2H),4.25(d,J＝3.6Hz,2H),3.80(d,J＝5.6Hz,2H),3.56-3.49(m,2H),3.27–3.11(m,2H),2.95–2.85(m,2H),2.72–2.63(m,1H),2.53-2.51(m,2H),1.43(d,J＝6.8Hz,3H),1.22(t,J＝7.2Hz,3H).

Example 91 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 114)

Step 1 Ethyl 2-methyl-1H-pyrrole-3-carboxylate (114-a, 1.52g,9.92 mmol), benzenesulfonyl chloride (2.63 g,14.88 mmol), tetrabutylammonium bromide (0.32 g,0.99 mmol) were dissolved in toluene/H ₂ O (10:1) mixed solution (50 mL), and sodium hydroxide (3.97 g,99.22 mmol) was slowly added at room temperature and stirred at room temperature for 1H. To the reaction solution was added an aqueous solution, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:6) to give ethyl 2-methyl-1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (114-b, 2.3g,7.84mmol,79.3% yield). MS Calcd:293.07;MS Found:294.2 ([ M+H ] ⁺).

Step 2 Ethyl 2-methyl-1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (114-b, 1.22g,4.16 mmol), BPO (100 mg,0.42 mmol), NBS (1.11 g,6.24 mmol) were added sequentially to a carbon tetrachloride solution (50 mL) and stirred overnight at 80 ℃. The reaction solution was concentrated completely, water was added to the residue, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:5) to give ethyl 2- (bromomethyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (114-c, 0.8g,2.15mmol,51.7% yieldd). MS Calcd:370.98;MS Found:372.0 ([ M+H ] ⁺).

Step 3 Ethyl 2- (bromomethyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (114-c, 1.95g,5.24 mmol) and methyl N- (p-toluenesulfonyl) glycinate (1.25 g,5.14 mmol) were added sequentially to an acetonitrile solution (10 mL), followed by K ₂CO₃ (1.178 g,13.10 mmol) and stirred at room temperature for 1H. To the reaction solution was added saturated ammonium chloride solution, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:2) to give ethyl 2- (((N- (2-methoxy-2-oxoethyl) -4-methylphenyl) sulfonylamino) methyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (114-d, 0.68g,1.27mmol,25.2% yieldd).

Step 4 Ethyl 2- (((N- (2-methoxy-2-oxoethyl) -4-methylphenyl) sulphonamido) methyl) -1- (phenylsulphonyl) -1H-pyrrole-3-carboxylate (114-d, 0.68g,1.27 mmol) is dissolved in THF solution (5 mL), the solution is replaced 3 times by vacuum nitrogen, liHMDS (3.82 mL,3.82 mmol) is slowly added dropwise at-78 ℃ and stirring is continued for 1H at this temperature. To the reaction mixture was added saturated ammonium chloride to terminate the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:2) to give methyl 4-hydroxy-1- (phenylsulfonyl) -1H-pyrrolo [2,3-c ] pyridine-5-carboxylate (114-e, 0.2g,0.6mmol,47.3% yieldd). MS Calcd:332.05;MS Found:332.97 ([ M+H ] ⁺).

Step 5 methyl 4-hydroxy-1- (phenylsulfonyl) -1H-pyrrolo [2,3-C ] pyridine-5-carboxylate (114-e, 0.18g,0.54 mmol) and benzyl bromide (111 mg,0.65 mmol) were dissolved in THF solution (5 mL), then cesium carbonate (0.44 g,1.35 mmol) was added and heated to 70℃and stirred for 2H. To the reaction mixture was added saturated ammonium chloride to terminate the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:2) to give methyl 4- (benzyloxy) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-c ] pyridine-5-carboxylate (114-f, 0.21g,0.5mmol,91.7% yield). MS Calcd:422.09;MS Found:422.93 ([ M+H ] ⁺).

Step 6 methyl 4- (benzyloxy) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-c ] pyridine-5-carboxylate (114-f, 0.18g,0.43 mmol) was dissolved in 2mL acetonitrile, then potassium methoxide (60 mg,0.85 mmol) was added and left to stir at room temperature for 4H. The reaction solution was concentrated completely to give 4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 120mg,0.43mmol,99.8% yield). MS Calcd:282.10;MS Found:283.05 ([ M+H ] ⁺).

Step 7 4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 47mg,0.17 mmol), DIPEA (48 mg,0.38 mmol), pyBOP (94 mg,0.18 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, 85mg,0.15 mmol) were added to DMF (2 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-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-chloro-4- (trifluoromethyl) phenyl) acetamide (114-H, 100mg,0.12mmol,80.2% yield). MS Calcd:829.27;MS Found:829.95 ([ M+H ] ⁺).

Step 8 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-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-chloro-4- (trifluoromethyl) phenyl) acetamide (114-H, 100mg,0.12 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.24 mmol,0.24 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight with stirring. Adding a small amount of methanol to terminate the reaction, concentrating under reduced pressure, purifying the residue 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- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (114,8mg,0.01mmol,8.6％yield).MS Calcd:739.22;MS Found:740.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.39(s,1H),8.02(d,J＝8.4Hz,1H),7.94(d,J＝2.0Hz,1H),7.71(dd,J＝8.8,2.0Hz,1H),7.46(d,J＝3.6Hz,1H),6.83(s,1H),6.69(d,J＝2.8Hz,1H),5.30(s,2H),4.60(d,J＝12.0Hz,2H),4.25(q,J＝2.8Hz,2H),3.88(s,3H),3.80(t,J＝5.6Hz,2H),3.55–3.47(m,3H),3.02–2.98(m,3H),2.76-2.69(m,2H),2.53-2.51(m,2H),1.30–1.06(t,J＝7.2Hz,3H).

Example 92 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) 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 115)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 74mg,0.26 mmol), DIPEA (77 mg,0.6 mmol), pyBOP (150 mg,0.29 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, 135mg,0.24 mmol) were added to DMF (2 mL) and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-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- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (115-a, 120mg,0.14mmol,60.5% yield). MS Calcd:827.32;MS Found:828.25 ([ M+H ] ⁺).

Step 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-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- (3-fluoro-2-methyl-4- (trifluoromethyl) phenyl) acetamide (115-a, 120mg,0.14 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.24 mmol,0.24 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight with stirring. The reaction was quenched by the addition of a small amount of methanol, concentrated under reduced pressure, and the residue was purified under high pressure to give the product 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-carbonyl) 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 (115, 4mg,0.005mmol,3.3% yield). MS Calcd:737.27;MS Found:738.37 ([ M+H ] ⁺).

Example 93 preparation of (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 116)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 50mg,0.28 mmol), DIEA (75 mg,0.58 mmol), pyBOP (157 mg,0.3 mmol) and (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-c, 130mg,0.23 mmol) were added to DMF (3 mL) and left at room temperature for stirring overnight. LCMS was monitored for completion of the reaction by adding water to the reaction solution, DCM extraction, washing with saturated brine, concentrating under reduced pressure, and purifying the residue by prep-HPLC to give the title compound, (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (116,15mg,0.02mmol,8.9％yield).MS Calcd:720.26;MS Found:721.29([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, -heavy water exchange )δ8.37(s,1H),8.08(s,1H),7.70(d,J＝8.4Hz,1H),7.62(d,J＝2.0Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.19(s,1H),6.83(t,J＝2.0Hz,1H),5.24(s,2H),4.26(q,J＝2.8Hz,2H),3.81(t,J＝5.6Hz,3H),3.73-3.47(m,4H),3.27–3.10(m,2H),2.98–2.81(m,2H),2.71-2.62(m,1H),2.53-2.51(m,1H),2.34(s,3H),1.44(d,J＝6.8Hz,3H),1.22(t,J＝7.2Hz,3H).

Example 94 preparation of N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 117)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 36mg,0.2 mmol), DIPEA (54 mg,0.42 mmol), pyBOP (113 mg,0.22 mmol) and N- (2, 5-dichloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl l) -5-ethyl-7-oxo-6- (piperazin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (52-e, 100mg,0.17 mmol) were added to DMF (2 mL) and left to stir at room temperature overnight. Water was added to the reaction mixture, which was washed with saturated brine, concentrated under reduced pressure, and the residue was prep-HPLC purified 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-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (117,12mg,0.01mmol,8.3％yield).MS Calcd:760.15;MS Found:761.17([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g heavy water exchange )δ8.49(s,1H),8.24(d,J＝2.4Hz,1H),8.11(s,1H),8.03(s,1H),7.20(s,1H),6.82(s,1H),5.32(s,2H),4.25(m,2H),3.82-3.748(m,2H),3.53-3.47(m,3H),3.26(s,1H),3.02-2.98(m,4H),2.83(s,1H),2.65(s,1H),2.53-2.51(m,2H),1.22(t,J＝7.2Hz,3H).

