Azabicyclo derivative as well as preparation method and application thereof

Abstract

The invention relates to an azabicyclo derivative, a preparation method of the azabicyclo derivative and application of a pharmaceutical composition containing the azabicyclo derivative in medicine. Specifically, the invention relates to an azabicyclo derivative as shown in a general formula (I), a preparation method and a medicinal salt thereof, and application of the azabicyclo derivative as a therapeutic agent, especially as a WRN inhibitor, and definition of each substituent in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an azabicyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a WRN inhibitor. Background Art

[0002] Human WRN is composed of 1432 amino acid residues, and contains five important components from the N-terminus to the C-terminus—the exonuclease domain, the ATPase domain, the RecQ carbon-terminal domain, the helicase / ribonuclease D carbon-terminal domain, and the nuclear localization signal. Among the five RecQ helicases in the human body, WRN is the only one with 3'→5' exonuclease activity, which is achieved by the specific activation of its N-terminal exonuclease domain by the Ku70 / 80 complex bound to the DNA end. The ATPase domain is the largest and most conserved component of the RecQ helicase family, acting as an ATP-dependent DNA translocation module by binding and hydrolyzing ATP. The RecQ carbon-terminal domain is the main site for binding to DNA and catalyzes the unwinding of the DNA double helix. Therefore, the ATPase domain and the RecQ carbon-terminal domain together constitute the core of the WRN helicase. WRN is a DNA helicase with multiple enzymatic activities that can bind to both DNA and other proteins. This enables the enzyme to play an important role in maintaining genome integrity and stability, including participating in DNA damage repair, replication and transcription, and maintaining the stability of telomeres and heterochromatin.

[0003] Synthetic lethality refers to the phenomenon that two non-lethal genes are simultaneously inhibited (the forms of inhibition include gene mutation, gene silencing and other genetic defects and / or gene expression knockout, drug inhibition and other molecular perturbations) leading to cell death. By using this mechanism to find a specific mutation in cancer, and then find its "synthetic lethal partner" and inhibit it, cancer cells with this mutation can be specifically killed.

[0004] Studies have shown that WRN is a "synthetic lethal partner" of genomic damage called high microsatellite instability (MSI-H). High microsatellite instability (MSI-H) is a hypervariable state caused by defects in DNA mismatch repair (MMR) that lead to frequent insertion and / or deletion mutations in nucleotide repeat regions. It is common in cancers such as endometrial cancer (31%), colorectal cancer (25%), and gastric cancer (19%). In MSI-H cancer cells, thymine / adenine dinucleotide (TA) repeat sequences are highly unstable and undergo large-scale amplification to form non-classical right-handed double helix (non-B) DNA secondary structures (such as cruciform and G-quadruplex), which require WRN-specific unwinding to complete replication. In the absence of WRN, these DNA secondary structures are cleaved by the MUS81-EME1-SLX4 endonuclease complex, leading to extensive DNA end resection, depletion of replication protein A (RPA), chromosome fragmentation, and cell death. In addition, in tumor models with MMR defects, the loss of WRN leads to the activation of multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, thereby inhibiting the proliferation of tumor cells. Recent studies have shown that WRN small molecule inhibitors can specifically cause tumor regression in MSI-H tumor models, but have no effect in microsatellite stable (MSS) tumor models. Therefore, small molecule chemical drugs that can inhibit WRN helicase activity are expected to become a new method for effectively treating MSI-H cancers.

[0005] There are no new drugs targeting WRN targets on the market, nor is there any information on clinical compounds. As a relatively cutting-edge research direction, there is still a huge room for exploration in the research of WRN targets, and it is necessary to continue to develop new inhibitors. Summary of the invention

[0006] In view of the above technical problems, the present invention provides an azabicyclic derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0007]

[0008] in:

[0009] W is selected from N or CH;

[0010] X is selected from O or S;

[0011] Y is selected from CH2, O or S;

[0012] Z is selected from NH, CH2 or CD2;

[0013] L is selected from -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0014] Select from single or double bonds as required so that each atom thereof assumes a normal valence state;

[0015] Q is selected from C, N or CR d ;

[0016] R d is selected from a hydrogen atom, a hydroxyl group, a cyano group, a halogen group or a methoxy group;

[0017] Select from single or double bonds as required so that each atom thereof assumes a normal valence state;

[0018] The conditions are:

[0019] when When it is a single bond, K is selected from -(CH2) p - or -NH-, J is N; p is selected from 0, 1 or 2;

[0020] when When it is a double bond, K is CH and J is C;

[0021] R a , R b are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 1-6 Alkoxy; or, R a , R b Together with the carbon atom to which they are attached, they form a C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, carbonyl or -NR 6 R 7 substituted by a substituent;

[0022] R c are the same or different, each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, carbonyl or -NR 6 R 7 substituted by a substituent;

[0023] Or, two R c Together with the same carbon atom to which it is attached, it forms a -C(=O)-;

[0024] Or, two R c Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more N, O or S (=O) r ;

[0025] Or, two R c Together with the different carbon atoms to which they are attached, they form a C 4-6 Cycloalkyl or 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S (=O) r ;

[0026] R 1 Selected from alkyl, alkenyl, alkynyl, -NR 15 R 16 , alkoxy or alkylthio, wherein the alkyl, alkoxy or alkylthio group is optionally further substituted with one or more selected from R A The alkenyl or alkynyl is substituted by at least one or more substituents selected from aryl, heteroaryl, cycloalkyl, heterocyclic or condensed ring; provided that the heterocyclic group is not morpholinyl;

[0027] R 15 , R 16 are each independently selected from a hydrogen atom, a deuterium atom or a C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxyl or cyano;

[0028] Ring A is selected from:

[0029] 4) C 3-8 Saturated monocyclic alkyl, C 7-8 Partially unsaturated monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cyclic alkyl, wherein the spirocyclic alkyl, fused cyclic alkyl or bridged cyclic alkyl contains 0 or 1 double bond;

[0030] 5) 4-membered monocyclic heterocyclic group, 7-8-membered monocyclic heterocyclic group, spiro heterocyclic group, wherein the monocyclic heterocyclic group or spiro heterocyclic group contains 0 or 1 double bond, provided that any ring constituting the spiro heterocyclic group is not cyclopropane, wherein the monocyclic heterocyclic group can be further connected by two atoms not directly connected to the ring through C 1-2Alkylene groups are connected to form a bridged heterocyclic group (i.e., the whole group is a bridged heterocyclic group);

[0031] 6) Bicyclic aryl, bicyclic heteroaryl;

[0032] Select from single or double bonds as required so that each atom thereof assumes a normal valence state;

[0033] The conditions are: When selected from a double bond, U is CH, and ring B is selected from a cycloalkyl group, a heterocyclic group or a condensed cyclic group;

[0034] When selected from a single bond, U is selected from -O-, -N(R e )- or -S-, Ring B is selected from cycloalkyl, heterocyclic, aryl, heteroaryl or fused cyclic groups;

[0035] R e Selected from hydrogen atoms or C 1-6 alkyl;

[0036] R A are the same or different and are each independently selected from a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -SF5, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-N(R 6 )C(=O)R 7 、-N(R 6 )C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R10 、-S(=O)2NR 9 R 10 、-N(R 9 )C(=O)R 10 or -N(R 9 )C(=O)OR 10 substituted by a substituent;

[0037] Or, two R A Together with the same carbon atom to which it is attached, it forms a -C(=O)- or -C(=S)-;

[0038] R 2 is selected from hydrogen atom, deuterium atom, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, -OR 5 、-S(=O) r R 5 or -NR 6 R 7 ;

[0039] R 3 Selected from hydrogen atoms, C 1-6 Alkyl, amino, hydroxylamino, aryl, heteroaryl, The C 1-6 The alkyl, aryl or heteroaryl groups are optionally further substituted with one or more R B replaced by;

[0040] R B are the same or different and are each independently selected from a deuterium atom, an alkyl group, a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -SF5, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-N(R 6 )C(=O)R 7 、-N(R 6 )C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5wherein the alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 、-N(R 9 )C(=O)R 10 or -N(R 9 )C(=O)OR 10 substituted by a substituent;

[0041] R 13 , R 14 are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 1-6 Alkoxy, or, R 13 , R 14 Together with the carbon atom to which they are attached, they form a C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy or cyano;

[0042] R 4 The condensed ring is selected from aryl, heteroaryl or bicyclic fused ring, wherein the bicyclic fused ring is preferably a condensed ring composed of a monocyclic aryl or a monocyclic heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl, wherein the aryl, heteroaryl or bicyclic fused ring is optionally further substituted by one or more halogen, hydroxyl, cyano, -SF5, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkenyl, C 1-6 Alkynyl, -NR 6 R 7 、-C(=O)R 5 or -S(=O) r R 5 substituted by a substituent;

[0043] R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent;

[0044] R 6 and R 7 Each is independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group may be further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent;

[0045] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a complex containing one or more N, O, or S(=O) r wherein the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent;

[0046] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amine group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group may be further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amine group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0047] n is 0, 1, 2, 3 or 4;

[0048] m is 0, 1, 2, 3, 4 or 5; and

[0049] r is independently 0, 1 or 2.

[0050] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein W is a nitrogen atom;

[0051] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X and Y are O atoms;

[0052] A preferred embodiment of the present invention is a compound of the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Z is NH and L is -C(=O)-.

[0053] A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein is a single bond; Q is selected from N;

[0054] is a single bond, K is CH2, and J is N;

[0055] R c A hydrogen atom.

[0056] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R a , R b A hydrogen atom.

[0057] A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0058]

[0059] Where: R 1 , R 2 , R 3 and R 4 The definition of is as described in the general formula (I).

[0060] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from C 1-6 Alkyl, -NR 15 R 16 or C 1-6 alkenyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens, wherein the alkenyl group is substituted with at least one substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl or fused ring; provided that the heterocyclyl group is not morpholinyl;

[0061] R 15 selected from hydrogen atoms;

[0062] R 16 Selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens.

[0063] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from Wherein ring A is selected from C 3-8 Saturated monocyclic alkyl, C 7-8 Partially unsaturated monocyclic alkyl, spirocyclic alkyl, condensed cyclic alkyl, bridged cyclic alkyl, 4-membered monocyclic heterocyclic radical, 7-8-membered monocyclic heterocyclic radical, spiro heterocyclic radical or bicyclic heteroaryl, wherein the spirocyclic alkyl, condensed cyclic alkyl, bridged cyclic alkyl, 4-membered monocyclic heterocyclic radical, 7-8-membered monocyclic heterocyclic radical or spiro heterocyclic radical contains 0 or 1 double bond, provided that any one of the rings constituting the spiro heterocyclic radical is not cyclopropane;

[0064] R A Selected from hydrogen atoms, or two R A Together with the same carbon atom to which they are attached, they form a C(=O).

[0065] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from in is selected from a double bond, U is CH, and ring B is selected from a cycloalkyl or heterocyclyl group;

[0066] R A Selected from hydrogen atoms.

[0067] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from in is selected from a single bond, U is selected from O, and ring B is selected from aryl or heteroaryl;

[0068] R A Selected from hydrogen atoms.

[0069] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from the following groups:

[0070]

[0071]

[0072] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, deuterium atoms, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 The haloalkyl group is preferably a methyl group or an ethyl group.

[0073] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 The 5- or 6-membered heteroaryl or phenyl group is optionally further substituted by one or more substituents selected from deuterium atoms, hydroxyl groups, halogen groups, alkyl groups, alkylthio groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, and haloalkoxy groups.

[0074] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 Selected from the following groups:

[0075] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 is selected from phenyl, wherein the phenyl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkenyl, C 1-6 Alkynyl, -NR 6 R 7 、-C(=O)R 5 or -S(=O) r R 5 substituted by a substituent;

[0076] R 5 , R 6 , R 7 are independently selected from a hydrogen atom or C 1-6 alkyl;

[0077] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a complex containing one or more N, O, or S(=O) r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 is substituted by an alkoxy, amino or =O substituent;

[0078] r is 0, 1 or 2.

[0079] A preferred embodiment of the present invention is a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 Selected from the following groups:

[0080]

[0081] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0098] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0099] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0100] The present invention provides a use of a compound described in general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preparing a WRN inhibitor.

[0101] The present invention also provides a use of a compound of general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by WRN, wherein the disease mediated by WRN is preferably high microsatellite instability (MSI-H) cancer; wherein the disease mediated by WRN is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenal cortical carcinoma, uterine sarcoma, cervical cancer, Wilms tumor, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0102] The present invention further provides a use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating high microsatellite instability (MSI-H) cancer.

[0103] The present invention provides a compound described in general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing drugs for colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenal cortical carcinoma, uterine sarcoma, cervical cancer, Wilms' tumor, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

[0104] Detailed description of the invention

[0105] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0106] "Alkyl" as a group or a part of a group refers to a group consisting of C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0107] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Preferably C2-C4 alkenyl. Alkenyl can be optionally substituted or unsubstituted.

[0108] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. 10 The alkynyl group of any of the preceding claims may be substituted or unsubstituted.

[0109] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring is a carbon atom, including monocyclic, polycyclic, fused, bridged and spirocyclic rings, preferably having a 3- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring.

[0110] Examples of "monocyclic cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl,

[0111] The monocyclic cycloalkyl groups can be substituted or unsubstituted.

[0112] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the single rings, containing 0, 1 or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 4 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, The spirocycloalkyl group can be substituted or unsubstituted.

[0113] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms. One or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrenyl, The fused cycloalkyl group may be substituted or unsubstituted.

[0114] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-14 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl, The bridged cycloalkyl group may be substituted or unsubstituted.

[0115] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a non-aromatic heterocyclic group in which one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0116] The heterocyclic group may be substituted or unsubstituted.

[0117] Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,

[0118] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, containing 0, 1 or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group. More preferably, it is 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0119] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

[0120] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain 0, 1 or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0121] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, the aromatic group is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[0122] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridinyl, pyridin- 2(1H)-onyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyrimidin-2(1H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolyl, quinazolinyl, 2H-isoindolyl, furano[3,2-b]pyridinyl, furano[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0123] A heteroaryl group can be substituted or unsubstituted.

[0124] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated π-electron aromatic system, and at least one ring may contain 0, 1 or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, 1 or more selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl. Preferably, it includes 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include, but are not limited to:

[0125]

[0126] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0127] "Alkylthio" refers to a group of (alkyl-S-). Wherein, alkyl is as defined herein. C1-C6 alkylthio is preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, and the like.

[0128] "Nitro" refers to a -NO2 group.

[0129] "Hydroxy" refers to an -OH group.

[0130] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0131] "Amino" refers to -NH2.

[0132] "Hydroxyamino" refers to -NHOH.

[0133] "Cyano" refers to -CN.

[0134] "Benzyl" refers to -CH2-phenyl.

[0135] "Carboxy" refers to -C(=O)OH.

[0136] The "carboxylate group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein the alkyl group and the cycloalkyl group are as defined above.

[0137] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group wherein alkyl is as defined above.

[0138] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0139] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0140] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0141] "DMSO" refers to dimethyl sulfoxide.

[0142] "BOC" refers to tert-butoxycarbonyl.

[0143] "Bn" refers to benzyl.

[0144] "THP" refers to 2-tetrahydropyranyl.

[0145] "TFA" refers to trifluoroacetic acid.

[0146] "Ts" refers to p-toluenesulfonyl.

[0147] "Bn" refers to benzyl.

[0148] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0149] "Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

[0150] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0151] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, OR 5 、-C(=O)R 5 、-C(=O)OR 5 、-NHC(=O)R 5 、-NHC(=O)OR 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-CH2NHC(=O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 substituted by a substituent;

[0152] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0153] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0154] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10、-SO2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0155] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0156] r is independently 0, 1 or 2.

[0157] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0158] Unless otherwise indicated, structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.

[0159] "Pharmaceutically acceptable salts" refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0160] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0161] Synthesis method of the compound of the present invention

[0162] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:

[0163] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0164] Method 1:

[0165]

[0166] The compound of general formula (Ia) undergoes an SN2 nucleophilic substitution reaction with the compound of general formula (Ib-1) in the presence of a base, or undergoes a coupling reaction with the compound of general formula (Ib-2) in the presence of a catalyst to obtain a compound of general formula (Ic), the compound of general formula (Ic) is further subjected to a deprotection reaction to obtain a compound of general formula (Id), the compound of general formula (Id) is subjected to a condensation reaction with the compound of general formula (Ie), and optionally further subjected to a deprotection reaction to obtain a compound of general formula (I);

[0167] in:

[0168] is a single bond, J is N;

[0169] PG is an amino protecting group, preferably tert-butyloxycarbonyl;

[0170] Y1 is selected from boric acid or boric acid ester;

[0171] L is selected from -(C=O)-;

[0172] X1 is selected from hydroxyl or halogen

[0173] W, K, X, Y, Z, Q, R 1 -R 4 , R a , R b , R c and n are as defined in claim 1.

