Azabicyclic derivatives, their preparation methods and uses

Abstract

This invention relates to an azabicyclic derivative, its preparation method, and the pharmaceutical application of pharmaceutical compositions containing the derivative. Specifically, this invention relates to an azabicyclic derivative of general formula (I), its preparation method, its pharmaceutically usable salts, and their use as therapeutic agents, particularly as WRN inhibitors, wherein the definitions of each substituent in general formula (I) are the same as those in the specification.

Description

Azabicyclic derivatives and their preparation methods and uses 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 consists of 1432 amino acid residues and comprises five key components from the N-terminus to the C-terminus: the exonuclease domain, the ATPase domain, the RecQ C-terminal domain, the helicase / RNase D C-terminal domain, and a nuclear localization signal. Of the five human RecQ helicases, WRN is the only one with 3'→5' exonuclease activity. This activity is achieved through the specific activation of its N-terminal exonuclease domain by the Ku70 / 80 complex bound to DNA ends. The ATPase domain is the largest and most conserved component of the RecQ helicase family and serves as the ATP-dependent DNA translocation module by binding and hydrolyzing ATP. The RecQ C-terminal domain is the primary site of DNA binding and catalyzes the unwinding of the DNA duplex. Thus, the ATPase domain and the RecQ C-terminal domain together constitute the core of the WRN helicase. WRN is a DNA helicase with multiple enzymatic activities that can bind 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 of cell death caused by the simultaneous suppression of two non-lethal genes (in the form of genetic defects such as gene mutation and gene silencing and / or molecular perturbations such as gene expression knockout and drug inhibition). By exploiting this mechanism, we can identify a specific mutation in cancer, then identify its "synthetic lethal partner" and inhibit it, thereby specifically killing cancer cells harboring that mutation.

[0004] Studies have shown that WRN is a "synthetic lethal partner" in the genomic damage known as high microsatellite instability (MSI-H). High microsatellite instability (MSI-H) is a hypervariable state caused by defects in DNA mismatch repair (MMR), which leads to frequent insertion and / or deletion mutations in nucleotide repeat regions. It is commonly seen 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 expansion, forming non-canonical right-handed double-helix (non-B) DNA secondary structures (such as cruciform and G-quadruplex). These DNA secondary structures 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, replication protein A (RPA) depletion, chromosome fragmentation, and cell death. Furthermore, in MMR-deficient tumor models, WRN deficiency leads to activation of multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, thereby inhibiting tumor cell proliferation. Recent studies have demonstrated that small molecule WRN inhibitors can specifically induce tumor regression in MSI-H (microsatellite instability-high) tumor models, but have no effect in microsatellite stable (MSS) tumor models. Therefore, small molecule drugs that inhibit WRN helicase activity hold promise as a new and effective treatment for MSI-H cancers.

[0005] Currently, there is a lack of effective inhibitors targeting the WRN target, and no such drugs have been approved for marketing, so there is a huge unmet clinical need.

[0006] Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[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 -NR g C(=O)-;

[0014] R g Selected from hydrogen atoms or C 1-6 alkyl;

[0015] in is selected from a single bond or a double bond;

[0016] Q is selected from C, N or CR d ;

[0017] R d is selected from a hydrogen atom, a hydroxyl group, a cyano group, a halogen group or a methoxy group;

[0018] in Selected from single bonds, double bonds or Does not exist, when Formed when not present

[0019] The conditions are:

[0020] when in When it is a single bond, K is selected from -(CH2) p - or -NH-, J is N; p is selected from 1 or 2;

[0021] when in When it is a double bond, K is CH and J is C;

[0022] R a 、R b are independently selected from hydrogen atoms, deuterium atoms, halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the halogen is preferably fluorine; or, R a 、R b Together with the carbon atoms 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;

[0023] R c the same or different, each independently selected from hydrogen atoms, deuterium atoms, C 1-6Alkyl 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;

[0024] Or, two R c Together with the carbon atom to which it is attached, it forms a -C(=O)-;

[0025] 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 ;

[0026] 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 ;

[0027] 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 group is substituted by one or more substituents selected from R AA substituted by a substituent;

[0028] R AA Selected from halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, fused ring or -C(=O)NR 6 R 7 wherein the aryl, heteroaryl, cycloalkyl, heterocyclic or fused ring is optionally further substituted by one or more selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted by a haloalkoxy, halogen, hydroxyl or cyano substituent, provided that: the heterocyclic group is not morpholinyl;

[0029] R 15 、R 16 are independently selected from hydrogen atoms, deuterium atoms, C 1-6Alkyl or aryl, wherein the C 1-6 The alkyl or aryl group is optionally further substituted with one or more substituents selected from halogen, hydroxy or cyano;

[0030] Ring A is selected from:

[0031] 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;

[0032] 2) 4-membered monocyclic heterocyclic group, 7-8-membered monocyclic heterocyclic group, spiro heterocyclic group, fused heterocyclic group, wherein the monocyclic heterocyclic group, spiro heterocyclic group or fused heterocyclic group contains 0 or 1 double bond, provided that any one ring 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;

[0033] 3) bicyclic aryl, bicyclic heteroaryl or bicyclic fused ring;

[0034] in is selected from a single bond or a double bond;

[0035] The conditions are: in When selected from a double bond, U is CR bb , Ring B is selected from a cycloalkyl group, a heterocyclic group or a fused ring group;

[0036] in 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 group;

[0037] R bb Selected from hydrogen atoms or C 1-6 alkyl;

[0038] R e Selected from hydrogen atoms or C 1-6 alkyl;

[0039] R A the same or different, 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)OR5 、-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, heterocyclic, aryl or heteroaryl radicals are optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, 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;

[0040] Or, two R A Together with the carbon atom to which it is attached, it forms a -C(=O), -C(=S) or -C(=NR cc );

[0041] R cc Selected from hydrogen atoms, hydroxyl groups or C 1-6 alkoxy;

[0042] R 2 Selected from hydrogen atom, deuterium atom, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, -OR 5 、-S(=O) r R 5 or -NR 6 R 7 ;

[0043] R 3 Selected from hydrogen atoms, C 1-6 Alkyl, amino, hydroxylamino, aryl, heteroaryl, The C 1-6 Alkyl, aryl or heteroaryl groups are optionally further substituted with one or more R B replaced by;

[0044] R B the same or different, 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;

[0045] R 13 、R 14 are independently selected from hydrogen atoms, deuterium atoms, C 1-6 Alkyl or C 1-6 Alkoxy, or R 13 、R 14 Together with the carbon atoms to which they are attached, they form a C3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy or cyano;

[0046] R 4 is selected from aryl, heteroaryl or bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring composed of a monocyclic aryl or 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 selected from halogen, hydroxyl, cyano, -SF5, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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;

[0047] R 5 are each 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 are optionally further substituted by one or more deuterium atoms, a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =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;

[0048] R 6 and R 7Each independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be 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 、-S(=O)2NR 9 R 10 or -N(R 9 )C(=O)R 10 substituted by a substituent;

[0049] 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;

[0050] 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 may be further substituted with 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;

[0051] n is 0, 1, 2, 3, 4, 5 or 6;

[0052] m is 0, 1, 2, 3, 4 or 5; and

[0053] r is each independently 0, 1 or 2.

[0054] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein W is a nitrogen atom.

[0055] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein W is CH.

[0056] A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X and Y are O atoms.

[0057] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Z is NH and L is -C(=O)-.

[0058] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein in is a single bond; Q is selected from N or CH;

[0059] in is a single bond, K is CH2 or CH2CH2, and J is N;

[0060] R c A hydrogen atom.

[0061] 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.

[0062] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0063] Where: R 1 、R 2 、R 3 and R 4 The definition of is as described in the general formula (I).

[0064] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0065] Where: R 1 、R 2 、R 3 and R 4 The definition of is as described in the general formula (I).

[0066] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein in is a single bond; Q is selected from N;

[0067] in is a single bond, K is CH2, and J is CH;

[0068] R c is a hydrogen atom;

[0069] L is -NHC(=O)-.

[0070] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from C 1-6 Alkyl, -NR 15 R 16 、C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens, wherein the C 2-6 Alkenyl or C 2-6 Alkynyl is at least one or more selected from R AA substituted by a substituent;

[0071] R AA Selected from halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, fused ring or -C(=O)NR 6 R 7 wherein the aryl, heteroaryl, cycloalkyl, heterocyclic group or fused ring is optionally further substituted by one or more substituents selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, halogen, hydroxyl or cyano; provided that: the heterocyclic group is not morpholinyl;

[0072] R 6 、R 7are each independently selected from a hydrogen atom or an alkyl group; or, R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic group;

[0073] R 15 selected from hydrogen atoms;

[0074] R 16 Selected from C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl or aryl group is optionally further substituted with one or more halogens.

[0075] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) 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, fused cycloalkyl, bridged cycloalkyl, 4-membered monocyclic heterocyclic radical, 7-8-membered monocyclic heterocyclic radical, spiro heterocyclic radical, fused heterocyclic radical, bicyclic heteroaryl or bicyclic fused ring, wherein the spirocyclic alkyl, fused 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 ring constituting the spiro heterocyclic radical is not cyclopropane;

[0076] R A Selected from deuterium atoms, halogens, hydroxyl groups, methoxy groups, NR 6 R 7 、-C(=O)NR 6 R 7 、C 1-6 Alkyl or 5-6 membered heterocyclic group; wherein the C 1-6 The alkyl or 5-6 membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium atoms, hydroxyl groups, halogen groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, or two R A Together with the carbon atom to which they are attached, they form a -C(=O) or -C(=NR cc );

[0077] R 6 、R 7 selected from hydrogen atoms;

[0078] R cc Selected from hydroxyl or methoxy;

[0079] m is 0, 1, 2, 3, 4 or 5.

[0080] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from in in Selected from double bonds, U is CR bb , Ring B is selected from cycloalkyl or heterocyclyl;

[0081] R bb is selected from a hydrogen atom or a methyl group;

[0082] R A Selected from deuterium atoms, halogen, hydroxyl, methyl, methoxy, NR 6 R 7 or -C(=O)NR 6 R 7 ;

[0083] R 6 、R 7 selected from hydrogen atoms;

[0084] m is 0, 1, 2, 3, 4 or 5.