Example 95 preparation of (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -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 118)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 45mg,0.25 mmol), DIPEA (80 mg,0.62 mmol), pyBOP (140 mg,0.27 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, 120mg,0.21 mmol) were added to DMF (3 mL) and left to stir at room temperature overnight. Water was added to the reaction, DCM was extracted, washed with saturated brine, 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-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -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 (118,13mg,0.02mmol,8.2％yield).MS Calcd:738.25;MS Found:739.34([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, -heavy water exchange )δ8.49(d,J＝4.8Hz,1H),8.10(d,J＝2.0Hz,1H),7.75(d,J＝12.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.20(t,J＝2.8Hz,1H),6.82(t,J＝2.0Hz,1H),5.28(s,2H),4.25(q,J＝2.8Hz,2H),3.87–3.72(m,4H),3.55–3.44(m,2H),3.27–3.08(m,2H),2.94–2.82(m,2H),2.74–2.60(m,1H),2.53-2.51(m,2H),2.33(s,3H),1.44(d,J＝6.8Hz,1.5H),1.38(d,J＝6.8Hz,1.5H),1.20(t,J＝7.2Hz,3H).

Example 96 preparation of N- (2-chloro-5-fluoro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 119)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 37mg,0.21 mmol), DIPEA (66 mg,0.51 mmol), pyBOP (116 mg,0.22 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, 100mg,0.17 mmol) were added to DMF (3 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, and the residue was 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-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (119,13mg,0.02mmol,10.2％yield).MS Calcd:744.18;MS Found:745.30([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.37(s,1H),8.08(s,1H),8.05(s,1H),7.98(d,J＝7.6Hz,1H),7.18(s,1H),6.82(t,J＝2.4Hz,1H),5.34(s,2H),4.24(d,J＝2.8Hz,1H),3.80(t,J＝5.6Hz,2H),3.72-3.65(m,3H),3.52-3.48(m,2H),3.28(brs,1H),3.01-2.96(m,3H),2.82(brs,1H),2.69-2.65(m,1H),2.53-2.51(m,2H),1.18(t,J＝7.2Hz,3H).

Example 97 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-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 120)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 38mg,0.21 mmol), DIPEA (58 mg,0.44 mmol), pyBOP (111 mg,0.21 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, 100mg,0.18 mmol) were added to DMF (3 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, 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- (4-hydroxyfuro [2,3-c ] pyridine-5-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 (120,16mg,0.02mmol,12.1％yield).MS Calcd:724.24;MS Found:725.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, -heavy water exchange )δ8.51(s,1H),8.12(d,J＝2.0Hz,1H),7.76(d,J＝12.8Hz,1H),7.66(d,J＝8.0Hz,1H),7.21(d,J＝2.0Hz,1H),6.83(t,J＝2.0Hz,1H),5.28(s,2H),4.26(d,J＝2.8Hz,2H),3.81(t,J＝5.6Hz,2H),3.73-3.66(m,2H),3.51(t,J＝11.2Hz,2H),3.27(brs,1H),3.02-2.96(m,3H),2.84(brs,1H),2.65(brs,1H),2.53-2.51(m,2H),2.34(s,3H),1.19(t,J＝7.2Hz,3H).

Example 98 preparation of (R) -N- (2-chloro-5-fluoro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 121)

Step 1 4-hydroxyfuro [2,3-c ] pyridine-5-carboxylic acid (110-e, 83mg,0.46 mmol), DIPEA (162 mg,1.25 mmol), pyBOP (228 mg,0.44 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, 250mg,0.42 mmol) were added to DMF (3 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound (R) -N- (2-chloro-5-fluoro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxyfuro [2,3-c ] pyridin-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (121,16mg,0.02mmol,12.1％yield).MS Calcd:758.20;MS Found:759.23([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g of water exchange )δ8.37(s,1H),8.09-8.05(m,2H),7.98(d,J＝7.2Hz,1H),7.19(s,1H),6.82–6.80(m,1H),5.33(s,2H),4.24(q,J＝2.8Hz,2H),3.81-3.70(m,4H),3.55-3.48(m,2H),3.27–3.07(m,2H),2.94–2.81(m,2H),2.72–2.62(m,1H),2.53-2.51(m,2H),1.44-1.37(m,3H),1.20(t,J＝7.2Hz,3H).

Example 99 preparation of N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxythieno [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 122)

Step 1 thiophene-3-carboxylic acid (122-a, 5.0g,39.03 mmol) was dissolved in THF (50 mL), TMEDA (14.54 mL,97.58 mmol) was slowly added at-78℃and stirred for 10min at this temperature, then n-butyllithium (39.03 mL,97.58 mol) was slowly added dropwise, after which stirring was continued for 1h at this temperature, finally DMF (6.68 mL,85.87 mol) was added and stirring continued for 30min. Dilute hydrochloric acid is added into the reaction solution to terminate the reaction, ethyl acetate extraction, saturated saline solution washing, anhydrous sodium sulfate drying and reduced pressure concentration are carried out, thus obtaining crude 2-formylthiophene-3-carboxylic acid (122-b, 5.8g,37.13mmol,95.1% yield). MS Calcd:155.99;MS Found:155.210 ([ M-H ] ^-).

Step 2-formylthiophene-3-carboxylic acid (122-b, 5.8g,37.13 mmol) and potassium carbonate (12.03 g,87.04 mmol) were added sequentially to DMF solution (50 mL), followed by iodoethane (6.78 g,43.52 mmol) and stirred at 50℃for 3h. The reaction solution was concentrated completely, water was added to the residue, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:5) to obtain ethyl 2-formylthiophene-3-carboxylate (122-c, 3.56g,19.33mmol,52.1% yieldd). MS Calcd:184.02;MS Found:185.0 ([ M+H ] ⁺).

Step 3 Ethyl 2-formylthiophene-3-carboxylate (122-C, 3.08g,16.72 mmol) and a solution in THF/MeOH (7:1) mixture (25 mL) were placed at 0deg.C and sodium borohydride (0.95 g,25.08 mmol) was added in portions and stirred at room temperature for 10min. The reaction solution was concentrated completely, a saturated ammonium chloride solution was added to the residue, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:5) to give ethyl 2- (hydroxymethyl) thiophene-3-carboxylate (122-d, 2.5g,13.43mmol,80.3% yield). MS Calcd:186.04;MS Found:169.0 ([ M-OH) ⁺).

Step 4 Ethyl 2- (hydroxymethyl) thiophene-3-carboxylate (122-d, 2.2g,11.82 mmol) was added to DCM solution (20 mL), phosphorus tribromide (1.28 g,4.73 mmol) was added in portions at 0deg.C, and stirred for 30min at room temperature. To the residue was added water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:5) to give ethyl 2- (bromomethyl) thiophene-3-carboxylate (122-e, 2.5g,10.04mmol,84.9% yield).

Step 5 Ethyl 2- (bromomethyl) thiophene-3-carboxylate (122-e, 2.09g,8.39 mmol), methyl N- (p-toluenesulfonyl) glycinate (2.45 g,10.07 mmol) and potassium carbonate (2.55 g,18.46 mmol) were added sequentially to an acetonitrile solution (30 mL) and stirred at room temperature overnight. To the reaction solution was added saturated ammonium chloride solution, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:2) to give ethyl 2- (((N- (2-methoxy-2-oxo-ethyl) -4-methylphenyl) sulfonamide) methyl) thiophene-3-carboxylate (122-f, 3.2g,7.78mmol,92.7% yieldd). MS Calcd:411.08;MS Found:412.2 ([ M+H ] ⁺).

Step 6. Ethyl 2- (((N- (2-methoxy-2-oxoethyl) -4-methylphenyl) sulfamido) methyl) thiophene-3-carboxylate (122-f, 2.0g,4.86 mmol) was dissolved in THF solution (20 mL), the solution was replaced 3 times with nitrogen under vacuum, liHMDS (19.44 mL,19.44 mmol) was slowly added dropwise at-78℃and stirring was continued at this temperature for 1h. To the reaction solution was added saturated ammonium chloride to terminate the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (EA: pe=1:2) to give methyl 4-hydroxythieno [2,3-c ] pyridine-5-carboxylate (122-g, 0.7g,3.35mmol,68.8% yield). MS Calcd:209.01;MS Found:210.10 ([ M+H ] ⁺).

Step 7 methyl 4-hydroxythieno [2,3-C ] pyridine-5-carboxylate (122-g, 0.2g,0.96 mmol) and sodium hydroxide (115 mg,2.87 mmol) were added sequentially to a 4mL MeOH/H ₂ O (4:1) mixture and warmed to 80℃and stirred overnight. TLC was used to monitor the completion of the reaction, the reaction was concentrated completely, 5N HCl solution was added to the residue until solid precipitated, and 4-hydroxythieno [2,3-c ] pyridine-5-carboxylic acid (122-h, 100mg,0.51mmol,53.6% yield) was obtained by suction filtration. MS Calcd:195.00;MS Found:196.08 ([ M+H ] ⁺).

Step 8 4-Hydroxythieno [2,3-c ] pyridine-5-carboxylic acid (122-H, 42mg,0.21 mmol), DIEA (68 mg,0.53 mmol), pyBOP (120 mg,0.23 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, 100mg,0.18 mmol) were added to DMF (2 mL) and left to stir at room temperature overnight. Water was added to the reaction, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, and the residue purified by prep-HPLC as the title compound N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxythieno [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (122,14mg,0.02mmol,10.6％yield).MS Calcd:742.17;MS Found:743.24([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, g water exchange )δ8.76(s,1H),8.04-8.01(m,2H),7.94(d,J＝2.0Hz,1H),7.73–7.69(m,2H),6.84-6.82(m,1H),5.31(s,2H),4.60(brs,1H),4.25(q,J＝2.8Hz,2H),4.07(brs,1H),3.80(t,J＝5.6Hz,2H),3.56–3.49(m,2H),3.30(brs,1H),3.02-2.96(m,3H),2.84-2.68(m,2H),2.53-2.51(m,2H),1.20(t,J＝7.2Hz,3H).