[0174] Method 2:

[0175]

[0176]

[0177] The compound of the general formula (Ia) is subjected to a deprotection reaction to obtain a compound of the general formula (If), the compound of the general formula (If) is subjected to a condensation reaction with a compound of the general formula (Ie) to obtain a compound of the general formula (Ig), the compound of the general formula (Ig) is subjected to an SN2 nucleophilic substitution reaction with a compound of the general formula (Ib-1) in the presence of a base, or is subjected to a coupling reaction with a compound of the general formula (Ib-2) in the presence of a catalyst, and optionally further subjected to a deprotection reaction to obtain a compound of the general formula (I);

[0178] in:

[0179] is a single bond, J is N;

[0180] PG is an amino protecting group, preferably tert-butyloxycarbonyl;

[0181] Y1 is selected from boric acid or boric acid ester;

[0182] L is selected from -(C=O)-;

[0183] X1 is selected from hydroxyl or halogen

[0184] W, K, X, Y, Z, Q, R 1 -R 4 , R a , R b , R c and n are as defined in claim 1. DETAILED DESCRIPTION

[0185] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0186] Example

[0187] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0188] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0189] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0190] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0191] In the following examples, unless otherwise indicated, all temperatures are degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0192] CD3OD: deuterated methanol.

[0193] CDCl3: deuterated chloroform.

[0194] DMSO-d6: deuterated dimethyl sulfoxide.

[0195] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0196] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0197] The compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.

[0198] Example 1

[0199] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0200] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0201]

[0202] first step

[0203] 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

[0204] 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

[0205] 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 1a (2 g, 4.68 mmol, prepared according to patent publication WO2022249060 A1) and 2-bromo-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 1b (1.93 g, 6.08 mmol, prepared according to patent publication WO2022249060 A1) were added to N,N-dimethylformamide (20 mL), N,N-diisopropylethylamine (1.81 g, 14.04 mmol) was added, the temperature was raised to 50 ° C, and the reaction was carried out for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) 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 1c (2.9 g) in a yield of 93.47%.

[0206] MS m / z(ESI):563.7[M-100+1]

[0207] Step 2

[0208] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0209] 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 1c (70 mg, 105.60 μmol), 1,4-oxaazepane 1d (53.40 mg, 527.99 μmol, commercially available) and N,N-diisopropylethylamine (68.24 mg, 527.99 μmol) were added to a microwave tube, the temperature was raised to 100 °C, and the reaction was allowed to proceed overnight. The reaction solution was extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1,4-oxaazepine-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 1e (60 mg), yield: 83.18%.

[0210] MS m / z(ESI):626.8[M-56+1]

[0211] Step 3

[0212] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0213] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0214] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 1e (60 mg, 87.83 μmol) was added to dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was carried out at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 1f (50 mg) with a yield of 97.64%.

[0215] MS m / z(ESI):583.2[M+1]

[0216] Step 4

[0217] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(1,4-oxazepan-4-yl )-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0218] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0219] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-6-(piperazine-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-yl)acetamide 1f (50 mg, 85.76 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (27.23 mg, 111.49 μmol), according to the published patent WO2022249060 A1 preparation), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.66 mg, 128.64 μmol), 1-hydroxybenzotriazole (17.38 mg, 128.64 μmol) and N,N-diisopropylethylamine (55.42 mg, 428.81 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 1h (50 mg), yield: 72.04%.

[0220] MS m / z(ESI):790.3[M+1]

[0221] Step 5

[0222] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0223] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0224] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-5-ethyl-2-(1,4-oxazepan-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 1h (50 mg, 61.79 μmol) was added to dichloromethane (2 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. Methanol (1 mL) was added to the reaction solution to quench the reaction, and the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(1,4-oxaazepine-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 1 (2.67 mg) with a yield of 4.95%.

[0225] MS m / z(ESI):718.8[M+1]

[0226] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.25(s,1H),8.58(s,1H),8.05–7.91( m,2H),7.73(d,J=8.7Hz,1H),5.21(s,2H),4.51(d,J=12.5Hz,1H),3.65(td,J =14.7,5.5Hz,11H),3.22(d,J=13.1Hz,1H),3.02–2.84(m,3H),2.78(d,J=11. 4Hz,1H),2.59(s,1H),2.44(s,3H),1.84(t,J=5.9Hz,2H),1.26–1.01(m,4H).

[0227] Example 2

[0228] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopentyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0229] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopentyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0230]

[0231] first step

[0232] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0233] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0234] At room temperature, 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 1c (150 mg, 226.28 μmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborane 2a (52.70 mg, 271.54 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (18.34 mg, 22.63 μmol), sodium carbonate (71.95 mg, 678.85 μmol), and 1,4-dioxane (1 mL) were added to a 100 mL two-necked bottle, the argon gas was replaced four times, and the temperature was raised to 80 °C for reaction for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 2b (110 mg), yield: 74.78%.

[0235] MS m / z(ESI):650.3[M-56+1]

[0236] Step 2

[0237] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0238] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0239] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclopent-1-en-1-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 2b (110 mg, 169.21 μmol) was added to dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 2c (90 mg) with a yield of 96.71%.

[0240] MS m / z(ESI):559.8[M+1]

[0241] Step 3

[0242] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclopent-1-en-1-yl)-5-eth yl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0243] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0244] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 2c (90 mg, 163.64 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (51.96 mg, 21 2.74μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.06mg, 245.47μmol), 1-hydroxybenzotriazole (33.17mg, 245.47μmol), N,N-diisopropylethylamine (105.75mg, 818.22μmol) were added to N,N-dimethylformamide (2mL) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 ml×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 2d (80 mg), yield: 62.98%.

[0245] MS m / z(ESI):775.8[M+1]

[0246] Step 4

[0247] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopentyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0248] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopentyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0249] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclopent-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 2d (50 mg, 64.42 μmol) was added to methanol (1 mL), and 10% palladium on carbon (7.82 mg) was added, and the reaction was carried out at room temperature overnight. The reaction solution was filtered, concentrated under reduced pressure, and purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mmI.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopentyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 2 (7.12 mg), yield: 4.68%.

[0250] MS m / z(ESI):688.3[M+1]

[0251] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.23(s,1H),8.58(s,1H),8.03(d,J=8.6Hz,1H),7. 97(d,J=2.1Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),5.29(s,2H),4.52(d,J=12.5Hz,1H),3.49( d,J=11.3Hz,3H),3.28–3.11(m,2H),2.97(d,J=10.3Hz,3H),2.80(d,J=11.3Hz,1H),2.62( d,J=10.7Hz,1H),2.44(s,3H),2.02–1.90(m,2H),1.86–1.58(m,6H),1.17(t,J=7.4Hz,3H).

[0252] Example 3

[0253] 2-(2-(azepan-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0254]

[0255]

[0256] first step

[0257] 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0258] 2-(2-Bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0259] 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 1c (1 g, 1.51 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 2-(2-bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3a (840 mg), with a yield of 98.94%.

[0260] MS m / z(ESI):561.7[M+1]

[0261] Step 2

[0262] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0263] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0264] 2-(2-Bromo-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3a (840 mg, 1.49 mmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (473.93 mg, 1.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (429.20 mg, 2.24 mmol), 1-hydroxybenzotriazole (302.52 mg, 2.24 mmol) and N,N-diisopropylethylamine (964.53 mg, 7.46 mmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (700 mg), yield: 59.44%.

[0265] MS m / z(ESI):788.6[M+1]

[0266] Step 3

[0267] 2-(2-(azepan-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0268] 2-(2-(azepan-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0269] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), azepane 3c (62.85 mg, 633.71 μmol) and N,N-dimethylformamide (1 mL) were added to a microwave tube, heated to 80°C and reacted for 1 hour. The reaction solution was extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(2-(azepan-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3d (40 mg), yield: 78.19%.

[0270] MS m / z(ESI):806.8[M+1]

[0271] Step 4

[0272] 2-(2-(azepan-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0273] 2-(2-(azepan-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0274] 2-(2-(Azacycloheptane-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3d (40 mg, 49.55 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. Methanol (1 mL) was added to the reaction solution to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(azepan-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3 (2.28 mg) with a yield of 6.36%.

[0275] MS m / z(ESI):716.8[M+1]

[0276] 1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),10.23(s,1H),8.58(s,1H),8.03–7.94(m,2H), 7.72(dd,J=8.9,2.1Hz,1H),5.20(s,2H),4.51(d,J=12.6Hz,1H),3.53(d,J=5.9Hz,6 H),3.23(t,J=12.5Hz,1H),3.00–2.88(m,3H),2.77(d,J=11.3Hz,1H),2.64–2.55(m, 2H), 2.44 (s, 3H), 1.67 (q, J = 5.3Hz, 4H), 1.47 (p, J = 2.6Hz, 4H), 1.16 (t, J = 7.4Hz, 3H).

[0277] Example 4

[0278] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0279] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0280]

[0281] first step

[0282] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-eth yl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0283] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0284] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (110 mg, 139.42 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl -1,3,2-Dioxaborolane 4a (37.16 mg, 167.30 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (11.30 mg, 13.94 μmol), sodium carbonate (44.33 mg, 418.25 μmol) and 1,4-dioxane (1 mL) were added into a 100 mL double-necked bottle, argon was replaced four times, and the temperature was raised to 80 °C for reaction for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 4b (100 mg), yield: 89.18%.

[0285] MS m / z(ESI):804.2[M+1]

[0286] Step 2

[0287] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0288] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0289] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 4b (50 mg, 62.17 μmol) was added to methanol (1 mL), and 10% palladium on carbon (7.55 mg) was added at room temperature, and the reaction was allowed to react at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 4 (1.25 mg) with a yield of 2.76%.

[0290] MS m / z(ESI):715.8[M+1]

[0291] 1 H NMR (400MHz, MeOD-d4) δ8.57(s,1H),8.14(d,J=8.6Hz,1H),7.81(d,J=2.0Hz,1H),7.61(dd,J=8. 9,2.1Hz,1H),5.35(s,2H),4.70(d,J=12.8Hz,1H),4.09(d,J=13.0Hz,1H),3.72(d,J=12.6Hz,2H ),3.43(t,J=12.3Hz,2H),3.06(dd,J=18.3,10.8Hz,3H),3.02–2.85(m,2H),2.77(d,J=11.7Hz,1 H),2.52(s,3H),2.13–1.98(m,2H),1.92–1.74(m,4H),1.70–1.50(m,6H),1.30(t,J=7.5Hz,3H).

[0292] Example 5

[0293] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-isopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0294] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-isopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-ylacetamide

[0295]

[0296] first step

[0297] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(prop-1-en -2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0298] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0299] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (80 mg, 101.39 μmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-Dioxaborolane 5a (20.45 mg, 121.67 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (8.22 mg, 10.14 μmol), sodium carbonate (32.24 mg, 304.18 μmol) and 1,4-dioxane (1 mL) were added into a 100 mL double-necked bottle, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C for reaction for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 5b (50 mg) in a yield of 65.74%.

[0300] MS m / z(ESI):750.6[M+1]

[0301] Step 2

[0302] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-isopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0303] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-isopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-ylacetamide

[0304] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(prop-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 5b (50 mg, 66.65 μmol) was added to methanol (1 mL), 10% palladium on carbon (8.09 mg) was added, and the reaction was allowed to react at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-isopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-ylacetamide 5 (2.6 mg) with a yield of 5.70%.

[0305] MS m / z(ESI):661.8[M+1]

[0306] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.23(s,1H),8.58(s,1H),8.03(d,J=8.6Hz,1H) ,7.97(d,J=2.1Hz,1H),7.72(dd,J=8.7,2.2Hz,1H),5.30(s,2H),4.52(d,J=12.5Hz,1H ),3.48(t,J=10.9Hz,3H),3.24(t,J=12.2Hz,1H),3.05–2.89(m,4H),2.80(d,J=11.4Hz ,1H),2.62(d,J=10.6Hz,1H),2.44(s,3H),1.26(d,J=6.9Hz,6H),1.17(d,J=7.6Hz,3H).

[0307] Example 6

[0308] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0309] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0310]

[0311] Boron trichloride (1 mL) was added to 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 4b (50 mg, 62.17 μmol) (2.5 mL) at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol (1 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 6 (3.07 mg), yield: 6.90%.

[0312] MS m / z(ESI):713.8[M+1]

[0313] 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.24(s,1H),8.58(s,1H),8.06(d,J=8.6Hz,1H),7.97(d,J=2 .1Hz,1H),7.72(dd,J=8.7,2.2Hz,1H),7.10(t,J=6.7Hz,1H),5.30(s,2H),4.52(d,J=12.5Hz,1H),3. 56–3.44(m,3H),3.24(t,J=12.6Hz,1H),3.05–2.94(m,3H),2.86–2.71(m,3H),2.63(d,J=11.2Hz,1H) ,2.44(s,3H),2.36–2.25(m,2H),1.79(p,J=5.9Hz,2H),1.52(q,J=5.6Hz,4H),1.18(t,J=7.4Hz,3H).

[0314] Example 7

[0315] 2-(2-(azetidin-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0316] 2-(2-(azetidin-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0317]

[0318] first step

[0319] 2-(2-(azetidin-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0320] 2-(2-(azetidin-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0321] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol) and aziridine 7a (36.18 mg, 633.71 μmol) were added to a microwave tube and the temperature was raised to 80°C for reaction for 1.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(2-(azetidin-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 7b (30 mg), yield: 61.87%.

[0322] MS m / z(ESI):765.3[M+1]

[0323] Step 2

[0324] 2-(2-(azetidin-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0325] 2-(2-(azetidin-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0326] 2-(2-(azetidin-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 7b (30 mg, 39.21 μmol) was added to methanol (1 mL), 10% palladium on carbon (5.71 mg) was added, the temperature was warmed to room temperature, and the reaction was allowed to react overnight. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(azetidine-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 7 (2.06 mg), yield: 7.63%.

[0327] MS m / z(ESI):675.1[M+1]

[0328] 1 H NMR (400MHz, MeOD-d4) δ8.56(s,1H),8.16(d,J=8.6Hz,1H),7.81(d,J=2.1Hz,1H),7.62(d d,J=8.8,2.1Hz,1H),5.27(s,2H),4.68(d,J=12.8Hz,1H),4.08(t,J=7.5Hz,5H),3.72(s,2 H),3.41(t,J=12.2Hz,1H),3.14(d,J=12.4Hz,1H),3.04(d,J=7.5Hz,2H),2.90(d,J=11.6 Hz,1H),2.75(d,J=11.7Hz,1H),2.52(s,3H),2.40(p,J=7.5Hz,2H),1.28(d,J=7.6Hz,3H).

[0329] Example 8

[0330] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pipera zin-1-yl)-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0331] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0332]

[0333] first step

[0334] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(7-oxa-2-azaspiro[3 .5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0335] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0336] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol) and 7-oxa-2-azaspiro[3.5]nonane 8a (80.60 mg, 633.71 μmol) were added to a microwave tube and the temperature was raised to 80 °C for 1.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 8b (40 mg), yield: 75.57%.

[0337] MS m / z(ESI):835.2[M+1]

[0338] Step 2

[0339] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pipera zin-1-yl)-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0340] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0341] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 8b (40 mg, 47.89 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was complete, methanol (1 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(7-oxa-2-azaspiro[3.5]nonane-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 8 (3.73 mg), yield: 9.96%.

[0342] MS m / z(ESI):745.1[M+1]

[0343] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.23(s,1H),8.57(s,1H),8.07(d,J=8.5Hz,1H ),7.97(d,J=2.1Hz,1H),7.72(dd,J=8.8,2.1Hz,1H),5.21(s,2H),4.51(d,J=12.4Hz, 1H),3.54–3.45(m,7H),3.23(d,J=24.7Hz,1H),3.01–2.88(m,3H),2.77(d,J=11.3Hz, 1H), 2.59 (d, J = 10.6Hz, 1H), 2.44 (s, 3H), 1.71 (t, J = 5.1Hz, 4H), 1.15 (t, J = 7.4Hz, 3H).

[0344] Example 9

[0345] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0346] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0347]

[0348] first step

[0349] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0350] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0351] At room temperature, 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 1c (700 mg, 1.06 mmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dihydro-1,2,4-triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1c (700 mg, 1.06 mmol), Oxaborolane 9a (281.48 mg, 1.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (85.60 mg, 105.60 μmol), sodium carbonate (335.77 mg, 3.17 mmol) and 1,4-dioxane (3 mL) were added into a 100 mL double-necked flask, the argon gas was replaced four times, the temperature was raised to 80 °C and the reaction was carried out for 1.5 hours, and the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 9b (650 mg) in a yield of 90.77%.