[0085] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from in in is selected from a single bond, U is selected from O, and ring B is selected from aryl or heteroaryl;

[0086] R A selected from hydrogen atoms;

[0087] m is 0.

[0088] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 Selected from the following groups:

[0089] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, deuterium atoms, C 1-3 Alkyl, 3-6 membered cycloalkyl, C 1-3 Hydroxyalkyl or C 1-3The haloalkyl group is preferably a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a cyclobutyl group.

[0090] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 is selected from 5- or 6-membered heteroaryl or phenyl, wherein the 5- or 6-membered heteroaryl or phenyl is optionally further substituted by one or more substituents selected from deuterium atoms, hydroxyl, halogen, alkyl, alkylthio, alkoxy, haloalkyl, hydroxyalkyl, and haloalkoxy.

[0091] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 Selected from the following groups:

[0092] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally further substituted by one or more halogen, hydroxy, cyano, -SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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;

[0093] R 5 、R 6 、R 7 Each independently selected from a hydrogen atom or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more deuterium atoms or halogen;

[0094] 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 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 1-6substituted by an alkoxy, amino or =O substituent;

[0095] r is 0, 1, or 2.

[0096] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 Selected from the following groups:

[0097] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0098] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0099] 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.

[0100] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0101] The present invention provides a use of a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a WRN inhibitor.

[0102] The present invention also provides a use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 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 microsatellite instability-high (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, and is preferably colorectal cancer, gastric cancer or endometrial cancer.

[0103] The present invention further provides a use of a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, in the preparation of a medicament for treating microsatellite instability-high (MSI-H) cancer.

[0104] The present invention provides a use of a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preparing a medicament for treating colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical 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 in preparing a medicament for treating colorectal cancer, gastric cancer or endometrial cancer.

[0105] Detailed Description of the Invention

[0106] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0107] As used herein, "one or more" means 1, 2, 3, 4 or more.

[0108] In this document, when indicating the number of members of a group, C1-C 10 Alkyl and C 1-10 These two expressions of alkyl have the same meaning. 10 Aryl and C 6-10 Aryl has the same meaning.

[0109] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl, even more preferably C1-C4 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.

[0110] "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, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. Preferably, the alkenyl group is C2-C4. The alkenyl group may be optionally substituted or unsubstituted.

[0111] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group of any of the preceding claims is preferably a C2-C6 alkynyl group, more preferably a C2-C6 alkynyl group, most preferably a C2-C4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0112] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more ring atoms are carbon atoms, and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused, bridged and spirocyclic rings, preferably a monocyclic cycloalkyl group having 3 to 8 members, 3 to 7 members or 3 to 6 members, or a bicyclic or tricyclic cycloalkyl group having 7 to 10 members.

[0113] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl,

[0114] The monocycloalkyl group may be substituted or unsubstituted.

[0115] "Spiroalkyl" 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 monocyclic rings, containing 0, 1 or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 5 members, 4 / 4 members, 4 / 6 members, 3 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" 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.

[0116] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing 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.

[0117] "Bridged cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, which share 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 to 14 members, more preferably 7 to 10 members. 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 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.

[0118] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one, two, three, or four ring atoms are selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms; containing 0, 1 or more double bonds in the ring; including monocyclic, polycyclic, fused, 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. Preferably a 3- to 8-membered heterocyclic group, a 4- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group or a 7- to 10-membered heterocyclic group.

[0119] The heterocyclic group may be substituted or unsubstituted.

[0120] Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, 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,

[0121] "Spiroheterocyclyl" refers to a polycyclic group of 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) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroalkyl 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,

[0122] "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 zero, one 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 it is 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 fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0123] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two 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, 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.

[0124] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0125] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and / or sulfur; preferably C5-10 heteroaryl. 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, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridinyl, pyridinyl- 2(1H)-one, pyrimidinyl, pyrazin-2(1H)-one, pyrimidin-4(3H)-one, pyrimidin-2(1H)-one, pyridazin-3(2H)-one, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[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,

[0126] Heteroaryl groups can be substituted or unsubstituted.

[0127] "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 the same time, one or more rings 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 nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, 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 group and a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferably, it includes 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0128] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 or C1-C4 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0129] "Alkylthio" refers to a group of (alkyl-S-). Alkyl is as defined herein. C1-C6 or C1-C4 alkylthio groups are preferred. Examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and tert-butylthio.

[0130] "Nitro" refers to a -NO2 group.

[0131] "Hydroxy" refers to an -OH group.

[0132] "Halogen" refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine and bromine.

[0133] "Amino" refers to -NH2.

[0134] "Hydroxyamino" refers to -NHOH.

[0135] "Cyano" refers to -CN.

[0136] "Benzyl" refers to -CH2-phenyl.

[0137] "Carboxyl" refers to -C(=O)OH.

[0138] "Carboxylate" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

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

[0140] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0141] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0142] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0143] "DMSO" refers to dimethyl sulfoxide.

[0144] "BOC" refers to tert-butoxycarbonyl.

[0145] "Bn" refers to benzyl.

[0146] "THP" refers to 2-tetrahydropyranyl.

[0147] "TFA" refers to trifluoroacetic acid.

[0148] "Ts" refers to p-toluenesulfonyl.

[0149] "Bn" refers to benzyl.

[0150] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0151] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand 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 break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0152] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0153] As used herein, "substituted" or "substituted", 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, hydroxy, 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.

[0154] As used herein, when referring to being substituted by one or more substituents, the “one or more” includes 1, 2, 3, 4, 5 or more, preferably 1, 2 or 3.

[0155] In this document, the definitions of the above groups apply not only to the case where each group appears alone, but also to the case where it appears as a substituent.

[0156] 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 hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0157] R 6 and R 7 are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, 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;

[0158] 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;

[0159] R 8 、R 9 and R 10are each 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 with 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;

[0160] r is independently 0, 1 or 2.

[0161] 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 (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0162] Unless otherwise indicated, structures depicted herein also encompass all isomers (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 present compounds are within the scope of the invention.

[0163] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0164] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, and other components, such as physiologically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0165] Synthesis method of the compound of the present invention

[0166] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0167] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0168] Method 1:

[0169] 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);

[0170] in:

[0171] is a single bond, J is N;

[0172] PG is an amino protecting group, preferably tert-butyloxycarbonyl;

[0173] Y1 is selected from boronic acid or boronic acid ester;

[0174] L is selected from -(C=O)-;

[0175] X1 is selected from hydroxyl or halogen

[0176] W, K, X, Y, Z, Q, R 1 -R 4 、R a 、R b 、R c and n are as defined in claim 1.

[0177] Method 2:

[0178] The compound of general formula (Ia) is subjected to a deprotection reaction to obtain a compound of general formula (If), the compound of general formula (If) is subjected to a condensation reaction with a compound of general formula (Ie) to obtain a compound of general formula (Ig), the compound of general formula (Ig) is subjected to an SN2 nucleophilic substitution reaction with a compound of general formula (Ib-1) in the presence of a base, or is subjected to a coupling reaction with a compound of general formula (Ib-2) in the presence of a catalyst, and optionally further subjected to a deprotection reaction to obtain a compound of general formula (I);

[0179] in:

[0180] is a single bond, J is N;

[0181] PG is an amino protecting group, preferably tert-butyloxycarbonyl;

[0182] Y1 is selected from boronic acid or boronic acid ester;

[0183] L is selected from -(C=O)-;

[0184] X1 is selected from hydroxyl or halogen

[0185] 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

[0186] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0187] Example

[0188] 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 obtained using a Bruker instrument (400 MHz), and chemical shifts are 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.

[0189] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0190] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0191] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0192] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw 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.

[0193] CD3OD: deuterated methanol.

[0194] CDCl3: deuterated chloroform.

[0195] DMSO-d6: deuterated dimethyl sulfoxide.

[0196] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0197] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0198] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0199] Example 1

[0200] 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

[0201] 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

[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] 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), and N,N-diisopropylethylamine (1.81 g, 14.04 mmol) was added. The temperature was raised to 50°C and the reaction was allowed to react for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), 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 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%.

[0205] MS m / z(ESI):563.7[M-100+1]

[0206] Step 2

[0207] 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

[0208] 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), 1,4-oxazepane 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, heated to 100°C, and reacted 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 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 1e (60 mg) in a yield of 83.18%.

[0209] MS m / z(ESI):626.8[M-56+1]

[0210] Step 3

[0211] 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

[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] 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 1e (60 mg, 87.83 μmol) was added to dichloromethane (2.5 mL), and trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted 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) in a yield of 97.64%.

[0214] MS m / z(ESI):583.2[M+1]

[0215] Step 4

[0216] 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

[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] 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, 85.76 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1 g (27.23 mg, 111.49 μmol) were prepared 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 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)-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) in a yield of 72.04%.

[0219] MS m / z(ESI):790.3[M+1]

[0220] Step 5

[0221] 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

[0222] 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

[0223] 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 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 product 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 give 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 1 (2.67 mg) in a yield of 4.95%.

[0224] MS m / z(ESI):718.8[M+1]

[0225] 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).

[0226] Example 2

[0227] 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)-

[0228] 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] first step

[0231] 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

[0232] 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-Dioxaborolane 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 flask, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C 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) in a yield of 74.78%.

[0233] MS m / z(ESI):650.3[M-56+1]

[0234] Step 2

[0235] 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

[0236] 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

[0237] 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, 169.21 μmol) was added to dichloromethane (2.5 mL), and 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) in a yield of 96.71%.

[0238] MS m / z(ESI):559.8[M+1]

[0239] Step 3

[0240] 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

[0241] 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

[0242] 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 2.74 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.06 mg, 245.47 μmol), 1-hydroxybenzotriazole (33.17 mg, 245.47 μmol), N,N-diisopropylethylamine (105.75 mg, 818.22 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 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-(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) in a yield of 62.98%.

[0243] MS m / z(ESI):775.8[M+1]

[0244] Step 4

[0245] 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

[0246] 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

[0247] 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 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-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 2 (7.12 mg) in a yield of 4.68%.