Example 100 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxythieno [2,3-c ] pyridine-5-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 123)

Step 1 4-Hydroxythieno [2,3-c ] pyridine-5-carboxylic acid (122-H, 43mg,0.22 mmol), DIPEA (71 mg,0.55 mmol), pyBOP (124 mg,0.24 mmol) and 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, 100mg,0.18 mmol) were added to DMF (2 mL) and stirred at room temperature overnight. Water was added to the reaction, DCM was extracted, washed with saturated brine, concentrated under reduced pressure, and the residue purified by prep-HPLC as the title compound 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxythieno [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (123,15mg,0.02mmol,10.4％yield).MS Calcd:722.22;MS Found:723.26([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, -heavy water exchange )δ8.36(s,1H),8.00(brs,2H),7.71(t,J＝7.2Hz,1H),7.62(d,J＝2.0Hz,1H),7.53(dd,J＝8.8,2.0Hz,1H),6.84-6.82(m,1H),5.25(s,2H),4.61(brs,1H),4.26(q,J＝2.8Hz,2H),4.05(brs,1H),3.81(t,J＝5.6Hz,2H),3.56–3.50(m,2H),3.31(brs,1H),3.03-2.96(m,3H),2.83–2.68(m,2H),2.53-2.51(m,2H),2.34(s,3H),1.21(t,J＝7.2Hz,3H).

Example 101 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-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 124)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 100mg,0.35 mmol), DIPEA (103 mg,0.8 mmol), pyBOP (200 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, 180mg,0.32 mmol) were added to DMF (4 mL) and stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-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 (124-a, 140mg,0.17mmol,53.0% yield). MS Calcd:827.32;MS Found:828.41 ([ M+H ] ⁺).

Step 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-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 (124-a, 140mg,0.17 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.34 mmol,0.34 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight with stirring. Adding a small amount of saturated ammonium chloride solution to terminate the reaction, extracting with dichloromethane, concentrating under reduced pressure, purifying the residue by prep-HPLC to obtain the title compound 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-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 (124,14mg,0.02mmol,11.0％yield).MS Calcd:737.27;MS Found:738.27([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, -heavy water exchange )δ8.40(s,1H),7.75(d,J＝12.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.46(d,J＝3.2Hz,1H),6.82(s,1H),6.69(d,J＝3.2Hz,1H),5.28(s,2H),4.63(d,J＝12.4Hz,2H),4.25(d,J＝3.2Hz,2H),3.89(s,3H),3.80(t,J＝5.6Hz,2H),3.56-5.50(m,2H),3.16–2.98(m,4H),2.76(brs,2H),2.53-2.51(m,2H),2.33(s,3H),1.20(t,J＝7.2Hz,3H).

Example 102 preparation of (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (Compound 125)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 100mg,0.35 mmol), DIPEA (103 mg,0.8 mmol), pyBOP (200 mg,0.38 mmol) and (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazol [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (90-c, 180mg,0.32 mmol) were added to DMF (4 mL) and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give (R) -2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -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-methyl-4- (trifluoromethyl) phenyl) acetamide (125-a, 160mg,0.19mmol,60.4% yielda). MS Calcd:823.34;MS Found:824.35 ([ M+H ] ⁺).

Step 2 (R) -2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-carbonyl) -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-methyl-4- (trifluoromethyl) phenyl) acetamide (125-a, 160mg,0.19 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.83 mmol,0.83 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature and stirred overnight. Adding a small amount of saturated ammonium chloride solution to terminate the reaction, extracting with dichloromethane, concentrating under reduced pressure, purifying the residue by prep-HPLC to obtain the title compound (R) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (125,16mg,0.02mmol,9.7％yield).MS Calcd:733.29;MS Found:734.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.39(s,1H),7.69(d,J＝8.4Hz,1H),7.62(d,J＝2.4Hz,1H),7.53(dd,J＝8.4,2.4Hz,1H),7.46(d,J＝3.2Hz,1H),6.84-6.82(m,1H),6.69(d,J＝3.2Hz,1H),5.24(s,2H),4.26(q,J＝2.8Hz,2H),3.88(s,3H),3.81(t,J＝5.6Hz,2H),3.74-3.70(m,2H),3.57-3.51(m,2H),3.28–3.14(m,2H),3.00–2.81(m,2H),2.72–2.66(m,2H),2.53-2.51(m,2H),2.34(s,3H),1.45(d,J＝7.2Hz,3H),1.23(t,J＝7.2Hz,3H).

Example 103 preparation of (R) -N- (2-chloro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 126)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 100mg,0.28 mmol), DIPEA (84 mg,0.65 mmol), pyBOP (162 mg,0.31 mmol) and (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, 150mg,0.26 mmol) were added to DMF (2 mL) and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give (R) -2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -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 (126-a, 160mg,0.19mmol,73.3% yielda). MS Calcd:843.29;MS Found:844.21 ([ M+H ] ⁺).

Step 2 (R) -2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-carbonyl) -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 (126-a, 110mg,0.13 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.52 mmol,0.52 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight with stirring. Adding a small amount of methanol to terminate the reaction, concentrating under reduced pressure, purifying the residue 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- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) -3-methylpiperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (126,8mg,0.01mmol,8.1％yield).MS Calcd:753.24;MS Found:754.25([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.39(s,1H),8.04(d,J＝8.8Hz,1H),7.94(d,J＝2.4Hz,1H),7.71(dd,J＝8.8,2.4Hz,1H),7.46(d,J＝3.2Hz,1H),6.84–6.82(m,1H),6.69(d,J＝3.2Hz,1H),5.31(s,2H),4.86(brs,0.5H),4.66(brs,0.5H),4.50–4.44(m,0.5H),4.32-4.21(m,2.5H),3.88(s,3H),3.80(t,J＝5.6Hz,2H),3.75-3.69(m,1.5H),3.57-3.52(m,1.5H),3.27–3.13(m,1.5H),2.93–2.81(m,1.5H),2.71–2.65(m,1H),2.53-2.51(m,2H),1.44(t,J＝5.6Hz,3H),1.22(t,J＝7.2Hz,3H).

Example 104 preparation of 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-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 127)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 131mg,0.46 mmol), DIPEA (136 mg,1.05 mmol), pyBOP (263 mg,0.51 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- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (1-c, 230mg,0.42 mmol) were added to DMF (4 mL) and left to stir at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-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-methyl-4- (trifluoromethyl) phenyl) acetamide (127-a, 180mg,0.22mmol,52.7% yield). MS Calcd:809.33;MS Found:810.04 ([ M+H ] ⁺).

Step 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-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-methyl-4- (trifluoromethyl) phenyl) acetamide (127-a, 800mg,0.1 mmol) was dissolved in 2mL DCM and boric trichloride (0.4 mmol,0.4 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight. Adding a small amount of methanol to terminate the reaction, concentrating under reduced pressure, purifying the residue by prep-HPLC to obtain the title compound, namely 2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) -N- (2-methyl-4- (trifluoromethyl) phenyl) acetamide (127,16mg,0.02mmol,22.1％yield).MS Calcd:719.28;MS Found:720.3([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.42(s,1H),7.72(d,J＝8.4Hz,1H),7.63(d,J＝2.0Hz,1H),7.54(dd,J＝8.4,2.0Hz,1H),7.48(d,J＝2.8Hz,1H),6.85-6.83(m,1H),6.70(d,J＝2.8Hz,1H),5.26(s,2H),4.69(brs,2H),4.27(q,J＝2.8Hz,2H),3.90(s,3H),3.82(t,J＝5.6Hz,2H),3.61-3.51(m,2H),3.32-3.00(m,4H),2.77(brs,2H),2.53-2.51(m,2H),2.36(s,3H),1.23(t,J＝7.2Hz,3H).

Example 105 preparation of N- (2-chloro-5-fluoro-4- (trifluoromethyl) phenyl) -2- (2- (3, 6-dihydro-2H-pyran-4-yl) -5-ethyl-6- (4- (4-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (Compound 128)

Step 14- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridine-5-carboxylic acid (114-g, 106mg,0.38 mmol), DIPEA (110 mg,0.86 mmol), pyBOP (214 mg,0.41 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, 200mg,0.34 mmol) were added to DMF (4 mL) and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with DCM, washed with saturated brine and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: meOH=20:1) to give 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-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-chloro-5-fluoro-4- (trifluoromethyl) phenyl) acetamide (128-a, 120mg,0.14mmol,41.3% yield). MS Calcd:847.26;MS Found:847.92 ([ M+H ] ⁺).