[0352] MS m / z(ESI):622.2[M+1]

[0353] Step 2

[0354] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0355] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0356] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-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 9b (40 mg, 58.98 μmol) was added to dichloromethane (1 mL), followed by trifluoroacetic acid (0.3 mL) and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9c (34 mg) with a yield of 99.72%.

[0357] MS m / z(ESI):578.2[M+1]

[0358] Step 3

[0359] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0360] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0361] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9c (34 mg, 58.82 μmol), 3-hydroxyisonicotinic acid 9d (10.64 mg, 76.47 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.91 mg, 88.23 μmol), 1-hydroxybenzotriazole (11.92 mg, 88.23 μmol) and N,N-diisopropylethylamine (38.01 mg, 294.10 μmol) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature for 4 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9 (2.93 mg) in a yield of 6.91%.

[0362] MS m / z(ESI):699.3[M+1]

[0363] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.35(s,1H),8.29(s,1H),8.21(dd,J=5.1,1.7Hz,1H),8.05(d,J= 8.5Hz,1H),7.97(d,J=2.1Hz,1H),7.72(dd,J=8.8,2.2Hz,1H),7.41(d,J=4.8Hz,1H),7.10(t,J=6.8Hz,1H ),5.30(s,2H),4.51(s,1H),3.46(q,J=10.5Hz,2H),3.34–3.20(m,2H),3.01–2.88(m,3H),2.83–2.68(m, 3H), 2.63 (d, J = 11.2Hz, 1H), 2.31 (t, J = 6.1Hz, 2H), 1.79 (s, 2H), 1.57–1.44 (m, 4H), 1.18 (t, J = 7.4Hz, 3H).

[0364] Example 10

[0365] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0366] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0367]

[0368] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9c (100 mg, 173.00 μmol), 2-hydroxybenzoic acid 10a (31.06 mg, 224.90 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.75 mg, 259.50 μmol), 1-hydroxybenzotriazole (35.06 mg, 259.50 μmol) and N,N-diisopropylethylamine (111.79 mg, 865.01 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 10 (2.6 mg), yield: 2.12%.

[0369] MS m / z(ESI):698.3[M+1]

[0370] 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.84(s,1H),8.06(d,J=8.6Hz,1H),7.97(d,J=2.2Hz,1H),7.72 (dd,J=8.7,2.2Hz,1H),7.26–7.19(m,1H),7.15(dd,J=7.6,1.7Hz,1H),7.10(t,J=6.8Hz,1H),6.90–6. 81(m,2H),5.30(s,2H),4.53(s,1H),3.46(d,J=10.2Hz,2H),2.97(q,J=7.3Hz,3H),2.72(t,J=14.8Hz, 4H), 2.31 (q, J = 6.1Hz, 2H), 1.78 (q, J = 5.9Hz, 2H), 1.52 (dq, J = 16.2, 7.1Hz, 4H), 1.18 (t, J = 7.4Hz, 3H).

[0371] Embodiment 11

[0372] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0373] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0374]

[0375] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9c (100 mg, 173.00 μmol), 2-hydroxy-3-methylbenzoic acid 11a (34.22 mg, 224.90 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.75 mg, 259.50 μmol), 1-hydroxybenzotriazole (35.06 mg, 259.50 μmol) and N,N-diisopropylethylamine (111.79 mg, 865.01 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 11 (5.66 mg), yield: 4.55%.

[0376] MS m / z(ESI):712.2[M+1]

[0377] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.03(s,1H),8.06(d,J=8.5Hz,1H),7.97(d,J=2.1Hz,1H),7.72( dd,J=8.7,2.1Hz,1H),7.15(d,J=7.1Hz,1H),7.09(t,J=6.6Hz,1H),7.01(dd,J=7.6,1.7Hz,1H),6.81(t ,J=7.5Hz,1H),5.30(s,2H),3.45(t,J=11.4Hz,2H),3.09(s,2H),2.97(d,J=7.5Hz,2H),2.72(t,J=12. 2Hz, 4H), 2.33 (d, J = 7.4Hz, 2H), 2.20 (s, 3H), 1.79 (s, 2H), 1.52 (d, J = 6.6Hz, 4H), 1.18 (t, J = 7.4Hz, 3H).

[0378] Example 12

[0379] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclohexyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0380] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclohexyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0381]

[0382] first step

[0383] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohex-1-en-1-yl)-5-eth yl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0384] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0385] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (60 mg, 76.05 μmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolane 12a (18.99 mg, 91.25 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (6.16 mg, 7.60 μmol), sodium carbonate (24.18 mg, 228.14 μmol) and 1,4-dioxane (1 mL) were added to a 100 mL double-necked bottle, argon was replaced four times, the temperature was raised to 80 ° C for 1.5 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 12b (50 mg) in a yield of 83.20%.

[0386] MS m / z(ESI):790.2[M+1]

[0387] Step 2

[0388] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclohexyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0389] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclohexyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0390] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 12b (50 mg, 63.27 μmol) was added to methanol (1.5 mL), and 10% palladium on carbon (7.68 mg) was added, and the reaction was allowed to react at room temperature overnight. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclohexyl-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 12 (1.84 mg) with a yield of 3.99%.

[0391] MS m / z(ESI):702.1[M+1]

[0392] 1 H NMR (400MHz, DMSO-d6) δ10.35(d,J=6.5Hz,1H),10.24(s,1H),8.58(s,1H),8.03(d,J=8.7Hz,1H),7.97(d,J=2.1Hz ,1H),7.72(dd,J=8.7,2.2Hz,1H),5.30(d,J=6.2Hz,2H),4.52(d,J=12.7Hz,1H),3.49(d,J=11.6Hz,3H),3.03–2.9 1(m,3H),2.80(d,J=11.2Hz,1H),2.71(ddt,J=11.3,7.3,3.6Hz,1H),2.65–2.58(m,1H),2.44(s,3H),1.99–1.88(m ,2H),1.81–1.60(m,4H),1.51(qd,J=12.5,3.2Hz,2H),1.40–1.29(m,2H),1.29–1.22(m,1H),1.17(t,J=7.4Hz,3H).

[0393] Example 13

[0394] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazi n-1-yl)-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0395] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0396]

[0397] first step

[0398] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-

[0399] 2,8-diazaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0400] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-2,8-diazaspiro

[0401] [4.5]Decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0402] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 2,8-diazaspiro[4.5]decan-1-one 13a (24.17 mg, 126.74 μmol), cesium fluoride (28.88 mg, 190.11 μmol) and N,N-diisopropylethylamine (24.57 mg, 190.11 μmol) were added to a microwave tube and the temperature was raised to 100 °C for reaction overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 13b (35 mg), yield: 64.05%.

[0403] MS m / z(ESI):862.1[M+1]

[0404] Step 2

[0405] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazi n-1-yl)-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0406] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0407] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 13b (35 mg, 40.59 μmol) was added to dichloromethane (3 mL), BCl3 (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 h. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 13 (3.13 mg) in a yield of 9.69%.

[0408] MS m / z(ESI):772.1[M+1]

[0409] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.22(s,1H),8.57(s,1H),8.08–7.94(m,2H),7.72(d,J=9.1Hz, 1H),7.58(s,1H),5.21(s,2H),4.51(d,J=12.2Hz,1H),3.96(d,J=13.1Hz,2H),3.23(s,1H),3.18(t,J=6 .7Hz,2H),3.07(t,J=12.3Hz,2H),2.96(d,J=10.6Hz,3H),2.78(d,J=11.4Hz,1H),2.60(d,J=10.3Hz,1H ),2.44(s,3H),2.00(t,J=6.8Hz,2H),1.68–1.60(m,2H),1.36(d,J=13.3Hz,2H),1.16(t,J=7.4Hz,3H).

[0410] Embodiment 14

[0411] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-ox o-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0412] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0413]

[0414] first step

[0415] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6 a-hexahydropentalen-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0416] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0417] At room temperature, 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 1c (60 mg, 90.51 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydropenta-2(1H)-one 14a (26.95 mg, 108.62 μmol, according to the published patent WO2020086533) were added. A1 preparation), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (7.34 mg, 9.05 μmol), sodium carbonate (28.78 mg, 271.54 μmol) and 1,4-dioxane (1 mL) were added to a 100 mL double-necked bottle, argon was replaced four times, the temperature was raised to 80 ° C for 1.5 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 14b (45 mg) in a yield of 70.61%.

[0418] MS m / z(ESI):648.0[M-56+1]

[0419] Step 2

[0420] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0421] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0422] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 14b (45 mg, 63.91 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (0.3 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14c (35 mg) with a yield of 90.67%.

[0423] MS m / z(ESI):604.1[M+1]

[0424] Step 3

[0425] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-ox o-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0426] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0427] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14c (35 mg, 57.94 μmol), 3-hydroxyisonicotinic acid 9d (10.48 m g, 75.33 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.66 mg, 86.92 μmol), 1-hydroxybenzotriazole (11.74 mg, 86.92 μmol) and N,N-diisopropylethylamine (37.44 mg, 289.72 μmol) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature for 4 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14 (3.41 mg) in a yield of 7.85%.

[0428] MS m / z(ESI):725.2[M+1]

[0429] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),10.33(s,1H),8.27(s,1H),8.17(d,J=5.0Hz,1H),8.06(d,J=8.5 Hz,1H),7.95(d,J=2.1Hz,1H),7.71(dd,J=8.8,2.2Hz,1H),7.33(s,1H),6.52(s,1H),5.31(s,2H),4.5 2(d,J=12.6Hz,1H),3.28(d,J=22.0Hz,3H),3.15–2.91(m,6H),2.80(d,J=11.6Hz,1H),2.64(d,J=15.6 Hz,2H),2.59–2.52(m,1H),2.25(d,J=18.9Hz,2H),1.95(dd,J=18.8,6.9Hz,1H),1.18(t,J=7.4Hz,3H).

[0430] Embodiment 15

[0431] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-((3-chloropropyl)amino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0432] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-((3-chloropropyl)amino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0433]

[0434] 2-(2-(azetidin-1-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 7b (40 mg, 52.28 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure at room temperature. The residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-((3-chloropropyl)amino)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 15 (1.36 mg) with a yield of 3.52%.

[0435] MS m / z(ESI):711.0[M+1]

[0436] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.22(s,1H),8.57(s,1H),8.08(d,J=8.6Hz,1H),7.96(d,J= 2.1Hz,1H),7.74–7.67(m,1H),6.79(t,J=5.8Hz,1H),5.17(s,2H),4.51(d,J=12.8Hz,1H),3.68(t, J=6.5Hz,2H),3.50(d,J=12.3Hz,3H),3.25(dd,J=13.3,6.9Hz,2H),2.95(d,J=17.6Hz,3H),2.77(d ,J=11.3Hz,1H),2.59(d,J=11.0Hz,2H),2.44(s,3H),1.99(q,J=6.6Hz,2H),1.15(t,J=7.4Hz,3H).

[0437] Example 16

[0438] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pipera zin-1-yl)-7-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0439] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0440]

[0441] first step

[0442] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-oxa-6-azaspiro[3 .3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0443] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0444] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol) and 2-oxa-6-azaspiro[3.3]heptane 16a (8.17 mg, 82.38 μmol, commercially available) were added to a microwave tube and the temperature was raised to 80 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 16b (40 mg), yield: 78.19%.

[0445] MS m / z(ESI):807.1[M+1]

[0446] Step 2

[0447] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pipera zin-1-yl)-7-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0448] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0449] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 16b (30 mg, 37.16 μmol) was added to methanol (1.5 mL), palladium carbon (4.51 mg, 37.16 μmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 16 (8.23 mg) in a yield of 10.53%.

[0450] MS m / z(ESI):717.1[M+1]

[0451] 1H NMR (400MHz, DMSO-d6) δ10.32(d,J=2.4Hz,1H),10.23(s,1H),8.57(s,1H),8.06(d,J=8.5H z,1H),7.97(t,J=2.6Hz,1H),7.72(d,J=8.8Hz,1H),5.21(d,J=2.7Hz,2H),4.69(s,2H),4.5 1(d,J=12.7Hz,1H),4.13(s,2H),3.70(s,2H),3.22(t,J=12.8Hz,2H),2.98(d,J=12.0Hz,4H ),2.77(d,J=11.4Hz,1H),2.59(d,J=10.6Hz,1H),2.44(s,3H),1.15(td,J=7.5,2.4Hz,3H).

[0452] Embodiment 17

[0453] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1 -yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0454] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0455]

[0456] first step

[0457] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hex ahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0458] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0459] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (60 mg, 76.05 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 ,3a,4,6a-tetrahydropentane-2(1H)-one 17a (22.64 mg, 91.25 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (6.16 mg, 7.60 μmol), and sodium carbonate (24.18 mg, 228.14 μmol) were added to 1,4-dioxane (1 mL), and the argon gas was replaced four times. The temperature was raised to 80°C for 1.5 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 17b (30 mg) in a yield of 47.52%.

[0460] MS m / z(ESI):830.3[M+1]

[0461] Step 2

[0462] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1 -yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0463] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0464] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 17b (30 mg, 36.13 μmol) was added to dichloromethane (2 mL), and boron trichloride (0.5 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 17 (3.16 mg) with a yield of 11.77%.

[0465] MS m / z(ESI):740.1[M+1]

[0466] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.23(s,1H),8.58(s,1H),8.06(d,J=8.5Hz,1H),7.97(d,J=2.1Hz, 1H),7.71(dd,J=8.7,2.1Hz,1H),6.52(q,J=1.9Hz,1H),5.32(s,2H),4.52(d,J=12.5Hz,1H),3.25(t,J=12. 4Hz,1H),3.10(dd,J=16.6,8.6Hz,2H),3.01(d,J=14.1Hz,4H),2.81(d,J=11.3Hz,1H),2.64(d,J=14.9Hz,2 H),2.59–2.53(m,1H),2.44(s,3H),2.29–2.22(m,1H),1.94(dd,J=18.8,6.9Hz,1H),1.18(t,J=7.4Hz,3H).

[0467] Embodiment 18

[0468] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1 -yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0469] 2-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0470]

[0471] first step

[0472] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[3.1.0]hex-2-en-3-yl)-5 -ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0473] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0474] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 2-(bicyclo[3.1.0]hexane -2-en-3-yl)-4,4,,5,5-tetramethyl-1,3,2-dioxaborolane 18a (15.67 mg, 76.05 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4- The mixture was stirred for 1 h at 80 °C and the mixture was heated to 80 °C for 1.5 h. After the reaction was complete, water (10 mL) was slowly added dropwise to the reaction solution and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 18b (40 mg) in a yield of 80.08%.

[0475] MS m / z(ESI):788.1[M+1]

[0476] Step 2

[0477] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1 -yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0478] 2-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0479] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 18b (40 mg, 50.75 μmol) was added to dichloromethane (2 mL), and boron trichloride (0.5 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 18 (11.52 mg), yield: 8.54%.

[0480] MS m / z(ESI):698.2[M+1]

[0481] 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.23(s,1H),8.58(s,1H),8.05(d,J=8.6Hz,1H),7.97(d, J=2.1Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),6.81(q,J=2.0Hz,1H),5.30(s,2H),4.52(d,J=12.4Hz ,1H),3.49(d,J=12.2Hz,3H),3.26(d,J=12.1Hz,1H),3.04–2.89(m,5H),2.83–2.56(m,4H),2.44 (s,3H),2.03–1.91(m,1H),1.83–1.72(m,1H),1.17(t,J=7.4Hz,3H),1.01(td,J=7.8,3.8Hz,1H).

[0482] Embodiment 19

[0483] 2-(2-(benzofuran-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0484] 2-(2-(Benzofuran-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0485]

[0486]

[0487] first step

[0488] tert-butyl 4-(2-(benzofuran-2-yl)-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

[0489] tert-Butyl 4-(2-(Benzofuran-2-yl)-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

[0490] At room temperature, 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 1c (60 mg, 90.51 μmol), 2-(benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolane 19a (26.51 mg, 108.62 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (7.34 mg, 9.05 μmol), and sodium carbonate (28.78 mg, 271.54 μmol) were added to 1,4-dioxane (2 mL), and the atmosphere was replaced with argon four times, and the temperature was raised to 80°C for reaction for 1.5 hours. After the reaction was completed, water (10 mL) was slowly added dropwise to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 4-(2-(benzofuran-2-yl)-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 19b (40 mg) in a yield of 63.12%.

[0491] MS m / z(ESI):644.2[M-56+1]

[0492] Step 2

[0493] 2-(2-(benzofuran-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0494] 2-(2-(Benzofuran-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0495] 4-(2-(Benzofuran-2-yl)-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 19b (40 mg, 57.13 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (0.5 mL) and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give 2-(2-(benzofuran-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 19c (30 mg) with a yield of 87.51%.