[0248] MS m / z(ESI):688.3[M+1]

[0249] 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).

[0250] Example 3

[0251] 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

[0252] first step

[0253] 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

[0254] 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

[0255] 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 (1 g, 1.51 mmol) was added to dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 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) in a 98.94% yield.

[0256] MS m / z(ESI):561.7[M+1]

[0257] Step 2

[0258] 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

[0259] 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). 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) in a yield of 59.44%.

[0260] MS m / z(ESI):788.6[M+1]

[0261] Step 3

[0262] 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

[0263] 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

[0264] 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) in a yield of 78.19%.

[0265] MS m / z(ESI):806.8[M+1]

[0266] Step 4

[0267] 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

[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 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 give 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 3 (2.28 mg) in a yield of 6.36%.

[0269] MS m / z(ESI):716.8[M+1]

[0270] 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).

[0271] Example 4

[0272] 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

[0273] 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

[0274] first step

[0275] 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

[0276] 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

[0277] 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 to a 100 mL two-necked flask, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C 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) in a yield of 89.18%.

[0278] MS m / z(ESI):804.2[M+1]

[0279] Step 2

[0280] 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

[0281] 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

[0282] 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 give 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 4 (1.25 mg) in a yield of 2.76%.

[0283] MS m / z(ESI):715.8[M+1]

[0284] 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).

[0285] Example 5

[0286] 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

[0287] 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

[0288] first step

[0289] 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

[0290] 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

[0291] 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 to a 100 mL two-necked flask, 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 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)-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%.

[0292] MS m / z(ESI):750.6[M+1]

[0293] Step 2

[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)-yl)acetamide

[0295] 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

[0296] 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), and 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 give 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 5 (2.6 mg) in a yield of 5.70%.

[0297] MS m / z(ESI):661.8[M+1]

[0298] 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).

[0299] Example 6

[0300] 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

[0301] 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

[0302] 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. The reaction was quenched by the addition of methanol (1 mL) and concentrated under reduced pressure. The resulting residue was then purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH₃CN) to afford 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 6 (3.07 mg) in a 6.90% yield. MS m / z (ESI): 713.8 [M+1].

[0303] 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).

[0304] Example 7

[0305] 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

[0306] 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

[0307] first step

[0308] 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

[0309] 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

[0310] 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 1.5 hours. 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) in a yield of 61.87%.

[0311] MS m / z(ESI):765.3[M+1]

[0312] Step 2

[0313] 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

[0314] 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

[0315] 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 mixture was warmed to room temperature and reacted overnight. The mixture was filtered and 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 give 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 7 (2.06 mg) in a yield of 7.63%.

[0316] MS m / z(ESI):675.1[M+1]

[0317] 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(dd,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,2H),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= 11.6Hz, 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).

[0318] Example 8

[0319] 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

[0320] 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

[0321] first step

[0322] 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

[0323] 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

[0324] 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. 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) in a yield of 75.57%.

[0325] MS m / z(ESI):835.2[M+1]

[0326] Step 2

[0327] 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

[0328] 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

[0329] 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. 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 give 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]nonane-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 8 (3.73 mg) in a yield of 9.96%.

[0330] MS m / z(ESI):745.1[M+1]

[0331] 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).

[0332] Example 9

[0333] 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

[0334] 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

[0335] first step

[0336] 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

[0337] 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 -Dioxaborolane 4a (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 to a 100 mL two-necked flask, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C 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 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 9a (650 mg) in a yield of 90.77%.

[0338] MS m / z(ESI):622.2[M+1]

[0339] Step 2

[0340] 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

[0341] 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

[0342] 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 9a (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. 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 9b (34 mg) in a yield of 99.72%.

[0343] MS m / z(ESI):578.2[M+1]

[0344] Step 3

[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] 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 9b (34 mg, 58.82 μmol), 3-hydroxyisonicotinic acid 9c (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. The product was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) 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%.

[0348] MS m / z(ESI):699.3[M+1]

[0349] 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).

[0350] Example 10

[0351] 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

[0352] 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

[0353] 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 9b (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. 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-(2-hydroxybenzoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 10 (2.6 mg) in a yield of 2.12%.

[0354] MS m / z(ESI):698.3[M+1]

[0355] 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).

[0356] Example 11

[0357] 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

[0358] 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

[0359] 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 9b (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. 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-(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) in a yield of 4.55%.

[0360] MS m / z(ESI):712.2[M+1]

[0361] 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).

[0362] Example 12

[0363] 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

[0364] 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

[0365] first step

[0366] 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

[0367] 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

[0368] 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 two-necked flask, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C 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)-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%.

[0369] MS m / z(ESI):790.2[M+1]

[0370] Step 2

[0371] 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

[0372] 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

[0373] 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. 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-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 12 (1.84 mg) in a yield of 3.99%.

[0374] MS m / z(ESI):702.1[M+1]

[0375] 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).

[0376] Example 13

[0377] 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

[0378] 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]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0379] first step

[0380] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-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

[0381] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-2,8-diazaspiro

[0382] [4.5]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0383] 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. The reaction solution was extracted with ethyl acetate (30 mL × 2), 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 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]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 13b (35 mg) in a yield of 64.05%.

[0384] MS m / z(ESI):862.1[M+1]

[0385] Step 2

[0386] 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

[0387] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-

[0388] (1-Oxo-2,8-diazaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0389] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxo-2-(1-oxo-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 13b (35 mg, 40.59 μmol) was added to dichloromethane (3 mL), and BCl3 (1 mL) was added at 0°C, and the reaction was carried out at 0°C for 1 h. Methanol was added 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 give 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]decan-8-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 13 (3.13 mg) in a yield of 9.69%.

[0390] MS m / z(ESI):772.1[M+1]

[0391] 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).

[0392] Example 14

[0393] 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

[0394] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0395] first step

[0396] 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

[0397] 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-hexahydropenten-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0398] 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 two-necked flask, the argon atmosphere was replaced four times, and the temperature was raised to 80 ° C 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 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-hexahydropenten-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%.

[0399] MS m / z(ESI):648.0[M-56+1]

[0400] Step 2

[0401] 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

[0402] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0403] 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-hexahydropenten-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 14b (45 mg, 63.91 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added, and the mixture was reacted at room temperature for 1 hour. 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-hexahydropenten-2-yl)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14c (35 mg) in a yield of 90.67%.

[0404] MS m / z(ESI):604.1[M+1]

[0405] Step 3

[0406] 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

[0407] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0408] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-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 9c (10.48 μmol) 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. The mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 14 (3.41 mg) in a yield of 7.85%.

[0409] MS m / z(ESI):725.2[M+1]

[0410] 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).

[0411] Example 15

[0412] 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

[0413] 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

[0414] 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. 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 chromatography (AKZONOBEL Kromasil column; 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-((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 15 (1.36 mg) in a yield of 3.52%.

[0415] MS m / z(ESI):711.0[M+1]

[0416] 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),3.2 5(dd,J=13.3,6.9Hz,2H),2.95(d,J=17.6Hz,3H),2.77(d,J=11.3Hz,1H),2.5 9(d,J=11.0Hz,2H),2.44(s,3H),1.99(q,J=6.6Hz,2H),1.15(t,J=7.4Hz,3H).

[0417] Example 16

[0418] 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

[0419] 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

[0420] first step

[0421] 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

[0422] 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

[0423] 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 heated to 80°C for 2 h. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially 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)-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) in a yield of 78.19%.

[0424] MS m / z(ESI):807.1[M+1]

[0425] Step 2

[0426] 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

[0427] 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

[0428] 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), and palladium on carbon (4.51 mg, 37.16 μmol) was added, and the reaction was carried out at room temperature for 16 hours. 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-(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 16 (8.23 mg) in a yield of 10.53%.

[0429] MS m / z(ESI):717.1[M+1]

[0430] 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).

[0431] Example 17

[0432] 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

[0433] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0434] first step

[0435] 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

[0436] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0437] 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)-1,3,2-dioxaborolan-2-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) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl)-2-bromo-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)- )-3,3a,4,6a-tetrahydropentan-2(1H)-one 14a (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 atmosphere was replaced with argon four times. The temperature was raised to 80°C and the reaction was allowed to proceed 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 phases were 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 17a (30 mg) in a yield of 47.52%.

[0438] MS m / z(ESI):830.3[M+1]

[0439] Step 2

[0440] 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

[0441] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0442] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 17a (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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was 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 give 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 17 (3.16 mg) in a yield of 11.77%.

[0443] MS m / z(ESI):740.1[M+1]

[0444] 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).

[0445] Example 18

[0446] 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

[0447] 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

[0448] first step

[0449] 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

[0450] 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

[0451] 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]hex-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), 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. The temperature was raised to 80°C and the reaction was carried out for 1.5 hours. 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 phases were 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-(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%.

[0452] MS m / z(ESI):788.1[M+1]

[0453] Step 2

[0454] 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

[0455] 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

[0456] 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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was 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 give 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 18 (11.52 mg) in a yield of 8.54%.

[0457] MS m / z(ESI):698.2[M+1]

[0458] 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).

[0459] Example 19

[0460] 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

[0461] 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

[0462] first step

[0463] 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

[0464] 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

[0465] 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. The temperature was raised to 80°C and the reaction was carried out for 1.5 hours. 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 phases were 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-(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 19b (40 mg) in a yield of 63.12%.

[0466] MS m / z(ESI):644.2[M-56+1]

[0467] Step 2

[0468] 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

[0469] 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

[0470] 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 19b (40 mg, 57.13 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (0.5 mL), and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 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) in a yield of 87.51%.

[0471] MS m / z(ESI):600.1[M+1]

[0472] Step 3

[0473] 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

[0474] 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

[0475] 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. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially 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-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) in a yield of 72.62%.

[0476] MS m / z(ESI):826.2[M+1]

[0477] Step 4

[0478] 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

[0479] 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

[0480] 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. The reaction was quenched by adding methanol, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 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 19 (4.3 mg) in a yield of 15.61%.

[0481] MS m / z(ESI):736.0[M+1]

[0482] 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).