Step 2- (6- (4- (4- (benzyloxy) -1-methyl-1H-pyrrolo [2,3-C ] pyridine-5-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-chloro-5-fluoro-4- (trifluoromethyl) phenyl) acetamide (128-a, 120mg,0.14 mmol) was dissolved in 2mL DCM solution and boric trichloride (0.34 mmol,0.34 mL) was slowly added dropwise at-78℃and the mixture was slowly warmed to room temperature overnight with stirring. The reaction was quenched by the addition of a small amount of methanol, concentrated under reduced pressure and the residue 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-hydroxy-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-carbonyl) piperazin-1-yl) -7-oxo- [1,2,4] triazolo [1,5-a ] pyrimidin-4 (7H) -yl) acetamide (128,18mg,0.02mmol,15.9％yield).MS Calcd:757.22;MS Found:758.21([M+H]⁺).¹H NMR(400MHz,DMSO-d₆, heavy water exchange )δ8.41(s,1H),8.09(d,J＝12.8Hz,1H),7.99(d,J＝7.2Hz,1H),7.48(d,J＝3.2Hz,1H),6.83-6.80(m,1H),6.69(d,J＝3.2Hz,1H),5.35(s,2H),4.69(brs,2H),4.25(q,J＝2.8Hz,2H),3.90(s,3H),3.80(t,J＝5.6Hz,2H),3.56-3.50(m,2H),3.18–2.97(m,4H),2.77(brs,2H),2.53-2.51(m,2H),1.20(t,J＝7.2Hz,3H).

Example 106 in vitro enzymatic Activity evaluation:

the inhibitory activity of the compounds against human WRN helicase was evaluated by measuring IC ₅₀ values.

Main reagent and consumable:

experimental protocol two single stranded DNA Oligo were annealed to form dsDNA as substrate for the enzymatic reaction of WRN (aa 500-946). Reaction buffer composition and concentration were 5mM NaCl, 25mM Tris base (pH 8.0), 0.01% Tween20, 2mM MgCl ₂, 1mM TCEP, 0.02% BSA. The experimental reactions were all completed in microplate thermostatted shaker boxes with parameters set to 25 ℃ and 300rpm. The experiment was initiated using a 5. Mu.L reaction system, where first 2. Mu.L of WRN (aa 500-946) solution (final concentration 1.2 nM) and 1. Mu.L of compound solution (final concentration 10. Mu.M, 3 Xgradient dilution, 10 concentration points, DMSO final concentration 1%) were added to the compound group, 2. Mu.L of WRN (aa 500-946) solution (final concentration 1.2 nM) and 1. Mu.L of reaction buffer (DMSO final concentration 1%), the minimum signal group was added to 2. Mu.L of reaction buffer and 1. Mu.L of reaction buffer (DMSO final concentration 1%), each group was incubated for 30min, then 2. Mu.L of substrate solution (dsDNA containing final concentration 0.1nM and 10. Mu.M ATP) was added, then 5. Mu. L ADP Glo Reagent was added for incubation for 40min, finally 10. Mu. L Kinase Detection Reagent for 30min, and after completion of incubation Luminescences were read by TECAN SPARK. Inhibition ratio% = {1- [ (compound group luminescence signal-minimum signal group)/(maximum signal group-minimum signal group) ] } 100%. Data analysis using software GRAPHPAD PRISM, data was fitted using the "log (inhibitor) vs. response-Variable slope (four parameters)" method to give IC ₅₀ values for the compounds.

TABLE 1 half inhibition concentration of compounds of the invention against WRN IC ₅₀

The result shows that the compound has good inhibitory activity on WRN.

Example 107 cell Activity and Selectivity test experiments:

The cell activity and selectivity of the inhibitors were evaluated by testing the proliferation inhibitory activity of non-covalent inhibitors of WRN on MSI-H cell line SW48 and MSS cell line SW 620.

Main reagent and consumable:

When SW48 and SW620 cells were cultured to a growth density of about 80%, the cells were digested with Trypsin and counted, diluted to 1X 10≡4/mL with DMEM which is a culture medium for SW48 cells and DMEM-F12 which is a culture medium for SW620 cells, and then 100. Mu.L of the diluted cell suspension was added to a 96-well plate to make the number of cells in each well 1000, followed by culturing overnight in a carbon dioxide incubator (37 ℃ C., 5% CO ₂) until the cells adhere to the wall. The compound to be tested is dissolved and diluted to 5mM by using DMSO, then the compound is diluted by using an automatic microwell plate pipetting and pipetting system in a 96 well plate (V-shaped bottom) by using DMSO from 3 times of the initial concentration of 5mM to 0.0008mM (9 concentration points in total), and then the compound after gradient dilution is respectively diluted by 500 times by using corresponding culture solutions of SW48 and SW620 cells until the final concentration of DMSO is 0.2% and the final concentration of the compound is 10 mu M-0.0015 mu M. The corresponding culture medium containing only 0.2% dmso in the wells was a blank. The culture medium in the wells of SW48 and SW620 cell culture plates was thoroughly aspirated by a pipette, and then 100. Mu.L of culture medium containing the compound at the corresponding concentration was added to the compound group, and only 0.2% DMSO was added to the DMSO control group. Blank, compound and DMSO control were incubated in carbon dioxide incubator for 4 days. After 4 days, the plates were removed from the incubator and allowed to cool to room temperature, after which 50. Mu.L of the prepared CellTiter-Glo solution was added to each set of wells and incubated at 800rpm for 10min at 25℃in a microplate incubator. After incubation, 100. Mu.L of the reaction solution in each well was pipetted into a black 96-well plate and read on a microplate reader.

The percent (%) inhibition of each concentration of compound was calculated from the signals of the minimum fluorescent signal group (blank group) and the maximum fluorescent signal group (DMSO control group) contained in each assay plate. Wherein the minimum fluorescence signal group was cell-free, containing only SW48 and SW620 cell culture broth (0.2% dmso), and the maximum fluorescence signal group was compound-free, containing only SW48 and SW620 cells (0.2% dmso). The inhibition ratio of each compound concentration was calculated by%inhibition = {1- [ (compound group luminescence signal-minimum fluorescence signal group)/(maximum luminescence signal group-minimum luminescence signal group) ] }. 100%, using GRAPHPAD PRISM software to obtain GI ₅₀ values and nonlinear regression curve fitting, and compound cell selectivity = SW620GI ₅₀/SW48GI₅₀,GI₅₀ and selectivity values are shown in the following table.

TABLE 2 inhibition of cell proliferation and selectivity of the compounds SW48 and SW620 of the present invention

The result shows that the compound has strong proliferation inhibition activity on MSI-H cell SW48 and weak proliferation inhibition on MSS cell SW620, thus indicating that the compound has good selectivity.

Example 108 pharmacokinetic experiments:

experimental materials, methods and results analysis:

the experimental animals were healthy adult BALB/c female mice (supplied by the company of the biological technologies, inc. Of verruca Fukang, beijing);

Mode of administration and sample collection for mice:

BALB/c female mice were given a single gastric administration (10 mg/kg, vehicle: 5% DMSO+5% solutol+90% saline) (DMSO, chengdu Corp., solutol, BASF,42966-1KG; saline, sichuan Megaku Jiale pharmaceutical Co., ltd., 100mL_0.9 g), and the mice were collected at various time points from the fundus venous plexus at 60. Mu.L, and centrifuged at 4000rpm for 10min after administration, respectively, to obtain plasma.

Sample analysis:

a10. Mu.L sample of mouse plasma was taken, 190. Mu.L of acetonitrile solution containing an internal standard was added to precipitate the protein, vortexed for 10min, followed by centrifugation at 4000rpm for 10min, and the supernatant was taken in a 96-well plate. The sample was put into LC-MS/MS (Mass Spectrometry, TQ4500, liquid chromatograph, shimadzu 30 AD) for analysis.

The LC-MS/MS method is used for measuring the drug concentration in plasma at different moments after the compound of the example is administrated by the stomach of the mice, and calculating relevant pharmacokinetic parameters, researching the pharmacokinetic behavior of the compound in the mice and evaluating the pharmacokinetic characteristics of the compound.

Comparative example 1 was prepared with reference to example 58 of patent WO2022249060A1, and had the following structure:

TABLE 3 pharmacokinetic parameters of the compounds of the invention in mice

The results show that the compound of the invention exhibits good pharmacokinetic properties in mice, and that the compound of the invention has significantly improved exposure AUC and Cmax in plasma compared to comparative example 1.

Example 109 mouse tumor tissue distribution experiment:

experimental materials, methods and results analysis:

The experimental animal was a healthy adult Balb/c nude female mouse (supplied by the experimental animal technologies limited company, mitsubishi, sikawa);

administration mode and sample collection:

SW48 cells (nac) were inoculated subcutaneously in the right underarm of Balb/c nude female mice, each of which was inoculated at 0.1mL, at an inoculum size of 3×10 ⁶ cells. When the mean tumor volume of the animals reached 194mm ³, balb/c nude female mice were given gavage (10 mg/kg,10% DMSO+10% Solutol+80% H ₂ O) (DMSO: AR 500ml, colon; solutol:42966-1KG, BASF) and plasma and tumor samples were collected at different time points from the mice at 1h and 4h post-administration. Wherein, collecting fundus venous plexus whole blood 60 μl, centrifuging at 4000rpm for 6min to obtain blood plasma, collecting tumor tissue after animals are euthanized, wiping water with filter paper, weighing, adding a certain amount of physiological saline proportionally, homogenizing, and packaging in EP tube.