[0496] MS m / z(ESI):600.1[M+1]

[0497] Step 3

[0498] 2-(2-(benzofuran-2-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0499] 2-(2-(Benzofuran-2-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0500] 2-(2-(Benzofuran-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 19c (30 mg, 50.00 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (15.88 mg, 65.00 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.38 mg, 75.00 μmol), 1-hydroxybenzotriazole (10.13 mg, 75.00 μmol) and N,N-diisopropylethylamine (32.31 mg, 250.00 μmol) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(2-(benzofuran-2-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 19d (30 mg), yield: 72.62%.

[0501] MS m / z(ESI):826.2[M+1]

[0502] Step 4

[0503] 2-(2-(benzofuran-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0504] 2-(2-(Benzofuran-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0505] 2-(2-(Benzofuran-2-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 19d (30 mg, 36.31 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (0.5 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(benzofuran-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 19 (4.3 mg), yield: 15.61%.

[0506] MS m / z(ESI):736.0[M+1]

[0507] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),10.25(s,1H),8.59(s,1H),8.10(d,J=8.7Hz,1H),7.9 8(d,J=2.1Hz,1H),7.75(dd,J=17.2,7.9Hz,3H),7.62(s,1H),7.44(t,J=7.7Hz,1H),7.34(t ,J=7.5Hz,1H),5.42(s,2H),4.55(d,J=12.5Hz,1H),3.51(d,J=12.2Hz,4H),3.03(d,J=10.2 Hz,3H),2.86(d,J=11.2Hz,1H),2.68(d,J=10.7Hz,1H),2.45(s,3H),1.22(t,J=7.4Hz,3H).

[0508] Embodiment 20

[0509] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohexylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0510] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohexylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0511]

[0512] first step

[0513] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohexylidenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0514] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohexylidenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0515] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 2-(cyclohexylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 20a (16.89 mg, 76.05 μmol, European Journal of Organic Chemistry) were added by a known method. Chemistry (2019), 2019 (33), 5624-5635”), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol) and sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80 ° C for 2 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohexylidenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 20b (40 mg) in a yield of 78.48%.

[0516] MS m / z(ESI):804.2[M+1]

[0517] Step 2

[0518] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohexylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0519] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohexylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0520] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohexylidenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 20b (40 mg, 49.74 μmol) was added to dichloromethane (3 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohexylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 20 (13.0 mg), yield: 9.79%.

[0521] MS m / z(ESI):7 14.4[M+1]

[0522] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.23(s,1H),8.58(s,1H),8.04(d,J=8.6Hz,1H),7.97(d,J=2. 1Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),6.09(s,1H),5.29(s,2H),4.52(d,J=12.5Hz,1H),3.30–3.19(m ,1H),3.00(d,J=9.2Hz,3H),2.90(t,J=6.0Hz,2H),2.81(d,J=11.4Hz,1H),2.63(d,J=10.8Hz,1H),2. 44(s,3H),2.26(t,J=5.6Hz,2H),1.57(t,J=7.1Hz,3H),1.49(d,J=5.5Hz,2H),1.18(t,J=7.4Hz,3H).

[0523] Embodiment 21

[0524] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin -1-yl)-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0525] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0526]

[0527] first step

[0528] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((tetrahydro-4H-pyran- 4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0529] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0530] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 4,4,5,5-tetramethyl-2-(tetrahydropyran-4-ylidenemethyl)-1,3,2-dioxaborol Heterocyclopentane 21a (17.04 mg, 76.05 μmol, prepared according to the patent publication "WO2021210586"), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol) and sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80 °C for 2 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 21b (30 mg) in a yield of 58.72%.

[0531] MS m / z(ESI):806.1[M+1]

[0532] Step 2

[0533] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin -1-yl)-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0534] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0535] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 21b (30 mg, 37.21 μmol) was added to dichloromethane (3 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-((tetrahydro-4H-pyran-4-ylidene)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 21 (4.93 mg) in a yield of 8.61%.

[0536] MS m / z(ESI):716.1[M+1]

[0537] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.23(s,1H),8.58(s,1H),8.06–7.92(m,2H),7.7 2(dd,J=8.8,2.1Hz,1H),6.21(s,1H),5.29(s,2H),4.52(d,J=12.2Hz,1H),3.68(t,J=5.4 Hz,2H),3.56(t,J=5.5Hz,2H),3.31–3.20(m,2H),3.02(t,J=6.9Hz,6H),2.81(d,J=11.4H z,1H),2.63(d,J=10.9Hz,1H),2.44(s,3H),2.37(t,J=5.3Hz,2H),1.18(t,J=7.4Hz,3H).

[0538] Embodiment 22

[0539] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-

[0540] oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0541] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0542]

[0543] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14c (60 mg, 99.33 μmol), 3-hydroxypicolinic acid 22a (17.96 mg, 1 29.13μmol, commercially available), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.56mg, 149.00μmol), 1-hydroxybenzotriazole (20.13mg, 149.00μmol) and N,N-diisopropylethylamine (64.19mg, 496.67μmol) were added to N,N-dimethylformamide (1mL) and reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30mL×2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (20mL×2) in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazine-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 22 (3.74 mg), yield: 5.00%.

[0544] MS m / z(ESI):725.2[M+1]

[0545] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),10.35(s,1H),8.11–8.01(m,2H),7.96(d,J=2.1Hz,1H),7.71( dd,J=8.9,2.1Hz,1H),7.34–7.27(m,2H),6.52(d,J=2.1Hz,1H),5.36–5.27(m,2H),4.54(d,J=12.5H z,1H),3.48–3.37(m,3H),3.24(d,J=12.1Hz,1H),3.16–2.88(m,7H),2.79(d,J=11.4Hz,1H),2.62(s ,2H),2.59–2.53(m,1H),2.25(d,J=18.7Hz,2H),1.94(dd,J=19.0,7.0Hz,1H),1.18(t,J=7.4Hz,3H).

[0546] Embodiment 23

[0547] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin- 1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0548] 2-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0549]

[0550] first step

[0551] 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0552] 2-(Bicyclo[2.2.1]hept-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0553] 2-Bicyclo[2.2.1]hept-2-enyl trifluoromethanesulfonate 23a (90 mg, 371.57 μmol, prepared according to the known method "Organic Letters (2019), 21 (6), 1555-1558"), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan 23b (141.53 mg, 557.36 μmol, commercially available), potassium acetate (109.40 mg, 1.11 mmol) and bis(triphenylphosphine)palladium dichloride (26.08 mg, 37.16 μmol) were added to 1,4-dioxane (1 mL) and reacted at 80 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the aqueous layer was separated, and the combined organic phases were washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 23c (20 mg) in a yield of 24.45%.

[0554] Step 2

[0555] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[2.2.1]hept-2-en-2-yl)- 5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0556] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0557] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane 23c (16.74 mg, 76.05 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), and sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), and the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The aqueous layer was separated and the combined organic phases were washed successively with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 23d (30 mg) in a yield of 59.01%.

[0558] MS m / z(ESI):802.3[M+1]

[0559] Step 3

[0560] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin- 1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0561] 2-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0562] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 23d (30 mg, 37.40 μmol) was added to dichloromethane (2 mL), and boron trichloride (0.8 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 23 (2.6 mg), yield: 9.41%.

[0563] MS m / z(ESI):711.7[M+1]

[0564] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.24(s,1H),8.58(s,1H),8.06(d,J=8.5Hz,1H),7.97(d,J=2.0Hz ,1H),7.77–7.68(m,1H),6.75(d,J=3.1Hz,1H),5.30(s,2H),4.52(d,J=12.8Hz,1H),3.50(d,J=12.4Hz,4H ),3.26(d,J=12.8Hz,2H),3.01(d,J=22.4Hz,4H),2.81(d,J=11.4Hz,1H),2.64(s,1H),2.44(s,3H),1.78 (d,J=5.9Hz,2H),1.47(d,J=8.0Hz,1H),1.30–1.20(m,2H),1.18(t,J=7.4Hz,3H),1.03(d,J=27.2Hz,2H).

[0565] Embodiment 24

[0566] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0567] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0568]

[0569] first step

[0570] 2-bromo-N-(4-(tert-butyl)phenyl)acetamide

[0571] 2-Bromo-N-(4-(tert-butyl)phenyl)acetamide

[0572] 4-tert-Butylaniline 24a (1 g, 6.70 mmol, commercially available) was dissolved in dichloromethane (10 mL), 4-dimethylaminopyridine (818.66 mg, 6.70 mmol) was added under ice bath, and after stirring for 10 minutes, 2-bromoacetyl bromide 24b (1.62 g, 8.04 mmol, commercially available) was slowly added. After reacting at room temperature for 4 hours, the reaction was detected. Water (20 mL) was added to the reaction solution, and dichloromethane (20 mL×3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 2-bromo-N-(4-(tert-butyl)phenyl)acetamide 24c (1.5 g), with a yield of 82.86%.

[0573] MS m / z(ESI):270.0[M+1]

[0574] Step 2

[0575] tert-butyl 4-(2-bromo-4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-

[0576] [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0577] 4-(2-bromo-4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]

[0578] tert-Butyl pyrimidin-6-yl)piperazine-1-carboxylate

[0579] At room temperature, 2-bromo-N-(4-(tert-butyl)phenyl)acetamide 24c (303.49 mg, 1.12 mmol), tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1a (400 mg, 936.12 μmol), and N,N-diisopropylethylamine (362.95 mg, 2.81 mmol) were added to N,N-dimethylformamide (7 mL), and the temperature was raised to 70 °C for 2 hours. The reaction was complete when detected by mass spectrometry. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-bromo-4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 24d (290 mg) in a yield of 50.25%.

[0580] MS m / z(ESI):560.2[M-56+H]

[0581] Step 3

[0582] tert-butyl 4-(4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-

[0583] oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate4-(4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0584] tert-Butyl triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0585] At room temperature, 4-(2-bromo-4-(2-((4-(tert-butyl)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 24d (290 mg, 470.36 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolato)-1-carboxylic acid tert-butyl ester 24d (290 mg, 470.36 μmol) and 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolato)-1-carboxylic acid tert-butyl ester 24d (290 mg, 470.36 μmol) were added. Cyclopentane 9a (135.83 mg, 611.47 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (38.13 mg, 47.04 μmol), and sodium carbonate (149.56 mg, 1.41 mmol) were added to a mixed solution of 1,4-dioxane (5 mL) and water (1 mL). The argon atmosphere was replaced three times, the temperature was raised to 80 °C for 2 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 24e (260 mg) in a yield of 87.49%.

[0586] MS m / z(ESI):576.3[M-56+H]

[0587] Step 4

[0588] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-

[0589] [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamideN-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0590] Pyrimidin-4(7H)-yl)acetamide

[0591] Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl 4-(4-(2-((4-(tert-butyl)phenyl)amino)-2-oxoethyl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 24e (140 mg, 221.59 μmol) in dichloromethane (6 mL) at room temperature. The reaction mixture was added into a 4-nitro-2-nitro-2-thiazolyl-4-ol (2-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 24f (117 mg) with a yield of 99.31%. The crude product was used directly in the next step.

[0592] MS m / z(ESI):532.3[M+1]

[0593] Step 5

[0594] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0595] At room temperature, 3-hydroxyisonicotinic acid 9d (20.93 mg, 150.46 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.84 mg, 150.46 μmol), 1-hydroxybenzotriazole (20.33 mg, 150.46 μmol), N,N-diisopropylethylamine (48.61 mg, 376.16 μmol) were added to N,N-diisopropylethylamine. The mixture was added to methylformamide (1.5 mL) and reacted at room temperature for 30 minutes. Then, N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 24f (40 mg, 75.23 μmol) was added and reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 24 (19.42 mg) in a yield of 39.11%.

[0596] MS m / z(ESI):653.3[M+1]

[0597] 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.43(s,1H),8.44–8.17(m,2H),7.63–7.42(m,3H),7.34(d,J =8.5Hz,2H),7.06(t,J=6.7Hz,1H),5.13(s,2H),4.53(d,J=12.5Hz,1H),3.48(d,J=11.2Hz,2H),3.36 –3.23(m,2H),2.96(dt,J=16.0,9.0Hz,3H),2.81(d,J=11.2Hz,1H),2.79–2.70(m,2H),2.64(d,J=11 .2Hz,1H),2.32(d,J=8.8Hz,2H),1.78(s,2H),1.64–1.42(m,4H),1.25(s,9H),1.16(t,J=7.4Hz,3H).

[0598] Embodiment 25

[0599] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0600] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide

[0601]

[0602] first step

[0603] 2-bromo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0604] 2-Bromo-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0605] Under an ice bath and argon atmosphere, a solution of 2-bromoacetyl bromide 24b (574.66 mg, 2.85 mmol) in dichloromethane (5 mL) was added to a solution of 4-(pentafluorosulfanyl)aniline 25a (520 mg, 2.37 mmol, commercially available) in dichloromethane (7 mL), and the mixture was reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and dichloromethane (20 mL × 3) was used for extraction. The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-bromo-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25b (720 mg), yield: 89.23%.

[0606] MS m / z(ESI):339.9[M+1]

[0607] Step 2

[0608] tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-

[0609] carboxylate

[0610] 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[0611] 2-Bromo-N-(4-(pentafluoro-λ 6-sulfoalkyl)phenyl)acetamide 25b (382.06 mg, 1.12 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 1a (400 mg, 936.12 μmol), N,N-diisopropylethylamine (604.92 mg, 4.68 mmol) were added to N,N-dimethylformamide (7 mL), the temperature was raised to 50 ° C for 2 hours, and the reaction was completed under the monitoring of mass spectrometry. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 25c (710 mg), yield: 77.34%.

[0612] MS m / z(ESI):630.1[M-56+H]

[0613] Step 3

[0614] tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-

[0615] carboxylate

[0616] 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfonyl)phenyl)amino)ethyl)-4,7-

[0617] tert-Butyl dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0618] At room temperature, 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6To a mixed solution of 1,4-dioxane (12 mL) and water (2 mL) were added tert-butyl (2-(4-(2-((4-((2-( ... Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 25d (450 mg), yield: 62.00%.

[0619] MS m / z(ESI):646.2[M-56+H]

[0620] Step 4

[0621] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-

[0622] 4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0623] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-

[0624] (Pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide

[0625] At room temperature, trifluoroacetic acid (2 mL) was added to 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 A solution of tert-butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 25d (450 mg, 641.25 μmol) in dichloromethane (8 mL) was reacted at room temperature for 40 minutes. The reaction was completed under mass spectrometry. The product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25e (340 mg), yield: 88.13%.

[0626] MS m / z(ESI):602.3[M+1]

[0627] Step 5

[0628] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-

[0629] [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide

[0630] At room temperature, 3-hydroxyisonicotinic acid 9d (27.75 mg, 199.46 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.24 mg, 199.46 μmol), 1-hydroxybenzotriazole (26.95 mg, 199.46 μmol), N,N-diisopropylethylamine (64.44 mg, 498.64 μmol) were added to N,N-dimethylformamide (1.5 mL), and reacted at room temperature for 40 minutes. Then, 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25e (60 mg, 99.73 μmol) was added to the reaction mixture and reacted at room temperature for 16 hours. The reaction was monitored by mass spectrometry. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25 (24.53 mg), yield: 33.32%.

[0631] MS m / z(ESI):723.3[M+1]

[0632] 1H NMR (400MHz, DMSO-d6) δ10.95(s,2H),8.29(s,1H),8.22(d,J=5.1Hz,1H),7.95–7.84(m,2H),7.77( d,J=8.9Hz,2H),7.42(d,J=5.0Hz,1H),7.04(t,J=6.7Hz,1H),5.18(s,2H),4.53(d,J=12.6Hz,1H),3 .47(q,J=11.1Hz,2H),3.38–3.13(m,2H),3.14–2.87(m,3H),2.80(d,J=11.3Hz,1H),2.76–2.70(m, 2H), 2.64 (d, J = 11.3Hz, 1H), 2.29 (t, J = 8.1Hz, 2H), 1.77 (s, 2H), 1.51 (s, 4H), 1.16 (t, J = 7.4Hz, 3H).

[0633] Embodiment 26

[0634] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-

[0635] methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-

[0636] yl)acetamide

[0637] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)

[0638] 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0639]

[0640] first step

[0641] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(tert-butyl)phenyl)acetamide

[0642] Triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(tert-butyl)phenyl)acetamide

[0643] At room temperature, 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (68.91mg, 282.12μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.11mg, 376.16μmol), 1-hydroxybenzotriazole (50.83mg, 376.16μmol), N,N-diisopropylethylamine (121.54mg, 940.40μmol) were added to N,N-dimethylaminopropylcarbodiimide hydrochloride. The mixture was added to methylformamide (1.5 mL) and reacted at room temperature for 40 minutes, and then a solution of N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 24f (100 mg, 188.08 μmol) in N,N-dimethylformamide (2 mL) was added and reacted at room temperature for 16 hours. The reaction was detected to be complete, and water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(tert-butyl)phenyl)acetamide 26a (65 mg) in a yield of 45.60%.