[0483] Example 20

[0484] 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

[0485] 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

[0486] first step

[0487] 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

[0488] 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

[0489] 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) were reacted by a known method. Chemistry (2019), 2019 (33), 5624-5635” prepared), [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, 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 (40 mL×3). The combined organic phases were 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%.

[0490] MS m / z(ESI):804.2[M+1]

[0491] Step 2

[0492] 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

[0493] 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

[0494] 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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was 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 give 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 20 (13.0 mg) in a yield of 9.79%.

[0495] MS m / z(ESI):7 14.4[M+1]

[0496] 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).

[0497] Example 21

[0498] 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

[0499] 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

[0500] first step

[0501] 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

[0502] 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

[0503] 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 -Dioxaborolane 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), 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 mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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%. MS m / z (ESI): 806.1 [M+1].

[0504] Step 2

[0505] 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

[0506] 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

[0507] 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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was 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 give 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 21 (4.93 mg) in a yield of 8.61%.

[0508] MS m / z(ESI):716.1[M+1]

[0509] 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).

[0510] Example 22

[0511] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)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

[0512] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0513] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-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, The reaction mixture was added to N,N-dimethylformamide (1 mL) and reacted at room temperature for 16 hours. The reaction 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 (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm). 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-hydroxypicolinyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 22 (3.74 mg), yield: 5.00%.

[0514] MS m / z(ESI):725.2[M+1]

[0515] 1 H 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).

[0516] Example 23

[0517] 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

[0518] 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

[0519] first step

[0520] 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0521] 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 h. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially 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%.

[0522] Step 2

[0523] 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

[0524] 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

[0525] 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. The temperature was raised to 80°C and the mixture was reacted for 2 h. 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 sequentially 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%.

[0526] MS m / z(ESI):802.3[M+1]

[0527] Step 3

[0528] 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

[0529] 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

[0530] 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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was 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 give 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 23 (2.6 mg) in a yield of 9.41%.

[0531] MS m / z(ESI):711.7[M+1]

[0532] 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).

[0533] Example 24

[0534] 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

[0535] 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

[0536] first step

[0537] 2-bromo-N-(4-(tert-butyl)phenyl)acetamide

[0538] 2-Bromo-N-(4-(tert-butyl)phenyl)acetamide

[0539] 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-cooling. After stirring for 10 minutes, 2-bromoacetyl bromide 24b (1.62 g, 8.04 mmol, commercially available) was slowly added. The mixture was allowed to react at room temperature for 4 hours before monitoring the reaction. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-N-(4-(tert-butyl)phenyl)acetamide 24c (1.5 g) in an 82.86% yield.

[0540] MS m / z(ESI):270.0[M+1]

[0541] Step 2

[0542] 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

[0543] 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

[0544] 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 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were 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%.

[0545] MS m / z(ESI):560.2[M-56+H]

[0546] Step 3

[0547] 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

[0548] 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

[0549] At room temperature, 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, 470.36 μmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dihydro- Oxaborane 4a (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 atmosphere was replaced with argon three times, and the temperature was raised to 80°C for 2 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were 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%.

[0550] MS m / z(ESI):576.3[M-56+H]

[0551] Step 4

[0552] 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

[0553] 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

[0554] At room temperature, 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) and the mixture was reacted at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure to afford 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 (117 mg) in a yield of 99.31%, which was used directly in the next step.

[0555] MS m / z(ESI):532.3[M+1]

[0556] Step 5

[0557] 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

[0558] 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

[0559] At room temperature, 3-hydroxyisonicotinic acid 9c (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-dimethylformamide (1.5 mL), react at room temperature for 30 minutes, then add 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) and react at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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 phase separation (AKZONOBEL Kromasil column; 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%.

[0560] MS m / z(ESI):653.3[M+1]

[0561] 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).

[0562] Example 25

[0563] 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

[0564] 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 -sulfanyl)phenyl)acetamide

[0565] first step

[0566] 2-bromo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0567] 2-Bromo-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0568] 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 allowed to react at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to give 2-bromo-N-(4-(pentafluoro-λ)-phenyl)-1,2-di ... 6 -sulfanyl)phenyl)acetamide 25b (720 mg), yield: 89.23%.

[0569] MS m / z(ESI):339.9[M+1]

[0570] Step 2

[0571] 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-carboxylate

[0572] 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0573] 2-Bromo-N-(4-(pentafluoro-λ 6-sulfanyl)phenyl)acetamide 25b (382.06 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), N,N-diisopropylethylamine (604.92 mg, 4.68 mmol) were added to N,N-dimethylformamide (7 mL), and the temperature was raised to 50 ° C for 2 hours. 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 resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6

[0147]

[0148] tert-Butyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate 25c (710 mg), yield: 77.34%.

[0574] MS m / z(ESI):630.1[M-56+H]

[0575] Step 3

[0576] 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-carboxylate

[0577] 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0578] 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)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 25c (710 mg, 1.03 mmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4a (298.66 mg, 1.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (83.83 mg, 103.42 μmol), and sodium carbonate (328.86 mg, 3.10 mmol). The mixture was replaced with argon three times and the temperature was raised to 90 °C for 2 h. 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 resulting residue was purified by silica gel column chromatography (eluent: System B) to give 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -sulfanyl)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%.

[0579] MS m / z(ESI):646.2[M-56+H]

[0580] Step 4

[0581] 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 -sulfaneyl)phenyl)acetamide

[0582] 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 -sulfanyl)phenyl)acetamide

[0583] 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 6A 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 product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System B) 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) ...5-ethyl-7-oxo-6-(piperazin-1-yl)-5-ethyl-7-oxo-6-(piperazin-4(7H)-yl)-N-(4-(pentafluoro-λ)-en-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-5-ethyl-7-oxo-6-(piperazin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide 25e (340 mg), yield: 88.13%.

[0584] MS m / z(ESI):602.3[M+1]

[0585] Step 5

[0586] 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

[0587] 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 -sulfanyl)phenyl)acetamide

[0588] 3-Hydroxyisonicotinic acid 9c (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) at room temperature 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)-yl)-1-nitropropane-5-ol was added. 6-sulfanyl)phenyl)acetamide 25e (60 mg, 99.73 μmol) was reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide 25 (24.53 mg), yield: 33.32%.

[0589] MS m / z(ESI):723.3[M+1]

[0590] 1 H 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).

[0591] Example 26

[0592] N-(4-(tert-butyl)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

[0593] N-(4-(tert-Butyl)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

[0594] first step

[0595] 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

[0596] 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

[0597] 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 reaction mixture was added to methylformamide (1.5 mL) and reacted at room temperature for 40 minutes. 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. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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-(4-(tert-butyl)phenyl)acetamide 26a (65 mg) in a yield of 45.60%.

[0598] MS m / z(ESI):758.5[M+1]

[0599] Step 2

[0600] N-(4-(tert-butyl)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

[0601] N-(4-(tert-Butyl)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

[0602] Under an ice bath and argon atmosphere, boron trichloride (1.5 mL) was added to a dichloromethane (1 mL) 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). The reaction was allowed to proceed at room temperature for 16 hours. The product was quenched by adding ice water and dissolved in a small amount of methanol, followed by preparative liquid separation and purification (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)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 26 (12.35 mg) in a yield of 21.33%.

[0603] MS m / z(ESI):668.4[M+1]

[0604] 1 H 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).

[0605] Example 27

[0606] 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 6-sulfaneyl)phenyl)acetamide

[0607] 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 -sulfanyl)phenyl)acetamide

[0608] 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 -sulfanyl)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 phases were 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-(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-sulfanyl)phenyl)acetamide 27 (1.06 mg), yield: 1.35%.

[0609] MS m / z(ESI):738.3[M+1]

[0610] 1 H 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).

[0611] Example 28

[0612] 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

[0613] 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

[0614] first step

[0615] 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

[0616] 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

[0617] 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 atmosphere was replaced with argon four times, and the temperature was raised to 80°C 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 phases were 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%.

[0618] MS m / z(ESI):736.2[M+1]

[0619] Step 2

[0620] 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

[0621] 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

[0622] 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), and palladium on carbon (7.42 mg, 61.13 μmol) was added, and the reaction was carried out at room temperature for 16 hours. 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-(2,5-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 28 (2.61 mg) in a yield of 6.53%.

[0623] MS m / z(ESI):648.0[M+1]

[0624] 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).

[0625] Example 29

[0626] 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

[0627] 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

[0628] Example 30

[0629] 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

[0630] 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

[0631] 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 allowed to react at room temperature for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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)piperazin-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.

[0632] Example 29 MS m / z (ESI): 666.2 [M+1]

[0633] 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).

[0634] Example 30 MS m / z (ESI): 700.1 [M+1]

[0635] 1H 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).

[0636] Example 31

[0637] 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

[0638] 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

[0639] 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 the reaction was carried out at room temperature for 16 hours. 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+H 2 O, mobile phase B: CH 3 CN) 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%.

[0640] MS m / z(ESI):701.1[M+1]

[0641] 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).

[0642] Example 32

[0643] 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

[0644] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0645] first step

[0646] 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

[0647] 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

[0648] Tert-butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 32a (1 g, 2.42 mmol, prepared according to patent publication WO2022249060 A1) and 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), and the temperature was raised to 50 ° C and reacted for 4 hours. The reaction solution 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 (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-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 32b (1.1 g) in a yield of 70.06%.

[0649] MS m / z(ESI):547.7[M-100+1]

[0650] Step 2

[0651] 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

[0652] 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

[0653] 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 32b (260 mg, 400.70 μmol) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL), and the mixture was reacted at room temperature for 1 hour. The reaction was concentrated under reduced pressure to afford 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) in a 95.51% yield.

[0654] MS m / z(ESI):548.0[M+1]

[0655] Step 3

[0656] 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

[0657] 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

[0658] 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), and 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. The reaction mixture was added with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The aqueous layer was separated and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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%. MS m / z (ESI): 775.1 [M+1].

[0659] Step 4

[0660] 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

[0661] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0662] 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-dioxaborolane- 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 and the reaction was allowed to proceed 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 phases were 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-hexahydropenten-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%.