Sample analysis:

The plasma and tumor samples of 10. Mu.L were taken, and a volume of acetonitrile solution containing an internal standard was added to precipitate the protein, vortexed for 10min, followed by centrifugation at 4000rpm for 10min, and the supernatant was taken in a 96-well plate. LC-MS/MS (Shimadzu LC-30A, AB API 4500) was placed for analysis.

The LC-MS/MS method was used to determine the drug concentration in plasma and tumor at various times after administration of the compound of the examples by lavage in mice, and to calculate the relevant pharmacokinetic parameters, study the pharmacokinetic behavior of the compound in mice, and evaluate the pharmacokinetic profile.

TABLE 4 Table 4

The result shows that the compound has better distribution in tumor tissues of tumor-bearing mice.

Example 110 hERG inhibition study

Experimental operation:

hERG inhibition assays were performed using Predictor ^TM hERG Fluorescence Polarization Assay Kit (thermo fisher SCIENTIFIC PV 5365). 4X Predictor ^TM HERG TRACER RED and 4 XE-4031 positive controls were pre-formulated. 5 μ L PredictororhERG FP Assay Buffer and 5 μ L Predictor ^TM hERG Membrane were added to Assay Blank wells in 384 well plates. The negative control, positive control, and test compound wells were each filled with 2.5. Mu. L Predictor ^TM HERG FP ASSAY Buffer, 2.5. Mu.L of 4 XE-4031 Positive Control, 2.5. Mu.L of 4 Xtest compound, and then sequentially filled with 5. Mu. L Predictor ^TM hERG Membrane and 2.5. Mu.L of 4X Predictor ^TM HERG TRACER RED. Incubate at room temperature (25 ℃) for 3.5h protected from light. After the reaction was completed, the reaction was carried out in a microplate reader (Tecan, ) Fluorescence polarization was measured and G Factor was 2.14.

And (3) calculating inhibition rate:

The inhibition of the compound or positive control was calculated using the following formula. Inhibition% = (mP negative control-mP compound)/(mP negative control-mP positive control) ×100%

Table 5 herg inhibition assay results

Example 111 human liver microsomal stability experiment:

experimental materials, methods and results analysis:

Human liver microsomes (supplier: reed liver disease research (Shanghai) Co., ltd., brand: BIOIVT, cat# X008070), NADPH (reduced nicotinamide adenine dinucleotide phosphate, cat# 481973-500mg, sigma) were used for the experiments.

And (3) preparation of a reagent:

PBS, 0.1M KH ₂PO₄ and K ₂HPO₄ buffer, pH 7.4.

MgCl ₂ A quantity of MgCl ₂ was weighed and formulated into 16mM MgCl ₂ solution in PBS.

NADPH an amount of NADPH was weighed and formulated to 4mM with 16mM MgCl ₂ solution and the final incubation concentration was 1mM.

Compounds test compounds were formulated to 4. Mu.M with PBS and final incubation at 1. Mu.M.

Liver microsomes the liver microsomes were diluted to 1mg/mL with PBS and the final incubation concentration was 0.5mg/mL.

The experimental steps are as follows:

The test tube is filled with the test compound, and then with the formulated NADPH, and mixed well. Pre-incubating in an incubator at 37 ℃ and 220rpm for 5min, adding liver microsomes to initiate reaction, and repeating the pore operation.

At 0min, 5min, 15min, 30min, 60min, adding a certain volume of ice acetonitrile solution containing internal standard into the corresponding tube to precipitate protein, shaking and vortex for 5min, centrifuging at 4000rpm for 10min, and collecting supernatant in 96-well plate. Put into LC-MS/MS for analysis.

The concentration (peak area ratio) of the compound of the example was determined by LC-MS/MS, and the rate constant was obtained by plotting "Ln (residual amount of compound%)" versus "incubation time" in Excel, so as to calculate the half-life and intrinsic clearance of the drug, and provide a basis for the prediction of clearance in vivo.

Analysis of data CL _int＝(0.693/t_1/2, microsome) × [ hatching fluid volume (mL)/microsome protein mass (mg) ]× [ microsome protein mass (mg)/liver mass (g) ]× [ liver mass (g)/body weight (kg) ] ^[1]CL_H＝CL_int×f_u×Q_h/(CL_int×f_u+Q_h

In the middle of

CL _int - -intrinsic clearance (ml/min/kg)

CL _H - -liver clearance (ml/min/kg)

F _u - -plasma protein non-binding fraction 1

Q _h liver blood flow

TABLE 6 stability results of human liver particles

[1]Davies B,Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993;10:1093-5.

The results show that the compound of the invention has good stability in human liver microsomes.

Industrial applicability

The compound of the present invention has excellent WRN inhibitory activity and is useful as a drug for the treatment or prevention of diseases associated with such actions.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims

A compound of formula (I), or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof:

Wherein, the

R ₁ 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 heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more identical or different R _g;

Each R _g is independently selected from hydroxy, halogen, C _1-4 alkyl, C _1-4 alkoxy, HOC (O) - (CH ₂)_n-、H₃C-C(O)(CH₂)_n-、C_1-4 alkyl-O-C (O) (CH ₂)_n -, = O, azetidinyl, pyrrolidinyl, 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 is attached to the R ₁ main group through an N atom, the C _1-4 alkyl, C _1-4 alkoxy, azetidinyl, pyrrolidinyl are each independently unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, C _1-2 alkoxy;

r ₂ is selected from Wherein L is selected from 7-10 membered spiroheterocycloalkyl,The spiroheterocycloalkyl group contains 2 to 3N atoms;

R ₃ is selected from cyclopropyl, methoxy, -SCH ₃、C_1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more substituents selected from hydroxy or halogen;

R ₄ is selected from H, halogen, hydroxy, cyano, C _1-4 alkyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

R ₆ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more halogen;

R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

X is selected from N or CR ₈,R₈ is H or halogen;

R _2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each unsubstituted or each independently substituted with one or more R _c, which may be the same or different;

R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocycloalkyl, 5-14 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, -CH ₂ -on the 5-14 membered heterocycloalkylyl, 5-14 membered heterocycloalkenyl ring each independently optionally being replaced by-C (=O) -, 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocycloalkyl, 5-14 membered heterocycloalkenyl each independently being substituted by one or more R _d;

r _2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each being unsubstituted or each independently substituted with one or more R _f, which may be the same or different;

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 the group consisting of 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, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6-membered heteroaryl independently containing 1 to 3 heteroatoms selected from N, O or S, said 5-or 6-membered heteroaryl, phenyl being unsubstituted or 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 cycloalkyl;

Each R _f is independently selected from the group consisting of hydroxy, cyano, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _3-6 halocycloalkyl.
A compound of formula (I), or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, characterized in that:

Wherein, the

R ₁ 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 heterocyclyl, 5-or 6-membered heteroaryl, phenyl containing 1-2 heteroatoms selected from N, O or S, said alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl being unsubstituted or substituted with 1 or more R _g, which may be the same or different;

Each R _g is independently selected from hydroxy, halogen, C _1-4 alkyl, C _1-4 alkoxy, HOC (O) - (CH ₂)_n-、H₃C-C(O)(CH₂)_n-、C_1-4 alkyl-O-C (O) (CH ₂)_n -, = O, azetidinyl, pyrrolidinyl, 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 being attached to the R ₁ main group through an N atom, the C _1-4 alkyl, C _1-4 alkoxy, azetidinyl, pyrrolidinyl being unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, C _1-2 alkoxy;

r ₂ is selected from Wherein L is selected from 7-10 membered spiroheterocyclic groups,

R ₃ is selected from cyclopropyl, methoxy, -SCH ₃、C_1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more substituents selected from hydroxy or halogen;

R ₄ is selected from H, halogen, hydroxy, cyano, C _1-4 alkyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

R ₆ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more halogen;

R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

X is selected from N or CR ₈,R₈ is H or halogen;

R _2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each unsubstituted or each independently substituted with one or more R _c, which may be the same or different;

R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl independently substituted with one or more R _d;

r _2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each being unsubstituted or each independently substituted with one or more R _f, which may be the same or different;

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, 4-7 membered heterocycloalkyl, or halogen, each of said 4-7 membered heterocycloalkyl independently containing 1 or 2 heteroatoms selected from N, O or S;

Each R _f is independently selected from the group consisting of hydroxy, cyano, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _3-6 halocycloalkyl.
A compound of formula (I), or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, characterized in that:

Wherein, the

R ₁ 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 heterocyclyl, 5-or 6-membered heteroaryl, phenyl containing 1-2 heteroatoms selected from N, O or S, said alkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, heteroaryl, phenyl being unsubstituted or substituted with 1 or more R _g, which may be the same or different;

Each R _g is independently selected from hydroxy, halogen, C _1-4 alkyl, C _1-4 alkoxy, HOC (O) - (CH ₂)_n-、H₃C-C(O)(CH₂)_n-、C_1-4 alkyl-O-C (O) (CH ₂)_n -, = O, azetidinyl, pyrrolidinyl, 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 being attached to the R ₁ main group through an N atom, the C _1-4 alkyl, C _1-4 alkoxy, azetidinyl, pyrrolidinyl being unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, C _1-2 alkoxy;

r ₂ is selected from Wherein L is selected from 7-10 membered spiroheterocyclic groups,

R ₃ is selected from cyclopropyl, methoxy, -SCH ₃、C_1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more substituents selected from hydroxy or halogen;