[0644] MS m / z(ESI):758.5[M+1]

[0645] Step 2

[0646] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-

[0647] methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-

[0648] yl)acetamide

[0649] N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)

[0650] 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0651] Boron trichloride (1.5 mL) was added to a solution of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(tert-butyl)phenyl)acetamide 26a (65 mg, 85.76 μmol) in dichloromethane (1 mL) under an ice bath and argon atmosphere. The mixture was reacted at room temperature for 16 hours. Ice water was added to quench the reaction, and a small amount of methanol was dissolved and then separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(4-(tert-butyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 26 (12.35 mg), yield: 21.33%.

[0652] MS m / z(ESI):668.4[M+1]

[0653] 1H NMR (400MHz, DMSO-d6) δ10.43(d,J=4.4Hz,1H),10.25(s,1H),8.58(t,J=3.2Hz,1H),7.48(dd,J=8.7,4.2Hz,2H),7 .38–7.22(m,2H),7.06(q,J=6.1Hz,1H),5.13(d,J=4.3Hz,2H),4.52(d,J=12.6Hz,1H),3.52(s,3H),3.26(d,J=13.9 Hz,1H),2.97(d,J=17.0Hz,3H),2.81(d,J=10.7Hz,1H),2.78–2.69(m,2H),2.64(d,J=11.4Hz,1H),2.45(dd,J=4.6, 2.1Hz,3H),2.31(s,2H),1.88–1.72(m,2H),1.52(d,J=12.0Hz,4H),1.25(dd,J=4.8,2.1Hz,9H),1.20–1.10(m,3H).

[0654] Embodiment 27

[0655] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-

[0656] yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 6-

[0657] sulfaneyl)phenyl)acetamide

[0658] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide

[0659]

[0660]

[0661] At room temperature, 5-hydroxy-6-methylpyrimidine-4-carboxylic acid 27a (30.74 mg, 199.46 μmol, commercially available), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.24 mg, 199.46 μmol), 1-hydroxybenzotriazole (26.95 mg, 199.46 μmol), N,N-diisopropylethylamine (64.44 mg, 498.64 μmol) were added to N,N-dimethylformamide (1.5 mL) and reacted at room temperature for 40 minutes. Then, 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25e (60 mg, 99.73 μmol) was reacted at room temperature for 16 hours, and the product was detected by mass spectrometry. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 27 (1.06 mg), yield: 1.35%.

[0662] MS m / z(ESI):738.3[M+1]

[0663] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.24(s,1H),8.58(s,1H),7.93–7.85(m,2H),7.77(d,J=9.0 Hz,2H),7.04(t,J=6.7Hz,1H),5.18(s,2H),4.52(d,J=12.7Hz,1H),3.50(q,J=11.6,10.4Hz,3H),3. 25(t,J=12.7Hz,1H),2.98(d,J=12.1Hz,3H),2.81(d,J=11.3Hz,1H),2.73(d,J=9.6Hz,2H),2.64(d, J=10.9Hz,1H),2.45(s,3H),2.30(s,2H),1.77(d,J=7.6Hz,2H),1.51(s,4H),1.16(t,J=7.4Hz,3H).

[0664] Embodiment 28

[0665] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,5-diethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0666] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2,5-diethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0667]

[0668]

[0669] first step

[0670] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0671] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0672] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (110 mg, 139.42 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- Dioxaborolane 28a (25.77 mg, 167.30 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (11.30 mg, 13.94 μmol), and sodium carbonate (44.33 mg, 418.25 μmol) were added to 1,4-dioxane (1 mL), and the argon atmosphere was replaced four times. The temperature was raised to 80 °C for 1.5 hours, and the reaction was complete under mass spectrometry monitoring. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 28b (90 mg) in a yield of 87.69%.

[0673] MS m / z(ESI):736.2[M+1]

[0674] Step 2

[0675] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,5-diethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0676] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2,5-diethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0677] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 28b (45 mg, 61.13 μmol) was added to methanol (1 mL), palladium carbon (7.42 mg, 61.13 μmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,5-diethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 28 (2.61 mg), yield: 6.53%.

[0678] MS m / z(ESI):648.0[M+1]

[0679] 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.23(s,1H),8.58(s,1H),8.06(d,J=8.6Hz,1H), 7.96(d,J=2.1Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),5.31(s,2H),4.52(d,J=12.6Hz,1H), 3.24(t,J=12.3Hz,1H),2.97(d,J=10.5Hz,3H),2.80(d,J=11.4Hz,1H),2.70(q,J=7.6Hz ,2H),2.63(d,J=11.1Hz,1H),2.44(s,3H),1.24(t,J=7.6Hz,3H),1.18(t,J=7.4Hz,3H).

[0680] Embodiment 29

[0681] 2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide

[0682] 2-(2-Cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide

[0683]

[0684] Embodiment 30

[0685] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0686] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0687]

[0688] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 10 (50 mg, 71.62 μmol) was added to methanol (1.5 mL), followed by palladium carbon (8.70 mg, 71.62 μmol) and reacted at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), to obtain 2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide 29 (2.93 mg), yield: 6.02%; N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 30 (2.59 mg), yield: 4.93% yield.

[0689] Example 29MS m / z (ESI): 666.2[M+1]

[0690] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.85(s,1H),7.82–7.67(m,4H),7.30–7.12(m,2 H),6.94–6.81(m,2H),5.17(s,2H),4.53(s,1H),3.49(s,9H),2.91(ddd,J=13.8,11.2, 6.2Hz,4H),2.68(s,2H),1.96(ddt,J=9.9,6.4,3.9Hz,2H),1.71(dtt,J=15.4,6.6,3. 1Hz, 4H), 1.63–1.56 (m, 2H), 1.50 (tdd, J=12.5, 8.4, 5.3Hz, 4H), 1.16 (t, J=7.4Hz, 3H).

[0691] Example 30MS m / z (ESI): 700.1 [M+1]

[0692] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.84(s,1H),8.10–7.90(m,2H),7.72(dd,J=8.8,2.1Hz,1H),7 .23(dd,J=7.7,2.0Hz,1H),7.15(dd,J=7.5,1.7Hz,1H),6.89–6.80(m,2H),5.29(s,2H),4.53(s,1H) ,3.51–3.40(m,4H),3.02–2.87(m,4H),2.68(s,2H),1.98(ddt,J=14.5,7.5,3.1Hz,2H),1.75(ddd,J =20.8,10.5,6.2Hz,4H),1.61(d,J=7.6Hz,2H),1.52(qd,J=10.4,7.0Hz,4H),1.17(t,J=7.4Hz,3H).

[0693] Embodiment 31

[0694] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0695] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0696]

[0697] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9 (30 mg, 42.91 μmol) was added to methanol (1.5 mL), followed by palladium carbon (5.21 mg, 42.91 μmol) and reacted at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cycloheptyl-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 31 (3.49 mg) in a yield of 11.14%.

[0698] MS m / z(ESI):701.1[M+1]

[0699] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),10.35(d,J=6.3Hz,1H),8.27(d,J=2.5Hz,1H),8.23–8.16(m,1H),8.03(d,J =8.7Hz,1H),7.97(d,J=2.2Hz,1H),7.72(dd,J=8.8,2.1Hz,1H),7.38(s,1H),5.29(s,2H),4.52(d,J=12.5Hz,1H), 3.46(d,J=10.9Hz,2H),3.34–3.22(m,2H),2.92(ddd,J=13.9,9.6,4.7Hz,4H),2.79(d,J=11.6Hz,1H),2.62(d,J= 11.2Hz, 1H), 1.99 (dd, J=14.1, 7.0Hz, 2H), 1.74 (dt, J=10.9, 7.8Hz, 4H), 1.63–1.44 (m, 6H), 1.17 (t, J=7.5Hz, 3H).

[0700] Embodiment 32

[0701] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-me thyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0702] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0703]

[0704] first step

[0705] tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0706] tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0707] 4-(2-Bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 32a (1 g, 2.42 mmol, prepared according to patent WO2022249060 A1), 2-bromo-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 1b (995.61 mg, 3.15 mmol) were added to N,N-dimethylformamide (10 mL), followed by N,N-diisopropylethylamine (938.18 mg, 7.26 mmol), the temperature was raised to 50 ° C, and the reaction was carried out for 4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the water layer was separated, and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to give 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 32b (1.1 g) in a yield of 70.06%.

[0708] MS m / z(ESI):547.7[M-100+1]

[0709] Step 2

[0710] 2-(2-bromo-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0711] 2-(2-Bromo-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0712] 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 32b (260 mg, 400.70 μmol) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL) and reacted at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give 2-(2-bromo-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32c (210 mg) with a yield of 95.51%.

[0713] MS m / z(ESI):548.0[M+1]

[0714] Step 3

[0715] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0716] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0717] 2-(2-Bromo-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32c (210 mg, 382.69 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (121.51 mg, 497.50 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110.04 mg, 574.04 μmol), 1-hydroxybenzotriazole (77.56 mg, 574.04 μmol), N,N-diisopropylethylamine (247.30 mg, 1.91 mmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The aqueous layer was separated and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32d (200 mg) in a yield of 67.44%.

[0718] MS m / z(ESI):775.1[M+1]

[0719] Step 4

[0720] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hex ahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0721] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0722] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32d (55 mg, 70.97 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,3a,4,6a-Tetrahydropentan-2(1H)-one 14a (21.13 mg, 85.16 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.75 mg, 7.10 μmol), and sodium carbonate (22.57 mg, 212.91 μmol) were added to 1,4-dioxane (1 mL), and the atmosphere was replaced with argon four times. The temperature was raised to 80 °C for 1.5 hours, and the reaction was complete under mass spectrometry monitoring. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32e (36 mg) in a yield of 62.15%.

[0723] MS m / z(ESI):815.7[M+1]

[0724] Step 5

[0725] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-me thyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0726] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0727] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 32e (36 mg, 44.11 μmol) was added to dichloromethane (1 mL), and boron trichloride (0.8 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 32 (3.00 mg) in a yield of 9.13%.

[0728] MS m / z(ESI):725.7[M+1]

[0729] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),10.23(s,1H),8.58(s,1H),8.07(d,J=8.6Hz,1H),7.97(d,J=2.1Hz,1H), 7.71(dd,J=8.7,2.1Hz,1H),6.53(d,J=2.0Hz,1H),5.33(s,2H),4.50(d,J=12.6Hz,1H),3.59(d,J=7.3Hz,1H),3 .48(d,J=11.2Hz,3H),3.27(d,J=12.1Hz,2H),3.16–2.95(m,4H),2.79(d,J=11.3Hz,1H),2.65(d,J=14.3Hz,2H ),2.58(s,3H),2.44(s,3H),2.26(dd,J=18.3,3.0Hz,1H),1.95(dd,J=19.0,6.9Hz,1H),1.21(d,J=21.3Hz,1H).

[0730] Embodiment 33

[0731] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0732] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0733]

[0734] first step

[0735] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclobutylidenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0736] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclobutylenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0737] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 2-(cyclobutylenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 33a (14.76 mg, 76.05 μmol, according to the published patent WO2021007477) were added. A1 was prepared), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80 ° C for 1.5 hours, water (20 mL) was added to the reaction solution, and ethyl acetate (40 mL × 3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL), and anhydrous The product was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(cyclobutylenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 33b (35 mg) in a yield of 71.15%.

[0738] MS m / z(ESI):776.2[M+1]

[0739] Step 2

[0740] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0741] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0742] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclobutylenemethyl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 33b (35 mg, 45.09 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (0.8 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 33 (2.75 mg) in a yield of 8.71%.

[0743] MS m / z(ESI):686.2[M+1]

[0744] 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.23(s,1H),8.58(s,1H),8.04(d,J=8.6Hz,1H ),7.96(d,J=2.1Hz,1H),7.76–7.64(m,1H),6.14–6.02(m,1H),5.28(s,2H),4.52(d,J= 12.4Hz,1H),3.24(t,J=12.4Hz,1H),3.08(d,J=8.4Hz,2H),2.99(s,3H),2.91–2.78(m, 3H), 2.63 (d, J = 10.7Hz, 1H), 2.44 (s, 3H), 2.01 (p, J = 7.9Hz, 2H), 1.18 (t, J = 7.4Hz, 3H).

[0745] Embodiment 34

[0746] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(oxetan-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0747] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(oxetane-3-methylene)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0748]

[0749]

[0750] first step

[0751] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(oxetan-3-ylidenemet hyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0752] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(oxetane-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0753] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 4,4,5,5-tetramethyl-2-(oxetane-3-methylene)-1,3,2-dioxaborolane 34a (14.91 mg, 76.05 μmol, according to the published patent WO2021076938) were added. Prepared), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80 ° C for 1.5 hours, water (20 mL) was added to the reaction solution, and ethyl acetate (40 mL × 3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-5-ethyl-2-(oxetane-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 34b (40 mg), yield: 81.11%.

[0754] MS m / z(ESI):778.2[M+1]

[0755] Step 2

[0756] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(oxetan-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0757] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(oxetane-3-methylene)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0758] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(oxetane-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 34b (35 mg, 44.98 μmol) was dissolved in dichloromethane (1.5 mL), and then trifluoroacetic acid (1.5 mL) was added dropwise and reacted at room temperature for 48 hours. After the reaction was completed, it was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(oxetane-3-methylene)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 34 (4.07 mg) with a yield of 13.15%.

[0759] MS m / z(ESI):688.7[M+1]

[0760] 1H NMR (400MHz, DMSO-d6) δ10.66(d,J=2.4Hz,1H),10.23(s,1H),8.58(s,1H),8.16(d,J=8.6 Hz,1H),8.02(d,J=2.1Hz,1H),7.77(dd,J=8.7,2.1Hz,1H),6.98(q,J=1.8Hz,1H),5.71(s, 1H),5.54(s,2H),5.35(s,2H),4.53(d,J=19.6Hz,3H),3.29(t,J=11.8Hz,2H),3.10–2.98( m,2H),2.88(d,J=11.3Hz,1H),2.70(d,J=11.1Hz,1H),2.45(s,3H),1.21(t,J=7.4Hz,3H).

[0761] Embodiment 35

[0762] 2-(2-(benzofuran-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0763] 2-(2-(Benzofuran-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0764]

[0765] first step

[0766] tert-butyl 4-(2-(benzofuran-3-yl)-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

[0767] tert-Butyl 4-(2-(Benzofuran-3-yl)-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

[0768] At room temperature, 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 1c (70 mg, 105.60 μmol), 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolane 35a (25.78 mg, 105.60 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (8.56 mg, 10.56 μmol), and sodium carbonate (33.58 mg, 316.80 μmol) were added to 1,4-dioxane (1 mL), and the atmosphere was replaced with argon four times, and the temperature was raised to 80°C for reaction for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(benzofuran-3-yl)-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 35b (60 mg). Yield: 81.16%. MS m / z (ESI): 644.2 [M-56+1].

[0769] Step 2

[0770] 2-(2-(benzofuran-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0771] 2-(2-(Benzofuran-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0772] 4-(2-(Benzofuran-3-yl)-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 35b (60 mg, 85.70 μmol) was added to dichloromethane (3 mL), followed by the addition of trifluoroacetic acid. (0.3 mL), the reaction was continued for 1 hour, and concentrated under reduced pressure to give 2-(2-(benzofuran-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 35c (50 mg), yield: 97.24%, the crude product was directly used for the next step reaction.

[0773] MS m / z(M+1):600.1[M+1]

[0774] Step 3

[0775] 2-(2-(benzofuran-3-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0776] 2-(2-(Benzofuran-3-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0777] 2-(2-(Benzofuran-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 35c (50 mg, 83.33 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (26.46 mg, 108. 34μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.96mg, 125.00μmol), 1-hydroxybenzotriazole (16.89mg, 125.00μmol), N,N-diisopropylethylamine (53.85mg, 416.67μmol) were added to N,N-dimethylformamide (1.5mL) and reacted at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The aqueous layer was separated and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzofuran-3-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 35d (40 mg) in a yield of 58.09%.

[0778] MS m / z(ESI):826.3[M+1]

[0779] Step 4

[0780] 2-(2-(benzofuran-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0781] 2-(2-(Benzofuran-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0782] 2-(2-(Benzofuran-3-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 35d (40 mg, 48.41 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-(benzofuran-3-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 35 (2.83 mg), yield: 7.60%.

[0783] MS m / z(ESI):736.0[M+1]

[0784] 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.24(s,1H),8.71(s,1H),8.59(s,1H),8.34–8.2 6(m,1H),8.08(d,J=8.5Hz,1H),7.98(d,J=2.1Hz,1H),7.75–7.68(m,2H),7.42(dtd,J=1 9.0,7.4,1.4Hz,2H),5.42(s,2H),4.55(d,J=12.5Hz,1H),3.53(t,J=11.1Hz,3H),3.04( d,J=9.7Hz,4H),2.86(d,J=11.4Hz,1H),2.70(s,1H),2.45(s,3H),1.23(t,J=7.4Hz,3H).