[0663] MS m / z(ESI):815.7[M+1]

[0664] Step 5

[0665] 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

[0666] 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-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0667] 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-hexahydropenten-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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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)piperazin-1-yl)-5-methyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 32 (3.00 mg) in a yield of 9.13%.

[0668] MS m / z(ESI):725.7[M+1]

[0669] 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).

[0670] Example 33

[0671] 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

[0672] 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

[0673] first step

[0674] 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

[0675] 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

[0676] 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-(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 and the reaction was carried out 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 mixture 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)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) in a yield of 71.15%.

[0677] MS m / z(ESI):776.2[M+1]

[0678] Step 2

[0679] 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

[0680] 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

[0681] 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 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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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-(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 33 (2.75 mg) in a yield of 8.71%.

[0682] MS m / z(ESI):686.2[M+1]

[0683] 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).

[0684] Example 34

[0685] 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

[0686] 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

[0687] first step

[0688] 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

[0689] 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-2-(oxetan-3-ylidenemethyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0690] 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-(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 and the reaction was carried out 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; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 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 (40 mg) in a yield of 81.11%.

[0691] MS m / z(ESI):778.2[M+1]

[0692] Step 2

[0693] 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

[0694] 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

[0695] 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 trifluoroacetic acid (1.5 mL) was then added dropwise and reacted at room temperature for 48 hours. The product 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 give 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 34 (4.07 mg) in a yield of 13.15%.

[0696] MS m / z(ESI):688.7[M+1]

[0697] 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).

[0698] Example 35

[0699] 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

[0700] 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

[0701] first step

[0702] 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

[0703] 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

[0704] 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 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 phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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].

[0705] Step 2

[0706] 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

[0707] 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

[0708] 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, 85.70 μmol) was added to dichloromethane (3 mL), followed by 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)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 35b. (Trifluoromethyl)phenyl)acetamide 35c (50 mg), yield: 97.24%, was used directly in the next step reaction.

[0709] MS m / z(M+1):600.1[M+1]

[0710] Step 3

[0711] 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

[0712] 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

[0713] 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. 34 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.96 mg, 125.00 μmol), 1-hydroxybenzotriazole (16.89 mg, 125.00 μmol), N,N-diisopropylethylamine (53.85 mg, 416.67 μmol) were added to N,N-dimethylformamide (1.5 mL) and reacted at room temperature for 16 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 sequentially 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%.

[0714] MS m / z(ESI):826.3[M+1]

[0715] Step 4

[0716] 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

[0717] 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

[0718] 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. 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-(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 35 (2.83 mg) in a yield of 7.60%.

[0719] MS m / z(ESI):736.0[M+1]

[0720] 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),10.24(s,1H),8.71(s,1H),8.59(s,1H),8.34–8. 26(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 =19.0,7.4,1.4Hz,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).

[0721] Example 36

[0722] (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

[0723] (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

[0724] first step

[0725] (E)-2-(2-cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0726] (E)-2-(2-Cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0727] 2,2,6,6-Tetramethylpiperidine (379.53 mg, 2.69 mmol) was added to tetrahydrofuran (4.5 mL), and n-butyllithium (2.5 M solution in n-hexane) (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 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with petroleum ether (30 mL × 2). The aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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%.

[0728] Step 2

[0729] (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

[0730] (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

[0731] 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 a 1% ethanol solution. , 4-dioxane (1 mL), argon was replaced four times, the temperature was raised to 80°C, and the reaction mixture was reacted 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 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)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), yield: 59.91%.

[0732] MS m / z(ESI):790.3[M+1]

[0733] Step 3

[0734] (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

[0735] (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

[0736] (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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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%.

[0737] MS m / z(ESI):699.7[M+1]

[0738] 1 H NMR (400MHz, DMSO-d6) δ10.38–10.29(m,1H),10.24(s,1H),8.58(s,1H),8.05(t,J=8.5 Hz,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).

[0739] Example 37

[0740] (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

[0741] (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

[0742] first step

[0743] (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

[0744] (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

[0745] 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, and ethyl acetate (40 mL × 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution. The product was washed with 4-[ ...

[0746] MS m / z(ESI):813.3[M+1]

[0747] Step 2

[0748] (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

[0749] (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

[0750] (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. Methanol was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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)piperazin-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%.

[0751] MS m / z(ESI):722.7[M+1]

[0752] 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).

[0753] Example 38

[0754] 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

[0755] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0756] first step

[0757] 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

[0758] 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

[0759] 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 atmosphere was replaced with argon four times. The temperature was raised to 80 °C and the reaction was continued 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 phases were 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%.

[0760] MS m / z(ESI):605.7[M-56+1]

[0761] Step 2

[0762] 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

[0763] 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

[0764] 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, 63.43 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1 mL), and the reaction was carried out at room temperature for 1 hour. 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%), which was used directly in the next reaction.

[0765] MS m / z(ESI):561.8[M+1]

[0766] Step 3

[0767] 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

[0768] 2-(2-(bicyclo[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0769] 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 0.96 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.91 mg, 93.42 μmol), 1-hydroxybenzotriazole (12.62 mg, 93.42 μmol), N,N-diisopropylethylamine (40.24 mg, 311.40 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 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 (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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[3.1.0]hex-2-en-3-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-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) in a yield of 6.74%. MS m / z(ESI):683.2[M+1]

[0770] 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).

[0771] Example 39

[0772] 2-(2-cycloheptyl-5-ethyl-6-(4-(2-hydroxy-3-methylbenzoyl)piperazin-1-yl)-7-oxo-

[0773] [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide 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

[0774] 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 the reaction was carried out at room temperature for 16 hours. 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 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 39 (2.9 mg) in a yield of 7.34%.

[0775] MS m / z(ESI):680.2[M+1]

[0776] 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).

[0777] Example 40

[0778] 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

[0779] 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

[0780] first step

[0781] 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

[0782] 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

[0783] 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. The reaction mixture was heated to 70°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: System B) to obtain 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 40b (100 mg) in a yield of 49.02%.

[0784] MS m / z(ESI):620.2[M-55]

[0785] Step 2

[0786] 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

[0787] 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

[0788] 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 40b (100 mg, 147.91 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 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) in a 54.26% yield.

[0789] MS m / z(ESI):576.2[M+1]

[0790] Step 3

[0791] 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

[0792] 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) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.93 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 4-nitropropane-2-ol (5-nitropropane-2-ol) at room temperature. The product was prepared by adding 4-[[(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 40 (2 mg) in a 1.80% yield.

[0793] MS m / z(ESI):712.3[M+1]

[0794] 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).

[0795] Example 41

[0796] 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

[0797] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0798] first step

[0799] 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

[0800] 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

[0801] At room temperature, 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo- Tert-butyl 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 atmosphere was replaced with argon four times. The temperature was raised to 80°C and the reaction was reacted 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 phases were 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[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 41a (60 mg) in a yield of 98.04%.

[0802] MS m / z(ESI):675.8[M+1]

[0803] Step 2

[0804] 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

[0805] 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

[0806] 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 41a (60 mg, 88.74 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1 mL), and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 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) in a yield of 97.82%, which was used directly in the next step. MS m / z (ESI): 575.8 [M+1]

[0807] Step 3

[0808] 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

[0809] 2-(2-(bicyclo[2.2.1]hept-2-en-2-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0810] 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 .84 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.96 mg, 130.21 μmol), 1-hydroxybenzotriazole (17.59 mg, 130.21 μmol), N,N-diisopropylethylamine (56.09 mg, 434.02 μmol) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The aqueous layer was separated and the combined organic phases were washed successively 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 phase separation (AKZONOBEL Kromasil column; 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-hydroxypicolinyl)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%.

[0811] MS m / z(ESI):697.2[M+1]

[0812] 1 H 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).

[0813] Example 42

[0814] 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

[0815] 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

[0816] first step

[0817] 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0818] 2-Bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide

[0819] 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) in an ice bath under argon. The mixture was allowed to react at room temperature for 16 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 42b (640 mg) in a 75.72% yield.

[0820] MS m / z(ESI):296.0[M+1]

[0821] Step 2

[0822] 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

[0823] 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

[0824] At room temperature, 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide 42b (270.24 mg, 912.72 μmol), 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 (300 mg, 702.09 μmol), and 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. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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) in a yield of 99.98%.

[0825] MS m / z(ESI):586.1[M-56+H]

[0826] Step 3

[0827] 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

[0828] 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

[0829] 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 a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). The atmosphere was replaced with argon three times and the temperature was raised to 85 °C for 2 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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-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 (250 mg) in a yield of 97.68%.

[0830] MS m / z(ESI):658.3[M+1]

[0831] Step 4

[0832] 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

[0833] 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

[0834] 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) at room temperature and reacted at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure to afford 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) in a yield of 99.95%, which was used directly in the next step. MS m / z (ESI): 558.3 ​​[M+1]

[0835] Step 5

[0836] 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

[0837] 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

[0838] At room temperature, 3-hydroxyisonicotinic acid 9c (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 The mixture was added to a 5-nitro-2-nitro-1-yl-4-nitro-2-propenesulfonyl-2-yl) ... After monitoring 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 phases were 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 phase separation (AKZONOBEL Kromasil column; 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-methyl-4-(trifluoromethyl)phenyl)acetamide 42 (18.84 mg) in a yield of 34.53%.

[0839] MS m / z(ESI):679.3[M+1]

[0840] 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).

[0841] Example 43

[0842] 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

[0843] 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

[0844] first step

[0845] 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0846] 2-Bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

[0847] 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) in an ice bath under argon. The mixture was allowed to react at room temperature for 16 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43b (690 mg) in an 84.52% yield.

[0848] MS m / z(ESI):312.0[M+1]

[0849] Step 2

[0850] 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

[0851] 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

[0852] At room temperature, 2-bromo-N-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43b (350.58 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 (15 mL), and the temperature was raised to 60°C for 1.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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%.

[0853] MS m / z(ESI):604.1[M-56+H]

[0854] Step 3

[0855] 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

[0856] 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

[0857] 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 -Dioxaborolane 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 atmosphere was replaced with argon three times and the temperature was raised to 85 °C for 2 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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) in a yield of 99.69%.