R ₄ is selected from H, halogen, hydroxy, cyano, C _1-4 alkyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

R ₅ is selected from H, methoxy, hydroxy, cyano, methyl, halogen;

R ₆ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1 or more halogen;

R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, C _1-4 alkoxy, said alkyl, cycloalkyl, alkoxy being unsubstituted or substituted with 1 or more halogens;

X is selected from N or CR ₈,R₈ is H or halogen;

R _2a is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each unsubstituted or each independently substituted with one or more R _c, which may be the same or different;

R _2b is selected from the group consisting of 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl independently substituted with one or more R _d;

r _2e is selected from 5-14 membered heteroaryl, 6-14 membered aryl, 5-14 membered heterocyclyl, each independently containing 1-4 heteroatoms selected from N, O or S, each being unsubstituted or each independently substituted with one or more R _f, which may be the same or different;

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 the group consisting of hydroxy, cyano, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _3-6 halocycloalkyl.
The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

r ₂ is selected from

Preferably, R ₂ is selected from

Preferably, R ₂ is selected from

R _2b is selected from 5-membered heteroaryl, 8-14 membered heteroaryl, each of said 5-membered heteroaryl, 8-14 membered heteroaryl independently containing 1-4 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, 8-14 membered heteroaryl independently substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, each of said 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl independently containing 1-4 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl independently substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 5-membered heteroaryl-5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, each of said 5-membered heteroaryl, 6-membered heteroaryl independently containing 1-2 heteroatoms selected from N, O and S, said 5-membered heteroaryl, 5-membered heteroaryl-5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, benzo 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl independently substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl, each of said 5-membered heteroaryl, 6-membered heteroaryl independently containing 1-2 heteroatoms selected from N, O and S, each of said 5-membered heteroaryl, benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, benzo 6-membered heteroaryl independently substituted with one or more R _d;

Preferably, the method comprises the steps of, 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, benzooxazolyl, benzofuranyl, and benzofuranyl benzisoxazolyl, pyridopyrrolyl, pyridofuranyl, pyridothienyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridoisothiazolyl, pyridooxazolyl, pyridoisoxazolyl, benzopyridyl, benzopyrimidinyl; the pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, benzopyrrolyl, benzofuranyl, and the like benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl benzothienyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzidine;

Preferably, R _2b is selected from pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridopyrrolyl, pyridothienyl; the pyrazolyl, benzopyridyl, isoxazolyl, isothiazolyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridopyrrolyl, pyridothienyl are each independently substituted with one or more R _d;

Preferably, R _2b is selected from The said Each independently substituted with one or more R _d;

Preferably, R _2b is selected from

Preferably, R _2b is selected from

Each R _d is independently selected from the group consisting of 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 one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, said 5-or 6-membered heteroaryl each independently containing 1 to 3 heteroatoms selected from N, O and S;

Preferably, each R _d is independently selected from the group consisting of 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 one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, said 5-or 6-membered heteroaryl each independently containing 1,2 or 3 heteroatoms selected from N, O and S;

Preferably, each R _d is independently selected from the group consisting of C _1-4 alkyl, C _3-4 cycloalkyl, C _5-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 alkoxy, 4-7 membered heterocycloalkyl, 6 membered heteroaryl, phenyl, hydroxy, halogen wherein one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl containing 1 or 2O heteroatoms, said 6 membered heteroaryl containing 1 or 2N heteroatoms;

Preferably, each R _d is independently selected from the group consisting of 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl, hydroxy, halogen, wherein only one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl containing 1O heteroatom;

Preferably, each R _d is independently selected from the group consisting of 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, pyridinyl, hydroxy, F, cl, br, phenyl, wherein one and only one R _d is hydroxy, said 4-7 membered heterocycloalkyl containing 1O heteroatom;

Preferably, each R _d is independently selected from the group consisting of methyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃, and, Methoxy group, Cl, phenyl, hydroxy, wherein one and only one R _d is hydroxy;

Preferably, the hydroxyl group is substituted on a carbon atom ortho or meta to the point of attachment of R _2b to the main group;

Preferably, the hydroxyl group is substituted on a carbon atom ortho to the point of attachment of R _2b to the main group;

Most preferably, R _2b is selected from
The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

r ₂ is selected from

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl ring, -CH ₂ -each independently optionally replaced by-C (=O) -, said 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl each independently substituted by one or more R _d;

Preferably, R _2b is selected from the group consisting of 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 and 5-6-membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, -CH ₂ -on the heterocycloalkyl ring is each independently optionally replaced by-C (=O) -, and-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 and 5-6-membered heterocycloalkenyl are each independently substituted by one or more R _d;

Preferably, R _2b is selected from the group consisting of 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 and 5-6 membered heterocycloalkenyl, each independently containing 1-4 heteroatoms selected from N, O or S, -CH ₂ -on the heterocycloalkyl, heterocycloalkenyl ring is each independently optionally replaced by-C (=O) -, and-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 and 5-6 membered heterocycloalkenyl are each independently substituted by one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl, 5-or 6-membered heterocycloalkyl-5-or 6-membered heterocycloalkenyl, -CH ₂ -on the heterocycloalkenyl ring is each independently optionally replaced by-C (=O) -, the heteroaryl, heterocycloalkyl, heterocycloalkenyl each independently contains 1-2 heteroatoms selected from N, O or S, -the 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkyland 5-or 6-membered heterocycloalkenyl each independently is substituted by 1,2, 3 or 4R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 1, 5-dihydro-2H-pyrrol-2-onyl, pyridonyl, 6-membered heterocycloalkyl-pyridonyl, each independently containing 1-2 heteroatoms selected from N, O or S, said 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 1, 5-dihydro-2H-pyrrol-2-onyl, pyridonyl, 6-membered heterocycloalkyl-pyridonyl each independently substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, and the like, Each independently substituted with 1, 2, 3, or 4R _d;

Preferably, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, The isoxazolyl, pyrazolyl, isothiazolyl, and the like,Each independently substituted with 1, 2, 3, or 4R _d;

Preferably, R _2b is selected from The said Each independently substituted with 1, 2, 3, or 4R _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, 4-7 membered heterocycloalkyl, 5-or 6 membered heteroaryl, phenyl, amino, or hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6 membered heteroaryl independently contains 1 to 3 heteroatoms selected from N, O or S, each of said 5-or 6 membered heteroaryl, phenyl is unsubstituted or 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 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 of said 4-7 membered heterocycloalkyl independently containing 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6-membered heteroaryl independently containing 1,2 or 3 heteroatoms selected from N, O or S, each of said 5-or 6-membered heteroaryl, phenyl being unsubstituted or 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 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, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy, each of said 4-7 membered heterocycloalkyl independently containing 1O heteroatom, said phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl being 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, -CH ₂CF₃, 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 pyridinyl, fluoro-substituted pyridinyl, chloro-substituted pyridinyl, methyl-substituted pyridinyl, methoxy-substituted pyridinyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridinyl, trifluoromethoxy-substituted pyridinyl, cyano-substituted pyridinyl or hydroxy;

Preferably, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, Methoxy group, Or Cl;

Or 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, 4-7 membered heterocycloalkyl, 5-or 6 membered heteroaryl, phenyl, hydroxy or halo, wherein at least one R _d is 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 to 3 heteroatoms selected from N, O or S, each 5-or 6 membered heteroaryl, phenyl is unsubstituted or each independently substituted with one or more substituents selected from halo, 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, 4-7 membered heterocycloalkyl, 5-or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein at least one R _d is 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 to 3 heteroatoms selected from N, O or S, each 5-or 6-membered heteroaryl, phenyl is unsubstituted or 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 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, 4-7 membered heterocycloalkyl, 5-or 6-membered heteroaryl, phenyl, cyano or hydroxy, wherein one and only one R _d is 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 to 3 heteroatoms selected from N, O or S, each 5-or 6-membered heteroaryl, phenyl is unsubstituted or 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 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 one and only one R _d is hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1 or 2 heteroatoms selected from N, O or S, each of said 5-or 6-membered heteroaryl independently contains 1,2 or 3 heteroatoms selected from N, O or S, said 5-or 6-membered heteroaryl, phenyl is unsubstituted or 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 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, 4-7 membered heterocycloalkyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyano or hydroxy, wherein only one and only one R _d is hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1O heteroatom, said phenyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, furyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl being 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, -CH ₂CF₃, 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 pyridinyl, fluoro-substituted pyridinyl, chloro-substituted pyridinyl, methyl-substituted pyridinyl, methoxy-substituted pyridinyl, methyl-substituted pyrazolyl, trifluoromethyl-substituted pyridinyl, trifluoromethoxy-substituted pyridinyl, cyano-substituted pyridinyl or hydroxy, wherein only and none of R _d is hydroxy;

Preferably, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, Methoxy group, Or Cl, wherein one and only one R _d is hydroxy;

Preferably, each R _d is independently selected from phenyl, thienyl, pyridyl, hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, Methoxy group, Or Cl, wherein one and only one R _d is hydroxy, and the hydroxy is substituted ortho to the point of attachment of R _2b to the main group;