[0785] Embodiment 36

[0786] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0787] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0788]

[0789]

[0790] first step

[0791] (E)-2-(2-cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0792] 2,2,6,6-Tetramethylpiperidine (379.53 mg, 2.69 mmol) was added to tetrahydrofuran (4.5 mL), and n-butyllithium (2.5 M n-hexane solution) (2.5 M, 1.07 mL) was added dropwise at -30°C. The reaction was continued at -30°C for 30 minutes, cooled to -78°C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane 36b (600 mg, 2.24 mmol, commercially available) in tetrahydrofuran (4.5 mL) was added dropwise. After 30 minutes, a solution of 1-cyclopropylethanone 36a (188.34 mg, 2.24 mmol, commercially available) in tetrahydrofuran (4.5 mL) was added, and the mixture was heated to room temperature for reaction for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and petroleum ether (30 mL×2) was used for extraction. The water layer was separated and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (E)-2-(2-cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 36c (160 mg) in a yield of 34.34%.

[0793] Step 2

[0794] (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-cyclopropylprop-1-en-1-yl) -5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0795] (E)-2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0796] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), (E)-2-(2-cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 36c (15.83 mg, 76.05 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), and sodium carbonate (20.15 mg, 190.11 μmol) were added to 1% paraffin. , 4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80°C for reaction for 1.5 hours, water (20 mL) was added to the reaction solution, and ethyl acetate (40 mL×3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 36d (30 mg), yield: 59.91%.

[0797] MS m / z(ESI):790.3[M+1]

[0798] Step 3

[0799] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0800] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0801] (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 36d (30 mg, 37.96 μmol) was added to dichloromethane (3 mL), and boron trichloride (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-cyclopropylprop-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 36 (3.46 mg) in a yield of 12.24%.

[0802] MS m / z(ESI):699.7[M+1]

[0803] 1 H NMR (400MHz, DMSO-d6) δ10.38–10.29(m,1H),10.24(s,1H),8.58(s,1H),8.05(t,J=8.5Hz,1H),7.96(d,J=2.2Hz,1H),7 .73–7.65(m,1H),6.21(d,J=13.3Hz,1H),5.30(s,2H),4.52(d,J=12.4Hz,1H),3.50(d,J=10.7Hz,3H),3.40(s,1H),3.33 –3.18(m,2H),2.98(d,J=14.1Hz,3H),2.82(d,J=11.4Hz,1H),2.64(d,J=10.9Hz,1H),2.45(s,3H),2.00(d,J=1.2Hz,1H) ,1.68(ddd,J=13.3,8.9,5.9Hz,1H),1.63(s,1H),1.56(d,J=1.4Hz,1H),1.18(td,J=7.6,3.6Hz,3H),0.77–0.58(m,3H).

[0804] Embodiment 37

[0805] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl )piperazin-1-yl)-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0806] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl]acetamide

[0807]

[0808]

[0809] first step

[0810] (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-(pyridin- 2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0811] (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0812] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), (E)-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine 37a (17.57 mg, 76.05 μmol, according to the known method "European Journal of Organic Chemistry"). Chemistry (2019), 2019 (33), 5624-5635”), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), sodium carbonate (20.15 mg, 190.11 μmol) were added to 1,4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80 ° C for 1.5 hours, water (20 mL) was added to the reaction solution, ethyl acetate (40 mL × 3) was extracted, and the combined organic phase was washed with saturated sodium chloride solution. The residue was purified by silica gel column chromatography (eluent: System B) to give (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-5-ethyl-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 37b (40 mg) in a yield of 77.62%.

[0813] MS m / z(ESI):813.3[M+1]

[0814] Step 2

[0815] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl )piperazin-1-yl)-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0816] (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl]acetamide

[0817] (E)-2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 37b (40 mg, 49.19 μmol) was added to dichloromethane (3 mL), and boron trichloride (0.8 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(2-(pyridin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl]acetamide 37 (2.95 mg) in a yield of 8.15%.

[0818] MS m / z(ESI):722.7[M+1]

[0819] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),10.24(s,1H),8.65(d,J=4.6Hz,1H),8.58(s,1H),8.08(d,J= 8.5Hz,1H),7.98(d,J=2.1Hz,1H),7.90(s,1H),7.78(s,1H),7.72(dd,J=11.1,2.6Hz,1H),7.66(s, 1H),7.58(d,J=16.2Hz,1H),7.41(s,1H),5.38(s,2H),4.53(d,J=12.5Hz,1H),3.51(d,J=12.0Hz,3 H), 3.26 (t, J = 12.8Hz, 2H), 2.84 (d, J = 11.5Hz, 1H), 2.65 (s, 1H), 2.45 (s, 3H), 1.21 (t, J = 7.5Hz, 3H).

[0820] Embodiment 38

[0821] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0822] 2-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0823]

[0824] first step

[0825] tert-butyl 4-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-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

[0826] tert-Butyl 4-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-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

[0827] At room temperature, 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 1c (50 mg, 75.43 μmol), 2-(bicyclo[3.1.0]hex-2-en-3-yl)-4,4,,5,5-tetramethyl -1,3,2-Dioxaborolane 18a (18.65 mg, 90.51 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (6.11 mg, 7.54 μmol), and sodium carbonate (23.98 mg, 226.28 μmol) were added to 1,4-dioxane (1 mL), and the argon gas was replaced four times. The temperature was raised to 80 °C for 1.5 hours, and the reaction was complete under mass spectrometry monitoring. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-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 38a (42 mg) in a yield of 84.10%.

[0828] MS m / z(ESI):605.7[M-56+1]

[0829] Step 2

[0830] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0831] 2-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0832] 4-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-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 38a (42 mg, 63.43 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1 mL) and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 38b (35 mg, yield: 98.18%), and the crude product was used directly in the next reaction.

[0833] MS m / z(ESI):561.8[M+1]

[0834] Step 3

[0835] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0836] 2-(2-(Bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0837] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 38b (35 mg, 62.28 μmol), 3-hydroxypicolinic acid 22a (11.26 mg, 8 0.96μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.91mg, 93.42μmol), 1-hydroxybenzotriazole (12.62mg, 93.42μmol), N,N-diisopropylethylamine (40.24mg, 311.40μmol) were added to N,N-dimethylformamide (2mL) and reacted at room temperature for 4 hours. After the reaction was complete, water (20mL) was added to the reaction solution, and ethyl acetate (30mL×2) was used for extraction. The water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 38 (2.96 mg), yield: 6.74%.

[0838] MS m / z(ESI):683.2[M+1]

[0839] 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.36(s,1H),8.06(d,J=9.9Hz,2H),7 .97(s,1H),7.71(d,J=8.7Hz,1H),7.30(d,J=2.9Hz,2H),6.80(s,1H),5.29(s ,2H),4.54(d,J=12.6Hz,1H),3.43(dd,J=23.8,12.4Hz,4H),2.96(s,4H),2.8 2–2.58(m,4H),1.98(s,1H),1.79(s,1H),1.18(q,J=8.4Hz,3H),1.01(s,1H).

[0840] Embodiment 39

[0841] 2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide

[0842] 2-(2-Cycloheptyl-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide

[0843]

[0844] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 11 (40 mg, 56.17 μmol) was added to methanol (1.5 mL), followed by palladium carbon (6.82 mg, 56.17 μmol) and reacted at room temperature for 16 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure. The residue is purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide 39 (2.9 mg), yield: 7.34%.

[0845] MS m / z(ESI):680.2[M+1]

[0846] 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),9.04(s,1H),7.82–7.67(m,4H),7.19–7.09(m,1H),7.01(dd ,J=7.7,1.7Hz,1H),6.81(t,J=7.5Hz,1H),5.17(s,2H),3.98(s,1H),3.47(dd,J=11.7,3.0Hz,2H) ,3.09(s,2H),2.99–2.85(m,3H),2.70(d,J=10.7Hz,2H),2.20(s,3H),2.01–1.91(m,2H),1.71(dt t,J=15.3,6.5,3.0Hz,4H),1.58(dd,J=7.7,5.2Hz,2H),1.54–1.41(m,4H),1.16(t,J=7.4Hz,3H).

[0847] Embodiment 40

[0848] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-phenoxy-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0849] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-phenoxy-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0850]

[0851] first step

[0852] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-phenoxy-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0853] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-phenoxy-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0854] To a solution of phenol 40a (56.79 mg, 603.42 μmol, commercially available) in tetrahydrofuran (5 mL) was added sodium methoxide (40.75 mg, 754.28 μmol) at 0°C, and the mixture was reacted at 0°C for 1 hour. Then, 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 1c (200 mg, 301.71 μmol) was added to the reaction solution, and the reaction mixture was heated to 70°C and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL), extracted with ethyl acetate (10 mL×3), and the combined organic phase was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-phenoxy-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 40b (100 mg), yield: 49.02%.

[0855] MS m / z(ESI):620.2[M-55]

[0856] Step 2

[0857] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-phenoxy-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0858] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-phenoxy-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0859] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-phenoxy-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 40b (100 mg, 147.91 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-phenoxy-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 40c (90 mg), yield: 54.26%.

[0860] MS m / z(ESI):576.2[M+1]

[0861] Step 3

[0862] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-phenoxy-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0863] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-phenoxy-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0864] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-phenoxy-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 40c (90 mg, 156.26 μmol) in N,N-dimethylformamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.93 μmol) at room temperature. mg, 234.39 μmol), 5-hydroxy-6-methylpyrimidine-4-carboxylic acid 27a (72.25 mg, 468.78 μmol), 1-hydroxybenzotriazole (31.67 mg, 234.39 μmol) and N, N-diisopropylethylamine (60.58 mg, 468.78 μmol) were reacted at room temperature for 16 hours. After the reaction was completed, the filtrate was filtered and purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm I.D.; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to obtain N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-phenoxy-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 40 (2 mg) with a yield of 1.80%.

[0865] MS m / z(ESI):712.3[M+1]

[0866] 1 H NMR (400MHz, MeOD-d4) δ8.48 (s, 1H), 8.13 (d, J = 8.8Hz, 1H), 7.84–7.76 (m, 1H), 7.64–7. 59(m,1H),7.40–7.32(m,2H),7.26(d,J=7.6Hz,2H),7.20(t,J=7.2Hz,1H),5.29(s,2H) ,4.75–4.63(m,1H),4.13–3.92(m,1H),3.70(d,J=9.6Hz,2H),3.52–3.39(m,1H),3.17– 3.05(m,3H),2.92(d,J=11.2Hz,1H),2.77(d,J=10.8Hz,1H),2.49(s,3H),1.29(t,3H).

[0867] Embodiment 41

[0868] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0869] 2-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0870]

[0871] first step

[0872] tert-butyl 4-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-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

[0873] tert-Butyl 4-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-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

[0874] At room temperature, 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 1c (60 mg, 90.51 μmol), 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4,4,5,5-tetramethyl -1,3,2-Dioxaborolane 23c (23.91 mg, 108.62 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (7.34 mg, 9.05 μmol), and sodium carbonate (28.78 mg, 271.54 μmol) were added to 1,4-dioxane (1 mL), and the argon gas was replaced four times. The temperature was raised to 80 °C for 1.5 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 4-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-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 41a (60 mg) in a yield of 98.04%.

[0875] MS m / z(ESI):675.8[M+1]

[0876] Step 2

[0877] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0878] 2-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0879] 4-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-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 41a (60 mg, 88.74 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1 mL) and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 41b (50 mg) with a yield of 97.82%. The crude product was directly used in the next reaction.

[0880] MS m / z(ESI):575.8[M+1]

[0881] Step 3

[0882] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0883] 2-(2-(Bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0884] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 41b (50 mg, 86.80 μmol), 3-hydroxypicolinic acid 22a (15.70 mg, 112 .84μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.96mg, 130.21μmol), 1-hydroxybenzotriazole (17.59mg, 130.21μmol), N,N-diisopropylethylamine (56.09mg, 434.02μmol) were added to N,N-dimethylformamide (2mL) and reacted at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The water layer was separated and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 41 (3.28 mg) in a yield of 5.36%.

[0885] MS m / z(ESI):697.2[M+1]

[0886] 1H NMR (400MHz, DMSO-d6) δ10.47(s,1H),10.36(s,1H),8.14–8.01(m,2H),7.97(s,1H),7.71(d,J= 8.7Hz,1H),7.32(d,J=3.1Hz,2H),6.75(d,J=3.1Hz,1H),5.30(s,2H),4.55(d,J=12.8Hz,1H),3. 57–3.33(m,4H),3.00(d,J=27.0Hz,4H),2.79(d,J=11.3Hz,1H),2.62(d,J=10.5Hz,1H),1.78(d, J=7.2Hz,2H),1.46(s,1H),1.26(d,J=8.5Hz,1H),1.18(t,J=7.4Hz,3H),1.03(d,J=25.7Hz,2H).

[0887] Embodiment 42

[0888] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0889] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0890]

[0891] first step

[0892] 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0893] 2-Bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0894] In an ice bath, under argon, a solution of 2-bromoacetyl bromide 24b (605.01 mg, 3.00 mmol, 260.33 μL) in dichloromethane (7 mL) was added dropwise to a solution of 2-methyl-4-(trifluoromethyl)aniline 42a (500 mg, 2.85 mmol, commercially available) and 4-dimethylaminopyridine (348.76 mg, 2.85 mmol) in dichloromethane (20 mL), and the mixture was reacted at room temperature for 16 hours. The reaction was monitored to be complete, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 42b (640 mg) in a yield of 75.72%.

[0895] MS m / z(ESI):296.0[M+1]

[0896] Step 2

[0897] tert-butyl 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)piperazine-1-carboxylate

[0898] tert-Butyl 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)piperazine-1-carboxylate

[0899] At room temperature, 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 42b (270.24 mg, 912.72 μmol), 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 1a (300 mg, 702.09 μmol), N,N-diisopropylethylamine (453.69 mg, 3.51 mmol) were added to N,N-dimethylformamide (12 mL), and the temperature was raised to 60°C for 1.5 hours. The reaction was monitored for completion. Water (20 mL) was added to the solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 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)piperazine-1-carboxylate 42c (451 mg). Yield: 99.98%.

[0900] MS m / z(ESI):586.1[M-56+H]

[0901] Step 3

[0902] tert-butyl 4-(2-(cyclohept-1-en-1-yl)-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)piperazine-1-carboxylate

[0903] tert-Butyl 4-(2-(cyclohept-1-en-1-yl)-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)piperazine-1-carboxylate

[0904] At room temperature, tert-butyl 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)piperazine-1-carboxylate 42c (250 mg, 389.13 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4a (103.72 mg, 466.95 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31.54 mg, 38.91 μmol), and sodium carbonate (123.73 mg, 1.17 mmol) were added to 1,4-dioxane ( The mixture was added into a mixed solvent of 4-(2-(cyclohept-1-en-1-yl)-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)piperazine-1-carboxylic acid tert-butyl ester 42d (250 mg) was obtained in a yield of 97.68%.

[0905] MS m / z(ESI):658.3[M+1]

[0906] Step 4

[0907] 2-(2-(cyclohept-1-en-1-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

[0908] 2-(2-(Cyclohept-1-en-1-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

[0909] At room temperature, trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl 4-(2-(cyclohept-1-en-1-yl)-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)piperazine-1-carboxylate 42d (150 mg, 228.06 μmol) in dichloromethane (6 mL), and the mixture was reacted at room temperature for 40 minutes. The reaction was monitored for completion. The reaction solution was concentrated under reduced pressure to give 2-(2-(cyclohept-1-en-1-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 42e (127.1 mg) with a yield of 99.95%. The crude product was used directly in the next step.

[0910] MS m / z(ESI):558.3[M+1]

[0911] Step 5

[0912] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0913] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0914] At room temperature, 3-hydroxyisonicotinic acid 9d (15.72 mg, 112.98 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.88 mg, 150.64 μmol), 1-hydroxybenzotriazole (20.35 mg, 150.64 μmol), N,N-diisopropylethylamine (48.67 mg, 376.61 μmol) were added to N,N-dimethylformamide (1.5 mL) and reacted at room temperature for 40 minutes, then a solution of 2-(2-(cyclohept-1-en-1-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 42e (42 mg, 75.32 μmol) in N,N-dimethylformamide (2 mL) was added and reacted at room temperature for 16 hours. After the reaction was monitored, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 42 (18.84 mg) with a yield of 34.53%.