[0858] MS m / z(ESI):618.3[M-56+H]

[0859] Step 4

[0860] 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

[0861] 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

[0862] 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) was added trifluoroacetic acid (1.5 mL) at room temperature and reacted for 40 min. 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%, which was used directly in the next step.

[0863] MS m / z(ESI):574.3[M+1]

[0864] Step 5

[0865] 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

[0866] 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

[0867] At room temperature, 3-hydroxyisonicotinic acid 9c (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- The mixture was added to 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-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide 43e (50 mg, 87.17 μmol) was added and reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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 (AKZONOBEL Kromasil column; 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-methoxy-4-(trifluoromethyl)phenyl)acetamide 43 (21.52 mg) in a yield of 34.86%.

[0868] MS m / z(ESI):695.3[M+1]

[0869] 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).

[0870] Example 44

[0871] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-7-oxo-

[0872] [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 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

[0873] first step

[0874] 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0875] 2-Bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0876] 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) under argon in an ice bath. The mixture was allowed to react at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44b (1.6 g) in a 95.51% yield.

[0877] MS m / z(ESI):300.0[M+1]

[0878] Step 2

[0879] 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

[0880] 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

[0881] At room temperature, 2-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide 44b (421.32 mg, 1.40 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 (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. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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%.

[0882] MS m / z(ESI):590.2[M-56+H]

[0883] Step 3

[0884] tert-butyl 4-(2-(cyclohept-1-en-1-yl)-5-ethyl-4-(2-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-

[0885] 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

[0886] 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-Dioxaborolane 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, and the temperature was raised to 85°C for reaction for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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%.

[0887] MS m / z(ESI):606.3[M-56+H]

[0888] Step 4

[0889] 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

[0890] 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

[0891] To a solution of 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) was added trifluoroacetic acid (1.5 mL) at room temperature and reacted for 40 min. The reaction mixture was concentrated under reduced pressure to afford 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 (169 mg) with a yield of 99.56%, which was used directly in the next step.

[0892] MS m / z(ESI):562.3[M+1]

[0893] Step 5

[0894] 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

[0895] 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

[0896] At room temperature, 3-hydroxyisonicotinic acid 9c (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. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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 (AKZONOBEL Kromasil column; 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) in a yield of 26.88%.

[0897] MS m / z(ESI):683.2[M+1]

[0898] 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).

[0899] Example 45

[0900] 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

[0901] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[0902] 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-dimethylaminopropylcarbodiimide hydrochloride. The reaction mixture was added to methylformamide (1.5 mL) and reacted at room temperature for 40 minutes. Then, a solution of 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 9b (59 mg, 102.07 μmol) in N,N-dimethylformamide (2 mL) was added and reacted at room temperature for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 45 (24.45 mg) in a yield of 33.92%.

[0903] MS m / z(ESI):699.3[M+1]

[0904] 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).

[0905] Example 46

[0906] 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)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0907] 2-(2-(cyclohept-1-en-1-yl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0908] 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 -sulfanyl)phenyl)acetamide 25e (50 mg, 83.11 μmol) was reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide 46 (16 mg), yield: 26.32%.

[0909] MS m / z(ESI):723.3[M+1]

[0910] 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).

[0911] Example 47

[0912] 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

[0913] 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

[0914] first step

[0915] 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

[0916] 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

[0917] At room temperature, 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (55.19mg, 225.96μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.76mg, 301.29μmol), 1-hydroxybenzotriazole (40.71mg, 301.29μmol), N,N-diisopropylethylamine (97.35mg, 753.22μmol) were added to N,N-dimethylformamide. To the mixture was added 4-[ ... Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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-methyl-4-(trifluoromethyl)phenyl)acetamide 47a (118 mg) in a yield of 99.93%.

[0918] MS m / z(ESI):784.3[M+1]

[0919] Step 2

[0920] 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

[0921] 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

[0922] In an ice bath and under argon, boron trichloride (1.5 mL) was added to a dichloromethane (1 mL) 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) and the reaction was carried out at room temperature for 16 hours. The mixture was quenched with methanol and concentrated. The methanol solution was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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)piperazin-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%. MS m / z (ESI): 694.3 [M+1].

[0923] 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).

[0924] Example 48

[0925] 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

[0926] 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

[0927] 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. 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 (70 mg, 122.03 μmol) was reacted at room temperature for 48 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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-(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 48 (4.3 mg), yield: 4.91%.

[0928] MS m / z(ESI):710.3[M+1]

[0929] 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).

[0930] Example 49

[0931] 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

[0932] 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

[0933] first step

[0934] 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

[0935] 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

[0936] 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. The mixture was added to N,N-dimethylformamide (2 mL) and reacted at room temperature for 30 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-fluoro-4-(trifluoromethyl)phenyl)acetamide 44e (127 mg, 226.15 μmol) was added and reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were 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) in a yield of 99.91%.

[0937] MS m / z(ESI):788.3[M+1]

[0938] Step 2

[0939] 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

[0940] 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

[0941] In an ice bath and under argon, boron trichloride (2 mL) was added to a dichloromethane (2 mL) 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) and the reaction was carried out at room temperature for 3 hours. The product was quenched with ice water, concentrated, and the methanol solution was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH₄HCO₃, mobile phase B: CH₃CN) to afford 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 49 (9.51 mg) in a 13.29% yield. MS m / z (ESI): 698.3 [M+1].

[0942] 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).

[0943] Example 50

[0944] 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

[0945] 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

[0946] first step

[0947] 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

[0948] 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

[0949] 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 patent 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 two-necked flask, the atmosphere was replaced with argon four times, and the temperature was raised to 80 °C for 1.5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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) in a yield of 76.71%. MS m / z (ESI): 801.7 [M+1].

[0950] Step 2

[0951] 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

[0952] 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

[0953] 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 continued at 0°C for 1 hour. Methanol (2 mL) was added to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 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 50 (2.87 mg) in a yield of 8.12%.

[0954] MS m / z(ESI):711.7[M+1]

[0955] 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).

[0956] Example 51

[0957] 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

[0958] 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

[0959] first step

[0960] 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

[0961] 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

[0962] 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 to the mixture at room temperature. The product was added to a 10 mL two-necked flask, replaced with argon four times, and heated to 80° C. 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 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)-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%.

[0963] MS m / z(ESI):676.2[M+1]

[0964] Step 2

[0965] 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

[0966] 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

[0967] 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, 69.51 μmol) was added to dichloromethane (2.5 mL), and trifluoroacetic acid (0.8 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 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 reaction.

[0968] MS m / z(ESI):576.2[M+1]

[0969] Step 3

[0970] 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

[0971] 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

[0972] 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. The reaction solution was extracted with ethyl acetate (30 mL × 3), the aqueous layer was separated, and the combined organic phases were washed successively 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 phase separation (AKZONOBEL Kromasil column; 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) in a yield of 6.77%. MS m / z(ESI):696.7[M+1]

[0973] 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).

[0974] Example 52

[0975] 2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0976] 2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0977] first step

[0978] tert-butyl 4-(2-(cyclobutylidenemethyl)-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-carboxylate

[0979] 4-(2-(cyclobutylenemethyl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0980] At room temperature, 4-(2-bromo-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6To a mixed solution of water (0.5 mL) and 1,4-dioxane (2 mL) were added tert-butyl (4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 25c (85 mg, 123.82 μmol), 2-(cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 33a (48.06 mg, 247.64 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10.03 mg, 12.38 μmol), and sodium carbonate (26.25 mg, 247.64 μmol). After argon was replaced three times, the mixture was heated to 80°C and stirred for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 4-(2-(cyclobutylenemethyl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6

[0147] tert-Butyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]piperazine-1-carboxylate 52a (60 mg) in 71.93% yield.

[0981] MS m / z(ESI):617.8[M+H-56]

[0982] Step 2

[0983] 2-(2-(cyclobutylidenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0984] 2-(2-(cyclobutylidenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0985] 4-(2-(cyclobutylenemethyl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6tert-Butyl)-2-(2-(cyclobutylenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 52a (65 mg, 96.48 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give 2-(2-(cyclobutylenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide 52b (50 mg), yield 90.35%, was used directly in the next step.

[0986] MS m / z(ESI):573.8[M+H]

[0987] Step 3

[0988] 2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0989] 2-(2-(cyclobutylidenemethyl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0990] 3-Hydroxypicolinic acid 22a (21.83 mg, 156.91 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.42 mg, 174.34 μmol), 1-hydroxybenzotriazole (23.56 mg, 174.34 μmol) and N,N-diisopropylethylamine (56.33 mg, 435.86 μmol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at room temperature for 10 minutes. 2-(2-(cyclobutylidenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6The reaction mixture was reacted 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 resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 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-(cyclobutylidenemethyl)-5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ)-pyrimidin-5 ... 6 -sulfanyl)phenyl)acetamide 52 (15 mg), yield 23.53%.

[0991] MS m / z(ESI):694.7[M+H]

[0992] 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.45(s,1H),8.08(dd,J=3.8,2.2Hz,1H),7.91–7.8 4(m,2H),7.76(d,J=8.9Hz,2H),7.35–7.26(m,2H),6.07(p,J=2.4Hz,1H),5.16(s,2H),4.5 5(d,J=12.5Hz,1H),3.57–3.36(m,4H),3.22(t,J=12.2Hz,1H),3.06–2.91(m,5H),2.82(q, J=13.9,10.9Hz,3H),2.62(d,J=11.0Hz,1H),1.97(p,J=7.9Hz,2H),1.17(t,J=7.4Hz,3H).

[0993] Example 53

[0994] 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)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[0995] 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)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0996] first step

[0997] 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-(4-(pentafluoro-λ) 6 -sulfaneyl)phenyl)acetamide

[0998] 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-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[0999] 1 g (29.81 mg, 122.04 μmol) of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.42 mg, 174.34 μmol), 1-hydroxybenzotriazole (23.56 mg, 174.34 μmol) and N,N-diisopropylethylamine (56.33 mg, 435.86 μmol) were added to N,N-dimethylformamide (1.5 mL) in sequence and reacted at room temperature for 10 minutes. 2-(2-(cyclobutylidenemethyl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ 6-sulfanyl)phenyl)acetamide 52b (50 mg, 87.17 μmol) was reacted at room temperature for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 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-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide 53a (40 mg), yield 57.37%.