Preferably, R _2b is selected from

Most preferably, R _2b is selected from
The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

r ₂ is selected from

Or R ₂ is selected from

Or R ₂ is selected from

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, phenyl, naphthyl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10 membered heteroaryl, phenyl, naphthyl, 5-or 6-membered heterocyclyl, 8-10-membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10-membered heteroaryl, 5-or 6-membered heterocyclyl, 8-10-membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocyclyl-5-or 6-membered heterocyclyl, each of which independently contains 1-2 heteroatoms selected from N, O or S, and each of which is independently substituted with 1, 2,3 or 4R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl-pyridonyl, each of said heteroaryl, heterocyclyl independently containing 1-2 heteroatoms selected from N, O or S, said 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl-pyridonyl each independently being substituted with 1,2,3 or 4R _d;

Preferably, R _2b is selected from isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, The isoxazolyl, pyrazolyl, isothiazolyl, benzopyrrolyl, benzopyridyl, morpholinopyridone, 1, 5-dihydro-2H-pyrrol-2-one, and the like, Each independently substituted with 1, 2, 3, or 4R _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, 4-7 membered heterocycloalkyl, amino, or hydroxy, each of said 4-7 membered heterocycloalkyl independently containing 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 containing 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, 4-7 membered heterocycloalkyl, cyano or hydroxy, each independently containing 1O heteroatom;

Preferably, each R _d is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃, Methoxy, ethoxy, Or hydroxy;

Preferably, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, and, Methoxy group,Or Cl;

Or 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, 4-7 membered heterocycloalkyl, hydroxy or halogen, wherein at least one R _d is 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 _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein at least one R _d is 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 _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein one and only one R _d is 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 _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 one and only one R _d is hydroxy;

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, 4-7 membered heterocycloalkyl, cyano or hydroxy, wherein one and only one R _d is hydroxy, each of said 4-7 membered heterocycloalkyl independently contains 1O heteroatom;

Preferably, each R _d is independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂CF₃, Methoxy, ethoxy, Or hydroxy, wherein one and only one R _d is hydroxy;

Preferably, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, and, Methoxy group,Or Cl, wherein one and only one R _d is hydroxy;

Preferably, each R _d is independently selected from the group consisting of hydroxy, methyl, isopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclopropyl, -CH ₂CF₃, and, Methoxy group,Or Cl, wherein one and only one R _d is hydroxy, and the hydroxy is substituted ortho to the point of attachment of R _2b to the main group;

Preferably, R _2b is selected from

Most preferably, R _2b is selected from
The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

r ₂ is selected from

Or R ₂ is selected from

Or R ₂ is selected fromPreferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10 membered heteroaryl, 6-10 membered aryl, 5-10 membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, phenyl, naphthyl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10 membered heteroaryl, phenyl, naphthyl, 5-or 6-membered heterocyclyl, 8-10-membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, 8-10 membered heteroaryl, 5-or 6-membered heterocyclyl, 8-10 membered heterocyclyl, each of said heteroaryl, heterocyclyl independently containing 1-4 heteroatoms selected from N, O or S, each of said 5-membered heteroaryl, 8-10-membered heteroaryl, 5-or 6-membered heterocyclyl, 8-10-membered heterocyclyl independently being substituted with one or more R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl-5-or 6-membered heteroaryl, 5-or 6-membered heterocyclyl-5-or 6-membered heterocyclyl, each of which independently contains 1-2 heteroatoms selected from N, O or S, and each of which is independently substituted with 1, 2,3 or 4R _d;

Preferably, R _2b is selected from the group consisting of 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 6-membered heterocyclyl-pyridonyl, each of said heteroaryl, heterocyclyl independently containing 1-2 heteroatoms selected from N, O or S, said 5-membered heteroaryl, phenyl-6-membered heteroaryl, 6-membered heteroaryl-5-membered heteroaryl, 6-membered heterocyclyl-pyridonyl each independently being substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenyl-pyridopyridyl, pyridopyrrolyl, morpholino-pyridonyl, pyridonyl; the pyrazolyl, thiazolyl, thienyl, isothiazolyl, phenyl-pyridopyridyl, pyridopyrrolyl, morpholino-pyridonyl, pyridonyl are each independently substituted with 1, 2,3, or 4R _d;

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 hydroxy;

Or 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, wherein 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, wherein 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, wherein one and only 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 hydroxy, wherein only and only one R _d is hydroxy;

Preferably, each R _d is independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano, or hydroxy, wherein one and only one R _d is hydroxy;

Preferably, each R _d is independently selected from methyl, ethyl, propyl, F, cl, br, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, or hydroxy, wherein one and only one R _d is hydroxy;

preferably, each R _d is independently selected from methyl, cl, br, cyclopropyl or hydroxy, wherein one and only one R _d is hydroxy;

Preferably, each R _d is independently selected from methyl, cl, br, cyclopropyl or hydroxy, wherein one and only one R _d is hydroxy and the hydroxy is substituted ortho to the point of attachment of R _2b to the main group;

Preferably, R _2b is selected from Each independently may be further substituted with 1, 2, or 3R _d;

Most preferably, R _2b is selected from

Or preferably, R _2b is selected from 5-membered heteroaryl, each independently substituted with 1,2,3 or 4R _d;

Further preferred, R _2b is selected from pyrazolyl, thiazolyl, thienyl, isothiazolyl, each independently substituted with 1,2, 3 or 4R _d;

Further preferably, R _2b is selected from May be further substituted with 1, 2 or 3R _d;

Further preferably, R _2b is selected from May be further substituted with 1, 2 or 3R _d;

Or preferably, R _2b is selected from:

Further preferably, R _2b is selected from:

Preferably, R _2b is selected from the group consisting of a 6 membered heterocyclyl, a 6 membered heterocyclyl and a 6 membered heterocyclyl, said heterocyclyl containing 1-2 heteroatoms selected from N, O or S, said 6 membered heterocyclyl, 6 membered heterocyclyl and 6 membered heterocyclyl each independently being substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from morpholino-pyridonyl, each independently substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from the group consisting of pyridonyl, said pyridonyl being substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from 2-pyridonyl, said 2-pyridonyl being substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from May be further substituted with 1, 2 or 3R _d;

Preferably, R _2b is selected from May be further substituted with 1, 2 or 3R _d;

Preferably, R _2b is selected from

Or preferably, R _2b is selected from

Or preferably, R _2b is selected from phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl, said heteroaryl containing 1-2 heteroatoms selected from N, O or S, said phenyl-5-or 6-membered heteroaryl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl each independently substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from the group consisting of phenyl-6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl, said heteroaryl containing 1-2 heteroatoms selected from N, O or S, said phenyl-6-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl each independently substituted with 1,2, 3 or 4R _d;

Preferably, R _2b is selected from the group consisting of phenyl-and pyrido-pyridinyl, each independently substituted with 1,2, 3, or 4R _d;

Preferably, R _2b is selected from May be further substituted with 1, 2 or 3R _d;

Preferably, R _2b is selected from
The compound of any one of claims 1-7, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

R ₁ is selected from halogen, C _1-6 alkyl, 5-or 6-membered cycloalkenyl, 5-to 10-membered heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each of which independently contains 1-2 heteroatoms selected from N, O or S, each of which is independently unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from the group consisting of 5-or 6-membered cycloalkenyl, 5-10-membered heterocyclyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from the group consisting of 5-or 6-membered cycloalkenyl, 5-to 10-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl, 5-or 6-membered heteroaryl, phenyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently being unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from the group consisting of 6 membered cycloalkenyl, 6-9 membered heterocycloalkyl, 6 membered heterocycloalkenyl, pyridinyl, pyrimidinyl, pyridazinyl, each independently containing 1-2 heteroatoms selected from N, O or S, each independently unsubstituted or substituted with 1 or more R _g;

Preferably, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-4 alkyl, C _1-4 alkoxy, = O, R 'R "N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy, wherein R', R" are each independently selected from the group consisting of H, C _1-4 alkyl, C _1- ₄ haloalkyl;

Preferably, each R _g is independently selected from the group consisting of hydroxy, halogen, C _1-2 alkyl, C _3-4 alkyl, C _1-2 alkoxy, C _3-4 alkoxy, = O, R 'R' N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halogen, hydroxy, C _1-2 alkoxy, wherein R ', R' are each independently selected from the group consisting of 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 the group consisting of hydroxy, F, cl, C _1-2 alkyl, C _1-2 alkoxy, = O, R 'R' N-, each of which is independently unsubstituted or substituted with 1 or more substituents selected from the group consisting of halogen, hydroxy, C _1-2 alkoxy, wherein R ', R' are each independently selected from the group consisting of 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-, wherein each R', R" is independently selected from H, methyl, substituted with 1 or more substituents selected from F, cl, hydroxy, methoxy;

Preferably, R ₁ is selected from

Preferably, R ₁ is selected from

Most preferably, R ₁ is selected from
The compound of any one of claims 1-7, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

R ₁ is selected from halogen, C _1-6 alkyl, 5-or 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, said alkyl, heterocyclyl being unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from 5-or 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, said heterocyclyl being unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from the group consisting of 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S, said heterocycloalkyl, heterocycloalkenyl being unsubstituted or substituted with 1 or more R _g;