[0915] MS m / z(ESI):679.3[M+1]

[0916] 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.03(s,1H),8.32(s,1H),8.26(d,J=5.1Hz,1H),7.72(d,J=8.4Hz,1H),7.63 (d,J=2.1Hz,1H),7.60–7.47(m,2H),7.10(t,J=6.8Hz,1H),5.24(s,2H),4.53(d,J=12.5Hz,1H),3.47(q,J=10.8,10. 3Hz,2H),3.30(q,J=12.1,11.4Hz,2H),3.14–2.89(m,3H),2.80(d,J=11.2Hz,1H),2.78–2.70(m,2H),2.64(d,J=11.2 Hz, 1H), 2.36 (s, 3H), 2.32 (d, J = 6.2Hz, 2H), 1.79 (q, J = 6.0Hz, 2H), 1.53 (h, J = 9.0, 7.1Hz, 4H), 1.19 (t, J = 7.4Hz, 3H).

[0917] Embodiment 43

[0918] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0919] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0920]

[0921]

[0922] first step

[0923] 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0924] 2-Bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0925] In an ice bath and argon, a solution of 2-bromoacetyl bromide 24b (554.37 mg, 2.75 mmol, 238.54 μL) in dichloromethane (7 mL) was added dropwise to a solution of 2-methoxy-4-(trifluoromethyl)aniline 43a (500 mg, 2.62 mmol) and 4-dimethylaminopyridine (319.57 mg, 2.62 mmol) in dichloromethane (9.76 mL), and the mixture was reacted at room temperature for 16 hours. The reaction was monitored to be complete. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43b (690 mg) in a yield of 84.52%.

[0926] MS m / z(ESI):312.0[M+1]

[0927] Step 2

[0928] tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0929] tert-Butyl 4-(2-bromo-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0930] At room temperature, 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43b (350.58 mg, 1.12 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 1a (400 mg, 936.12 μmol), and N,N-diisopropylethylamine (362.95 mg, 2.81 mmol) were added to N,N-dimethylformamide (15 mL), and the temperature was raised to 60°C for 1.5 hours to monitor the completion of the reaction. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 43c (520 mg) in a yield of 84.36%.

[0931] MS m / z(ESI):604.1[M-56+H]

[0932] Step 3

[0933] tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0934] tert-Butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0935] At room temperature, tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 43c (250 mg, 379.67 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dihydro- Borolane 4a (109.64 mg, 493.57 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (30.77 mg, 37.97 μmol), and sodium carbonate (120.72 mg, 1.14 mmol) were added to a mixed solution of 1,4-dioxane (3 mL) and water (0.5 mL). The argon gas was replaced three times, the temperature was raised to 85 °C for 2 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 43d (255 mg), yield: 99.69%.

[0936] MS m / z(ESI):618.3[M-56+H]

[0937] Step 4

[0938] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0939] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0940] At room temperature, trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 43d (255 mg, 378.49 μmol) in dichloromethane (6 mL), and the mixture was reacted at room temperature for 40 minutes. The reaction was monitored for completion. The reaction mixture was concentrated under reduced pressure to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43e (217 mg) with a yield of 99.95%. The crude product was used directly in the next step.

[0941] MS m / z(ESI):574.3[M+1]

[0942] Step 5

[0943] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0944] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0945] At room temperature, 3-hydroxyisonicotinic acid 9d (18.19 mg, 130.75 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.42 mg, 174.33 μmol), 1-hydroxybenzotriazole (23.56 mg, 174.33 μmol), N,N-diisopropylethylamine (56.33 mg, 435.84 μmol) were added to N,N-dimethyl The mixture was added to formamide (2 mL) and reacted at room temperature for 40 minutes. Then 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43e (50 mg, 87.17 μmol) was added and reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43 (21.52 mg), yield: 34.86%.

[0946] MS m / z(ESI):695.3[M+1]

[0947] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.12(s,1H),8.31(s,1H),8.24(d,J=5.1Hz,1H),8.20(d,J=8.5Hz,1H),7.47(d, J=5.1Hz,1H),7.37(d,J=1.9Hz,1H),7.28(d,J=8.3Hz,1H),7.06(t,J=6.7Hz,1H),5.31(s,2H),4.52(d,J=12.6Hz,1H), 3.99(s,3H),3.47(q,J=10.2,9.7Hz,2H),3.28(dt,J=23.9,12.5Hz,2H),2.95(q,J=10.8,7.8Hz,3H),2.80(d,J=11.1Hz ,1H),2.73(d,J=8.7Hz,2H),2.63(d,J=11.1Hz,1H),2.30(s,2H),1.78(s,2H),1.70–1.43(m,4H),1.15(t,J=7.4Hz,3H).

[0948] Embodiment 44

[0949] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0950] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0951]

[0952]

[0953] first step

[0954] 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0955] 2-Bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0956] In an ice bath, under argon, a solution of 2-bromoacetyl bromide 24b (1.35 g, 6.70 mmol, 581.88 μL) in dichloromethane (5 mL) was added dropwise to a solution of 2-fluoro-4-(trifluoromethyl)aniline 44a (1 g, 5.58 mmol, commercially available) and 4-dimethylaminopyridine (682.08 mg, 5.58 mmol) in dichloromethane (10 mL), and the reaction was allowed to proceed at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and dichloromethane (20 mL×3) was used for extraction. The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44b (1.6 g) with a yield of 95.51%.

[0957] MS m / z(ESI):300.0[M+1]

[0958] Step 2

[0959] tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0960] tert-Butyl 4-(2-bromo-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0961] At room temperature, 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44b (421.32 mg, 1.40 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 1a (500 mg, 1.17 mmol), and N,N-diisopropylethylamine (756.15 mg, 5.85 mmol) were added to N,N-dimethylformamide (7 mL), and the temperature was raised to 50°C for 1.5 hours to react, and the reaction was monitored for completion. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44c (710 mg) in a yield of 93.86%.

[0962] MS m / z(ESI):590.2[M-56+H]

[0963] Step 3

[0964] tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0965] tert-Butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0966] At room temperature, tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44c (300 mg, 464.09 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44c (300 mg, 464.09 μmol) and tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44c (300 mg, 464.09 μmol) were added. Oxaborolane 4a (134.01 mg, 603.31 μmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (37.62 mg, 46.41 μmol), and sodium carbonate (147.57 mg, 1.39 mmol) were added to a mixed solution of 1,4-dioxane / water (10 / 1 mL), and the atmosphere was replaced with argon three times. The temperature was raised to 85 °C for 3 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44d (200 mg) in a yield of 65.13%.

[0967] MS m / z(ESI):606.3[M-56+H]

[0968] Step 4

[0969] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0970] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0971] At room temperature, trifluoroacetic acid (1.5 mL) was added to tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 44d (200 mg, 302.26 μmol) in dichloromethane (6 mL) and the mixture was stirred for 1 h. L) solution, react at room temperature for 40 minutes, monitor the reaction completion, and concentrate under reduced pressure to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazine-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44e (169 mg), yield: 99.56%, the crude product was directly used in the next step.

[0972] MS m / z(ESI):562.3[M+1]

[0973] Step 5

[0974] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0975] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0976] At room temperature, 3-hydroxyisonicotinic acid 9d (15.61 mg, 112.18 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.67 mg, 149.58 μmol), 1-hydroxybenzotriazole (20.21 mg, 149.58 μmol), N,N-diisopropylethylamine (48.33 mg, 373.95 μmol) were added to N,N- The mixture was added to dimethylformamide (1.5 mL) and reacted at room temperature for 30 minutes. Then, 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44e (42 mg, 74.79 μmol) was added and reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44 (14.02 mg), yield: 26.88%.

[0977] MS m / z(ESI):683.2[M+1]

[0978] 1H NMR (400MHz, DMSO-d6) δ11.32(s,1H),10.71(s,1H),8.59–8.15(m,3H),7.88–7.73(m,1H),7.55(dd,J=13. 3,6.9Hz,2H),7.07(t,J=6.7Hz,1H),5.30(s,2H),4.55(s,1H),3.48(q,J=10.6,9.9Hz,2H),3.31(q,J=12. 2Hz,2H),2.97(dq,J=14.1,8.5,7.6Hz,3H),2.81(d,J=11.1Hz,1H),2.78–2.70(m,2H),2.64(d,J=11.2Hz, 1H), 2.31 (q, J = 6.2Hz, 2H), 1.78 (q, J = 5.8, 5.3Hz, 2H), 1.51 (dt, J = 12.0, 6.0Hz, 4H), 1.17 (t, J = 7.4Hz, 3H).

[0979] Embodiment 45

[0980] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0981] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0982]

[0983] At room temperature, 3-hydroxypicolinic acid 22a (21.30 mg, 153.11 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.13 mg, 204.14 μmol), 1-hydroxybenzotriazole (27.58 mg, 204.14 μmol), N,N-diisopropylethylamine (65.96 mg, 510.36 μmol) were added to N,N-dimethylformamide (1.5 m L), react at room temperature for 40 minutes, then add N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 9c (59 mg, 102.07 μmol) in N,N-dimethylformamide (2 mL), react at room temperature for 4 hours, and monitor the completion of the reaction. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 45 (24.45 mg), yield: 33.92%.

[0984] MS m / z(ESI):699.3[M+1]

[0985] 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),10.37(s,1H),8.19–8.03(m,2H),7.97(d,J=2.0Hz,1H),7.72(dd, J=8.7,2.1Hz,1H),7.43–7.25(m,2H),7.10(t,J=6.8Hz,1H),5.31(s,2H),4.55(d,J=12.4Hz,1H),3.59– 3.34(m,3H),3.22(t,J=13.0Hz,1H),2.97(h,J=8.4,7.8Hz,3H),2.85–2.67(m,3H),2.62(d,J=10.9Hz,1 H), 2.31 (q, J=6.3, 5.7Hz, 2H), 1.78 (q, J=5.9Hz, 2H), 1.52 (h, J=8.7, 7.0Hz, 4H), 1.18 (t, J=7.4Hz, 3H).

[0986] Embodiment 46

[0987] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-

[0988] [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-

[0989] a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide

[0990]

[0991] At room temperature, 3-hydroxypicolinic acid 22a (17.34 mg, 124.66 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.86 mg, 166.21 μmol), 1-hydroxybenzotriazole (22.46 mg, 166.21 μmol), N,N-diisopropylethylamine (53.70 mg, 415.54 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 40 minutes. Then, 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 25e (50 mg, 83.11 μmol) was added to the reaction mixture and reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to obtain 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyeicosanoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfoalkyl)phenyl)acetamide 46 (16 mg), yield: 26.32%.

[0992] MS m / z(ESI):723.3[M+1]

[0993] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.47(s,1H),8.08(dd,J=3.8,2.1Hz,1H),7.88(d,J=9.0Hz,2H),7.77(d,J=8 .9Hz,2H),7.32(d,J=3.7Hz,2H),7.04(t,J=6.8Hz,1H),5.19(s,2H),4.55(d,J=11.8Hz,1H),3.42(d,J=15.1Hz,2H), 3.23(t,J=12.0Hz,1H),2.96(p,J=7.2,6.5Hz,3H),2.80(d,J=11.3Hz,1H),2.77–2.68(m,2H),2.62(d,J=11.1Hz,1H) ,2.30(q,J=6.3Hz,2H),2.08(s,1H),1.78(p,J=5.6Hz,2H),1.51(dp,J=17.2,6.1,5.6Hz,4H),1.16(t,J=7.4Hz,3H).

[0994] Embodiment 47

[0995] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-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

[0996] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-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

[0997]

[0998] first step

[0999] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-eth yl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[1000] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[1001] At room temperature, 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (55.19 mg, 225.96 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.76 mg, 301.29 μmol), 1-hydroxybenzotriazole (40.71 mg, 301.29 μmol), N,N-diisopropylethylamine (97.35 mg, 753.22 μmol) were added to N,N-dimethylformamide. The mixture was added to 4-nitropropene amide (1.5 mL) and reacted at room temperature for 40 minutes, and then a solution of 2-(2-(cyclohept-1-en-1-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 42e (84 mg, 150.64 μmol) in N,N-dimethylformamide (2 mL) was added and reacted at room temperature for 16 hours. The reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 47a (118 mg). Yield: 99.93%. MS m / z (ESI): 784.3 [M+1]

[1002] Step 2

[1003] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-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

[1004] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-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

[1005] In an ice bath and under argon, boron trichloride (1.5 mL) was added to a solution of 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 47a (118 mg, 150.54 μmol) in dichloromethane (1 mL). The reaction was allowed to react at room temperature for 16 hours and the reaction was monitored for completion. The product was quenched with methanol and concentrated. The methanol solution was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 47 (36.41 mg), 34.31%.

[1006] MS m / z(ESI):694.3[M+1]

[1007] 1H NMR (400MHz, DMSO-d6) δ10.25(s,1H),10.02(s,1H),8.58(s,1H),7.72(d,J=8.4Hz,1H),7.63(d,J=2.1Hz,1H),7.5 3(dd,J=8.5,2.2Hz,1H),7.10(t,J=6.8Hz,1H),5.24(s,2H),4.53(d,J=12.4Hz,1H),3.57–3.40(m,3H),3.25(t,J=1 2.1Hz,1H),2.99(q,J=9.1,8.6Hz,3H),2.81(d,J=11.3Hz,1H),2.75(d,J=8.6Hz,2H),2.63(d,J=10.6Hz,1H),2.45 (s,3H),2.36(s,3H),2.35–2.27(m,2H),1.79(d,J=7.0Hz,2H),1.53(dt,J=11.4,5.5Hz,4H),1.19(t,J=7.4Hz,3H).

[1008] Embodiment 48

[1009] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[1010] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[1011]

[1012] At room temperature, 5-hydroxy-6-methylpyrimidine-4-carboxylic acid 27a (28.21 mg, 183.05 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46.79 mg, 244.07 μmol), 1-hydroxybenzotriazole (32.98 mg, 244.07 μmol), N,N-diisopropylethylamine (78.86 mg, 610.17 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 40 minutes. 2-(2-(cyclohept-1-en-1-yl)-5- Ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43e (70 mg, 122.03 μmol) was reacted at room temperature for 48 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL×3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19mm ID; 10μm, 20mL / min; mobile phase A: 10mmol NH4HCO3, mobile phase B: CH3CN), to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 48 (4.3mg), yield: 4.91%.

[1013] MS m / z(ESI):710.3[M+1]

[1014] 1H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.12(s,1H),8.59(s,1H),8.20(d,J=8.4Hz,1H),7.37(d,J=1.9Hz,1H),7. 28(dd,J=8.6,1.9Hz,1H),7.06(t,J=6.8Hz,1H),5.31(s,2H),4.52(d,J=12.5Hz,1H),3.99(s,3H),3.50(q,J=11.0 ,10.1Hz,3H),3.24(t,J=12.7Hz,1H),3.06–2.87(m,3H),2.81(d,J=11.5Hz,1H),2.77–2.69(m,2H),2.63(d,J=11 .0Hz,1H),2.45(s,3H),2.35–2.24(m,2H),1.86–1.72(m,2H),1.53(dt,J=13.5,6.0Hz,4H),1.16(t,J=7.4Hz,3H).

[1015] Embodiment 49

[1016] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1017] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1018] first step

[1019] 2-(6-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(cyclohept-1-en-1-yl)-5-eth yl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1020] 2-(6-(1-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1021] At room temperature, 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (82.85mg, 339.23μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86.71mg, 452.30μmol), 1-hydroxybenzotriazole (61.11mg, 452.30μmol), N,N-diisopropylethylamine (146.14mg, 1.13mmol) were added. Add N,N-dimethylformamide (2 mL) and react at room temperature for 30 minutes, then add 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44e (127 mg, 226.15 μmol) and react at room temperature for 16 hours. Monitor the reaction until complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 49a (178 mg), yield: 99.91%.

[1022] MS m / z(ESI):788.3[M+1]

[1023] Step 2

[1024] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1025] 2-(2-(Cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[1026] In an ice bath and under argon, boron trichloride (2 mL) was added to a solution of 2-(6-(1-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 49a (80 mg, 101.55 μmol) in dichloromethane (2 mL). The reaction was allowed to react at room temperature for 3 hours and the reaction was monitored for completion. The mixture was quenched with ice water and concentrated. The methanol solution was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3, mobile phase B: CH3CN) to give 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 49 (9.51 mg) with a yield of 13.29%.

[1027] MS m / z(ESI):698.3[M+1]

[1028] 1H NMR (400MHz, DMSO-d6) δ10.70(s,1H),10.27(s,1H),8.59(s,1H),8.23(t,J=8.2Hz,1H),7.80(dd,J=11.0,2.0Hz,1H ),7.57(dd,J=8.7,2.0Hz,1H),7.07(t,J=6.8Hz,1H),5.29(s,2H),4.52(d,J=12.5Hz,1H),3.52(s,1H),3.48(d,J=9 .9Hz,2H),3.34–3.17(m,1H),3.07–2.89(m,3H),2.81(d,J=11.4Hz,1H),2.76–2.71(m,2H),2.64(d,J=11.0Hz,1H), 2.45(s,3H),2.31(q,J=6.4Hz,2H),1.78(q,J=5.0,3.7Hz,2H),1.53(dt,J=13.4,6.0Hz,4H),1.17(t,J=7.4Hz,3H).