[1000] MS m / z(ESI):799.7[M+H]

[1001] Step 2

[1002] 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)-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetamide

[1003] 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)-N-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)acetamide

[1004] 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-(4-(pentafluoro-λ 61-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-1-yl)-2-(2-(cyclobutylenemethyl)-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-yl)pyrimidin-1-yl)-1-( ...cyclobutylenemethyl)-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-yl)pyrimidin-1-yl)-1-(2-(cyclobutylenemethyl)-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-yl)pyrimidin-1-yl)-1-(2-(cyclobutylenemethyl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl) 6 -sulfanyl)phenyl)acetamide 53 (15 mg), yield 40.15%.

[1005] MS m / z(ESI):709.7[M+H]

[1006] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.22(s,1H),8.58(s,1H),7.88(d,J=9. 3Hz,2H),7.76(d,J=8.9Hz,2H),6.10–6.05(m,1H),5.16(s,2H),4.52(d,J=12. 6Hz,1H),3.57–3.44(m,3H),3.01(d,J=9.9Hz,5H),2.82(d,J=15.0Hz,3H),2.6 3(d,J=11.3Hz,1H),2.44(s,3H),1.97(p,J=7.9Hz,2H),1.17(t,J=7.4Hz,3H).

[1007] Example 54

[1008] 2-(2-(benzo[b]thiophen-5-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

[1009] 2-(2-(Benzo[b]thiophen-5-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

[1010] first step

[1011] 2-(2-(benzo[b]thiophen-5-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-et hyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1012] 2-(2-(Benzo[b]thiophen-5-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

[1013] 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-(benzo[b]thiophen-5-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborolane 54a (25.72 mg, 98.86 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.16 mg, 7.60 μmol) and sodium carbonate (16.12 mg, 152.09 μmol) were added to 1,4-dioxane (1.5 mL), the atmosphere was replaced with argon, and the temperature was raised to 80°C for 2 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzo[b]thiophen-5-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 54b (50 mg) in a yield of 78.06%.

[1014] MS m / z(ESI):843.2[M+H]

[1015] Step 2

[1016] 2-(2-(benzo[b]thiophen-5-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

[1017] 2-(2-(Benzo[b]thiophen-5-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

[1018] 2-(2-(Benzo[b]thiophen-5-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 54b (50 mg, 59.36 μmol) was dissolved in trifluoroacetic acid (3 mL), heated to 40°C and stirred for 4 hours. The product 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 give 2-(2-(benzo[b]thiophen-5-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 54 (15 mg) in a yield of 32.99%.

[1019] MS m / z(ESI):753.1[M+H]

[1020] 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.26(s,1H),8.65(s,1H),8.59(s,1H),8.19–8.05(m,3H) ,7.99(d,J=2.0Hz,1H),7.87(d,J=5.4Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),7.61(d,J=5.4Hz,1H) ,5.43(s,2H),4.55(d,J=12.5Hz,1H),3.55(q,J=12.1Hz,3H),3.26(d,J=12.0Hz,1H),3.03(q,J= 12.6,9.9Hz,3H),2.86(d,J=11.3Hz,1H),2.75–2.65(m,1H),2.45(s,3H),1.22(t,J=7.4Hz,3H).

[1021] Example 55

[1022] 2-(2-(benzo[b]thiophen-6-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

[1023] 2-(2-(Benzo[b]thiophen-6-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

[1024] first step

[1025] 2-(2-(benzo[b]thiophen-6-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

[1026] 2-(2-(Benzo[b]thiophen-6-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

[1027] 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-(benzo[b]thiophen-6-yl)-4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane 55a (25.72 mg, 98.86 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.16 mg, 7.60 μmol) and sodium carbonate (16.12 mg, 152.09 μmol) were added to 1,4-dioxane (1.5 mL), the atmosphere was replaced with argon, and the temperature was raised to 80 °C and stirred for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzo[b]thiophen-6-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 55b (40 mg) in a yield of 62.45%.

[1028] MS m / z(ESI):842.1[M+H]

[1029] Step 2

[1030] 2-(2-(benzo[b]thiophen-6-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

[1031] 2-(2-(Benzo[b]thiophen-6-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

[1032] 2-(2-(Benzo[b]thiophen-6-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 55b (40 mg, 47.49 μmol) was dissolved in trifluoroacetic acid (5 mL), heated to 40°C and stirred for 4 hours. The product 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 give 2-(2-(benzo[b]thiophen-6-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 55 (10 mg) in a yield of 27.72%.

[1033] MS m / z(ESI):752.1[M+H]

[1034] 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.26(s,1H),8.75(s,1H),8.59(s,1H),8.1 7–7.86(m,5H),7.72(dd,J=8.7,2.1Hz,1H),7.54(d,J=5.4Hz,1H),5.43(s,2H),4.5 5(d,J=12.5Hz,1H),3.61–3.44(m,3H),3.26(d,J=12.0Hz,1H),3.02(t,J=11.4Hz, 3H),2.89–2.82(m,1H),2.68(d,J=10.8Hz,1H),2.45(s,3H),1.23(t,J=7.4Hz,3H).

[1035] Example 56

[1036] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1037] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1038] first step

[1039] 2-bromo-5-ethyl-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1040] 2-Bromo-5-ethyl-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1041] 3-Bromo-1H-pyrazol-5-amine 56a (0.5 g, 3.09 mmol, commercially available) was dissolved in ethanol (8 mL), followed by the addition of tert-butyl 4-(1-methoxycarbonyl-2-oxobutyl)piperazine-1-carboxylate 56b (1.46 g, 4.63 mmol, commercially available) and polyphosphoric acid (1.04 g, 3.09 mmol). The mixture was heated to 85°C for 12 hours and used directly in the next step.

[1042] MS m / z(ESI):325.8[M+H]

[1043] Step 2

[1044] tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1045] tert-Butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1046] To the reaction mixture from the previous step, water (5 mL) and sodium bicarbonate (412.08 mg, 4.91 mmol) were added, and the mixture was stirred until gas evolution ceased. Di-tert-butyl dicarbonate (802.90 mg, 3.68 mmol) was then added, and the mixture was allowed to react at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: System B) to obtain tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 56d (0.4 g) in a yield of 76.52%.

[1047] MS m / z(ESI):425.8[M+H]

[1048] Step 3

[1049] tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1050] tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1051] Tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 56d (0.15 g, 351.86 μmol) and 2-bromo-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 1b (133.64 mg, 422.23 μmol) were added sequentially to N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (227.37 mg, 1.76 mmol), and the temperature was raised to 50 °C for 5 h. After the reaction was substantially completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and 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-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 56e (140 mg) in a yield of 60.11%.

[1052] MS m / z(ESI):604.6[M+H]

[1053] Step 4

[1054] 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-hexahydropentalen-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1055] 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-hexahydropenten-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1056] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydropentan-2(1H)-one 14a (78.72 mg, 317.27 μmol), 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine Tert-butyl 1,6-piperazine-1-carboxylate 56e (140 mg, 211.51 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17.13 mg, 21.15 μmol), and sodium carbonate (44.84 mg, 423.03 μmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (1 mL). The argon atmosphere was replaced three times, and the temperature was raised to 80 °C for 2 h. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 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-hexahydropenten-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 56f (100 mg) in a yield of 67.24%.

[1057] MS m / z(ESI):646.7[M+H-56]

[1058] Step 5

[1059] 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)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1060] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1061] 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-hexahydropenten-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 56f (100 mg, 142.22 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 g, 4.39 mmol) was added dropwise. The reaction was allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give 56 g (70 mg) of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, which was used directly in the next step.

[1062] MS m / z (ESI): [M+H-56]+=602.8

[1063] Step 6 N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)- 7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1064] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(3-hydroxypicolinyl)piperazin-1-yl)-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1065] 3-Hydroxypicolinic acid 22a (32.30 mg, 232.16 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.76 mg, 348.24 μmol), 1-hydroxybenzotriazole (47.05 mg, 348.24 μmol), N,N-diisopropylethylamine (75.01 mg, 580.40 μmol) were added to N,N-dimethylaminopropylcarbodiimide hydrochloride. Formamide (2 mL) was added and reacted at room temperature for 10 minutes, followed by the addition of 56 g (70 mg, 116.08 μmol) of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide and the reaction was continued at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. 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-(5-oxo-1,3a,4,5,6,6a-hexahydropenten-2-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 56 (30 mg), 34.91%.

[1066] MS m / z(ESI):723.7[M+H-56]

[1067] 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),10.34(s,1H),8.11(d,J=8.6Hz,1H),8.06(d,J=4.3Hz,1H),7.97(d,J=2 .1Hz,1H),7.71(dd,J=8.8,2.2Hz,1H),7.35–7.24(m,2H),6.55(s,1H),6.23(s,1H),5.20(s,2H),4.54(d,J=12 .5Hz,1H),3.53(dd,J=20.4,8.2Hz,4H),3.22(d,J=12.3Hz,2H),3.07(dd,J=16.4,8.4Hz,2H),2.99–2.89(m,3H ),2.77(d,J=11.7Hz,1H),2.68–2.52(m,4H),2.24(s,1H),1.92(dd,J=18.9,6.8Hz,1H),1.17(t,J=7.4Hz,3H).

[1068] Example 57

[1069] 2-(2-(benzofuran-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)- 7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1070] 2-(2-(Benzofuran-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1071] first step

[1072] tert-butyl 4-(2-(benzofuran-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1073] tert-Butyl 4-(2-(benzofuran-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1074] 2-(Benzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 57a (44.25 mg, 181.30 μmol), 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine Tert-butyl-1-carboxylate 56e (60 mg, 90.65 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.34 mg, 9.06 μmol), and sodium carbonate (19.22 mg, 181.30 μmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (1 mL). The argon atmosphere was replaced three times, and the temperature was raised to 80 °C for 16 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(benzofuran-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 57b (40 mg) in a yield of 63.12%.