Preferably, R ₁ is selected from 5-or 6-membered heterocycloalkenyl containing 1-2 heteroatoms selected from N or O, said heterocycloalkenyl being unsubstituted or substituted with 1 or more R _g;

or preferably, R ₁ is selected from Unsubstituted or substituted with 1 or more R _g;

Preferably, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-4 alkyl, C _1-4 alkoxy, said C _1-4 alkyl, C _1-4 alkoxy being unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy;

Preferably, each R _g is independently selected from the group consisting of hydroxy, halo, C _1-2 alkyl, C _3-4 alkyl, C _1-2 alkoxy, C _3-4 alkoxy, said alkyl, alkoxy being unsubstituted or substituted with 1 or more substituents selected from the group consisting of halo, hydroxy, C _1-2 alkoxy;

Preferably, each R _g is independently selected from the group consisting of hydroxy, F, cl, C _1-2 alkyl, C _1-2 alkoxy, said alkyl, alkoxy being unsubstituted or substituted with 1 or more substituents selected from the group consisting of halogen, hydroxy, C _1-2 alkoxy;

Preferably, each R _g is independently selected from hydroxy, F, methyl, ethyl, which is unsubstituted or substituted with 1 or more substituents selected from halogen, hydroxy, methoxy;

Preferably, R ₁ is selected from

Preferably, R ₁ is selected from

Preferably, R ₁ is selected from
The compound of any one of claims 1-9, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

R ₃ is selected from C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1,2 or 3 substituents selected from hydroxy or halogen;

Preferably, R ₃ is selected from C _1-4 alkyl, said alkyl being unsubstituted;

Preferably, R ₃ is selected from C _1-2 alkyl, said alkyl being unsubstituted;

Preferably, R ₃ is selected from methyl or ethyl;

Preferably, R ₃ is selected from ethyl.
The compound of any one of claims 1-10, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein:

R ₄ is selected from H, halogen, C _1-4 alkyl, said alkyl being unsubstituted or substituted with 1,2 or 3 halogens;

Preferably, R ₄ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₄ is selected from H, F, cl, br, C _1-4 alkyl, said C _1-4 alkyl being unsubstituted;

Preferably, R ₄ is selected from H, F, cl, br, C _1-2 alkyl, said C _1-2 alkyl being unsubstituted or substituted by 1,2 or 3F;

Preferably, R ₄ is selected from H, F, cl, br, methyl, ethyl, each independently unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₄ is selected from H, F, cl, br, methyl, -CF ₃;

Preferably, R ₄ is selected from Cl, methyl, -CF ₃;

Preferably, R ₄ is selected from H, F, cl, br, methyl, ethyl, which are unsubstituted;

Preferably, R ₄ is selected from H, F, cl, br or methyl;

Preferably, R ₄ is selected from Cl or methyl;

Or alternatively

R ₅ is selected from H, methyl, halogen;

Preferably, R ₅ is selected from H, F, cl or methyl;

Preferably, R ₅ is selected from H, cl or methyl;

Preferably, R ₅ is selected from H;

Or alternatively

R ₆ is selected from H, halogen, C _1-4 alkyl, said alkyl being unsubstituted or substituted with 1,2 or 3 halogens;

Preferably, R ₆ is selected from H, halogen, C _1-4 alkyl, which alkyl is unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₆ is selected from H, halogen, C _1-2 alkyl, which alkyl is unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₆ is selected from H, F, cl, methyl, ethyl, which is unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₆ is selected from H, F, cl, methyl or-CF ₃;

Preferably, R ₆ is selected from H, F or Cl;

Or preferably, R ₆ is selected from H, halogen, C _1-4 alkyl, said alkyl being substituted with 1,2 or 3F;

Preferably, R ₆ is selected from H, halogen, C _1-2 alkyl, said alkyl being substituted with 1,2 or 3F;

Preferably, R ₆ is selected from H, F, cl, methyl, ethyl substituted with 1,2 or 3F;

preferably, R ₆ is selected from H, F, cl or-CF ₃;

Preferably, R ₆ is selected from H, F or Cl;

Or alternatively

R ₇ is selected from H, -SF ₅, -C (O) H, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, said alkyl, cycloalkyl being unsubstituted or substituted with 1 or more halogen;

Preferably, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-4 alkyl, said alkyl being unsubstituted or substituted with 1,2 or 3 halogens;

Preferably, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-4 alkyl, said alkyl being unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, halogen, C _1-2 alkyl, said alkyl being unsubstituted or substituted with 1,2 or 3F;

Preferably, R ₇ is selected from the group consisting of-SF ₅, -C (O) H, F, cl, br, methyl, ethyl, which is unsubstituted or substituted with 1,2, or 3F;

Preferably, R ₇ is selected from-CF ₃、-CHF₂、-CH₂CH₃、Cl、Br、-SF₅ or-C (O) H;

Preferably, R ₇ is selected from-CF ₃;

Preferably, R ₇ is selected from-OCF ₃;

Or alternatively

X is selected from N or CR ₈,R₈ is selected from H, F, cl or Br;

Preferably, R ₈ is selected from H or F;

preferably, the functional groups Selected from the group consisting of

Preferably, the functional groupsSelected from the group consisting of

Preferably, the functional groupsSelected from the group consisting of

Preferably, the functional groupsSelected from the group consisting of

Preferably, the functional groupsSelected from the group consisting of
The compound of any one of claims 1-11, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein formula (I) has a general structure selected from formula (IB):

wherein each R ₁、R_2b、R₃、R₄ is defined as described in formula (I);

Preferably, formula (I) has a structure represented by formula (IB-1):

wherein R ₁、R_2b、R₄ is as defined in formula (I).
The compound of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein formula (I) has a structure selected from the group consisting of formula (IIA), formula (IIB):

Wherein R ₁、R_2b、R₄、R₅、R₆、R₇ is as defined in formula (I);

Further, the formula (IIA) has a structure shown in formula (IIA-1), formula (IIA-2) or formula (IIA-3):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I);

Further, the formula (IIA-1) has a structure shown in the formula (IIA-1-1):

wherein R ₁、R_d is as defined in formula (I);

wherein R ₁、R₄、R₅、R₆、R₇ is as defined in formula (I);

further, the formula (IIA-2) has a structure shown in the formula (IIA-2-1):

wherein R ₁ is as defined in formula (I);

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I);

further, the formula (IIA-3) has a structure shown in the formula (IIA-3-1):

wherein R ₁、R_d is as defined in formula (I);

Wherein R ₁、R_2b、R₄、R₅、R₆、R₇ is as defined in formula (I);

further, the formula (IIB) has a structure shown in the formula (IIB-1), the formula (IIB-2) or the formula (IIB-3):

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I);

Further, the formula (IIB-1) has a structure shown in the formula (IIB-1-1):

wherein R ₁、R_d is as defined in formula (I);

wherein R ₁、R₄、R₅、R₆、R₇ is as defined in formula (I);

further, the formula (IIB-2) has a structure shown in the formula (IIB-2-1):

wherein R ₁ is as defined in formula (I);

Wherein R ₁、R_d、R₄、R₅、R₆、R₇ is as defined in formula (I);

Further, the formula (IIB-3) has a structure shown in the formula (IIB-3-1):

Wherein R ₁、R_d is as defined in formula (I).
The compound of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein formula (I) has a structure selected from formula (IIA-4) or formula (IIB-4):

Wherein ring B is a 5-membered heteroaryl group, said 5-membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, said 5-membered heteroaryl group being unsubstituted or substituted with 1 or more C _1-4 alkyl groups;

preferably, ring B is a 5-membered heteroaryl group, said 5-membered heteroaryl group containing 1 heteroatom selected from N, O and S, said 5-membered heteroaryl group being unsubstituted or substituted with 1 or more C _1-4 alkyl groups;

Preferably, ring B is selected from furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, wherein each of the furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl is independently unsubstituted or substituted with 1 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, each of which is independently unsubstituted or substituted with 1 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, each of which is independently unsubstituted or substituted with 1 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, wherein the pyrrolyl is unsubstituted or substituted with 1 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, which is unsubstituted or substituted with 1 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, wherein the pyrrolyl is unsubstituted or substituted with 1 methyl group;

Preferably, ring B is selected from furyl, pyrrolyl, which is unsubstituted or substituted with 1 methyl group.
The compound of claim 1, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, wherein formula (I) is selected from the group consisting of:
A pharmaceutical composition for the treatment and/or prophylaxis of diseases which are associated with the biological activity of WRN, characterized in that the pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 15, or stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts thereof, and optionally pharmaceutical excipients;

preferably, the disease associated with biological activity of WRN is a tumor or cancer;

preferably, the disease associated with WRN biological activity is MSI tumor or MSI cancer;

Preferably, a pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient.
Use of a compound according to any one of claims 1-15, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with WRN biological activity, and/or for the treatment and/or prophylaxis of a disease associated with WRN biological activity;

preferably, the disease associated with biological activity of WRN is a tumor or cancer;

Preferably, the disease associated with biological activity of WRN is MSI tumor or MSI cancer.
A method of treating and/or preventing a disease associated with biological activity of WRN comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1-15, or a stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16;

preferably, the disease associated with biological activity of WRN is a tumor or cancer;

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

Preferably, the disease associated with biological activity of WRN is a tumor or cancer;

Preferably, the disease associated with biological activity of WRN is MSI tumor or MSI cancer.