[1029] Embodiment 50

[1030] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pi perazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1031] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1032]

[1033] first step

[1034] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(spiro[3.3]hept -1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1035] 2-(6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1036] At room temperature, 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 3b (50 mg, 63.37 μmol), 4,4,5,5-tetramethyl-2-(spiro[3.3]hept-1-en-2-yl)-1,3,2-dioxo- Borolane 50a (16.74 mg, 76.05 μmol, prepared according to the patent publication WO2020128768), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5.14 mg, 6.34 μmol), sodium carbonate (20.15 mg, 190.11 μmol) and 1,4-dioxane (1 mL) were added to a 10 mL double-necked bottle, argon was replaced four times, and the temperature was raised to 80 °C for reaction for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 50b (39 mg), yield: 76.71%. MS m / z (ESI): 801.7 [M+1]

[1037] Step 2

[1038] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pi perazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1039] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1040] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 50b (39 mg, 48.61 μmol) was added to dichloromethane (2.5 mL), and boron trichloride (0.8 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, methanol (2 mL) was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 50 (2.87 mg) in a yield of 8.12%.

[1041] MS m / z(ESI):711.7[M+1]

[1042] 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.24(s,1H),8.58(s,1H),8.08(d,J=8.6Hz,1H),7.9 7(d,J=2.1Hz,1H),7.71(dd,J=8.9,2.1Hz,1H),6.75(s,1H),5.32(s,2H),4.52(d,J=12.6Hz ,1H),3.48(t,J=11.7Hz,3H),3.23(d,J=12.5Hz,1H),3.04–2.93(m,3H),2.81(s,3H),2.63( d,J=10.8Hz,1H),2.44(s,3H),2.26–2.12(m,4H),1.94–1.79(m,2H),1.18(t,J=7.4Hz,3H).

[1043] Embodiment 51

[1044] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1045] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1046]

[1047] first step

[1048] tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1049] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1050] At room temperature, 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 1c (50 mg, 75.43 μmol), 4,4,5,5-tetramethyl-2-(spiro[3.3]hept-1-en-2-yl)-1,3,2-dioxaborolane 50a (19.92 mg, 90.51 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.11 mg, 7.54 μmol), sodium carbonate (23.98 mg, 226.28 μmol) and 1,4-dioxane were added. The residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 51a (47 mg) in a yield of 92.16%.

[1051] MS m / z(ESI):676.2[M+1]

[1052] Step 2

[1053] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1054] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1055] 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 51a (47 mg, 69.51 μmol) was added to dichloromethane (2.5 mL), trifluoroacetic acid (0.8 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 51b (40 mg), which was directly used for the next step reaction.

[1056] MS m / z(ESI):576.2[M+1]

[1057] Step 3

[1058] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1059] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1060] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 51b (40 mg, 69.44 μmol), 3-hydroxypicolinic acid 22a (12.56 mg, 90.28 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.97 mg, 104.16 μmol), 1-hydroxybenzotriazole (14.07 mg, 104.16 μmol) and N,N-diisopropylethylamine (44.87 mg, 347.21 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×3), the water layer was separated, and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-2-(spiro[3.3]hept-1-en-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 51 (3.30 mg), yield: 6.77%.

[1061] MS m / z(ESI):696.7[M+1]

[1062] 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.34(s,1H),8.11–8.03(m,2H),7.97(d,J=2.1Hz,1H),7 .71(dd,J=8.8,2.1Hz,1H),7.38–7.28(m,2H),6.75(s,1H),5.32(s,2H),4.54(d,J=12.7Hz,1H), 3.44(dd,J=21.8,11.7Hz,3H),3.22(t,J=12.2Hz,1H),2.99(d,J=5.6Hz,3H),2.81(s,3H),2.69– 2.53(m,1H),2.46–2.43(m,1H),2.19(q,J=6.4Hz,4H),1.93–1.81(m,2H),1.18(t,J=7.4Hz,3H).

[1063] Biological evaluation

[1064] Test Example 1: Test on the Inhibition of WRN Enzyme Activity (ATPase) by the Compounds of the Invention

[1065] The following method is used to determine the degree of inhibition of the recombinant human WRN ATPase activity by the compounds of the present invention under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay Kit (Cat. No. V9102). For detailed experimental procedures, please refer to the kit instructions.

[1066] The experimental process is briefly described as follows: the test compound was first dissolved in DMSO to prepare a storage solution, and then gradiently diluted using reaction buffer (30mM Tris, pH 7.5, 2mM MgCl2, 50mM NaCl, 0.02% BSA, 0.1% Pluronic F127). The final concentration range of the test compound in the reaction system was 1000nM to 0.004nM; the reaction buffer was used to prepare WRN protein (purchased from BPS, product number 101264), substrate Flap26 (commissioned to Shanghai Jierui Bioengineering Co., Ltd. for synthesis, sequence 5'-TTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC-3'), ATP working solution (from ADP-Glo TM Kinase Assay kit component V915A). The reaction was carried out in a 384-well microplate. First, the compound and recombinant human WRN protein (final concentration 5nM) were added to the wells and incubated at room temperature for 15 minutes. Then, Flap solution (final concentration 0.1nM) and ATP solution (final concentration 30uM) were added to the reaction solution and incubated at room temperature for 10 minutes. Then 5μL ADP-Glo ​​Reagent was added to the reaction system and incubated at room temperature for 40 minutes. Then 10μL KinaseDetection Reagent was added to the reaction system and incubated at room temperature for 30 minutes. After the incubation, the chemiluminescence intensity value of each well was measured in the luminescence mode of the microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration logarithm-inhibition rate was performed using GraphPad Prism 9 software to obtain the IC of the compound. 50 Values ​​are shown in Table 1.

[1067] IC of the compounds of the present invention 50 The value results are represented by AA and A, respectively:

[1068] "AA" means IC 50 ≤1nM; "A" means 1nM <IC 50 ≤100nM.

[1069] Table 1 IC50 of the compounds of the present invention for inhibiting WRN enzyme activity (ATPase)

[1070]

[1071]

[1072] Conclusion: The compounds of the present invention have a good inhibitory effect on WRN enzyme activity (ATPase).

[1073] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on SW48 cell proliferation

[1074] The following method was used to determine the effect of the compounds of the present invention on the proliferation of SW48 cells. SW48 cells (MSI-H cells) were purchased from the ATCC cell bank in the United States and cultured in Leibovitz's L-15 (Gibco, catalog number 11415064) medium containing 10% fetal bovine serum, 100 U penicillin and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).

[1075] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 10000nM to 1.52nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 500 cells per well, cultured overnight at 37°C in an air incubator, and then the test compound was added and continued to be cultured for 120 hours. After the culture was completed, 40uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then the luminescence value of each well of the sample was read on the microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.1% DMSO), and then a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration-inhibition rate to obtain the IC of the compound to inhibit cell proliferation. 50 Values ​​are shown in Table 2.

[1076] IC of the compounds of the present invention 50 The value result is expressed in A, where "A" means 1nM <IC50 ≤100nM.

[1077] Table 2 IC of the compounds of the present invention on the inhibition of SW48 cell proliferation 50 data

[1078] Example No. <![CDATA[IC 50 (nM)]]> 17 A 18 A 19 A 22 A 27 A 33 A 49 A

[1079] Conclusion: The compounds of the present invention have a good inhibitory effect on the proliferation of SW48 cells.

[1080] Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on RL95-2 cell proliferation

[1081] The following method was used to determine the effect of the compounds of the present invention on the proliferation of RL95-2 cells. RL95-2 cells (MSI-H cells) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in DMEM / F12 medium (Gibco, catalog number A4192001) containing 10% fetal bovine serum, 100 U penicillin and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).

[1082] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 10000nM to 1.52nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 500 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 120 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then the luminescence value of each well of the sample was read on the microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.1% DMSO), and then a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration-inhibition rate to obtain the IC of the compound to inhibit cell proliferation. 50 Values ​​are shown in Table 3.

[1083] IC of the compounds of the present invention 50 The value result is expressed in A, where "A" means 1nM <IC 50 ≤100nM.

[1084] Table 3 IC of the compounds of the present invention on the inhibition of RL95-2 cell proliferation50 data

[1085] Example No. <![CDATA[IC 50 (nM)]]> 17 A 18 A 19 A 22 A 27 A

[1086] Conclusion: The compounds of the present invention have a good inhibitory effect on the proliferation of RL95-2 cells.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: W is selected from N or CH; X is selected from O or S; Y is selected from CH2, O or S; Z is selected from NH, CH2 or CD2; L is selected from -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or Select from single or double bonds as required so that each atom thereof assumes a normal valence state; Q is selected from C, N or CR d ; R d is selected from a hydrogen atom, a hydroxyl group, a cyano group, a halogen group or a methoxy group; Select from single or double bonds as required so that each atom thereof assumes a normal valence state; The conditions are: when When it is a single bond, K is selected from -(CH2) p - or -NH-, J is N; p is selected from 0, 1 or 2; when When it is a double bond, K is CH and J is C; R a , R b are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 1-6 Alkoxy; or, R a , R b Together with the carbon atom to which they are attached, they form a C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, carbonyl or -NR 6 R 7 substituted by a substituent; R c are the same or different, each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, carbonyl or -NR 6 R 7 substituted by a substituent; Or, two R c Together with the same carbon atom to which it is attached, it forms a -C(=O)-; Or, two R c Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more N, O or S (=O) r ; Or, two R c Together with the different carbon atoms to which they are attached, they form a C 4-6 Cycloalkyl or 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S (=O) r ; R 1 Selected from alkyl, alkenyl, alkynyl, -NR 15 R 16 , alkoxy or alkylthio, wherein the alkyl, alkoxy or alkylthio group is optionally further substituted with one or more selected from R A The alkenyl or alkynyl is substituted by at least one or more substituents selected from aryl, heteroaryl, cycloalkyl, heterocyclic or condensed ring; provided that the heterocyclic group is not morpholinyl; R 15 , R 16 are each independently selected from a hydrogen atom, a deuterium atom or a C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxyl or cyano; Ring A is selected from: 1) C 3-8 Saturated monocyclic alkyl, C 7-8 Partially unsaturated monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cyclic alkyl, wherein the spirocyclic alkyl, fused cyclic alkyl or bridged cyclic alkyl contains 0 or 1 double bond; 2) 4-membered monocyclic heterocyclic group, 7-8-membered monocyclic heterocyclic group, spiro heterocyclic group, wherein the monocyclic heterocyclic group or spiro heterocyclic group contains 0 or 1 double bond, provided that any one of the rings constituting the spiro heterocyclic group is not cyclopropane, wherein the monocyclic heterocyclic group is optionally further connected by two atoms not directly connected to the ring through C 1-2 Alkylene groups are linked to form bridged heterocyclic groups; 3) Bicyclic aryl, bicyclic heteroaryl; Select from single or double bonds as required so that each atom thereof assumes a normal valence state; The conditions are: When selected from a double bond, U is CH, and ring B is selected from a cycloalkyl group, a heterocyclic group or a condensed cyclic group; When selected from a single bond, U is selected from -O-, -N(R e )- or -S-, Ring B is selected from cycloalkyl, heterocyclic, aryl, heteroaryl or fused cyclic groups; R e Selected from hydrogen atoms or C 1-6 alkyl; R A are the same or different and are each independently selected from a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -SF5, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-N(R 6 )C(=O)R 7 、-N(R 6 )C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 、-N(R 9 )C(=O)R 10 or -N(R 9 )C(=O)OR 10 substituted by a substituent; Or, two R A Together with the same carbon atom to which it is attached, it forms a -C(=O)- or -C(=S)-; R 2 is selected from hydrogen atom, deuterium atom, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, -OR 5 、-S(=O) r R 5 or -NR 6 R 7 ; R 3 Selected from hydrogen atoms, C 1-6 Alkyl, amino, hydroxylamino, aryl, heteroaryl, The C 1-6 The alkyl, aryl or heteroaryl groups are optionally further substituted with one or more R B replaced by; R B are the same or different and are each independently selected from a deuterium atom, an alkyl group, a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -SF5, -OR 5 、-OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-N(R 6 )C(=O)R 7 、-N(R 6 )C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 、-N(R 9 )C(=O)R 10 or -N(R 9 )C(=O)OR 10 substituted by a substituent; R 13 , R 14 are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or C 1-6 Alkoxy, or, R 13 , R 14 Together with the carbon atom to which they are attached, they form a C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy or cyano; R 4 The condensed ring is selected from aryl, heteroaryl or bicyclic fused ring, wherein the bicyclic fused ring is preferably a condensed ring composed of a monocyclic aryl or a monocyclic heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl, wherein the aryl, heteroaryl or bicyclic fused ring is optionally further substituted by one or more halogen, hydroxyl, cyano, -SF5, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkenyl, C 1-6 Alkynyl, -NR 6 R 7 、-C(=O)R 5 or -S(=O) r R 5 substituted by a substituent; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent; R 6 and R 7 Each is independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group may be further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a complex containing one or more N, O, or S(=O) r wherein the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent; R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amine group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group may be further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amine group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; and r is independently 0, 1 or 2.

2. The compound according to claim 1, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein W is a nitrogen atom.

3. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X and Y are O atoms. 4 . The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Z is NH and L is —C(═O)—.

5. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein is a single bond; Q is selected from N; is a single bond, K is CH2, and J is N; R c A hydrogen atom.

6. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R a , R b A hydrogen atom.

7. The compound according to any one of claims 1 to 6, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described by general formula (II): in: R 1 , R 2 , R 3 and R 4 The definition is as stated in claim 1.

8. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, -NR 15 R 16 or C 1-6 alkenyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens, wherein the alkenyl group is substituted with at least one substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl or fused ring; provided that the heterocyclyl group is not morpholinyl; R 15 selected from hydrogen atoms; R 16 Selected from C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens.

9. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from Wherein ring A is selected from C 3-8 Saturated monocyclic alkyl, C 7-8 Partially unsaturated monocyclic alkyl, spirocyclic alkyl, condensed cycloalkyl, bridged cycloalkyl, 4-membered monocyclic heterocyclic radical, 7-8-membered monocyclic heterocyclic radical, spiro heterocyclic radical or bicyclic heteroaryl, wherein the spirocyclic alkyl, condensed cycloalkyl, bridged cycloalkyl, 4-membered monocyclic heterocyclic radical, 7-8-membered monocyclic heterocyclic radical or spiro heterocyclic radical contains 0 or 1 double bond, provided that any one of the rings constituting the spiro heterocyclic radical is not cyclopropane; R A Selected from hydrogen atoms, or two R A Together with the same carbon atom to which they are attached, they form a C(=O).

10. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from in is selected from a double bond, U is CH, and ring B is selected from a cycloalkyl or heterocyclyl group; R A Selected from hydrogen atoms.

11. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from in is selected from a single bond, U is selected from O, and ring B is selected from aryl or heteroaryl; R A Selected from hydrogen atoms.

12. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following groups:

13. The compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, deuterium atoms, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 The haloalkyl group is preferably a methyl group or an ethyl group.

14. The compound according to any one of claims 1 to 13, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 The 5- or 6-membered heteroaryl or phenyl group is optionally further substituted by one or more substituents selected from deuterium atoms, hydroxyl groups, halogen groups, alkyl groups, alkylthio groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, and haloalkoxy groups.

15. The compound according to claim 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the following groups:

16. The compound according to any one of claims 1 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from phenyl, wherein the phenyl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkenyl, C 1-6 Alkynyl, -NR 6 R 7 、-C(=O)R 5 or -S(=O) r R 5 substituted by a substituent; R 5 , R 6 , R 7 are independently selected from a hydrogen atom or C 1-6 alkyl; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a complex containing one or more N, O, or S(=O) r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 is substituted by an alkoxy, amino or =O substituent; r is 0, 1 or 2.

17. The compound according to claim 16 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 Selected from the following groups:

18. The compound according to any one of claims 1 to 17 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the compound is:

19. A pharmaceutical composition comprising an effective dose of a compound according to any one of claims 1 to 18 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

20. Use of the compound according to any one of claims 1 to 18 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a WRN inhibitor.

21. Use of a compound according to any one of claims 1 to 18 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for treating a disease mediated by WRN; preferably, the disease mediated by WRN is highly microsatellite instability cancer.

22. The method of claim 21, wherein the highly microsatellite instability cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenal cortical carcinoma, uterine sarcoma, cervical cancer, Wilms tumor, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

23. Use of the compound according to any one of claims 1 to 18 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a drug for treating highly microsatellite instability cancer.

24. The method of claim 23, wherein the highly microsatellite instability cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenal cortical carcinoma, uterine sarcoma, cervical cancer, Wilms tumor, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, bile duct cancer, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, skin melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

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