[1075] MS m / z(ESI):642.7[M+H-56]

[1076] Step 2

[1077] 2-(2-(benzofuran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1078] 2-(2-(Benzofuran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1079] Tert-butyl 4-(2-(Benzofuran-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 57b (40 mg, 57.21 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 g, 8.77 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (AKZONOBEL Kromasil column; 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-(benzofuran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 57c (20 mg) in a yield of 58.36%.

[1080] MS m / z(ESI):598.7[M+H]

[1081] Step 3

[1082] 2-(2-(benzofuran-6-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1083] 2-(2-(Benzofuran-6-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1084] 1 g (16.31 mg, 66.78 μmol) of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.80 mg, 66.78 μmol), 1-hydroxybenzotriazole (9.02 mg, 66.78 μmol) and N,N-diisopropylethylamine (21.58 mg, 166.94 μmol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at room temperature for 15 minutes. 2-(2-(benzofuran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 57c (20 mg, 33.39 μmol) was then added and reacted at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzofuran-6-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 57d (12 mg) in a yield of 43.55%.

[1085] MS m / z(ESI):824.6[M+H]

[1086] Step 4

[1087] 2-(2-(benzofuran-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1088] 2-(2-(Benzofuran-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1089] 2-(2-(Benzofuran-6-yl)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-5-ethyl-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 57d (12 mg, 14.54 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (3 g, 26.31 mmol) was added. The temperature was raised to 45 °C and the reaction was allowed to proceed for 6 hours. The product 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 give 2-(2-(benzofuran-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 57 (8 mg) in a yield of 73.94%.

[1090] MS m / z(ESI):734.6[M+H]

[1091] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.25(s,1H),8.59(s,1H),8.14(d,J=8.6Hz,1H),8. 11–8.04(m,2H),7.99(d,J=2.2Hz,1H),7.89–7.83(m,1H),7.79–7.67(m,2H),7.05–6.95(m ,2H),5.25(s,2H),4.53(d,J=12.5Hz,1H),3.27(d,J=12.6Hz,1H),2.98(d,J=11.3Hz,3H), 2.83(d,J=11.2Hz,1H),2.64(s,1H),2.58–2.52(m,1H),2.45(s,3H),1.21(t,J=7.5Hz,3H).

[1092] Example 58

[1093] 2-(2-(2,3-dihydrobenzofuran-6-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-λ6 -sulfaneyl)phenyl)acetamide

[1094] 2-(2-(2,3-dihydrobenzofuran-6-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 -sulfanyl)phenyl)acetamide

[1095] first step

[1096] tert-butyl 4-(2-(2,3-dihydrobenzofuran-6-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-carboxylate

[1097] 4-(2-(2,3-dihydrobenzofuran-6-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6 -butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1098] 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 (7 mL) and water (1 mL) were added tert-butyl (2-(2,3-dihydrobenzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) 58a (69.91 mg, 284.05 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17.71 mg, 21.85 μmol), and sodium carbonate (69.48 mg, 655.51 μmol). The atmosphere was replaced with argon three times, and the temperature was raised to 85°C for 2 hours. 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 resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-(2-(2,3-dihydrobenzofuran-6-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ 6

[0147] tert-Butyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 58b (110 mg) in 69.37% yield.

[1099] MS m / z(ESI):670.2[M-56+H]

[1100] Step 2

[1101] 2-(2-(2,3-dihydrobenzofuran-6-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 -sulfaneyl)phenyl)acetamide

[1102] 2-(2-(2,3-dihydrobenzofuran-6-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 -sulfanyl)phenyl)acetamide

[1103] At room temperature, trifluoroacetic acid (1.5 mL) was added to 4-(2-(2,3-dihydrobenzofuran-6-yl)-5-ethyl-7-oxo-4-(2-oxo-2-((4-(pentafluoro-λ6 The mixture was stirred for 40 minutes in a solution of tert-butyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 58b (110 mg, 151.57 μmol) in dichloromethane (6 mL). The mixture was reacted at room temperature for 40 minutes. The mixture was concentrated under reduced pressure to give 2-(2-(2,3-dihydrobenzofuran-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-λ)-pyrimidin-6-yl)- ... 6 -sulfanyl)phenyl)acetamide 58c (94.8 mg), yield 99.97%, was used directly in the next step.

[1104] MS m / z(ESI):626.2[M+1]

[1105] Step 3

[1106] 2-(2-(2,3-dihydrobenzofuran-6-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 -sulfaneyl)phenyl)acetamide

[1107] 2-(2-(2,3-dihydrobenzofuran-6-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-(...

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 -NR g C(=O)-; R g Selected from hydrogen atoms or C 1-6 alkyl; In is selected from a single bond or a double bond; 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; In Selected from single bonds, double bonds or Does not exist, when Formed when not present 5-membered ring; The conditions are: when In When it is a single bond, K is selected from -(CH2) p - or -NH-, J is N; p is selected from 1 or 2; when In 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 halogen, a C 1-6 Alkyl or C 1-6 Alkoxy, the halogen is preferably fluorine; 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 group is substituted by one or more substituents selected from R AA substituted by a substituent; R AA is selected from halogen, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, fused ring or -C(=O)NR 6 R 7 wherein the aryl, heteroaryl, cycloalkyl, heterocyclic group or fused ring is optionally further substituted by one or more selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by a haloalkoxy, halogen, hydroxyl or cyano substituent, provided that: the heterocyclic group is not morpholinyl; R 15 , R 16 are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl or aryl group is optionally further substituted with one or more substituents selected from halogen, hydroxyl or cyano; Ring A is selected from: 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; 5) 4-membered monocyclic heterocyclic group, 7-8-membered monocyclic heterocyclic group, spiro heterocyclic group, fused heterocyclic group, wherein the monocyclic heterocyclic group, spiro heterocyclic group or fused 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; 6) bicyclic aryl, bicyclic heteroaryl or bicyclic fused ring; In is selected from a single bond or a double bond; The conditions are: In When selected from double bonds, U is CR bb , Ring B is selected from a cycloalkyl group, a heterocyclic group or a condensed cyclic group; In 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 bb Selected from hydrogen atoms or C 1-6 alkyl; 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, heterocyclic, aryl or heteroaryl radicals are optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, 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 carbon atom to which it is attached, it forms a -C(=O), -C(=S) or -C(=NR cc ); R cc Selected from hydrogen atoms, hydroxyl groups or C 1-6 Alkoxy; 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 Halogenated alkoxy, 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 deuterium atoms, hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =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 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 may be further substituted with 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; n is 0, 1, 2, 3, 4, 5 or 6; 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 2, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein W is CH.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X and Y are O atoms. 5 . 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)—.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein In is a single bond; Q is selected from N or CH; In is a single bond, K is CH2 or CH2CH2, and J is N; R c A hydrogen atom.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R a , R b A hydrogen atom.

8. The compound according to any one of claims 1-2, 4-7 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.

9. The compound according to any one of claims 1, 3 to 7, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described in general formula (III): in: R 1 , R 2 , R 3 and R 4 The definition is as stated in claim 1.

10. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein In is a single bond; Q is selected from N; In is a single bond, K is CH2, and J is CH; R c is a hydrogen atom; L is -NHC(=O)-.

11. The compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, -NR 15 R 16 , C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens, wherein the C 2-6 Alkenyl or C 2-6 Alkynyl is at least one or more selected from R AA substituted by a substituent; R AA is selected from halogen, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, fused ring or -C(=O)NR 6 R 7 ; wherein the alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclic group or fused ring is optionally further substituted by one or more substituents selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, halogen, hydroxyl or cyano; provided that: the heterocyclic group is not morpholinyl; R 6 , R 7 are independently selected from a hydrogen atom or an alkyl group, or, R 6 and R 7 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic group; R 15 selected from hydrogen atoms; R 16 Selected from C 1-6 Alkyl or aryl, wherein the C 1-6 The alkyl or aryl group is optionally further substituted with one or more halogens.

12. The compound according to any one of claims 1 to 10, 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, condensed heterocyclic radical, bicyclic heteroaryl or bicyclic condensed ring, 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 deuterium atoms, halogens, hydroxyl groups, methoxy groups, NR 6 R 7 、-C(=O)NR 6 R 7 , C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-6 membered heterocyclic group, wherein the C 1-6 The alkyl or 5-6 membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium atoms, hydroxyl groups, halogen groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, or two R A Together with the carbon atom to which they are attached, they form a -C(=O) or -C(=NR cc ); R 6 , R 7 selected from hydrogen atoms; R cc Selected from hydroxyl or methoxy; m is 0, 1, 2, 3, 4 or 5.

13. The compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from in In Selected from double bonds, U is CR bb , Ring B is selected from cycloalkyl or heterocyclyl; R bb is selected from a hydrogen atom or a methyl group; R A Selected from deuterium atoms, halogen, hydroxyl, methyl, methoxy, NR 6 R 7 or -C(=O)NR 6 R 7 ; R 6 , R 7 Each is independently a hydrogen atom; m is 0, 1, 2, 3, 4 or 5.

14. The compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from in In is selected from a single bond, U is selected from O, and ring B is selected from aryl or heteroaryl; m is 0.

15. The compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 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 2 Selected from hydrogen atoms, deuterium atoms, C 1-3 Alkyl, 3-6 membered cycloalkyl, C 1-3 Hydroxyalkyl or C 1-3 The haloalkyl group is preferably methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.

17. The compound according to any one of claims 1 to 16, 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.

18. The compound according to claim 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the following groups:

19. The compound according to any one of claims 1 to 18, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from phenyl or heteroaryl, wherein the phenyl or heteroaryl 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 Halogenated alkoxy, 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, wherein the C 1-6 The alkyl group is optionally further substituted with one or more deuterium atoms or halogens; 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.

20. The compound according to claim 19, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the following groups:

21. The compound according to any one of claims 1 to 20, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

23. Use of the compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the preparation of a WRN inhibitor.

24. Use of a compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22 in the preparation of a medicament for treating a disease mediated by WRN; preferably, the disease mediated by WRN is high microsatellite instability cancer.

25. The use according to claim 24, wherein the high 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.

26. Use of the compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating microsatellite instability-high cancer.

27. The method of claim 26, wherein the high 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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